U.S. patent application number 09/906980 was filed with the patent office on 2002-04-04 for pyrrolidine derivatives.
Invention is credited to Aebi, Johannes, Bur, Daniel, Chucholowski, Alexander, Dehmlow, Henrietta, Kitas, Eric Argirios, Obst, Ulrike, Wessel, Hans Peter.
Application Number | 20020040146 09/906980 |
Document ID | / |
Family ID | 8169226 |
Filed Date | 2002-04-04 |
United States Patent
Application |
20020040146 |
Kind Code |
A1 |
Aebi, Johannes ; et
al. |
April 4, 2002 |
Pyrrolidine derivatives
Abstract
The present invention relates to pyrrolidine derivatives useful
as inhibitors of metalloproteases, e.g. zinc proteases, and which
are effective in treating disease states associated with
vasoconstriction.
Inventors: |
Aebi, Johannes; (Basel,
CH) ; Bur, Daniel; (Therwil, CH) ;
Chucholowski, Alexander; (San Diego, CA) ; Dehmlow,
Henrietta; (Grenzach-Wyhlen, DE) ; Kitas, Eric
Argirios; (Arlesheim, CH) ; Obst, Ulrike;
(Grenzach-Wyhlen, DE) ; Wessel, Hans Peter;
(Heitersheim, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
8169226 |
Appl. No.: |
09/906980 |
Filed: |
July 17, 2001 |
Current U.S.
Class: |
546/195 ;
546/207; 546/235 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 31/04 20180101; A61P 25/08 20180101; C07D 401/12 20130101;
A61P 1/04 20180101; A61P 9/10 20180101; A61P 35/00 20180101; A61P
9/00 20180101; C07D 405/12 20130101; C07D 207/48 20130101; Y02P
20/582 20151101; A61P 9/12 20180101; C07D 409/12 20130101; A61P
11/06 20180101; A61P 13/12 20180101; A61P 17/02 20180101; A61P
37/06 20180101; C07D 207/36 20130101; A61P 3/10 20180101; A61P 9/06
20180101; A61P 43/00 20180101; C07D 413/12 20130101; A61P 27/06
20180101; A61P 15/08 20180101; C07D 403/06 20130101; C07D 417/12
20130101 |
Class at
Publication: |
546/195 ;
546/207; 546/235 |
International
Class: |
C07D 41/02; C07D
211/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 19, 2000 |
EP |
00114949.1 |
Claims
What is claimed is:
1. A compound selected from the group consisting of compounds of
formula I 14wherein R.sup.1 is hydrogen, alkylcarbonyl, or
arylcarbonyl; R.sup.2 is alkyl, alkenyl, alkinyl, cyanoalkyl,
hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, alkylcarbonylalkyl,
alkylcycloalkyl, alkylcycloalkylalkyl, alkylsulfonyl, aryl,
arylalkyl, arylalkoxyalkyl, aryl(alkoxycarbonyl)alkyl,
arylcarbamoyl, diarylalkyl, aryl(carboxyalkyl)amide, arylamino,
arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl,
cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, or
the group YR.sup.2 is heterocyclyl or R.sup.2 is a group of the
formula 15R.sup.3 is alkyl, alkylcycloalkyl, alkylcycloalkylalkyl,
cycloalkyl, halogenalkyl, carboxyalkyl, aminoalkyl,
dialkylaminoalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkinyl, aryl,
arylalkyl, arylalkyl(alkoxycarbonyl)a- lkyl, arylcarbonylalkyl,
aryloxyalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, heteroaryl,
heteroarylalkyl, heterocyclyl or hetercycylalkyl, and R.sup.3 is
hydroxy in case of X is SO.sub.2; R.sup.4 is hydrogen in case m=1
or alkyl or hydrogen in case m=0; R.sup.5 is hydrogen, alkyl, aryl,
or carboxyalkyl; R.sup.6 is hydrogen, alkyl, aryl, carboxyalkyl,
arylcarbonyl, alkylcarbonyl, arylalkoxycarbonyl, or arylalkyl;
R.sup.7 is hydrogen, aryl, alkyl, arylalkyl, heterocyclylalkyl,
arylamino, alkyl(arylalkyl)amino, alkoxycarbonylalkyl,
carboxyalkyl, or alkylthioalkyl; R.sup.8 is hydroxy, alkyl, aryl,
cyanoalkyl, alkoxy, arylalkyl, arylalkoxy, mono- or dialkylamino,
arylamino, aryl(alkyl)amino, cyanoalkylamino,
arylalkyl(alkyl)amino, heteroaryl, heteroarylalkyl, or
heterocyclyl; X is --S(O).sub.2--, --S(O).sub.2--NH--, --C(O)--,
--C(O)NR.sup.5--, or C(O)O--; Y is --CH.sub.2, --O--, --NR.sup.6--
or --S--; and m and p independently are 0 or 1, n and q
independently are 1, 2 or 3 and o is 0, 1 or 2 with the proviso
that the sum of n, o and p is .gtoreq.2 and .gtoreq.3;
pharmaceutically acceptable esters, and pharmaceutically acceptable
salts thereof.
2. The compound according to claim 1 of formula III 16wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, X and Y are as defined in
formula (I).
3. The compound according to claim 1 wherein R.sup.1 is hydrogen or
alkylcarbonyl.
4. The compound according to claim 3 wherein said alkylcarbonyl is
acetyl.
5. The compound according to claim 1 wherein R.sup.1 is
hydrogen.
6. The compound according to claim 1 wherein R.sup.2 is aryl,
arylalkyl, arylalkoxyalkyl, arylcarbamoyl, arylamino, arylcarbonyl,
arylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylalkyl or
heteroarylalkyl.
7. The compound according to claim 6 wherein R.sup.2 is aryl,
arylalkyl, arylcarbamoyl, arylamino, arylcarbonyl, arylsulfonyl or
heteroarylalkyl.
8. The compound according to claim 7 wherein R.sup.2 is
arylalkyl.
9. The compound according to claim 8 wherein arylalkyl of R.sup.2
is phenylalkyl or phenylalkyl substituted with 2 or 3 halogen
atoms.
10. The compound according to claim 1 wherein R.sup.3 is alkyl,
halogenalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, cycloalkyl,
halogenalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkinyl, aryl,
arylalkyl, arlyalkyl(alkoxycarbonyl)alkyl, arylcarbonylalkyl,
aryloxyalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, heteroaryl,
heteroarylalkyl or heterocyclyl.
11. The compound according to claim 10 wherein R.sup.3 is alkyl,
arylalkyl, arylcarbonylalkyl, aryloxylakyl, alkylcycloalkyl,
alkylcycloylkylalkyl, cycloalkyl, heteroarylalkyl or
halogenalkyl.
12. The compound according to claim 10 wherein R.sup.3 is alkyl,
arylalkyl, aryl, aryloxyalkyl or halogenalkyl.
13. The compound according to claim 1 wherein R.sup.4 is
hydrogen.
14. The compound according to claim 1 wherein X is --S(O).sub.2--,
--S(O).sub.2--NH--, --C(O)NR.sup.5-- or C(O)O--.
15. The compound according to claims 14 wherein X is
--S(O).sub.2--, --C(O)NH-- or C(O)O--.
16. The compound according to claim 1 wherein R.sup.5is hydrogen,
alkyl or carboxyalkyl.
17. The compound according to claim 16 wherein R.sup.5 is
hydrogen.
18. The compound according to claim 1 wherein R.sup.6 is hydrogen,
alkyl or arylalkyl.
19. The compound according to claim 18 wherein R.sup.6 is
hydrogen.
20. The compound according to claim 1 wherein R.sup.7 is hydrogen
or aryl.
21. The compound according to claim 1 wherein R.sup.8 is hydroxy or
alkoxy.
22. The compound according to claim 1 wherein Y is --O--.
23. The compound according to claim 1 wherein Y is --NH--.
24. The compound according to claim 1 wherein R.sup.1 is hydrogen
or alkylcarbonyl; R.sup.2 is arylalkyl which is phenylalkyl
substituted with 2 or 3 halogen atoms; R.sup.3 is alkyl, aryl,
arylalkyl, aryloxyalkyl or halogenalkyl; X is --SO.sub.2--,
--CONH--, --C(O)--O--; and Y is --NH-- or --O--.
25. The compound according to claim 24 wherein said alkylcarbonyl
of R.sup.1 is acetyl, and R.sup.2 is difluorobenzyl or
trifluorobenzyl.
26. The compound according to claim 1 of formula (IV) 17wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, X and Y are as defined in
formula (I).
27. The compound according to claim 1 selected from the group
consisting of: a)
(3R,5S)-5-[(2,5-Difluoro-benzylamino)-methyl]-1-(naphthalene-2-sul-
fonyl)-pyrrolidine-3-thiol; b)
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methy-
l]-4-mercapto-pyrrolidine-1-carboxylic acid
(2-fluoro-phenyl)-amide; c)
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-ca-
rboxylic acid 4-methoxy-phenyl ester; d)
(2S,4R)-2-[(2,5-Difluoro-benzylam-
ino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid
4-fluoro-phenyl ester; e)
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrol-
idine-1-carboxylic acid isopropyl ester; f)
(2S,4R)-2-[(2,5-Difluoro-benzy-
lamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid
naphthalen-2-yl ester; g)
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrol-
idine-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester; h)
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-ca-
rboxylic acid butyl ester; i)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyl-
oxymethyl)-pyrrolidine-1-carboxylic acid isopropyl ester; j)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carb-
oxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester; k)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carb-
oxylic acid tert-butyl ester; l)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-ben-
zyloxymethyl)-pyrrolidine-1-carboxylic acid butyl ester; m)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carb-
oxylic acid 2-fluoro-phenyl ester; n)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluor-
o-benzyloxymethyl)-pyrrolidine-1-carboxylic acid
2-methoxycarbonyl-phenyl ester; o)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolid-
ine-1-carboxylic acid 2-bromo-phenyl ester; p)
(3R,5S)-1-(Butane-1-sulfony-
l)-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol; q)
(3R,5S)-1-Methanesulfonyl-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-
-3-thiol; r)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrol-
idine-1-sulfonic acid benzylamide; s)
4-Mercapto-2-(2,4,5-trifluoro-benzyl-
oxymethyl)-pyrrolidine-1-sulfonic acid butylamide; t)
4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonic
acid (2-phenoxy-ethyl)-amide; u)
4-Mercapto-2-(2,4,5-trifluoro-benzyloxym-
ethyl)-pyrrolidine-1-sulfonic acid (2,2,2-trifluoro-ethyl)-amide;
v)
4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonic
acid 4-fluoro-benzylamide; w)
4-{[4-Mercapto-2-(2,4,5-trifluoro-benzyloxy-
methyl)-pyrrolidine-1-sulfonylamino]-methyl}-benzoic acid; x)
(2S,4R)-4-Acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine--
1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester; y)
(2S,4R)-4-Acetylsulfanyl-2-[(2,5-difluoro-benzylamino)-methyl]-pyrrolidin-
e-1-carboxylic acid butyl ester; and z)
(2S,4R)-4-Acetylsulfanyl-2-(2,4,5--
trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid
2-methoxycarbonyl-phenyl ester.
28. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable excipient.
29. A dimeric form of a compound of formula I 18wherein R.sup.1 is
hydrogen, alkylcarbonyl, or arylcarbonyl; R.sup.2 is alkyl,
alkenyl, alkinyl, cyanoalkyl, hydroxyalkyl, carboxyalkyl,
alkoxycarbonyl, alkylcarbonylalkyl, alkylcycloalkyl,
alkylcycloalkylalkyl, alkylsulfonyl, aryl, arylalkyl,
arylalkoxyalkyl, aryl(alkoxycarbonyl)alkyl, arylcarbamoyl,
diarylalkyl, aryl(carboxyalkyl)amide, arylamino, arylcarbonyl,
arylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylalkyl,
heteroaryl, heteroarylalkyl, heterocyclylalkyl, or the group
YR.sup.2 is heterocyclyl or R.sup.2 is a group of the formula
19R.sup.3 is alkyl, alkylcycloalkyl, alkylcycloalkylalkyl,
cycloalkyl, halogenalkyl, carboxyalkyl, aminoalkyl,
dialkylaminoalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkinyl, aryl,
arylalkyl, arylalkyl(alkoxycarbonyl)a- lkyl, arylcarbonylalkyl,
aryloxyalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, heteroaryl,
heteroarylalkyl, heterocyclyl or hetercycylalkyl, and R.sup.3 is
hydroxy in case of X is SO.sub.2; R.sup.4 is hydrogen in case m=1
or alkyl or hydrogen in case m=0; R.sup.5 is hydrogen, alkyl, aryl,
or carboxyalkyl; R.sup.6 is hydrogen, alkyl, aryl, carboxyalkyl,
arylcarbonyl, alkylcarbonyl, arylalkoxycarbonyl, or arylalkyl;
R.sup.7 is hydrogen, aryl, alkyl, arylalkyl, heterocyclylalkyl,
arylamino, alkyl(arylalkyl)amino, alkoxycarbonylalkyl,
carboxyalkyl, or alkylthioalkyl; R.sup.8 is hydroxy, alkyl, aryl,
cyanoalkyl, alkoxy, arylalkyl, arylalkoxy, mono- or dialkylamino,
arylamino, aryl(alkyl)amino, cyanoalkylamino,
arylalkyl(alkyl)amino, heteroaryl, heteroarylalkyl, or
heterocyclyl; X is --S(O).sub.2--, --S(O).sub.2--NH--, --C(O)--,
--C(O)NR.sup.5--, or C(O)O--; Y is --CH.sub.2, --O--, --NR.sup.6--
or --S--; and m and p independently are 0 or 1, n and q
independently are 1, 2 or 3 and o is 0, 1 or 2 with the proviso
that the sum of n, o and p is .gtoreq.2 and .ltoreq.3.
Description
BACKGROUND OF THE INVENTION
[0001] Endothelins are peptides, that exist in three isoforms ET-1,
ET-2, and ET-3, each encoded by a distinct gene. They have been
originally discovered in the conditioned medium of porcine
endothelial cells in 1988 by Yanagisawa (Yanagisawa M; Kurihara H;
Kimura S; Tomobe Y; Kobayashi M; Mitsui Y; Yazaki Y; Goto K; Masaki
T: A novel potent vasoconstrictor peptide produced by vascular
endothelial cells [see comments]. NATURE (1988 Mar 31), 332(6163),
411-5.). The active ETs are peptides of 21 amino acids with two
intramolecular disulfide bridges. They are produced from
preproproteins of 203 to 212 amino acids which are processed by
furin-like endopeptidases to the biologically inactive
big-endothelin (big-ET). The big-ETs are specifically processed to
mature ETs by a hydrolytic cleavage between amino acids 21 and 22
that are Trp.sup.21-Val.sup.22 (big-ET-1, big ET-2) and
Trp.sup.21-Ile.sup.22 in big-ET-3 respectively. Already in 1988 a
specific metalloprotease was postulated to be responsible for this
specific cleavage. In 1994 ECE-1 (endothelin converting enzyme-1)
was purified and cloned from bovine adrenal (Xu D, Emoto N, Giaid
A, Slaughter C, Kaw S, de Witt D, Yanagisawa M: ECE-1: a
membrane-bound metalloprotease that catalyzes the proteolytic
activation of big endothelin-1. Cell (1994) 78: 473-485).
[0002] ECE-1 is a membrane bound type II zinc-endopeptidase with a
neutral pH optimum and a zinc binding motif HExxHx(>20)E. It
belongs to subfamily M13 and has a large 681 amino acid ectodomain
that comprises the active site. Other members of the M13 family are
NEP24.11 (neutral endopeptidase), PEX, a phosphate regulating
neutral endopeptidase, and Kell blood group protein that has
recently been described as a big-ET-3 processing enzyme. Members of
the M13 family of human origin are characterized by a high
molecular weight (>80 kDa) a number of conserved disulfide
bridges and a complex glycosylation pattern. The structure of NEP
has recently been solved. (Oefner et al, J. Mol. Biol. 2000, 296,
341-349). The catalytic domain of ECE and related human M13
proteinases are significantly larger (>650 amino acids) than
members of matrix metalloproteases (MMPs). Unlike the family of the
MMPs which belong to the metzincins and display a typical
HExxHxxGxxH pattern members of the M13 family are gluzincins
comprising a HExxHx(>20)E pattern. These two families are
clearly different in size of catalytic domains, structure and zinc
coordinating pattern of ligands. Active sites of the two families
show clear differences which has clear impact on type of inhibitors
and the potential selectivity.
SUMMARY OF THE INVENTION
[0003] The present invention relates to compounds of formula (I)
1
[0004] wherein
[0005] R.sup.1 is hydrogen, alkylcarbonyl, or arylcarbonyl;
[0006] R.sup.2 is alkyl, alkenyl, alkinyl, cyanoalkyl,
hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, alkylcarbonylalkyl,
alkylcycloalkyl, alkylcycloalkylalkyl, alkylsulfonyl, aryl,
arylalkyl, arylalkoxyalkyl, aryl(alkoxycarbonyl) alkyl,
arylcarbamoyl, diarylalkyl, aryl(carboxyalkyl)amide, arylamino,
arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl,
cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, or
the group YR.sup.2 is heterocyclyl or R.sup.2 is a group of the
formula 2
[0007] R.sup.3 is alkyl, alkylcycloalkyl, alkylcycloalkylalkyl,
cycloalkyl, halogenalkyl, carboxyalkyl, aminoalkyl,
dialkylaminoalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkinyl, aryl,
arylalkyl, arylalkyl(alkoxycarbonyl)alkyl, arylcarbonylalkyl,
aryloxyalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, heteroaryl,
heteroarylalkyl, heterocyclyl or hetercycylalkyl, and R.sup.3 is
hydroxy in case of X is SO.sub.2;
[0008] R.sup.4 is hydrogen in case m=1 or alkyl or hydrogen in case
m=0;
[0009] R.sup.5 is hydrogen, alkyl, aryl, or carboxyalkyl;
[0010] R.sup.6 is hydrogen, alkyl, aryl, carboxyalkyl,
arylcarbonyl, alkylcarbonyl, arylalkoxycarbonyl, or arylalkyl;
[0011] R.sup.7 is hydrogen, aryl, alkyl, arylalkyl,
heterocyclylalkyl, arylamino, alkyl(arylalkyl)amino,
alkoxycarbonylalkyl, carboxyalkyl, or alkylthioalkyl;
[0012] R.sup.8 is hydroxy, alkyl, aryl, cyanoalkyl, alkoxy,
arylalkyl, arylalkoxy, mono- or dialkylamino, arylamino,
aryl(alkyl)amino, cyanoalkylamino, arylalkyl(alkyl)amino,
heteroaryl, heteroarylalkyl, or heterocyclyl; and
[0013] X is --S(O).sub.2--, --S(O).sub.2--NH--, --C(O)--,
--C(O)NR.sup.5--, C(O)O--;
[0014] Y is --CH.sub.2, --O--, --NR.sup.6-- or --S--;
[0015] m and p independently are 0 or 1, n and q independently are
1, 2 or 3 and o is 0, 1 or 2 with the proviso that the sum of n, o
and p is >2 and <3; and
[0016] dimeric forms, and/or pharmaceutically acceptable esters,
and/or pharmaceutically acceptable salts thereof, preferably
pharmaceutically acceptable esters, and/or pharmaceutically
acceptable salts thereof, and most preferably pharmaceutically
acceptable salts thereof.
[0017] The present invention is directed to compounds which are
useful as inhibitors of metalloproteases, e.g. zinc proteases,
particularly zinc hydrolases, and which are effective in the
prophylaxis and treatment of disease states which are associated
with vasoconstriction of increasing occurrences. Examples of such
disorders are high blood pressure, coronary disorders, cardiac
insufficiency, renal and myocardial ischaemia, renal insufficiency,
dialysis, cerebral ischaemia, cardiac infarct, migraine,
subarachnoid haemorrhage, Raynaud syndrome and pulmonary high
pressure. In addition the compounds are useful as cytostatic and
cerebroprotective agents for inhibition of graft rejection, for
organ protection and for treatment of ophthalmological
diseases.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention is directed to compounds of formula
(I): 3
[0019] wherein
[0020] R.sup.1 is hydrogen, alkylcarbonyl, or arylcarbonyl;
[0021] R.sup.2 is alkyl, alkenyl, alkinyl, cyanoalkyl,
hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, alkylcarbonylalkyl,
alkylcycloalkyl, alkylcycloalkylalkyl, alkylsulfonyl, aryl,
arylalkyl, arylalkoxyalkyl, aryl(alkoxycarbonyl)alkyl,
arylcarbamoyl, diarylalkyl, aryl(carboxyalkyl)amide, arylamino,
arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl,
cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, or
the group YR.sup.2 is heterocyclyl or R is a group of the formula
4
[0022] R.sup.3 is alkyl, , alkylcycloalkyl, alkylcycloalkylalkyl,
cycloalkyl, halogenalkyl, carboxyalkyl, aminoalkyl,
dialkylaminoalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkinyl, aryl,
arylalkyl, arylalkyl(alkoxycarbonyl)alkyl, arylcarbonylalkyl,
aryloxyalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, heteroaryl,
heteroarylalkyl, heterocyclyl or hetercycylalkyl, and R.sup.3 is
hydroxy in case of X is SO.sub.2;
[0023] R.sup.4 is hydrogen in case m=1 or alkyl or hydrogen in case
m=0;
[0024] R.sup.5 is hydrogen, alkyl, aryl, or carboxyalkyl;
[0025] R.sup.6 is hydrogen, alkyl, aryl, carboxyalkyl,
arylcarbonyl, alkylcarbonyl, arylalkoxycarbonyl, or arylalkyl;
[0026] R.sup.7 is hydrogen, aryl, alkyl, arylalkyl,
heterocyclylalkyl, arylamino, alkyl(arylalkyl)amino,
alkoxycarbonylalkyl, carboxyalkyl, or alkylthioalkyl;
[0027] R.sup.8 is hydroxy, alkyl, aryl, cyanoalkyl, alkoxy,
arylalkyl, arylalkoxy, mono- or dialkylamino, arylamino,
aryl(alkyl)amino, cyanoalkylamino, arylalkyl(alkyl)amino,
heteroaryl, heteroarylalkyl, or heterocyclyl;
[0028] X is --S(O).sub.2--, --S(O).sub.2--NH--, --C(O)--,
--C(O)NR.sup.5--, C(O)O--;
[0029] Y is --CH.sub.2, --O--, --NR.sup.6-- or --S--;
[0030] m and p independently are 0 or 1, n and q independently are
1, 2 or 3 and 0 is 0, 1 or 2 with the proviso that the sum of n, o
and p is .gtoreq.2 and .ltoreq.3; and
[0031] dimeric forms, and/or pharmaceutically acceptable esters,
and/or pharmaceutically acceptable salts thereof.
[0032] The term "alkyl", alone or in combination, means a
straight-chain or branched-chain alkyl group containing a maximum
of 7, preferably a maximum of 4, carbon atoms, e.g., methyl, ethyl,
n-propyl, 2-methylpropyl (iso-butyl), 1-methylethyl (iso-propyl),
n-butyl, and 1,1-dimethylethyl (t-butyl).
[0033] The term "carboxy" refers to the group --C(O)OH.
[0034] The term "carbamoyl" refers to the group --C(O)NH.sub.2.
[0035] The term "carbonyl" refers to the group --C(O)--.
[0036] The term "halogen" refers to the group fluoro, bromo, chloro
and iodo.
[0037] The term "sulfonyl" refers to the group --S(O.sub.2)--.
[0038] The term "alkenyl" refers to a hydrocarbon chain as defined
for alkyl having at least one olefinic double bond (including for
example, vinyl, allyl and butenyl).
[0039] The term "alkinyl" refers to a hydrocarbon chain as defined
for alkyl having at least one olefinic triple bond (including for
example propinyl, butin-(1)-yl, etc.
[0040] The term "alkoxy", alone or in combination, means an alkyl
ether group in which the term `alkyl` has the significance given
earlier, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
isobutoxy, sec.butoxy, tert.butoxy and the like.
[0041] The term "alkoxycarbonyl" refers to a group of the formula
--C(O)R.sub.c wherein R.sub.c is alkoxy as defined above.
[0042] The term "hydroxy" refers to the group --OH, the term
"cyano" to the group --CN.
[0043] The term "hydroxyalkyl" means an alkyl group as defined
above which is substituted by a hydroxy group.
[0044] The term "thioalkyl" and "cyanoalkyl" refer to an alkyl
group as defined above which is substituted by a --SH group or an
--CN group, respectively.
[0045] The term "halogenalkyl" refers to an alkyl group as defined
above which is substituted by one to three halogen atoms,
preferably fluoro, e.g. trifluoromethyl, 2,2,2-trifluoroethyl,
etc.
[0046] The term "alkylthioalkyl" is a group of the formula
alkyl-S-alkyl.
[0047] "Carboxyalkyl" means an alkyl as defined above which is
substituted by a HOOC-group.
[0048] The term "alkylcarbonyl", alone or in combination, means an
acyl group derived from an alkanecarboxylic acid, i.e.
alkyl-C(O)--, such as acetyl, propionyl, butyryl, valeryl,
4-methylvaleryl etc.
[0049] The term "cycloalkyl" signifies a saturated, cyclic
hydrocarbon group with 3-8, preferably 3-6 carbon atoms, i.e.
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and the
like.
[0050] The term "amino" refers to the group --NH.sub.2.
[0051] The term "aryl" for R.sup.2--alone or in combination--,
refers to an aromatic carbocyclic radical, i.e. a 6 or 10 membered
aromatic or partially aromatic ring, e.g. phenyl, naphthyl or
tetrahydronaphthyl, preferably phenyl or naphthyl, and most
preferably phenyl. The aryl moiety is optionally substituted with
one or more groups independently selected from halogen, preferably
fluoro, alkoxycarbonyl, e.g. methylcarbonyl, carboxy, cyano, alkyl,
alkoxy, phenyl, phenoxy, trifluormethyl, trifluormethoxy,
1,3-dioxolyl, or 1,4-dioxolyl, more preferably fluor,
alkoxycarbonyl, alkyl, trifluoromethyl and trifluoromethoxy and
most preferably fluor. The most preferred aromatic groups are
2,5-difluorobenzyl and 2,4,5-trifluorobenzyl.
[0052] The term "aryl" for R.sup.3--alone or in combination--,
refers to an aromatic carbocyclic radical, i.e. a 6 or 10 membered
aromatic or partially aromatic ring, e.g. phenyl, naphthyl or
tetrahydronaphthyl, preferably phenyl or naphthyl, and most
preferably phenyl. The aryl moiety is optionally substituted with
one or more groups independently selected from halogen,
alkoxycarbonyl, e.g. methylcarbonyl, carboxy, cyano, alkyl, alkoxy,
phenyl, phenoxy, trifluormethyl, trifluormethoxy, 1,3-dioxolyl, or
1,4-dioxolyl, cyclohexyl, hydroxy, alkylamido, e.g. acetamido,
nitro, alkylsulfonyl, e.g. methylsulfonyl, more preferably fluor,
chlor, brom, alkoxy, carboxy, 1,4-dioxolyl, alkoxycarbonyl. The
most preferred aromatic groups are phenyl, 4-fluorobenzyl,
4-carboxybenzyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2-bromophenyl,
2-fluorophenyl, 2-methoxycarbonylphenyl, naphthyl and
4-methoxyphenyl.
[0053] The term "aryl" for R.sup.4 to R.sup.10--alone or in
combination--refers to an aromatic carbocyclic radical, i.e. a 6 or
10 membered aromatic or partially aromatic ring, e.g. phenyl,
naphthyl or tetrahydronaphthyl, preferably phenyl or naphthyl, and
most preferably phenyl. The aryl moiety is optionally substituted
with one or more groups independently selected from halogen,
preferably fluor, alkoxycarbonyl, e.g. methylcarbonyl, carboxy,
cyano, alkyl, alkoxy, phenyl, phenoxy, trifluormethyl,
trifluormethoxy, hydroxy, alkylamido, e.g. acetamido, nitro,
alkylsulfonyl, e.g. methylsulfonyl, more preferably alkyl or
alkoxy.
[0054] The term "aryloxy" refers to an aryl group as defined above
attached to a parent structure via an oxy radical, i.e.,
aryl-O--.
[0055] The term "heteroaryl" for R.sup.2 and R.sup.4 to
R.sup.10--alone or in combination--refers to an aromatic mono- or
bicyclic radical having 5 to 10, preferably 5 to 6 ring atoms,
containing one to three heteroatoms, preferably one heteroatom,
e.g. independently selected from nitrogen, oxygen or sulfur.
Examples of heteroaryl groups are thiophenyl, isoxazolyl,
thiazolyl, pyridinyl, pyrrolyl, imidazolyl, tetrazolyl, preferably
pyridinyl, isoxazolyl or thiazolyl. Optionally, the heteroaryl
group can be mono-, di- or tri-substituted, independently, with
phenyl, alkyl, alkylcarbonyl, alkoxycarbonyl, hydroxy, amino,
alkylamino, dialkylamino, carboxy, alkoxycarbonylalkyl, preferably
alkyl.
[0056] The term "heteroaryl" for R.sup.3--alone or in
combination--refers to an aromatic mono- or bicyclic radical having
5 to 10, preferably 5 to 6 ring atoms, containing one to three
heteroatoms, preferably one heteroatom, e.g. independently selected
from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are
pyridinyl, thiophenyl, isoxyzolyl, isoquinolyl, quinolyl, and
1H-benzo[d][1,3]oxazin-2,4-dione and indolyl, pyrimidine,
pyridazine, and pyrazine, preferably pyridinyl, thiophenyl,
isoxazolyl, isoquinolyl, quinolyl, and
1H-benzo[d][1,3]oxazin-2,4-dione and indolyl. Optionally, the
heteroaryl group can be mono-, di- or tri-substituted,
independently, with phenyl, alkyl, alkylcarbonyl, alkoxycarbonyl,
hydroxy, amino, alkylamino, dialkylamino, carboxy, oxo,
alkoxycarbonylalkyl, preferably alkyl.
[0057] The term "heterocyclyl"--alone or in combination--refers to
a non-aromatic mono- or bicyclic radical having 5 to 10, preferably
5 to 6 ring atoms, containing one to three heteroatoms, preferably
one heteroatom, e.g. independently selected from nitrogen, oxygen
or sulfur. Optionally the heterocyclic ring can be substituted by a
group independently selected from halogen, alkyl, alkoxy,
oxocarboxy, alkoxycarbonyl, etc. and/or on a secondary nitrogen
atom (i.e. --NH--) by alkyl, arylalkoxycarbonyl, alkylcarbonyl or
on a tertiary nitrogen atom (i.e. .dbd.N--) by oxido. Examples for
heterocyclic groups are morpholinyl, pyrrolidinyl, piperidyl, etc.,
and especially for R.sup.2 alkyl-pyran-triol-yl.
[0058] The term "dimeric form" means a compound wherein the two
R.sup.1 groups of two identical compounds of formula I have been
replaced by a common single bond or wherein R.sup.1 is
glutathione-S-- or cysteine-S-- or ester and/or alkylcarbonyl or
arylcarbonyl derivatives thereof, e.g. acetylcysteine-S-- or
benzoylcysteine-S--, preferably glutathione-S--, cysteine-S--,
acetylcysteine-S-- or benzoylcysteine-S--.
[0059] The term "pharmaceutically acceptable salt" refers to those
salts which retain the biological effectiveness and properties of
the free bases or free acids, which are not biologically or
otherwise undesirable. The salts are formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid and the like, and organic acids such as
acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic
acid, maleic acid, malonic acid, succinic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid, N-acetylcystein and the like. In addition
these salts may be prepared from addition of an inorganic base or
an organic base to the free acid. Salts derived from an inorganic
base include, but are not limited to, the sodium, potassium,
lithium, ammonium, calcium, magnesium salts and the like. Salts
derived from organic bases include, but are not limited to salts of
primary, secondary, and tertiary amines, substituted amines
including naturally occurring substituted amines, cyclic amines and
basic ion exchange resins, such as isopropylamine, trimethylamine,
diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,
arginine, N-ethylpiperidine, piperidine, polymine resins and the
like.
[0060] "Pharmaceutically acceptable esters" means that compounds of
general formula (I) may be derivatised at functional groups to
provide derivatives which are capable of conversion back to the
parent compounds in vivo. Examples of such compounds include
physiologically acceptable and metabolically labile ester
derivatives, such as methoxymethyl esters, methylthiomethyl esters
and pivaloyloxymethyl esters. Additionally, any physiologically
acceptable equivalents of the compounds of general formula (I),
similar to the metabolically labile esters, which are capable of
producing the parent compounds of general formula (I) in vivo, are
within the scope of this invention.
[0061] The compounds of formula (I) are useful in inhibiting
mammalian metalloprotease activity, particularly zinc hydrolase
activity. More specifically, the compounds of formula (I) are
useful as medicaments for the treatment and prophylaxis of
disorders which are associated with diseases caused by
endothelin-converting enzyme (ECE) activity. Inhibiting of this
enzyme would be useful for treating myocardial ischaemia,
congestive heart failure, arrhythmia, hypertension, pulmonary
hypertension, asthma, cerebral vasospasm, subarachnoid haemorrhage,
pre-eclampsia, kidney diseases, atherosclerosis, Buerger's disease,
Takayasu's arthritis, diabetic complications, lung cancer,
prostatic cancer, gastrointestinal disorders, endotoxic shock and
septicaemia, and for wound healing and control of menstruation,
glaucoma. In addition the compounds are useful as cytostatic and
cerebroprotective agents for inhibition of graft rejection, for
organ protection and for treatment of ophthalmological
diseases.
[0062] In a preferred embodiment, the present invention comprises
compounds of formula (I) wherein m and p are 0, n, o and q are 1.
More specifically, the present invention comprises the above
defined compounds of general formula (III). 5
[0063] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, X and Y are as
defined as above.
[0064] In a preferred embodiment of the present invention, R.sup.1
is hydrogen or alkylcarbonyl, preferably hydrogen or acetyl, and
more preferably hydrogen.
[0065] In a further preferred embodiment of the present R.sup.2 is
aryl, arylalkyl, arylalkoxyalkyl, arylcarbamoyl, arylamino,
arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl,
cycloalkylalkyl or heteroarylalkyl, more preferably aryl,
arylalkyl, arylcarbamoyl, arylamino, arylcarbonyl, arylsulfonyl or
heteroarylalkyl. In the most preferred R.sup.2 is arylalkyl and
specifically phenylalkyl optionally substituted with 2 to 3 halogen
atoms, e.g. 2,4,5-trifluoro-benzyl or 2,5-difluoro-benzyl.
[0066] According to the present invention R.sup.3 is preferably
alkyl, halogenalkyl, alkylcycloalkyl, alkylcycloalkylalkyl,
cycloalkyl, halogenalkyl, alkoxyalkyl, alkoxycarbonylalkyl,
alkinyl, aryl, arylalkyl, arylalkyl(alkoxycarbonyl)alkyl,
arylcarbonylalkyl, aryloxyalkyl, arylalkenyl,
aryl(alkoxycarbonyl)alkyl, heteroaryl, heteroarylalkyl or
heterocyclyl, more preferably alkyl, arylalkyl, arylcarbonylalkyl,
aryloxylakyl, alkylcycloalkyl, alkylcycloylkylalkyl, cycloalkyl,
heteroarylalkyl or halogenalkyl and most preferably alkyl,
arylalkyl, aryl, aryloxyalkyl or halogenalkyl, e.g. phenoxy-ethyl,
2,2,2-trifluoro-ethyl, 4-fluoro-benzyl, 4-carboxy-benzyl,
2,3-dihydrobenzo[1,4]dioxin-5-yl, 2-bromophenyl, butane-1-yl,
methyl, benzyl, tert-butyl, 2-fluoro-phenyl, 4-fluoro-phenyl,
2-methoxy-carbonylphenyl, isopropyl, naphthalen-2-yl,
naphthalen-2-yl, or 4-methoxy-phenyl.
[0067] In a preferred embodiment R.sup.4 is hydrogen.
[0068] In the above-defined compounds X is preferably
--S(O).sub.2--, --S(O).sub.2--NH--, --C(O)NR.sup.5-- or C(O)O--,
and more preferably --S(O).sub.2--, --C(O)NH-- or C(O)O--.
[0069] The invention comprises compounds as defined above, wherein
R.sup.5 is hydrogen, alkyl or carboxyalkyl, preferably
hydrogen.
[0070] R.sup.6 in the compounds described above is preferably
hydrogen, alkyl or arylalkyl and more preferably hydrogen.
[0071] In further preferred embodiments of the present invention
R.sup.7 is hydrogen or aryl and R.sup.8 is hydroxy or alkoxy.
[0072] In the present invention Y preferably is --O-- or
--NH--.
[0073] More specifically the invention comprises the above
compounds wherein R.sup.1 is hydrogen or alkylcarbonyl, R.sup.2 is
phenylalkyl substituted with 2 to 3 halogen; R.sup.3 is alkyl,
aryl, arylalkyl, aryloxyalkyl or halogenalkyl, e.g. e.g.
phenoxy-ethyl, 2,2,2-trifluoro-ethyl, 4-fluoro-benzyl,
4-carboxy-benzyl, 2,3-dihydrobenzo[1,4]dioxin-5-yl, 2-bromophenyl,
butane-1-yl, methyl, benzyl, tert-butyl, 2-fluoro-phenyl,
4-fluoro-phenyl, 2-methoxy-carbonylphenyl, isopropyl,
naphthalen-2-yl, naphthalen-2-yl, or 4-methoxy-phenyl; X is
--SO.sub.2--, --CONH--, --C(O)--O--; and Y is --NH-- or --O--.
[0074] The present invention comprises compounds as defined above
with the stereochemistry shown in formula (IV) 6
[0075] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, X and Y are as
defined above.
[0076] In the most preferred embodiment the invention comprises
compounds of formula (IV) wherein R.sup.1 is hydrogen or acetyl and
R.sup.2 is difluorobenzyl or trifluorobenzyl, e.g.
2,4,5-trifluoro-benzyl or 2,5-difluoro-benzyl- and R.sup.3 is
phenoxy-ethyl, 2,2,2-trifluoro-ethyl, 4-fluoro-benzyl,
4-carboxy-benzyl, 2,3-dihydrobenzo[1,4]dioxin-5-yl, 2-bromophenyl,
butane-1-yl, methyl, benzyl, tert-butyl, 2-fluoro-phenyl,
4-fluoro-phenyl, 2-methoxy-carbonylphenyl, isopropyl,
naphthalen-2-yl, naphthalen-2-yl, or 4-methoxy-phenyl and R.sup.4
is hydrogen, X is --S(O).sub.2--, --C(O)NH-- or C(O)O-- and Y is
--O-- or --NH--.
[0077] Preferred embodiments of the present invention are the
compounds exemplified in the examples. Especially, the invention
comprises the following compounds selected from the group
consisting of
[0078] a)
(3R,5S)-5-[(2,5-Difluoro-benzylamino)-methyl]-1-(naphthalene-2-s-
ulfonyl) pyrrolidine-3-thiol;
[0079] b)
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrroli-
dine-1-carboxylic acid (2-fluoro-phenyl)-amide;
[0080] c)
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrroli-
dine-1-carboxylic acid 4-methoxy-phenyl ester;
[0081] d)
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrroli-
dine-1-carboxylic acid 4-fluoro-phenyl ester;
[0082] e)
2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolid-
ine-1-carboxylic acid isopropyl ester;
[0083] f)
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrroli-
dine-1-carboxylic acid naphthalen-2-yl ester;
[0084] g)
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrroli-
dine-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester;
[0085] h)
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrroli-
dine-1-carboxylic acid butyl ester;
[0086] i)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidi-
ne-1-carboxylic acid isopropyl ester;
[0087] j)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidi-
ne-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester;
[0088] k)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidi-
ne-1-carboxylic acid tert-butyl ester;
[0089] l)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidi-
ne-1-carboxylic acid butyl ester;
[0090] m)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidi-
ne-1-carboxylic acid 2-fluoro-phenyl ester;
[0091] n)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidi-
ne-1-carboxylic acid 2-methoxycarbonyl-phenyl ester;
[0092] o)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidi-
ne-1-carboxylic acid 2-bromo-phenyl ester;
[0093] p)
(3R,5S)-1-(Butane-1-sulfonyl)-5-(2,4,5-trifluoro-benzyloxymethyl-
)-pyrrolidine-3-thiol;
[0094] q)
(3R,5S)-1-Methanesulfonyl-5-(2,4,5-trifluoro-benzyloxymethyl)-py-
rrolidine-3-thiol;
[0095] r)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidi-
ne-1-sulfonic acid benzylamide;
[0096] s)
4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sul-
fonic acid butylamide;
[0097] t)
4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sul-
fonic acid (2-phenoxy-ethyl)-amide;
[0098] u)
4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sul-
fonic acid (2,2,2-trifluoro-ethyl)-amide;
[0099] v)
4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sul-
fonic acid 4-fluoro-benzylamide;
[0100] w)
4-{[4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-
-sulfonylamino]-methyl}-benzoic acid;
[0101] x)
(2S,4R)-4-Acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyr-
rolidine-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl
ester;
[0102] y)
(2S,4R)-4-Acetylsulfanyl-2-[(2,5-difluoro-benzylamino)-methyl]-p-
yrrolidine-1-carboxylic acid butyl ester; and
[0103] z)
(2S,4R)-4-Acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyr-
rolidine-1-carboxylic acid 2-methoxycarbonyl-phenyl ester.
[0104] These compounds show activity values of 0.5 nM to 100 nM in
the radioimmunoassay (E and F), see below.
[0105] The invention also refers to pharmaceutical compositions
containing a compound as defined above and a pharmaceutically
acceptable excipient.
[0106] A further embodiment of the present invention refers to the
use of compounds as defined above as active ingredients in the
manufacture of medicaments comprising a compound as defined above
for the prophylaxis and treatment of disorders which are caused by
endothelin-converting enzyme (ECE) activity especially myocardial
ischaemia, congestive heart failure, arrhythmia, hypertension,
pulmonary hypertension, asthma, cerebral vasospasm, subarachnoid
haemorrhage, pre-eclampsia, kidney diseases, atherosclerosis,
Buerger's disease, Takayasu's arthritis, diabetic complications,
lung cancer, prostatic cancer, gastrointestinal disorders,
endotoxic shock and septicaemia, and for wound healing and control
of menstruation, glaucoma, graft rejection, diseases associated
with cytostatic, ophthalmological, and cerebroprotective
indications, and organ protection.
[0107] Further the invention refers to the use of compounds as
described above for the treatment or prophylaxis of diseases which
are associated with myocardial ischaemia, congestive head failure,
arrhythmia, hypertension, pulmonary hypertension, asthma, cerebral
vasospasm, subarachnoid haemorrhage, pre-eclampsia, kidney
diseases, atherosclerosis, Buerger's disease, Takayasu's arthritis,
diabetic complications, lung cancer, prostatic cancer,
gastrointestinal disorders, endotoxic shock and septicaemia, and
for wound healing and control of menstruation, glaucoma, graft
rejection, diseases associated with cytostatic, ophthalmological,
and cerebroprotective indications, and organ protection.
[0108] In addition the invention comprises compounds as described
above for use as therapeutic active substances, in particular in
context with diseases which are associated with zinc hydrolase
activity such as myocardial ischaemia, congestive heart failure,
arrhythmia, hypertension, pulmonary hypertension, asthma, cerebral
vasospasm, subarachnoid haemorrhage, pre-eclampsia, kidney
diseases, atherosclerosis, Buerger's disease, Takayasu's arthritis,
diabetic complications, lung cancer, prostatic cancer,
gastrointestinal disorders, endotoxic shock and septicaemia, and
for wound healing and control of menstruation, glaucoma, graft
rejection, diseases associated with cytostatic, ophthalmological,
and cerebroprotective indications, and organ protection.
[0109] The invention also comprises a method for the therapeutic
and/or prophylactic treatment of myocardial ischaemia, congestive
heart failure, arrhythmia, hypertension, pulmonary hypertension,
asthma, cerebral vasospasm, subarachnoid haemorrhage,
pre-eclampsia, kidney diseases, atherosclerosis, Buerger's disease,
Takayasu's arthritis, diabetic complications, lung cancer,
prostatic cancer, gastrointestinal disorders, endotoxic shock and
septicaemia, and for wound healing and control of menstruation,
glaucoma, graft rejection, diseases associated with cytostatic,
ophthalmological, and cerebroprotective indications, and organ
protection, which method comprises administering a compound as
defined above to a human being or animal.
[0110] The invention also relates to the use of compounds as
defined above for the inhibition of zinc hydrolase activity.
[0111] The invention also refers to the above compounds whenever
manufactured by a process as described below.
[0112] Compounds of formula (I) can be prepared by methods known in
the art or as described below. Unless otherwise indicated, the
substituents R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, X, Y, m, p, n, q are as described above.
[0113] Step a) of scheme I describes the persilylation of hydroxy-
and amino groups, e.g. by reaction of compound 1 with
hexamethyldisilazan/140- .degree. C. followed by reaction with
R.sup.3SO.sub.2Cl in THF or di-t-butyldicarbonate/NaHCO.sub.3 in
dioxane/H.sub.2O (BOC protection). For inversion of the
configuration (via mesylate) the resulting alcohol 2 is treated
with MeSO.sub.3H/Ph.sub.3P/DIAD in toluene (room temperature to
80.degree. C.) or (via bromide) with LiBr/DEAD/Ph.sub.3P in THF
(4.degree. C. to room temperature) or (via chloride) with
Ph.sub.3P/CCl.sub.4 in CH.sub.2Cl.sub.2 (3.degree. C. to room
temperature). In case of retention of the configuration (via
mesylate) alcohol 2 can be transformed to a compound of formula 3
by reaction with MeSO.sub.2Cl/pyridine/DMAP (0.degree. C. to room
temperature).
[0114] For the introduction of a protected thio moiety, e.g.
triphenylmethanethiol or 4-methoxy-benzylmercaptane, compound of
formula 3 are treated with K-Ot-Bu in DMF (for Br: 0.degree. C. to
room temperature; for Cl: 0.degree. C.; for Mes: room temperature
to 100.degree. C. For step d the corresponding compounds of formula
4, 8 and 9 can be obtained according to methods known in the art,
e.g. LAH in THF at -20.degree. C. or Red-Al in Toluene/THF at
-50.degree. C. 7
[0115] For the reaction of compound 6 to compound 7 the
Arndt-Eistert reaction may be used (in case q=2: hydrolysis with
NaOH in EtOH at room temperature followed by addition of
(COCl).sub.2, cat DMF in CH.sub.4Cl.sub.2 at 0.degree. C. to room
temperature to give the corresponding acid chloride followed by
reaction with trimethylsilyldiazomethane in THF/CH.sub.3CN at
0.degree. C. to room temperature to give the corresponding
diazoethanone and rearrangement to the methylester with silver
benzoate in MeOH/THF at -25.degree. C. to room temperature gave 7).
For q=3 compounds of formula 6 are hydrolyzed (NaOH in EtOH at room
temperature), followed by formation of the corresponding Weinreb
amide (e.g. HCl.H.sub.2NOMe/NMM, EDCI, HOBT) and conversion to an
aldehyde (LAH, -78 to -30.degree. C. in THF). The obtained compound
can be converted by a Horner-Emmons reaction (e.g.
(EtO).sub.2P(.dbd.O)CH.sub.2COOEt, NaH in THF) followed by
reduction of the double bond and reduction of the ester (a) Mg in
MeOH, (b) LAH in THF at -20.degree. C.) and BOC replacement (e.g.
(a) TFA in CH.sub.2Cl.sub.2-20.degree. C. to room temperature, (b)
NaHCO.sub.3/EtOAc, (c) ClCOOR.sup.3/Et.sub.3N or conversion to all
other R.sup.3X described later).
[0116] For the introduction of Y=NR.sup.2, SR.sup.2 or a
N-heterocycle (step g) a compound of formula 8 or 9 maybe mesylated
(1.1 eq MeSO.sub.2 Cl/1.5 pyridine/1 eq DMAP; in case Y is an amine
the reaction is performed with e.g. 1 eq NaI, amine neat
100.degree. C., for Y R.sup.2 is pyrrole, imidazole or X is S, the
reaction is performed with 1 eq NaI, NaH in DMF at 0.degree. C. to
room temperature, followed by thiol deprotection, e.g. by treatment
with TFA/Et.sub.3SiH, 0.degree. C. to room temperature (R.sup.1 is
Trt) or TFA/Et.sub.3SiH, 0 to 80.degree. C. (R.sup.1 is PMB). An
alternative method for the introduction of Y=NR.sup.2 would
comprise the reaction of compound 8 or 9 with 1.1 eq
MeSO.sub.2Cl/1.5 eq pyridine/1 eq DMAP (mesylation) followed by
treatment with NaN.sub.3, DMF for 16 hours at 80.degree. C. to
obtain the azide. This compound is then converted to the Y=NR.sup.2
(=amines or triazoles) after the introduction of new R.sup.3X.
[0117] For the introduction of a new R.sup.3X in case R.sup.3X is
BOC, the azide may be BOC deprotected by reaction with TFA,
CH.sub.2Cl.sub.2 at -20.degree. C. to room temperature, followed by
reaction with ClCO.sub.2R.sup.3, iPr.sub.2NEt, CH.sub.2Cl.sub.2 or
R.sup.3NCO in THF at 0.degree. C. to room temperature (or
conversion to all other R.sup.3X described later), followed by
reduction of the azide (e.g. Ph.sub.3P, THF, H.sub.2O or
NaBH.sub.4, MeOH), followed by reductive amination (e.g. aldehyde,
SnCl.sub.2, NaBH.sub.3CN, MeOH). In case R.sup.6 has to be
introduced the compound is treated with R.sup.6Br/K.sub.2CO.sub.3
in acetonitrile at room temperature followed by thiol deprotection
(e.g. Et.sub.3SiH, TFA, 0.degree. C. to room temperature or
Et.sub.3SiH, TFA, MeCN at room temperature or, for selective
trityl-thiol deprotection in the presence of BOC by for example
treatment with iPr.sub.3SiH in TFA/CH.sub.2Cl.sub.2, 0.degree. C.
to room temperature).
[0118] A further method for the introduction of new substituents
YR.sup.2 and XR.sup.3 comprises the oxidation of an alcohol 8 or 9
to the aldehyde (e.g. with (COCl).sub.2/DMSO/iPr.sub.2NEt at
-65.degree. C. to room temperature in CH.sub.2Cl.sub.2), an imine
formation (e.g. corresponding primary amine/MgSO.sub.4, room
temperature, 16 hours in CH.sub.2Cl.sub.2), reduction to the amine
(e.g. NaBH.sub.4 in MeOH at 40.degree. C., FMOC-protection of
Y=NHR.sup.2 (e.g. FMOC-Cl/iPr.sub.2NEt/cat DMAP, 0.degree. C. to
room temperature), BOC-deprotection (e.g. TFA in CH.sub.2Cl.sub.2,
0.degree. C. to room temperature), followed by reaction with
R.sup.3NHSO.sub.2Cl (in e.g. iPr.sub.2NEt, 0.degree. C. to room
temperature) (or conversion to all other R.sup.3X described later),
FMOC-deprotection (e.g. Et.sub.2NH in THF), and thiol deprotection
(e.g. Et.sub.3SiH in TFA at 80.degree. C.).
[0119] Compounds wherein YR.sup.2 is triazol may be prepared via
step g by reaction of the above mentioned azide with the
corresponding alkyl/amineCOCH.sub.2keton/ester/amide/aryl and
K.sub.2CO.sub.3 (in DMSO, 40.degree. C. for 3 days) followed by
thiol deprotection (e.g. Et.sub.3SiH, TFA, 0.degree. C. to room
temperature or Et.sub.3SiH, TFA, MeCN, room temperature). An
alternative is the reaction of the corresponding azide with
alkyl/amineCOCH.sub.2ester, K.sub.2CO.sub.3, DMSO, 40.degree. C.
for 3 days, followed by hydrolysis of the ester(e.g. LiOH, THF) and
thiol deprotection as described above.
[0120] In case of an introduction of a new substituent R.sup.3X in
case R.sup.3X is BOC, the corresponding compound may be prepared
via step g by BOC deprotection (TFA, CH.sub.2Cl.sub.2, -20.degree.
C. to room temperature), followed by reaction with a compound of
formula R.sup.3OCOCl and iPr.sub.2NEt/CH.sub.2Cl.sub.2 or
conversion to all other R.sup.3X described later.
[0121] In case YR.sup.2 represents a phenolether the phenol may be
introduced via step g under Mitsunobu conditions (e.g.
DEAD/Ph.sub.3P/PhOH in THF) and in case R.sup.1 is Trt followed by
reaction with e.g. TFA/Et.sub.3SiH at 0.degree. C. to room
temperature or, in case R.sup.1 is PMB, followed by reaction with
e.g. TFA/Et.sub.3SiH, at 0 to 80.degree. C. In case YR.sup.2
represents carbamates, the corresponding compounds 5 may by
obtained via step g by reaction with isocyanate/NMM in toluene at
room temperature followed optionally by reaction with the
corresponding alkyl-, cycloalkyl-halogenide, alkylbromoacetate with
NaH in DMF at 0.degree. C. to room temperature. If YR.sup.2
represents an ether the corresponding compounds 5 may be obtained
via step g by O-alkylation (e.g. NaH, R.sup.2-halogenide, DMF
0.degree. C. to room temperature) or by O-alkylation with phase
transfer conditions (e.g. R.sup.2-halogenide/50% NaOH,
Bu.sub.4NHSO.sub.4). This reaction may be followed by reaction with
e.g. TFA/Et.sub.3SiH at 0.degree. C. to room temperature (R.sup.1
is Trt) or, in case R.sup.3 is PMB, followed by reaction with e.g.
TFA/Et.sub.3SiH, at 0 to 80.degree. C.
[0122] Compounds containing a group of formula (II) may be prepared
via step g by reaction of the corresponding starting compound 8 or
9 with NaH, R.sup.2-halogenide/NaI, DMF and in case R.sup.2
contains a COOtBu (a) reaction with TFA in CH.sub.2Cl.sub.2 at
-20.degree. C. and (b) reaction with EDCI/HOBT amine in
CH.sub.2Cl.sub.2 for formation of the corresponding amide- or, in
case 2 R contains a COO-alkyl- (a) reaction with 1N NaOH in
THF/EtOH to give the acid. Both pathways are completed by reaction
with Et.sub.3SiH in TFA at 0.degree. C. to room temperature.
[0123] Compounds wherein YR.sup.2 is an ether the group R.sup.3X
may be varied as followed: For O-alkylation compounds of formula 8
or 9 may be reacted with e.g. NaH/reactive R.sup.2Br in DMF at
0.degree. C. to room temperature followed be BOC deprotection (e.g.
TFA in CH.sub.2Cl.sub.2 at -20.degree. C. to room temperature to
get the amine as starting material.
[0124] In case R.sup.3X is a carbamate these starting compounds may
be reacted with R.sup.3OCOCl/pyridine in THF or by reaction with
(a) R.sup.3OH/Cl.sub.3COCl/quinoline (formation of the
chloroformate) followed by reaction with NaH. In case R.sup.3X is a
sulfonamide the starting compounds may be reacted with
R.sup.3SO.sub.2Cl/(i-Pr).sub.2EtN/- cat DMAP in
ClCH.sub.2CH.sub.2Cl at room temperature. In case R.sup.3X is urea
the starting compounds may be reacted with isocyanate in EtOH at
room temperature. In case R.sup.3X is an alkylated urea, (i.e.
introduction of R.sup.5) the starting compounds may be reacted with
isocyanate in EtOH at room temperature followed by reaction with
the corresponding alkylhalogenide/K-OtBu at 0.degree. C. to room
temperature. In case R.sup.3X is an amide, the starting compounds
may be reacted with RCOOH/EDCI/DMAP (with an hydride formation, and
subsequent addition of the starting amine, -10.degree. C. to room
temperature) or as alternative with RCOOH/EDCI/DMAP at room
temperature. In case R.sup.3X is a sulfamide (for R.sup.3 is
NH.sub.2) the starting compounds may be reacted with sulfamic acid
2,4,6-trichlorophenylester/Et.sub.3N in CH.sub.2Cl.sub.2 at
40.degree. C. or with other methods which are known in the art. In
case R.sup.3X is SO.sub.2OH the starting compounds maybe reacted
with chlorosuphonic acid/2-picoline. In case R.sup.3X is an
alkylated sulfamide (i.e. introduction of R.sup.5) the starting
compounds maybe reacted with NaH/alkyl halide in DMF at 0.degree.
C. at room temperature. Thiol liberation can than be achieved by
reaction in TFA/Et.sub.3SiH at room temperature.
[0125] Step h of scheme 1 includes a reaction pathway for the
preparation of further derivatives by reaction of compounds of
formula 4 with (a) NaH/ reactive R.sup.2Br in DMF at 0.degree. C.
to room temperature followed by (b) reaction with KSAc in DMF at
100.degree. C. The corresponding thiols could be obtained by
reaction of the the above compounds with LiOH aqueous in EtOH at
0.degree. C. to room temperature.
[0126] Step i of scheme 1 shows the preparation of compounds of
formula 5 wherein Y is C. Compounds of formula 4 are treated with
NaOH in EtOH at room temperature, followed by formation of a
Weinreb amide (e.g. by reaction with HCl.H.sub.2NOMe/NMM, EDCI,
HOBT at 0.degree. C. to room temperature), followed by formation of
the corresponding ketone (e.g. by reaction with R.sup.2--MgBr in
THF, at 0.degree. C. to room temperature), BOC deprotection (e.g.
TFA in CH.sub.2Cl.sub.2, at -20.degree. C. to room temperature)
followed by reaction with R.sup.3OCOCl/NMM in CH.sub.2Cl.sub.2 (or
conversion to all other R.sup.3X described before) and reduction of
the ketone to the methylene and thiol deprotection (e.g.
Et.sub.3SiH in TFA at 80.degree. C. for 18 hours). 8
[0127] Further reaction pathways are shown in scheme 2: Compounds
of formula 2 may be obtained by persilylation of the hydroxy- and
amino groups of compounds 1 (e.g. reaction with HMDS, neat
120.degree. C.) and preparation of the corresponding methyl ester
(step a) (e.g. R.sup.3SO.sub.2Cl, iPr.sub.2NEt, THF, if acid, then
e.g. MeOH, HCl). Step b of scheme 2 shows the formation of the
corresponding t-Butyldimethylsilylether or for example the
t-butylether (e.g. by reaction with TBDMSCl/DBU in CH.sub.3CN at
0.degree. C. to room temperature, or by reaction with isobutylene,
BF.sub.3.OEt.sub.2 in CH.sub.2Cl.sub.2 at -30 to -20.degree. C.
Step c comprises the reaction of compound 2 with LiBH.sub.4 in THF
at -20.degree. C. to room temperature or LAH at -15.degree. C. in
ether to obtain compounds 4.
[0128] In case R.sup.2Y is R.sup.2N, step d of scheme 2 shows the
introduction of a phthalimide under Mitsunobu conditions (e.g.
phthalimide, DEAD/Ph.sub.3P in THF, 3 to 80.degree. C. This may be
followed by t-butyldimethylsilylether deprotection (e.g. for
t-BuMe.sub.2Si: reaction with TBAF in THF at room temperature),
followed by reaction with e.g. MeSO.sub.3H/DIAD/Ph.sub.3P in
toluene at room temperature -80.degree. C., followed by e.g.
reaction with KSCOCH.sub.3 in DMF at 100.degree. C., followed by
phthalimide deprotection and disulfide formation (e.g. by reaction
with CH.sub.3NH.sub.2, EtOH for 2 days at room temperature which
may be followed by reaction with R.sup.2SO.sub.2Cl or R.sup.2COCl,
DMAP in CH.sub.2Cl.sub.2 or R.sup.2CO.sub.2H, TPTU or N-alkylation
by reaction with R.sup.2Br and N-methylmorpholine in
CH.sub.2Cl.sub.2. This may be followed by side chain manipulation
e.g. hydrolysis with LiOH in THF/H.sub.2O. Step e of scheme 2 shows
the reduction of the disulfide to the thiol (e.g. by
nBu.sub.3P/CF.sub.3CH.sub.2OH/H.sub.2O at 0.degree. C. or DTT, 2 M
K.sub.2CO.sub.3, MeCN).
[0129] In case R.sup.2Y is R.sup.2O: Compounds of this type may be
obtained by reaction shown in step f and g. These reaction may
comprise (step f) reaction of compounds 4 with R.sup.2Br/NaH in
DMSO at room temperature or
benzyl-2,2,2-trichloroacetimidate/CF.sub.3SO.sub.3H in
CH.sub.2Cl.sub.2/cyclohexane at room temperature (here the
R.sup.2-side chains may be manipulated by reaction with 10%
Pd/C/H.sub.2 in EtOH/dioxane) or the reaction is performed with
PhOH/Ph.sub.3P/DIAD in THF at room temperature. All reactions may
be followed by removal of the t-Bu-ether in TFA at 0.degree. C. to
room temperature. For the preparation of compounds of formula 7
(step g) compounds 6 (if m=0: for inversion of the configuration)
may be obtained by thioacetate formation under Mitsunobu conditions
(e.g. CH.sub.3COSH/Ph.sub.3P/DIAD in THF at 0.degree. C. to room
temperature) followed by formation of the thiol (e.g. by reaction
with MeONa in MeOH at 0.degree. C.; plus potential side chain
manipulation with 1 N Na.sub.2CO.sub.3 in MeOH) or (if m=0: for
retention of configuration) reaction of compounds 6 for e.g.
formation of the mesylate (MeSO.sub.3H/Et.sub.3N/Ph.sub.3P/DIAD in
toluene at 0.degree. C. to 85.degree. C.) followed by preparation
of the thioacetate (e.g. KSCOCH.sub.3 in DMF at 100.degree. C.) and
formation of the thiol (MeONa in MeOH at 0.degree. C.).
[0130] Scheme 3 shows a further route for the preparation of
compounds of formula (I). Step a comprises the preparation of
compounds 2 by reaction of compounds 1 with e.g.
R.sup.3SO.sub.2Cl/DMAP in CH.sub.2Cl.sub.2 at room temperature or
Et.sub.3N in CH.sub.2Cl.sub.2 (reflux)) followed by monohydrolysis
(e.g. 1 M NaOH in MeOH/H.sub.2O for 20 min reflux and reduction of
the acid with e.g. BH.sub.3.THF in THF at 0.degree. C. Step c shows
an alkylation (e.g. with R.sup.2Br/NaH in DMSO at room temperature)
followed by ester reduction (e.g. LAH at -15.degree. C. in ether).
Step e comprises the formation of the thioacetate (e.g. by
CH.sub.3COSH/Ph.sub.3P/DIAD in THF at 0.degree. C. to room
temperature followed by formation of the thiol (e.g. with MeONa in
MeOH at 0.degree. C. Step f shows the reduction of both esters
(e.g. with LAH in THF at 0.degree. C.) followed by monoalkylation
(e.g. with R.sup.2Br/NaH in DMF at -15.degree. C., step g). This
pathway may be continued by formation of the mesylate (e.g. with
MeSO.sub.2Cl/Et.sub.3N in Et.sub.2O at -20.degree. C. to room
temperature), formation of the thioacetate (e.g. with KSCOCH.sub.3
in DMF at 100.degree. C.) and formation of the thiol (LAH in
Et.sub.2O reflux). Step h depicts an additional way for preparing a
mono-p-tosylate (e.g. with p-TosCl/Et.sub.3N/cat DMAP in THF at
room temperature) followed by introduction of the tritylthiolate
(e.g. with Ph.sub.3CSH/KOt-Bu in DMF at room temperature),
formation of the mesylate (step i, with MeSO.sub.2Cl/Et.sub.3N in
THF at 0.degree. C. to room temperature) followed by the formation
of the phenolether (e.g. with PhOH/NaH in DMF at room temperature)
or alternatively alkylation of the alcohol directly with
R.sup.2Br/NaH in DMF at -15.degree. C. to room temperature and
finally formation of the thiol (e.g. with Et.sub.3SiH in TFA at
0.degree. C. to room temperature). 9 10
[0131] Scheme 4 shows in step a the selective protection of the
thiol group (e.g. by reaction with Ac.sub.2O/pyridine in
CH.sub.2Cl.sub.2 at room temperature; the starting compound can be
received by a deprotection of a STrt or SPMB protected alcohol
described above, e.g. Et.sub.3SiH in TFA). The S-acetylated alcohol
was then reacted with (a)
1,2,3,4-tetra-O-acetyl-t-deoxy-beta-L-mannospyranose/trimethylsilyl-trifl-
uoromethanesulphonate in CH.sub.2Cl.sub.2 at 0.degree. C. followed
by cleavage of all acetyl group with NaOMe in MeOH at 0.degree.
C.
[0132] Scheme 5 shows the reaction pathway for the synthesis of
sterically hindered thiols. Step a represents a Swern-oxidation of
the starting material which is known in the art (e.g.
(COCl).sub.2/DMSO/Et(i-Pr).sub.2- N in CH.sub.2Cl.sub.2). Step b
shows the methylene introduction by a Wittig reaction (e.g. with
Kt-BuO/CH.sub.3PPh.sub.3Br in THF at room temperature to 70.degree.
C. Step c shows a reduction via a mixed anhydride (e.g. with
iBuOCOCl/NMM in THF at -5.degree. C. to room temperature, then the
mixture is added to NaBH.sub.4 in water at 0.degree. C. and warmed
up to room temperature) followed by alkylation of the corresponding
alcohol (e.g. with NaH/R.sup.2Br in THF at 0.degree. C. to room
temperature). Step d represents the formation of an epoxide (e.g.
with mCPBA in CH.sub.2Cl.sub.2 at room temperature) followed by the
formation of a thiirane (e.g. with KSCN in EtOH/H.sub.2O at room
temperature or PO(OMe).sub.2SCl in CH.sub.2Cl.sub.2). The resulting
diastereomers are separable with methods known in the art. Step e
shows the opening of the thiirane (e.g. with LiHBEt.sub.3 in THF
and LAH) and reduction of the resulting disulfide (e.g. with
P(Bu).sub.3/H.sub.2O in trifluoroethanol/CH.sub.2Cl.sub.2). 11
[0133] Scheme 6 shows the synthesis of further derivatives: for Y
being NH: Step a comprises the N-acylation (protection of NH, e.g.
with AcCl, iPr.sub.2NEt, 4-(N-benzyl-N-methylamino)pyridine
polymer-supported, CH.sub.2Cl.sub.2) or by N-CBz-Protection (e.g.
with BnOCOCl, iPr.sub.2NEt, 4-Benzyl-N-methylamino)pyridine polymer
supported, CH.sub.2Cl.sub.2), followed by selective BOC
deprotection (e.g. with TFA, CH.sub.2Cl.sub.2 at -20.degree. C. to
room temperature) and reaction with a reactive R.sup.3 derivative
(e.g. R.sup.3CO.sub.2Cl, iPr.sub.2NEt,
4-(N-Benzyl-N-methylamino)pyridine polymer-supported,
CH.sub.2Cl.sub.2; step c(or conversion to all other R.sup.3X
described before)) and formation of the thiol (e.g. with
iPr.sub.3SiH, TFA, CH.sub.2Cl.sub.2).
[0134] For Y being C-, protected-N-, O- or S-substituents step e of
scheme 6 shows formation of S-compounds of thiol inhibitors of
formula (I) by (a) reaction of the free thiol with for example AcCl
in pyridine or PhCOCl in pyridine at 0.degree. C. to room
temperature or (b) a S-derivative synthesis (e.g. with
BOC-Cys(Npys)-OH=2-(BOC-Cys)disulfanyl-- 3-nitro-pyridine or
Ac-Cys(Npys)-OH=2-(acetyl-Cys)disulfanyl-3-nitro-pyrid- ine) in
DMF/0.1 M phosphate buffer (pH 6.2). The reaction for Y being
protected N-atoms (Y deprotection) can be performed selective with
for example HBr/AcOH in EtOAc. Step f shows the formation of the
thiol as described above. 12
[0135] The present invention also refers to the above described
processes, especially to processes for the preparation of a
compound of the present invention comprising reaction of a compound
of formula V 13
[0136] wherein R.sup.1, R.sup.3, R.sup.4, X, Y, m, n, o, q and p
are as defined above and A is a HS-protecting group
[0137] a) with a R.sup.2-halogenide for introduction of a
--OR.sup.2 group: or
[0138] b) mesylation of a compound of formula (V), followed by
reaction with H R.sup.6N--R.sup.2 or HSR.sub.2 or HN-heterocycles
for introduction of a --NR.sup.6--R.sup.2 or --SR.sup.2 group or
--N-heterocycle;
[0139] optionally followed by conversion of a R.sup.3--X group into
a different one and/or deprotection and/or thiol liberation.
[0140] Dimeric forms of a compound of formula I may be prepared by
oxidative treatment of the formula I monomers.
[0141] On the basis of their capability of inhibiting
metalloprotease activity, especially zinc hydrolase activity, the
compounds of formula I can be used as medicaments for the treatment
and prophylaxis of disorders which are associated with
vasoconstriction of increasing occurrences. Examples of such
disorders are high blood pressure, coronary disorders, cardiac
insufficiency, renal and myocardial ischaemia, renal insufficiency,
dialysis, cerebral ischaemia, cardiac infarct, migraine,
subarachnoid haemorrhage, Raynaud syndrome and pulmonary high
pressure. They can also be used in atherosclerosis, the prevention
of restenosis after balloon-induced vascular dilation,
inflammations, gastric and duodenal ulcers, ulcus cruris,
gram-negative sepsis, shock, glomerulonephtritis, renal colic,
glaucoma, asthma, in the therapy and prophylaxis of diabetic
complications and complications in the administration of
cyclosporin, as well as other disorders associated with endothelin
activities.
[0142] The ability of the compounds of formula (I) to inhibit
metalloprotease activity, particularly zinc hydrolase activity, may
be demonstrated by a variety of in vitro and in vivo assays known
to those of ordinary skill in the art. Pharmaceutically acceptable
esters, pharmaceutically acceptable salts and dimeric forms of the
compounds of formula I can also be tested by those of ordinary
skill in the art for their ability to inhibit metalloprotease
activity.
[0143] A) Cell Culture
[0144] A stable human umbilical vein endothelial cell line (ECV304)
was cultured in "cell factories" as described until confluency
(Schweizer et al. 1997, Biochem. J. 328: 871-878). At confluency
cells were detached with a trypsin/EDTA solution and collected by
low speed centrifugation. The cell pellet was washed once with
phosphate buffered saline pH 7.0 and stored at -80.degree. C. until
use.
[0145] B) Solubilization of ECE from ECV304 Cells
[0146] All procedures were performed at 0-4.degree. C. if not
stated otherwise. The cell pellet of 1.times.10.sup.9 cells was
suspended in 50 ml of buffer A (20 mM Tris/HCl, pH 7.5 containing 5
mM MgCl.sub.2, 100 .mu.M PMSF, 20 .mu.M E64, 20 .mu.M leupeptin)
and sonicated. The resulting cell homogenate was centrifuged at
100,000 g.sub.av for 60 minutes. The supernatant was discarded and
the resulting membrane pellet was homogenized in 50 ml buffer A and
centrifugated as described. The washing of the membrane fraction in
buffer A was repeated twice. The final membrane preparation was
homogenized in 50 ml of buffer B (buffer A+0.5% Tween 20 (v/v),
0.5% CHAPS (w/v), 0.5% Digitonin (w/v)) and stirred at 4.degree. C.
for 2 hours. Thereafter the remaining membrane fragments were
sedimented as described. The resulting clear supernatant containing
the solubilized ECE was stored in 1.0 ml aliquots at -120.degree.
C. until use.
[0147] C) ECE Assay
[0148] The assay measured the production of ET-1 from human big
ET-1. To measure high numbers of samples an assay performed in 96
well plates was invented. The enzyme reaction and the
radioimmunological detection of the produced ET- 1 was performed in
the same well, using a specifically developed and optimized coating
technique.
[0149] D) Coating of Plates
[0150] Fluoronunc Maxisorp White (code 437796) 96 well plates were
irradiated with 1 joule for 30 minutes in a UV Stratalinker 2400
(Stratagene). The 96 well plates were then fill with 300 .mu.l
protein A solution (2 .mu.g/ml in 0.1 M Na.sub.2CO.sub.3 pH 9.5)
per well and incubated for 48 hours at 4.degree. C. Coated plates
can be stored for up to 3 weeks at 4.degree. C. until use.
[0151] Before use the protein A solution is discarded and the
plates are blocked for 2 hours at 4.degree. C. with 0.5% BSA in
0.1M Na.sub.2CO.sub.3, pH 9.5.
[0152] Plates were washed with bidestilled water and were ready to
perform the ECE assay.
[0153] E) Screening assay
[0154] Test compounds are solved and diluted in DMSO. 10 .mu.l of
DMSO was placed in the wells, followed by 125 .mu.l of assay buffer
(50 mM Tris/HCl, pH 7.0, 1 .mu.M Thiorphan, 0,1% NaN.sub.3, 0.1%
BSA) containing 200 ng big ET-1. The enzyme reaction was started by
the addition of 50 .mu.l of solubilized ECE (diluted in assay
buffer 1:30 to 1:60 fold (v/v)). The enzyme reaction was carried
out for 30 minutes at 37.degree. C. The enzyme reaction was stopped
by addition of 10 .mu.l 150 mM ETDA, pH 7.0.
[0155] F) Radioimmunoassay
[0156] The ET-1 RIA was performed principally as described earlier
(Loffler, B. -M. and Maire, J. -P. 1994, Endothelium 1: 273-286).
To plates containing the EDTA stopped enzyme reaction mixture 25
.mu.l of assay buffer containing 20000 cpm
(3-(.sup.125I)Tyr)-endothelin-1 and 25 .mu.l of the ET specific
antiserum AS-3 (dilution in assay buffer 1:1000) was added. Plates
were incubated under mixing at 4.degree. C. over night. Thereafter,
the liquid phase was sucked with a plate washer and plates were
washed once with bidestilled water. To the washed plates 200 .mu.l
scintillation cocktail (Microscint 40 LSC-Cocktail, Packard, code
6013641) was added and plates were counted for 2 minutes per well
in a Topcount.
[0157] Standard curves were prepared in plates with synthetic ET-1
with final concentrations of 0 to 3000 pg ET-1 per well. In all
plates controls for maximal ECE activity (in the presence of 10
.mu.l DMSO) and for background production of ET-1 immunoreactivity
(in the presence of 10 mM EDTA or 100 .mu.M phosphoramidon) were
performed. Assays were run in triplicate.
[0158] G) Kinetic Assay
[0159] The described assay format could be used to determine the
kinetic characteristics of the used ECE preparation as well as
different ECE inhibitors (i.e. Km, Ki) by variation of the
substrate concentration used in the assay.
[0160] H) Cell Based ECE Assay
[0161] Human ECE-1c was stable expressed in MDCK cells as described
(Schweizer et al. 1997, Biochem. J. 328: 871-878). Cells were
cultured in 24 well plates to confluency in Dulbecco's modified
Eagles's medium (DMEM) supplemented with 10% (v/v) fetal bovine
serum (FBS), 0.8 mg/ml geneticin, 100 i.u./ml penicillin and 100
.mu.g/ml streptomycin in a humidified air/CO.sub.2 (19:1)
atmosphere. Before ECE assay the medium was replaced by 0.5 ml
DMEM-HBSS 1:1, 10 mM HEPES pH 7.0 supplemented with 0.1% (w/v) BSA.
The inhibitors were added in DMSO at a final concentration of 1%.
The enzyme reaction was started by the addition of 0.42 .mu.M human
big ET-1 and performed for 1.5 hours at 37.degree. C. in an
incubator. At the end of incubation, the incubation medium was
quickly removed and aliquots were analysed by radioimmunoassay for
produced ET-1 as described above.
[0162] The ECE screening assay was validated by the measurement of
the characteristic inhibitor constants of phosphoramidon (IC.sub.50
0.8.+-.0.2 .mu.M) and CGS 314447 (IC.sub.50 20.+-.4 nM) [De
Lombaert, Stephane; Stamford, Lisa B.; Blanchard, Louis; Tan,
Jenny; Hoyer, Denton; Diefenbacher, Clive G.; Wei, Dongchu;
Wallace, Eli M.; Moskal, Michael A.; et al. Potent non-peptidic
dual inhibitors of endothelin-converting enzyme and neutral
endopeptidase 24.11. Bioorg. Med. Chem. Lett. (1997), 7(8),
1059-1064]. All three inhibitors were measured with IC.sub.50
values not significantly different from those described in the
literature but measured with different assay protocols. In the cell
based assay phosphoramidon showed an IC.sub.50 of 4 .mu.M. This
assay gave additional information about the inhibitory potency of
inhibitors under much more physiologic conditions, as e.g. the ECE
was embedded in a normal plasma membrane environment. It is
important to state, that the screening assay was performed in the
presence of 1 .mu.M Thiorphan to block any potential big ET-1
degradation due to the action of NEP24.11. No NEP activity was
present in MDCK-ECE-1c transfected cells in preliminary experiments
when ET-1 production was measured in presence or absence of
thiorphan. In subsequent experiments no thiorphan was added in the
incubation medium.
[0163] According to the above methods, the compounds of the present
invention show activity values in the radioimmunoassay (E and F) of
about 0.5 nM to about 100 .mu.M. The preferred compounds show
values of 0.5 nM to 100 nM.
[0164] As mentioned earlier, medicaments containing a compound of
formula I are also an object of the present invention as is a
process for the manufacture of such medicaments, which process
comprises bringing one or more compounds of formula I and, if
desired, one or more other therapeutically valuable substances into
a galenical administration form.
[0165] The pharmaceutical compositions may be administered orally,
for example in the form of tablets, coated tablets, drages, hard or
soft gelatin capsules, solutions, emulsions or suspensions.
Administration can also be carried out rectally, for example using
suppositories; locally or percutaneously, for example using
ointments, creams, gels or solutions; or parenterally, for example
using injectable solutions.
[0166] For the preparation of tablets, coated tablets, dragees or
hard gelatin capsules the compounds of the present invention may be
admixed with pharmaceutically inert, inorganic or organic
excipients. Examples of suitable excipients for tablets, dragees or
hard gelatin capsules include lactose, maize starch or derivatives
thereof, talc or stearic acid or salts thereof.
[0167] Suitable excipients for use with soft gelatin capsules
include for example vegetable oils, waxes, fats, semi-solid or
liquid polyols etc. According to the nature of the active
ingredients, it may, however, be the case that no excipient is
needed at all for soft gelatin capsules.
[0168] For the preparation of solutions and syrups, excipients
which may be used include for example water, polyols, saccharose,
invert sugar and glucose. For injectable solutions, excipients
which may be used include for example water, alcohols, polyols,
glycerin, and vegetable oils. For suppositories, and local or
percutaneous application, excipients which may be used include for
example natural or hardened oils, waxes, fats and semi-solid or
liquid polyols.
[0169] The pharmaceutical compositions may also contain preserving
agents, antioxidants, solubilising agents, stabilizing agents,
wetting agents, emulsifiers, sweeteners, colorants, odorants, salts
for the variation of osmotic pressure, buffers, coating agents or
antioxidants. They may also contain other therapeutically valuable
agents.
[0170] The dosages in which the compounds of formula I are
administered in effective amounts depend on the nature of the
specific active ingredient, the age and the requirements of the
patient and the mode of application. In general, dosages of 0.1-100
mg/kg body weight per day come into consideration, although the
upper limit quoted can be exceeded when this is shown to be
indicated.
[0171] The following specific examples are provided as a guide to
assist in the practice of the invention, and are not intended as a
limitation on the scope of the invention.
EXAMPLES
[0172] All reactions are done under argon.
[0173] A) Abbreviations:
[0174] EtOAc ethylacetate, EtOH ethanol, THF tetrahydrofurane,
Et.sub.2O diethylether, MeOH methanol, CH.sub.2Cl.sub.2
dichloromethane, EDCI
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, HOBT
1-Hydroxybenzotriazole, DBU
1,8-Diazabicyclo[5.4.0]undec-7-ene(1,5-5), LAH Lithium aluminum
hydride, LDA lithium diisopropylamide, DEAD Diethyl
azodicarboxylate, DIAD Diisopropyl azodicarboxylate, DMAP
4-Dimethylaminopyridine, TBAF tetrabutylammonium fluoride,
iPr.sub.2NEt N-ethyldiisopropylamine, Ph.sub.3P triphenylphosphine,
P(Bu).sub.3 tributylphosphine, Red-Al solution
Natrium-dihydrido-bis-(2-methoxyethoxy- )-aluminat-solution, NMM
N-methylmorpholine, Et.sub.3N triethylamine,
Cl.sub.3COCl=di-phosgene=trichloromethyl-chloroforamate, PMB
p-methoxy-benzyl, Trt trityl=Ph.sub.3CSH, DTT
1,4-Dithio-DL-threitol, BOC-Cys(Npys)-OH
2-(BOC-Cys)disulfanyl-3-nitro-pyridine, Ac-Cys(Npys)-OH
2-(acetyl-Cys)disulfanyl-3-nitro-pyridine.
[0175] B) General Method for a Selective BOC-deprotection:
[0176] A solution of 15.1 mmol N-BOC-S-Trityl compound in 30 ml
CH.sub.2Cl.sub.2 was treated at -20.degree. C. with 34 ml TFA and
warmed up to room temperature during 5.5 h. The reaction was
evaporated and treated with aqueous saturated NaHCO.sub.3
solution/EtOAc (3.times.) to give the free aminotritylsulfanyl.
[0177] C) General Method for EDCI-coupling:
[0178] Weinreb-amide formation: A solution of 13.6 mmol carboxylic
acid in 150 ml CH.sub.2Cl.sub.2 was treated at 0.degree. C. with
95.2 mmol N-methylmorpholine, 0.37 g (2.72 mmol) HOBT, 6.26 g
(32.64 mmol) EDCI and 2.92 g (29.92 mmol) N,O-dimethyllydroxylamine
hydrochloride. The reaction was stirred over night at room
temperature and partitioned between aqueous 10% KHSO.sub.4/EtOAc
(3.times.). The organic phases were washed with aqueous saturated
NaCl and dried over Na.sub.2SO.sub.4. Purification by
flash-chromatography on silica gel (Hexane/EtOAc 1:1) gave of
methoxy-methyl-carbamoyl derivative.
[0179] D) General Method for Ester Hydrolysis:
[0180] A solution of 5.38 mmol carboxylic acid methyl ester was
dissolved in 150 ml EtOH and treated at RT with 10.8 ml (10.8 mmol)
aqueous 1 N NaOH. After 3h the reaction was evaporated and poured
into aqueous 10% KHSO.sub.4/EtOAc (3.times.). The organic phases
were washed with aqueous 10% NaCl solution and dried over
Na.sub.2SO.sub.4 to give the carboxylic acid.
[0181] E) General Method for S-deprotection:
[0182] Method 1: TFA/triethylsilane deprotection for labile
p-methoxy-benzylsulfanyl compounds: A solution of 0.15 mmol
p-methoxy-benzylsulfanyl was dissolved in 2 ml TFA, cooled to
0.degree. C. and treated with 0.24 ml (1.5 mmol) triethylsilane,
stirred for 22 h at room temperature (the reaction was followed by
TLC, if necessary treated again with 0.24 ml (1.51 mmol)
triethylsilane and stirred for 30 h). The evaporated residue was
purified by flash silica gel column to give the thiol compound.
[0183] Method 2: TFA/triethylsilane deprotection for not labile
p-methoxy-benzylsulfanyl compounds: A solution of 0.25 mmol
p-methoxy-benzylsulfanyl and 0.4 ml (2.5 mmol) triethylsilane was
heated for 1 min-1.5 h at 80.degree. C. (followed by TLC), cooled
to RT and evaporated. Crystallization from Et.sub.2O/pentane gave
the thiol-compound.
[0184] Method 3: Trityl deprotection for single compound: A
solution of 0.58 mmol tritylsulfanyl in 5.8 ml TFA was treated at
0.degree. C. with 0.92 ml (5.78 mmol) triethylsilane and after 10
min at room temperature evaporated and purified by flash
chromatography on silica gel (Hexane/EtOAc 4:1) to give the
thiol-compound.
[0185] Method 4: Trityl deprotection for parallel synthesis: A
solution of 0.32 mmol trityl-protected compound was dissolved in
1.5 ml acetonitril/0.4 ml TFA/0.1 ml triethylsilane and after 1
night at room temperature purified by preparative HPLC (RP18,
CH.sub.3CN/H.sub.2O 80:20 to 95:5) to give the free thiols.
[0186] Method 5: Trityl deprotection in the presence of BOC: 1 eq
Trityl-protected compound in CH.sub.2Cl.sub.2 (15-20 ml/mmol) was
treated with 10 eq triisopropyl silane and 10 eq TFA at 0.degree.
C. or RT until no starting material could be detected. The solution
was poured on saturated NaHCO.sub.3 solution and the inorganic
phase was extracted with CH.sub.2Cl.sub.2, the organic phases were
washed with brine, dried over Na.sub.2SO.sub.4 and evaporated and
purified by flash chromatography to give the free amine.
Example 1
Starting Materials
Example 1.a
[0187] Alcohols:
[0188] 40 g (220 mmol) of L-hydroxyproline methylester
hydrochloride (twice suspended in toluene and evaporated under
reduced pressure to remove water) was suspended in 600 ml
hexamethyldisilazane and refluxed for 2 h. The solution was
evaporated under reduced pressure and dissolved in 100 ml THF. 49.9
g (220 mmol) of 2-naphthalene-sulphonyl chloride in 200 ml of THF
were added slowly and stirred for 16 h at room temperature. 150 ml
H.sub.2O were added and after 1 h the solvents were evaporated. The
residue was partitioned between water/EtOAc (3.times.), the organic
phases were washed with 10% NaCl and dried over Na.sub.2SO.sub.4 to
give 60.4 g (82%) of
(2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine--
2-carboxylic acid methyl ester, MS: 335 (M.sup.+).
[0189] The following compounds were prepared in an analogous
manner:
[0190] L-hydroxyproline benzylester hydrochloride and
1-naphthalenesulfonyl chloride gave
(2S,4R)-4-hydroxy-1-(naphthalene-2-su-
lfonyl)-pyrrolidine-2-carboxylic acid benzyl ester, MS: 411
(MH.sup.+);
[0191] L-hydroxyproline benzylester hydrochloride and
methanesulfonyl chloride gave
(2S,4R)-4-hydroxy-1-methanesulfonyl-pyrrolidine-2-carboxyli- c acid
benzyl ester, mp 132-133.degree. C., MS: 300 (MH.sup.+);
[0192] L-hydroxyproline methylester hydrochloride and
methanesulfonyl chloride gave after extraction with
CH.sub.2Cl.sub.2
(2S,4R)-4-hydroxy-1-methanesulfonyl-pyrrolidine-2-carboxylic acid
methyl ester, mp 115.5-117.degree. C., MS: 164 (M-COOMe.).
Example 1.b
[0193] Via Mesylate:
[0194] A biphasic solution of 13.9 ml (215 mmol) methanesulfonic
acid, 29.8 ml (215 mmol) triethylamine and 58.7 g (224 mmol)
triphenylphosphine in 150 ml toluene was added to a suspension of
60 g (179 mmol)
(2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic
acid methyl ester in 300 ml toluene which was stirred mechanically.
After adding 44.9 ml (233 mmol) of diisopropyl azodicaboxylate
(exothermic!) the solution was heated for 2.5 h at 80.degree. C.
300 ml water was added at room temperature and extracted with EtOAc
(3.times.300 ml). The organic phase was washed with aqueous 10%
KHSO.sub.4 (2.times.100 ml), 10% NaCl (2.times.150 ml) dried over
Na.sub.2SO.sub.4 and evaporated to give 180 g of crude product.
Flash chromatography (EtOAc/hexane 1:1) gave 63.7 g (86%) of (4S,
2S)-4-methanesulfonyloxy-1-(naphthalene-2-sulfonyl)--
pyrrolidine-2-carboxylic acid methylester.
[0195] 64.2 g (167 mmol) of triphenylmethanthiol was slowly added
at room temperature to a solution of 17.9 g (160 mmol) of potassium
tert-butylate in 300 ml DMF and stirred mechanically for 30 min.
Then 63 g (152 mmol) of (4S,
2S)-4-methanesulfonyloxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-
-carboxylic acid methylester in 300 ml DMF were added at 20.degree.
C. by cooling at the end with an ice bath. The reaction was heated
for 1.3 h at 100.degree. C., cooled, evaporated to 400 ml and
extracted with 250 ml aqueous saturated NH.sub.4Cl/EtOAc
(3.times.300). The organic phases were washed with aq. 10% NaCl,
dried (Na.sub.2SO.sub.4) and evaporated. Flash chromatography
(CH.sub.2Cl.sub.2/MeOH 99:1) gave 58.6 g (65%,
(2S,4R)/(2R,4R)-isomer ca 4:1, 1H-NMR) and 9.2 g (10%,
(2S,4R)/(2R,4R)-isomer ca 1:1, 1H-NMR) of
(2S,4R)-1-(naphthalene-2-sulfon-
yl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid methyl ester,
MS: 594 (MH.sup.+).
[0196] The following compounds were prepared:
[0197] (2S,4R)-4-hydroxy-1-methanesulfonyl-pyrrolidine-2-carboxylic
acid methyl ester gave after 3.75 h at 80.degree. C. (4S,
2S)-4-methanesulfonyloxy-1-(methylsulfonyl)-pyrrolidine-2-carboxylic
acid methylester which was heated for 45 min at 100.degree. C. with
triphenyl-methanthiolate to give
(2S,4R)-1-methanesulfonyl-4-tritylsulfan-
yl-pyrrolidine-2-carboxylic acid methyl ester
(2S,4R)/(2R,4R)-isomer ca 9:1, 1H-NMR), MS: 482 (MH.sup.+);
[0198] (2S,4R)-4-hydroxy-1-methanesulfonyl-pyrrolidine-2-carboxylic
acid benzyl ester gave after 5 h at 80.degree. C.
(2S,4S)-1-methanesulfonyl-4--
methanesulfonyloxy-pyrrolidine-2-carboxylic acid benzyl ester which
was heated for 30 min with 4-methoxybenzylthiol/potassium
tert-butylate to give
(2S,4S)-1-methanesulfonyl-4-methanesulfonyloxy-pyrrolidine-2-carboxy-
lic acid benzyl ester, mp 91-92.degree. C., MS: 453
(M+NH.sub.4.sup.+).
Example 1.c
[0199] Via bromid:
[0200] To a solution of 76.5 g (291.6 mmol, 6 eq)
triphenylphosphine in 650 ml THF were added 44.6 ml (286.8 mmol,
5.9 eq) DEAD in 70 ml THF at a temperature between 1.5-4.5.degree.
C. over a period of 0.5 h. The solution was stirred for 0.5 h
before 42.2 g (486.1 mmol, 10 eq) LiBr were added, and the reaction
mixture was recooled to 4.degree. C. for the addition of 20 g (48.6
mmol) (2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-
-pyrrolidine-2-carboxylic acid benzyl ester in 75 ml THF. After
stirring at room temperature for 3 h, water was added and the
suspension concentrated and redissolved in 700 ml EtOAc and water.
The layers were separated, the inorganic one was extracted with 100
ml of EtOAc (3.times.), and the combined organic layers were washed
with brine, dried over MgSO.sub.4 and evaporated.
Triphenylphosphine oxide was removed by crystallization from
EtOAc/hexane and the mother liquid was purified by colum
chromatography on silica gel with hexane: EtOAc 3:1 yielding 13.4 g
(62%) of
(2S,4S)-4-bromo-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxy-
lic acid benzyl ester as colorless solid, mp 97-98.degree. C., MS:
473 (MH.sup.+).
[0201] 3.38 g (30.1 mmol, 1.1 eq) potassium tert. butylate in 150
ml DMF were treated with 4.4 ml (31.5 mmol, 1.15 eq)
4-methoxybenzyl mercaptane at 0.degree. C. The solution was stirred
for 1 h at RT before 12.99 g (27.4 mmol)
(2S,4S)-4-bromo-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carb-
oxylic acid benzyl ester in 100 ml DMF were added. The reaction was
stirred at room temperature overnight, DMF was removed under
vacuum, and the residue redissolved in EtOAc and 1M aqueous
KHSO.sub.4. The layers were separated, and the organic one washed
with brine, dried over Na.sub.2SO.sub.4 and evaporated. The crude
oil was purified by flash chromatography on silica gel with
hexane/EtOAc (3:1-2:1) as eluent yielding 7.23 g (48%)
(2S,4R)-4-(4-methoxy-benzylsulfanyl)-1-(naphthalene-
-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester as light
yellow solid, mp 90-91.degree. C., MS: 547 (M.sup.+).
[0202] The following compounds were prepared:
[0203] (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester 2-methyl ester with 4-methoxybenzylthiol
potassium tert-butylate gave
(2S,4R)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester 2-methyl ester, MS: 382 (MH.sup.+).
Example 1.d
[0204] Via chloride:
[0205] A solution of 374 g (1.48 mol)
(2S,4R)-4-hydroxy-pyrrolidine-1,2-di- carboxylic acid 1-tert-butyl
ester 2-methyl ester in 1.6 1 CH.sub.2Cl.sub.2 was treated with 680
g (2.6 mol) triphenylphosphine, cooled to 3-5.degree. C. and
treated in 10 min with 1.241 (12.8 mol) CCl.sub.4, after 2 h at
this temperature cooling was stopped, the reaction temperature was
raised during 2 h to 35.degree. C. It was cooled down to 20.degree.
C. and stirred for further 45 min. After addition of 4 1 of
n-heptane, the reaction was evaporated to 2.9 l, cooled to
0.degree. C., filtered, the residue was treated twice the same way,
the third time by dissolving the residue again in 2 l of
CH.sub.2Cl.sub.2. The solvents were evaporated and filtered through
silica gel with hexane/tert.-butyl-methylether 9:1 as eluent.
Evaporation of the solvents gave 347 g (89%) of
(2S,4S)-4-chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl
ester 2-methyl ester, MS: 246 (MH.sup.+).
[0206] A solution of 76 g (0.68 mol) potassium-tert.-butylate in
1.5 1 DMF was cooled (-3.degree. C.) and treated slowly (1.5 h)
with 202 g (0.73 mol) triphenylmethanethiole in 0.8 1 DMF (at max
1.degree. C.). After 2.5 h at 0.degree. C., a solution of 161 g
(0.61 mol) of (2S,4S)-4-chloro-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester 2-methyl ester in 0.35 l DMF was added. The
reaction was stirred over night at 2.degree. C., evaporated,
dissolved in 1.5 l EtOAc, poured into 2.7 l aqueous saturated
NH.sub.4Cl solution and extracted with EtOAc (2.times.). The
organic phase was washed with aqueous saturated NaHCO.sub.3, dried
over Na.sub.2SO.sub.4 and evaporated. Column chromatography on
silica gel with hexane/EtOAc (95:5 to 7:3) gave 268 g (87%)
(2S,4R)-4-tritylsulfanyl-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester 2-methyl ester, MS: 504 (MH.sup.+).
Example 1.e
[0207] Ester reduction, Method A:
[0208] 57 ml (57 mmol, 1M THF solution) of LAH was added during 15
min to a cold solution (-20.degree. C.) of 28.2 g (47.5 mmol, ca.
(2S,4R)/(2R,4R)-isomer ca 4:1)
(2S,4R)-1-(naphthalene-2-sulfonyl)-4-trity-
lsulfanyl-pyrrolidine-2-carboxylic acid methyl ester in 460 ml THF.
The reaction was stirred for 20 min, cooled to -78.degree. C. and
quenched with a suspension of 15 g silica gel/15 g MgSO.sub.4.
7H.sub.2O in 60 ml aqueous 10% KHSO.sub.4. The suspension was
stirred for 15 min at room temperature, filtered and washed with
THF. After evaporation of the THF, the residue was taken up in
CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4 and evaporated to
give 29.2 g crude product. Flash column chromatography on silica
gel with CH.sub.2Cl.sub.2/EtOAc(2.5%) to
CH.sub.2Cl.sub.2/EtOAc(10%) gave 21.7 g (81%) of
(2S,4R)-[1-(naphthalene--
2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methanol and 1.0 g
(4%) of
[(2R,4R)-4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-methanol,
MS: 566 (MH.sup.+).
[0209] The following compounds were prepared:
[0210]
(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidine-2-carboxylic
acid methyl ester [(2S,4R)/(2R,4R)-isomer ca. 9:1] gave
isomerically pure
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-methanol,
MS: 471 (M+NH.sub.4.sup.+);
[0211]
(2S,4S)-1-methanesulfonyl-4-methanesulfonyloxy-pyrrolidine-2-carbox-
ylic acid benzyl ester gave
(2S,4R)-[1-methanesulfonyl-4-(4-methoxy-benzyl-
sulfanyl)-pyrrolidin-2-yl]-methanol, MS: 331 (M);
[0212]
(2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyr-
rolidine-2-carboxylic acid benzyl ester gave
(2S,4R)-[4-(4-methoxy-benzyls-
ulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-methanol as
colorless solid, mp 114-115.degree. C., MS: 444 (MH.sup.+);
[0213]
(2S,4R)-4-(4-Methoxy-benzylsulfanyl)-pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester 2-methyl ester gave
(2S,4R)-2-hydroxymethyl-4-(4--
methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl
ester, MS: 252 (M-COOt-Bu);
[0214] (2S,4S)-4-Chloro-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester 2-methyl ester gave
(2S,4S)-4-chloro-2-hydroxymethyl-pyrrolidine-1-- carboxylic acid
tert-butyl ester; MS: 162 (M-t-BuO).
Example 1.f
[0215] Ester reduction, Method B:
[0216] A solution of 35 g (69 mmol)
(2S,4R)-4-Tritylsulfanyl-pyrrolidine-1- ,2-dicarboxylic acid
1-tert-butyl ester 2-methyl ester in 380 ml toluene/60 ml THF was
treated at -47.degree. C. to -50.degree. C. with 44 g (152 mmol) of
a 70% solution of sodium dihydrido-bis(2-methoxy-ethoxo)a- luminate
in toluene (3.5 M Red-Al in toluene). After 3h at -50.degree. C.
and 1 h at -30.degree. C. the solution was poured into water (1l)
with 40 g of citric acid and extracted with EtOAc (2.times.). The
organic phase was dried over Na.sub.2SO.sub.4 and evaporated.
Column chromatography on silica gel with hexane/EtOAc (7:3) gave
23.0 g (69%)
(2S,4R)-2-hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic
acid tert-butyl ester, MS: 476 (MH.sup.+).
Example 1.g
[0217] Synthesis According to Podlech & Seebach, Liebigs Ann.
(1995), 7, 1217-28:
[0218] A solution of 3.0 g (5.38 mmol)
(2S,4R)-1-methanesulfonyl-4-trityls-
ulfanyl-pyrrolidine-2-carboxylic acid methyl ester was dissolved in
150 ml EtOH and treated at room temperature with 10.8 ml (10.8
mmol) aqueous 1 N NaOH. After 3 h the reaction was evaporated and
poured into aqueous 10% KHSO.sub.4/EtOAc (3.times.). The organic
phases were washed with aqueous 10% NaCl solution and dried over
Na.sub.2SO.sub.4 to give 2.43 g (97%) of
(2S,4R)-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxy-
lic acid, mp 64-69.degree. C., MS: 466 (M-H).sup.-.
[0219] A solution of 25 g (93 mmol)
(2S,4R)-1-methanesulfonyl-4-tritylsulf-
anyl-pyrrolidine-2-carboxylic acid in 265 ml CH.sub.2Cl.sub.2 at
0.degree. C. was treated with 2 drops of DMF followed by 8 ml (99
mmol) oxalylchloride. After 15 min at 0.degree. C. the reaction was
stirred 2 h at room temperature, evaporated and dissolved in 260 ml
THF/CH.sub.3CN 1:1. 58.5 ml (117 mmol) 2M
trimethylsilyldiazomethane solution in hexane was then added at
0.degree. C. The reaction was stirred 16 h at room temperature,
evaporated and poured in H.sub.2O/EtOAc. The organic phase was
dried over Na.sub.2SO.sub.4, evaporated and purified by flash
column chromatography on silica gel with hexane/EtOAc (7:3 to 1:1)
to give 12.4 g (48%) of
(2S,4R)-2-diazo-1-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolid-
in-2-yl)-ethanone, MS: 509 (M+NH.sub.4.sup.+).
[0220] In analogy to above,
(2S,4R)-2-diazo-1-[1-(naphthalene-2-sulfonyl)--
4-tritylsulfanyl-pyrrolidin-2-yl]-ethanone was obtained from
(2S,4R)-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxy-
lic acid (with 2.3 eq. Trimethylsilyldiazomethane) in 57% yield,
MS: 621 (M+NH.sub.4.sup.+).
[0221] A solution of 12 g (24.4 mmol)
(2S,4R)-2-diazo-1-(1-methanesulfonyl-
-4-tritylsulfanyl-pyrrolidin-2-yl)-ethanone in 96 ml MeOH/67 ml THF
was cooled (-25.degree. C.) and treated in the dark with 0.62 g
(2.7 mmol) silver benzoate in 13.9 ml (99.7 mmol) triethylamine.
The reaction was warmed to room temperature and stirred 1 h at RT,
evaporated, extracted with H.sub.2O/EtOAc and flash column
chromatography on silica gel with hexane/EtOAc (7:3) gave 8.7 g
(72%) of (2R,4R)-(1-methanesulfonyl-4-trity-
lsulfanyl-pyrrolidin-2-yl)-acetic acid methyl ester, MS: 496
(MH.sup.+).
[0222] In analogy to above,
(2R,4R)-[1-(naphthalene-2-sulfonyl)-4-tritylsu-
lfanyl-pyrrolidin-2-yl]-acetic acid methyl ester was obtained from
(2S,4R)-2-diazo-1-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-
-2-yl]-ethanone in 72% yield, MS: 625 (M+NH.sub.4.sup.+).
[0223] Following the procedure of ester reduction, Method A,
(2R,4R)-(1-methane-sulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-acetic
acid methyl ester gave
(2R,4R)-2-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidi-
n-2-yl)-ethanol, MS: 468 (MH.sup.+).
[0224] Following the procedure of ester reduction, Method A,
(2S,4R)-2-diazo-1-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-
-2-yl]-ethanone gave
(2R,4R)-2-[1-(naphthalene-2-sulfonyl)-4-tritylsulfany-
l-pyrrolidin-2-yl]-ethanol, MS: 580 (MH.sup.+).
Example 1.h
[0225] Further Starting Compounds:
[0226] Hydrolysis (see General Method for hydrolysis of an ester)
of
(2S,4R)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester 2-methyl ester gave
(2S,4R)-4-(4-Methoxy-benzylsulfany- l)-pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester, MS: (M-H).sup.-366.
[0227] A solution of 5 g (13.6 mmol)
(2S,4R)-4-(4-Methoxy-benzylsulfanyl)-- pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester 20-5620 in 150 ml CH.sub.2Cl.sub.2 was
treated with 10.5 ml (95.2 mmol) N-methylmorpholine, 0.37 g (2.72
mmol) 1-hydroxybenzotriazole, 6.26 g (32.64 mmol) EDCI and 2.92 g
(29.92 mmol) N,O-dimethylhydroxylamine hydrochloride. The reaction
was stirred over night at room temperature and partitioned between
aqueous 10% KHSO.sub.4/EtOAc (3.times.). The organic phases were
washed with aqueous saturated NaCl and dried over Na.sub.2SO.sub.4.
Purification by flash-chromatography on silica gel (Hexane/EtOAc
1:1) gave 3.6 g (62%) of
(2S,4R)-4-(4-methoxy-benzylsulfanyl)-2-(methoxy-methyl-carbamoyl)-pyrr-
olidine-1-carboxylic acid tert-butyl ester, MS: 411 (MH.sup.+).
[0228] A solution of 1.5 g (3.5 mmol)
(2S,4R)-4-(4-methoxy-benzylsulfanyl)-
-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid
tert-butyl ester dissolved in 15 ml was added to 4.2 ml (4.2 mmol,
1M THF solution) of LAH in 50 ml THF at -78.degree. C. The reaction
was was warmed up to -30.degree. C., cooled to -78.degree. C. and
quenched with a suspension of 1.2 g silica gel/1.2 g
MgSO.sub.4.7H.sub.2O in 5 ml aqueous 10% KHSO.sub.4. The suspension
was stirred for 15 min at room temperature, filtered and washed
with THF. After evaporation of the THF, the residue was taken up in
CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4 and evaporated to
give 1.2 g (98%) of (2S,4R)-2-formyl-4-(4-methoxy-benzylsul-
fanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 351
(M.sup.+).
[0229] A solution of 0.91 g (4.08 mmol) triethyl phosphonoacetate
in 10 ml THF was first treated with 0.18 g (4.08 mmol) 55% NaH and
after cooling (-78.degree. C.) with 1.2 g (3.4 mmol)
(2S,4R)-2-formyl-4-(4-methoxy-benz-
ylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The
reaction was warmed up to room temperature and stirred over night.
The solution was cooled (0.degree. C.) and treated with 1 ml MeOH
followed by 10 ml saturated aqueous Na/K-tartrate and after 10 min
with aqueous 10% NaHCO.sub.3 solution. The aqueous phase was
filtered, extracted (EtOAc 2.times.) and the organic phase was
dried (Na.sub.2SO.sub.4), evaporated and purified on silica gel
column (Hexane/EtOAc 9:1 to 7:3) to give 0.57 g (40%) of
(2S,4R)-2-(2-ethoxycarbonyl-vinyl)-4-(4-methoxy-benzylsulfanyl-
)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 422
(MH.sup.+).
[0230] In analogy to literature [Hudlicky, T.; Sinai-Zingde, G.;
Natchus, M. G. Tetrahedron Lett. (1987), 28(44), 5287-90] a
solution of 0.35 g (0.84 mmol)
(2S,4R)-2-(2-ethoxycarbonyl-vinyl)-4-(4-methoxy-benzylsulfany-
l)-pyrrolidine-1-carboxylic acid tert-butyl ester in 20 ml MeOH was
treated with 0.122 g (5.04 mmol) magnesium and stirred at room
temperature for 5 h. The reaction was evaporated, suspended twice
in EtOAc and filtered to give 0.38 g (quantitative) of
(2R,4R)-4-(4-methoxy-benzylsulfanyl)-2-(2-methoxycarbonyl-ethyl)-pyrrolid-
ine-1-carboxylic acid tert-butyl ester, MS: 410 (MH.sup.+).
[0231] Following the procedure of ester reduction, Method A,
(2R,4R)-4-(4-methoxy-benzylsulfanyl)-2-(2-methoxycarbonyl-ethyl)-pyrrolid-
ine-1-carboxylic acid tert-butyl ester gave
(2R,4R)-2-(3-hydroxy-propyl)-4-
-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid
tert-butyl ester, MS: 382 (MH.sup.+).
[0232] Following the procedure for the BOC-deprotection (general
method for a selective BOC-deprotection),
(2R,4R)-2-(3-hydroxy-propyl)-4-(4-meth-
oxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester
gave
(2R,4R)-3-[4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-yl]-propan-1-ol
MS: 282 (MH.sup.+).
[0233] A solution of 615 mg (2.19 mmol)
(2R,4R)-3-[4-(4-methoxy-benzylsulf-
anyl)-pyrrolidin-2-yl]-propan-1-ol and 0.34 ml (2.40 mmol)
triethylamine in 5 ml CH.sub.2Cl.sub.2 was cooled to -10.degree. C.
and treated slowly with 0.31 ml (2.29 mmol) butylchloroformate.
After 20 min at this temperature the reaction was extracted with
cold (0.degree. C.) aqueous 10% KHSO.sub.4 /Et.sub.2O (3.times.).
The organic phase was washed with aqueous saturated NaHCO.sub.3
dried over Na.sub.2SO.sub.4 and evaporated. Flash column
chromatography on silica gel with hexane/EtOAc (2:1 to 1:1) gave
340 mg (32%) of
(2R,4R)-2-(3-butoxycarbonyloxy-propyl)-4-(4-methoxy--
benzylsulfanyl)-pyrrolidine-1-carboxylic acid butyl ester and 230
mg (28%) of
(2R,4R)-2-(3-hydroxy-propyl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine--
1-carboxylic acid butyl ester, MS: 382 (MH.sup.+).
[0234] In analogy:
(2S,4R)-2-Hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-- carboxylic
acid tert-butyl ester gave via (2S,4R)-(4-tritylsulfanyl-pyrrol-
idin-2-yl)-methanol,
(2S,4R)-2-hydroxymethyl-4-tritylsulfanyl-pyrrolidine-- 1-carboxylic
acid butyl ester, MS: 476 (MH.sup.+).
Example 2
Amines (Via Mesylate)
[0235] A solution of 14.14 g (25 mmol) of
(2S,4R)-[1-(naphthalene-2-sulfon-
yl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methanol in 300 ml
CH.sub.2Cl.sub.2 was treated at 0.degree. C. with 2.14 ml (27.7
mmol) methane sulfonylchloride, 3.02 ml (37.5 mmol) pyridine, 3.05
g (25 mmol) DMAP and stirred at room temperature for 4 h. The
reaction mixture was poured into EtOAc/H.sub.2O acidified with 1 N
HCl. The organic phase was washed with 10 % aqueous NaCl, dried
over Na.sub.2SO.sub.4 and evaporated to give 15.98 g (99%) of
methanesulfonic acid (2S,4R)-1-(naphthalene-2-sulfonyl)--
4-tritylsulfanyl-pyrrolidin-2-ylmethyl ester, MS: 644
(MH.sup.+).
[0236] The following compounds were prepared in an analogous
manner:
[0237]
(2S,4R)-[1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin--
2-yl]-methanol gave (2S,4R)-methanesulfonic acid
1-methanesulfonyl-4-(4-me-
thoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl ester in 82%, MS: 410
(MH.sup.+).
[0238]
(2R,4R)-2-(3-hydroxy-propyl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidi-
ne-1-carboxylic acid butyl ester gave
(2R,4R)-2-(3-methanesulfonyloxy-prop-
yl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid
butyl ester, MS: 460 (MH.sup.+).
[0239]
(2R,4R)-2-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-etha-
nol gave methanesulfonic acid
(2R,4R)-2-(1-methanesulfonyl-4-tritylsulfany-
l-pyrrolidin-2-yl)-ethyl ester, MS: 563 (MH.sup.+).
[0240]
(2S,4R)-[4-(4-methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-py-
rrolidin-2-yl]-methanol gave methanesulfonic acid
(2S,4R)-4-(4-methoxy-ben-
zylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethyl ester
as white solid, mp 127.degree. C., MS: 522(MH.sup.+).
[0241]
(2S,4R)-2-hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic
acid tert-butyl ester gave
(2S,4R)-2-methanesulfonyloxymethyl-4-tritylsul-
fanyl-pyrrolidine-1-carboxylic acid tert-butyl ester as white foam,
MS: 554 (MH.sup.+);
[0242]
(2R,4R)-2-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-
-yl]-ethanol gave (2R,4R)-methanesulfonic acid
2-[1-(naphthalene-2-sulfony-
l)-4-tritylsulfanyl-pyrrolidin-2-yl]-ethyl ester as white foam, MS:
658 (MH.sup.+).
[0243]
(2R,4R)-3-[4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-yl]-propan-1-o-
l gave with 2.2 equivalent methansulfonylchloride and 2 equivalent
DMAP (2R,4R)-methanesulfonic acid
3-[1-methanesulfonyl-4-(4-methoxy-benzylsulf-
anyl)-pyrrolidin-2-yl]-propyl ester, MS: 438 (MH.sup.+).
[0244] Method A: 200 mg (0.31 mmol) Methanesulfonic acid
(2S,4R)-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl
ester and 47 mg (0.31 mmol, 1.0 eq) sodium iodide were dissolved in
5 ml ethyl isonipecotate, heated to 100.degree. C. for 3 h and the
excess of the amine was removed under vacuum. The resulting residue
was dissolved in EtOAc and 5% aqueous NaHCO.sub.3 solution, the
layers were separated, the organic one was extracted with water
(3.times.) and washed with brine, dried over Na.sub.2SO.sub.4, and
evaporated.
[0245] The crude material
(2S,4R)--[1-(Naphthalene-2-sulfonyl)-4-tritylsul-
fanyl-pyrrolidin-2-ylmethyl]-piperidine-4-carboxylic acid ethyl
ester was dissolved in 6.5 ml acetonitrile and 3 ml TFA, 0.5 ml
(3.1 mmol) triethylsilane were added, and the reaction was stirred
at 40.degree. C. for 3 h. 40 ml aqueous saturated NaHCO.sub.3
solution were added carefully, the layers were separated and the
inorganic one was extracted with EtOAc. The organic layer was
washed with water and brine, dried over Na.sub.2SO.sub.4 and
evaporated. The residue was purified by flash chromatography on
silica gel with EtOAc/hexane 1:2 yielding 45 mg (30%, 2steps) of
(2S,4R)-1-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2--
ylmethyl]-piperidine-4-carboxylic acid ethyl ester as colorless
oil, MS: 463(MH.sup.+).
[0246] In a similar manner, but replacing ethyl isonipecotate (5
ml, 100.degree. C., 3 h) with piperidine (5 ml, 100.degree. C., 2
h), aniline (4 ml, 100.degree. C., 12 h), benzylamine (4 ml,
100.degree. C., 8 h), 2-fluorobenzylamine (2 ml, 100.degree. C., 8
h), N-benzylmethylamine (4 ml, 100.degree. C., 8 h), diethylamine
(4 ml, 100.degree. C., 8 h), 2,4-difluoro benzylamine (3 ml,
100.degree. C., 8 h), 2,5-difluorobenzylamine (3 ml, 100.degree.
C., 8 h), N-ethyl-o-fluorobenzylamine (3 ml, 100.degree. C., 12 h),
2,3-difluorobenzylamine (3 ml, 100.degree. C., 12 h),
2,3,5-triflorobenzylamine (2 ml, 100.degree. C., 12 h),
2,3,6-trifluorobenzylamine (2 ml, 100.degree. C., 12 h),
N-methyl-2-phenyl-ethylamine (4 ml, 100.degree. C., 2 h),
phenethylamine (4 ml, 100.degree. C., 2 h), i) dibenzylamine (4 ml,
100.degree. C., 12 h.
[0247] The following compounds were prepared:
[0248]
(3R,5S)-1-(naphthalene-2-sulfonyl)-5-piperidin-1-ylmethyl-pyrrolidi-
ne-3-thiol as white solid, mp 90.degree. C., MS: 391
(MH.sup.+);
[0249]
(3R,5S)-1-(naphthalene-2-sulfonyl)-5-phenylaminomethyl-pyrrolidine--
3-thiol as orange oil, MS: 399 (MH.sup.+);
[0250]
(3R,5S)-5-(benzylamino-methyl)-1-(naphthalene-2-sulfonyl)-pyrrolidi-
ne-3-thiol as colorless solid, mp 90.degree. C., MS: 413
(MH.sup.+);
[0251]
(3R,5S)-5-[(2-fluoro-benzylamino)-methyl]-1-(naphthalene-2-sulfonyl-
)-pyrrolidine-3-thiol as colorless oil, MS: 431 (MH.sup.+);
[0252]
(3R,5S)-5-[(benzyl-methyl-amino)-methyl]-1-(naphthalene-2-sulfonyl)-
-pyrrolidine-3-thiol as colorless oil, MS: 427 (MH.sup.+);
[0253]
(3R,5S)-5-diethylaminomethyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-
-3-thiol as light yellow oil, MS: 379 (MH.sup.+);
[0254]
(3R,5S)-5-[(2,4-difluoro-benzylamino)-methyl]-1-(naphthalene-2-sulf-
onyl)-pyrrolidine-3-thiol as orange oil, MS: 449 (MH.sup.+);
[0255]
(3R,5S)-5-[(2,5-difluoro-benzylamino)-methyl]-1-(naphthalene-2-sulf-
onyl)-pyrrolidine-3-thiol as orange oil, MS: 449 (MH.sup.+);
[0256]
(3R,5S)-5-{[ethyl-(2-fluoro-benzyl)-amino]-methyl}-1-(naphthalene-2-
-sulfonyl)-pyrrolidine-3-thiol as yellow oil, MS: 459
(MH.sup.+);
[0257]
(3R,5S)-5-[(2,3-difluoro-benzylamino)-methyl]-1-(naphthalene-2-sulf-
onyl)-pyrrolidine-3-thiol as orange oil, MS: 449 (MH.sup.+);
[0258]
(3R,5S)-1-(naphthalene-2-sulfonyl)-5-[(2,3,5-trifluoro-benzylamino)-
-methyl]-pyrrolidine-3-thiol as colorless oil, MS: 467
(MH.sup.+);
[0259]
(3R,5S)-1-(naphthalene-2-sulfonyl)-5-[(2,3,6-trifluoro-benzylamino)-
-methyl]-pyrrolidine-3-thiol as orange oil, MS: 467 (MH.sup.+);
[0260]
(3R,5S)-5-[(methyl-phenethyl-amino)-methyl]-1-(naphthalene-2-sulfon-
yl)-pyrrolidine-3-thiol as orange oil, MS: 441 (MH.sup.+);
[0261]
(3R,5S)-1-(naphthalene-2-sulfonyl)-5-(phenethylamino-methyl)-pyrrol-
idine-3-thiol as orange oil, MS: 427 (MH.sup.+).
[0262]
(3R,5S)-5-[(dibenzylamino)-methyl]-1-(naphthalene-2-sulfonyl)-pyrro-
lidine-3-thiol as white gum, MS: 503 (MH.sup.+).
[0263] Method B: A slurry of 300 mg (0.73 mmol)
(2S,4R)-methanesulfonic acid
1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl
ester and 109 mg (0.73 mmol) of NaI in 5 ml benzylamine was heated
in the oil bath to 100.degree. C., evaporated in the kugelrohr at
50-70.degree. C./1 Torr and extracted with aqueous saturated
NaHCO.sub.3 solution/Et.sub.2O (3.times.). The organic phase was
dried over Na.sub.2SO.sub.4, evaporated and the residue was
crystallized from Et.sub.2O/pentane at -20.degree. C. to give 200
mg (65%) of
(2S)4R)-benzyl-[1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin
-2-ylmethyl]-amine, mp 63-64.degree. C., MS: 421 (MH.sup.+).
[0264] (Method 2): 100 mg (0.24 mmol) of
(2S,4R)-benzyl-[1-methanesulfonyl-
-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl]-amine was
dissolved in 8.5 ml TFA and treated at 0.degree. C. with 0.38 ml
(2.38 mmol) triethylsilane. The reaction was warmed up over night,
heated 1.5 h at 80.degree. C. and evaporated, partitioned between
water (10 ml)/Et.sub.2O (2.times.10 ml). The water was lyophilized
to give 90 mg (91%) of
(3R,5S)-5-(benzylamino-methyl)-1-methanesulfonyl-pyrrolidine-3-thiol
trifluoro-acetate, MS: 301 (MH.sup.+).
[0265] In analogy: Methanesulfonic acid
(2R,4R)-2-(1-methanesulfonyl-4-tri-
tylsulfanyl-pyrrolidin-2-yl)-ethyl ester and aniline gave
(3R,5R)-1-methanesulfonyl-5-(2-phenyl-amino-ethyl)-pyrrolidine-3-thiol
trifluoro-acetate (1:1), mp 122.5-123.degree. C., MS: 301
(MH.sup.+);
[0266] (2S,4R)-methanesulfonic acid
1-methanesulfonyl-4-(4-methoxy-benzyls-
ulfanyl)-pyrrolidin-2-ylmethyl ester with N-benzylmethylamine gave
(3R,5S)-5-[(benzyl-methyl-amino)-methyl]-1-methanesulfonyl-pyrrolidine-3--
thiol trifluoro-acetate, MS: 315 (MH.sup.+).
[0267] Method C: A solution of 130 mg (0.257 mmol)
(2R,4R)-2-(3-methane-su-
lfonyloxy-propyl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic
acid butyl ester, 0.037 ml (0.514 mmol) pyrrole and 38.6 mg (0.257
mmol) NaI in 0.4 ml DMF was treated at 0.degree. C. with 22.4 mg
(0.514 mmol) 55% NaH and warmed up over night to room temperature.
The reaction was neutralized with cooled aqueous saturated
NH.sub.4Cl and extracted (EtOAc 3.times.). The organic phase was
washed with aqueous 10% NaCl, dried (Na.sub.2SO.sub.4) evaporated
and purified by flash silica gel column (Hexane/ EtOAc 9:1) to give
75 mg (68%) of (2R,4R)-4-(4-methoxy-benzylsul-
fanyl)-2-(3-pyrrol-1-yl-propyl)-pyrrolidine-1-carboxylic acid butyl
ester, MS: 431 (MH.sup.+).
[0268] (Method 1): A solution of 0.065 g (0.151 mmol)
(2R,4R)-4-(4-methoxy-benzylsulfanyl)-2-(3-pyrrol-1-yl-propyl)-pyrrolidine-
-1-carboxylic acid butyl ester was dissolved in 2 ml TFA, cooled to
0.degree. C. and treated with 0.24 ml (1.51 mmol) triethylsilane,
stirred for 22 h at room temperature and treated again with 0.24 ml
(1.51 mmol) triethylsilane after further 30 h the evaporated
residue was purified by flash silica gel column
(CH.sub.2Cl.sub.2/EtOAc 99:1) to give 10 mg of
(2S,4R)-4-mercapto-2-(3-pyrrol-1-yl-propyl)-pyrrolidine-1-carboxylic
acid butyl ester, MS: 311 (MH.sup.+).
[0269] In analogy:
(2R,4R)-2-(3-methanesulfonyloxy-propyl)-4-(4-methoxy-be-
nzylsulfanyl)-pyrrolidine-1-carboxylic acid butyl ester with
imidazol gave
(2S,4R)-2-(3-imidazol-1-yl-propyl)-4-mercapto-pyrrolidine-1-carboxylic
acid butyl ester, MS: 312 (MH.sup.+);
[0270] (2R,4R)-methanesulfonic acid
3-[1-methanesulfonyl-4-(4-methoxy-benz-
ylsulfanyl)-pyrrolidin-2-yl]-propyl ester with pyrrole gave
(3R,5R)-1-methanesulfonyl-5-(3-pyrrol-1-yl-propyl)-pyrrolidine-3-thiol,
MS: 289 (MH.sup.+).
Example 3
Thioether
[0271] A slurry of 300 mg (0.73 mmol) (2S,4R)-methanesulfonic acid
1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl
ester and 109 mg (0.73 mmol) of NaI in 3 ml DMF at 0.degree. C. was
treated with 0.35 ml (2.93 mmol) benzylmercaptane and 96 mg (2.2
mmol) 55% NaH. The reaction was warmed up during 2 h to room
temperature and worked up with aqueous saturated NH.sub.4Cl
solution/EtOAc (3.times.). The organic phase was dried over
Na.sub.2SO.sub.4, evaporated and purified by crystallization
(Et.sub.2O) to give 158 mg (49%) of
(2S,4R)-2-benzylsulfanylmethyl-1-methanesulfonyl-4-(4-methoxy-benzylsulfa-
nyl)-pyrrolidine, mp 69-71.degree. C., MS: 438 (MH.sup.+).
[0272] (TFA/triethylsilane for not labile methoxy-benzylsulfanyl,
Method 2): 100 mg (0.23 mmol) of
(2S,4R)-2-benzylsulfanylmethyl-1-methanesulfony-
l-4-(4-methoxy-benzylsulfanyl)-pyrrolidine was dissolved in 8.2 ml
TFA and treated at 0.degree. C. with 0.35 ml (2.38 mmol)
triethylsilane. The reaction was warmed up over night, heated 2.5
min at 80.degree. C. and evaporated. Flash silica gel column
(CH.sub.2Cl.sub.2/EtOAc 99:1) gave 15 mg (21 %)of
(3R,5S)-5-benzylsulfanylmethyl-1-methanesulfonyl-pyrrolidine--
3-thiol, mp 101.5-103.5.degree. C., MS: 318 (MH.sup.+).
Example 4
Amines (Via Azide)
[0273] To a solution of 10.12 g (19.4 mmol) methanesulfonic acid
(2S,4R)-4-(4-methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidi-
n-2-ylmethyl in 65 ml DMF were added 1.78 g (27.4 mmol, 1.4 eq)
NaN.sub.3. The solution was stirred at 80.degree. C. overnight,
recooled and water was added. The phases were separated and the
inorganic one was extracted with Et.sub.2O, the combined organic
layers were washed with water and brine, dried over
Na.sub.2SO.sub.4 and evaporated. Trituration with hexane gave 7.8 g
(86%) (2S,4R)-2-azidomethyl-4-(4-methoxy-benzylsulfanyl-
)-1-(naphthalene-2-sulfonyl)-pyrrolidine as white solid, mp
143.degree. C., MS: 469 (MH.sup.+).
[0274] Analogously the following compounds were prepared:
[0275] From methanesulfonic acid
(2S,4R)-1-(naphthalene-2-sulfonyl)-4-trit-
ylsulfanyl-pyrrolidin-2-ylmethyl ester:
(2S,4R)-2-azidomethyl-1-(naphthale-
ne-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine as white foam, MS: 591
(MH.sup.+).
[0276] From
(2S,4R)-2-methanesulfonyloxymethyl-4-tritylsulfanyl-pyrrolidin-
e-1-carboxylic acid tert-butyl ester:
(2S,4R)-2-azidomethyl-4-tritylsulfan- yl-pyrrolidine-1-carboxylic
acid tert-butyl ester as yellow oil, MS: 501 (MH.sup.+).
[0277] From (2S,4R)-methanesulfonic acid
1-methanesulfonyl-4-(4-methoxy-be-
nzylsulfanyl)-pyrrolidin-2-ylmethyl ester:
(2S,4R)-2-azidomethyl-1-methane-
sulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine as white
crystalline, MS: 357 (MH.sup.+).
[0278] From methanesulfonic acid
(2R,4R)-2-(1-methanesulfonyl-4-tritylsulf-
anyl-pyrrolidin-2-yl)-ethyl ester:
(2S,4R)-2-(2-azido-ethyl)-1-methanesulf-
onyl-4-tritylsulfanyl-pyrrolidine as light yellow foam, MS: 493
(MH.sup.+).
[0279] From (2R,4R)-methanesulfonic acid
2-[1-(naphthalene-2-sulfonyl)-4-t-
ritylsulfanyl-pyrrolidin-2-yl]-ethyl ester: (2R,
4R)-2-(2-azido-ethyl)-1-(-
naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine as white foam,
MS: 605 (MH.sup.+).
Example 4.a
Methylamine-optimization
[0280] Staudinger-NH.sub.2 Formation:
[0281] 1.7 g (2.9 mmol)
(2S,4R)-2-Azidomethyl-1-(naphthalene-2-sulfonyl)-4-
-tritylsulfanyl-pyrrolidine were treated with 2.3 g (8.8 mmol, 3
eq) of triphenyl phosphine in 12 ml THF and 0.5 ml H.sub.2O for 2
days at RT. The solution was diluted with EtOAc, extracted with
H.sub.2O and aqueous saturated NaHCO.sub.3 solution, washed with
brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was
purified by flash chromatography on silica gel with
CH.sub.2Cl.sub.2/MeOH 95:5 yielded 1.6 g (99%)
(2S,4R)-C-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-
-2-yl]-methylamine as white foam, MS: 565 (MH.sup.+).
[0282] Analogously the following compounds were prepared:
[0283] From
(2S,4R)-2-azidomethyl-4-(4-methoxy-benzylsulfanyl)-1-(naphthal-
ene-2-sulfonyl)-pyrrolidine:
(2S,4R)-C-[4-(4-methoxy-benzylsulfanyl)-1-(na-
phthalene-2-sulfonyl)-pyrrolidin-2-yl]-methylamine as light yellow
solid, mp 88-89.degree. C., MS: 443 (MH.sup.+).
[0284] From (2R,
4R)-2-(2-azido-ethyl)-1-(naphthalene-2-sulfonyl)-4-trityl-
sulfanyl-pyrrolidine:
(2R,4R)-2-[1-(naphthalene-2-sulfonyl)-4-tritylsulfan-
yl-pyrrolidin-2-yl]-ethylamine as white foam MS: 579
(MH.sup.+).
[0285] Reductive Amination:
[0286] 250 mg (0.56 mmol)
(2S,4R)-C-[1-(naphthalene-2-sulfonyl)-4-tritylsu-
lfanyl-pyrrolidin-2-yl]-methylamine and 58 .mu.l (0.5 mmol)
o-tolualdehyde in 1 ml MeOH were treated with a solution of 57 mg
(0.3 mmol, 0.6 eq) SnCl.sub.2 and 38 mg (0.6 mmol, 1.2 eq)
NaBH.sub.3CN in 1 ml MeOH at room temperature and subsequent
cleavage of the protecting group (Method 3) gave
(3R,5S)-5-[(2-methyl-benzylamino)-methyl]-1-(naphthalene-2-sulfonyl)-
-pyrrolidine-3-thiol as white solid, mp 122.degree. C., MS: 427
(MH.sup.+).
[0287] Analogously the following compounds were prepared:
[0288] From
(2S,4R)-C-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrroli-
din-2-yl]-methylamine
[0289] a) and 2,4-dimethoxybenzaldehyde and subsequent cleavage of
the protecting group (trityl deprotection, Method 3)
(3R,5S)-5-[(2,4-dimethox-
y-benzylamino)-methyl]-1-(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol
as colorless oil, MS: 473 (MH.sup.+).
[0290] b) and 4-pyridinecarboxaldehyde and subsequent cleavage of
the protecting group (trityl deprotection, Method 3)
(3R,5S)-1-(naphthalene-2-
-sulfonyl)-5-[[(pyridin-4-ylmethyl)-amino]-methyl]-pyrrolidine-3-thiol
as yellow oil, MS: 414 (MH.sup.+).
[0291] c) and 3-pyridinecarboxaldehyde and subsequent cleavage of
the protecting (Method 3)
(3R,5S)-1-(naphthalene-2-sulfonyl)-5-[[(pyridin-3-y-
lmethyl)-amino]-methyl]-pyrrolidine-3-thiol as colorless oil, MS:
414 (MH.sup.+).
[0292] d) and 3-fluoro-p-anisaldehyde and subsequent cleavage of
the protecting group (trityl deprotection, Method 3)
(3R,5S)-5-[(3-fluoro-4-m-
ethoxy-benzylamino)-methyl]-1-(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol
as colorless oil, MS: 461 (MH.sup.+).
[0293] e) and benzyloxyacetaldehyde and subsequent cleavage of the
protecting group (trityl deprotection, Method 3)
(3R,5S)-5-[(2-benzyloxy--
ethylamino)-methyl]-1-(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol
as colorless oil, MS: 457 (MH.sup.+).
[0294] f) and 2-thiophenecarboxaldehyde and subsequent cleavage of
the protecting group (trityl deprotection, Method 3)
(3R,5S)-1-(naphthalene-2-
-sulfonyl)-5-{[(thiophen-2-ylmethyl)-amino]-methyl}-pyrrolidine-3-thiol
as colorless oil, MS: 419 (MH.sup.+).
[0295] g) and cyclohexanecarboxaldehyde and subsequent cleavage of
the protecting group (trityl deprotection, Method 3)
(3R,5S)-5-[(cyclohexylme-
thyl-amino)-methyl]-1-(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol
as colorless oil, MS: 418 (MH.sup.+).
[0296] From
(2S,4R)-C-[4-(4-methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfo-
nyl)-pyrrolidin-2-yl]-methylamine and isobutylaldehyde and
subsequent cleavage of the protecting group (Method 2)
(3R,5S)-5-(isobutylamino-meth-
yl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol as white solid,
mp 73.degree. C., MS: 379 (MH.sup.+).
[0297] From
(2R,4R)-2-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrroli-
din-2-yl]-ethylamine and 2,5-difluorobenzaldehyde and subsequent
cleavage of the protecting group
(3R,5R)-5-[2-(2,5-difluoro-benzylamino)-ethyl]-1--
(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol as colorless oil, MS:
463 (MH.sup.+).
[0298] From
(2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxyli- c
acid tert-butyl ester was prepared via
(2S,4R)-2-aminomethyl-4-tritylsul- fanyl-pyrrolidine-1-carboxylic
acid tert-butyl ester [as light brown foam, MS: 475 (MH.sup.+)] and
further reaction with 2,5-difluoro benzaldehyde analogously to
reductive amination gave (2S,4R)-2-[(2,5-difluoro-benzylam-
ino)-methyl]-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid
tert-butyl ester as colorless oil MS: 601 (MH.sup.+) which was
treated according to trityl cleavage (method 5) to give
(2S,4R)-2-[(2,5-difluoro-benzylamino)--
methyl]-4-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester
as colorless liquid MS: 359 (MH.sup.+).
Example 4.b
N-Pyrrolidine: Carbamates
[0299]
(2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic
acid tert-butyl with TFA in CH.sub.2Cl.sub.2 (following the general
method for a selective BOC-deprotection) gave
(2S,4R)-2-azidomethyl-4-tri- tylsulfanyl-pyrrolidine as light
yellow oil, MS: 501 (MH.sup.+).
[0300] (2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine and
benzyl chloroformate/N-ethyldiisopropylamine in CH.sub.2Cl.sub.2
(see cabamate synthesis, Method A)--followed by Staudinger
reduction gave
(2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic
acid benzyl ester as white foam, MS: 509 (MH.sup.+).
[0301]
(2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic
acid benzyl ester and 2,5-difluorobenzaldehyde and subsequent
cleavage of the trityl protecting group analogously to reductive
amination and deprotection gave
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapt-
o-pyrrolidine-1-carboxylic acid benzyl ester as colorless oil, MS:
393 (MH.sup.+).
[0302] In a similar manner, the following compounds were prepared
from
[0303] (2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine, but
replacing benzyl chloroformate with 4-fluorophenyl chloroformate,
isopropyl chloroformate, chloroformic acid 2-naphthyl ester,
1,4-benzodioxan-5-yl chloroformate[Eitel & Hammann, I.
Benzodioxan-N-methylcarbamates useful as insecticides or
acaricides. S. African, 14 pp. ZA 6800512 680627.] and in situ
prepared chloroformates from 1-naphthalene ethanol and
2-naphthalene ethanol, respectively, (by treatment with
trichloromethyl chloroformate, quinoline in CH.sub.2Cl.sub.2, see
Carbamate, Method B).
[0304]
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidin-
e-1-carboxylic acid 4-fluoro-phenyl ester as colorless oil, MS: 397
(MH.sup.+).
[0305]
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidin-
e-1-carboxylic acid isopropyl ester as colorless oil, MS: 345
(MH.sup.+).
[0306]
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidin-
e-1-carboxylic acid naphthalen-2-yl ester as colorless oil, MS: 429
(MH.sup.+).
[0307]
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidin-
e-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester as
colorless oil, MS: 437 (MH.sup.+).
[0308]
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidin-
e-1-carboxylic acid butyl ester as colorless oil, MS: 359
(MH.sup.+).
[0309]
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidin-
e-1-carboxylic acid 2-naphthalen-1-yl-ethyl ester as colorless oil,
MS: 457 (MH.sup.+).
[0310]
(2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidin-
e-1-carboxylic acid 2-naphthalen-2-yl-ethyl ester ester as
colorless oil, MS: 457 (MH.sup.+).
Example 4.c
N-Pyrrolidine: Sulfamides
[0311] To 4.2 ml (48.65 mmol, 1.2 eq) oxalyl chloride in 100 ml
CH.sub.2Cl.sub.2 were added 6.5 ml (89.19 mmol, 2.2 eq) DMSO in 20
ml CH.sub.2Cl.sub.2 at -65.degree. C., followed after 10 min by
14.33 g (40.54 mmol, 1.0 eq)
(2S,4R)-2-hydroxymethyl-4-(4-methoxy-benzylsulfanyl)-
-pyrrolidine-1-carboxylic acid tert-butyl ester in 60 ml
CH.sub.2Cl.sub.2 over a period of 20 min. The solution was stirred
at -68.degree. C. for 1.5 h before 28 ml (162.16 mmol, 4 eq)
iPr.sub.2NEt were added, and the reaction mixture was warmed to
room temperature. The solution was extracted with 1M KHSO.sub.4,
the combined inorganic phases were extracted with CH.sub.2Cl.sub.2
and the organic phase dried over Na.sub.2SO.sub.4 and evaporated,
yielding 14.18 g (99%)
(2S,4R)-2-formyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic
acid tert-butyl ester. The crude product was subjected to the
following reaction without further purification.
[0312] To 14.18 g (40.54 mmol)
(2S,4R)-2-formyl-4-(4-methoxy-benzylsulfany-
l)-pyrrolidine-1-carboxylic acid tert-butyl ester in 250 ml
CH.sub.2Cl.sub.2were added 4.88 g MgSO.sub.4, followed by 4.8 ml
(40.9 mmol, 1.0 eq) 2,5-difluoro-benzylamine. The suspension was
stirred at RT overnight, filtered and evaporated. The crude yellow
oil was purified by flash chromatography with EtOAc/hexane 1:3
yielding 17.31 g
(2S,4R)-2-[(2,5-difluoro-benzylimino)-methyl]-4-(4-methoxy-benzylsulfanyl-
)-pyrrolidine-1-carboxylic acid tert-butyl ester (90%, 2 steps) as
yellow oil.
[0313] To 17.31 g (36.32 mmol)
(2S,4R)-2-[(2,5-difluoro-benzylimino)-methy-
l]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid
tert-butyl ester in 120 ml MeOH were added 1.64 g (43.58 mmol, 1.2
eq) NaBH.sub.4 slowly at 40.degree. C. The solution was stirred at
that temperature for additional 90 min, water was added carefully
and the solution was concentrated. The residue was redissolved in
EtOAc and washed with NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4 and evaporated. Flash chromatography with
EtOAc/hexane 1:1 yielded 11.57 g (67%)
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-(4-methoxy-benzylsulfanyl-
)-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow oil, MS:
479 (MH.sup.+).
[0314] To 3.19 g (6.67 mmol, 1 eq)
(2S,4R)-2-[(2,5-difluoro-benzylamino)-m-
ethyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid
tert-butyl ester in 10 ml CH.sub.2Cl.sub.2 were added 1.35 ml (8.0
mmol, 1.2 eq) EtNiPr.sub.2, followed by 2.07 g (8.0 mmol, 1.2 eq)
9-fluorenylmethyl chloroformate and a catalytic amount of DMAP at
0.degree. C. The solution was stirred at room temperature
overnight, 5% NaHCO.sub.3 solution was added (pH 9), the layers
were separated and the inorganic one was extracted with
CH.sub.2Cl.sub.2. The combined organic layers were washed with 1M
KHSO.sub.4 and brine, dried over Na.sub.2SO.sub.4 and evaporated.
The crude product was purified by flash chromatography with
EtOAc/hexane 1:3 as eluent yielding 3.81 g (82%)
(2S,4R)-2-{[(2,5-difluoro-benzyl)-(9H-fluoren-9-ylmethoxy-carbonyl)-amino-
]-methyl}-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic
acid tert-butyl ester as white foam, which was subjected to the
next reaction directly.
[0315] To 2.27 g (3.24 mmol)
(2S,4R)-2-{[(2,5-Difluoro-benzyl)-(9H-fluoren-
-9-ylmethoxycarbonyl)-amino]-methyl}-4-(4-methoxy-benzylsulfanyl)-pyrrolid-
ine-1-carboxylic acid tert-butyl ester in 10 ml CH.sub.2Cl.sub.2
were added 3.4 ml TFA at 0.degree. C., and the solution was stirred
at room temperature for 2 h. The solvent was evaporated and the
crude oil redissolved and evaporated successively with toluene,
hexane and Et.sub.2O yielding 2.46 g
(2S,4R)-(2,5-difluoro-benzyl)-[4-(4-methoxy-ben-
zylsulfanyl)-pyrrolidin-2-ylmethyl]-carbamic acid
9H-fluoren-9-ylmethyl ester as TFA salt as brown oil.
[0316] To 300 mg (0.42 mmol)
(2S,4R)-2,5-difluoro-benzyl)-[4-(4-methoxy-be-
nzylsulfanyl)-pyrrolidin-2-ylmethyl]-carbamic acid
9H-fluoren-9-ylmethyl ester as TFA salt in 5 ml CH.sub.2Cl.sub.2
were added 290 .mu.l (1.68 mmol, 4 eq) EtNiPr.sub.2, followed by
121 mg (0.59 mmol, 1.4 eq) benzylsulfamoyl chloride at 0.degree. C.
The solution was stirred at room temperature for 48 h, 1M
KHSO.sub.4 was added, the layers were separated and the inorganic
one was extracted with CH.sub.2Cl.sub.2. The combined organic
layers were washed with 1M KHSO.sub.4 and brine, dried over
Na.sub.2SO.sub.4 and evaporated. The crude product was dissolved in
4.2 ml Et.sub.2NH:THF (1:1) at 0.degree. C. and stirred 5 h at room
temperature. The solvent was evaporated, the residue redissolved
and evaporated twice with hexane and dried in vacuum. The brown oil
was dissolved in 4 ml TFA and 0.7 ml (4.2 mmol) Et.sub.3SiH and
stirred at 80.degree. C. for 2h. The solution was concentrated,
redissolved in EtOAc and NaHCO.sub.3 solution, the layers were
separated and the inorganic one was extracted with EtOAc, the
combined organic ones were washed with brine, dried over
Na.sub.2SO.sub.4 and evaporated. The crude product was purified
purified by flash chromatography with CH.sub.2Cl.sub.2/MeOH 95:5
yielding 16.8 mg (10%, 3 steps)
(2S,4R)-2-[(2,5-difluoro-benzylamino)-met-
hyl]-4-mercapto-pyrrolidine-1-sulfonic acid benzylamide as white
oil, MS: 427 (MH.sup.+).
[0317] In a similar manner, but replacing benzylsulfamoyl chloride
with cyclopropyl-sulfamoyl chloride and n-butylsulfamoyl chloride
the following compounds were prepared:
[0318]
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidin-
e-1-sulfonic acid cyclopropylamide as colorless oil, MS: 377
(MH.sup.+).
[0319]
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidin-
e-1-sulfonic acid butylamide as colorless oil, MS: 393
(MH.sup.+).
Example 4.c
N-Pyrrolidines: Ureas
[0320] From
(2S,4R)-2-Azidomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxyli- c
acid tert-butyl ester was prepared
(2S,4R)-2-azidomethyl-4-tritylsulfany- l-pyrrolidine according to
BOC-cleavage example general method B (variation 0.degree. C.,
2h).
[0321] 280 mg (0.7 mmol)
(2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidin- e were treated
with 87 .mu.M (0.77 mol, 1.1 eq) butyl isocyanate in 5 ml THF at
0.degree. C., and the solution was stirred at RT for 45 min. The
solvent was evaporated, and the residue was purified by flash
chromatography yielding 278 mg (80%)
(2S,4R)-2-azidomethyl-4-tritylsulfan- yl-pyrrolidine-1-carboxylic
acid butylamide as white foam.
[0322] 275 mg (0.55 mmol)
(2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidi- ne-1-carboxylic
acid butylamide in 8 ml ethanol was treated with 83 mg (2.2 mmol)
NaBH.sub.4 at 80.degree. C. for 18 h. Additional 175 mg (4.6 mmol)
NaBH.sub.4 were added in portions, and the reaction was stirred at
80.degree. C. until no starting material could be detected. The
solution was poured into a saturated NH.sub.4Cl solution, and was
extracted with EtOAc, the organic phase was washed with brine,
dried over Na.sub.2SO.sub.4 and evaporated. Column chromatography
yielded 213 mg (82%)
(2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic
acid butylamide as white foam, which was directly subjected to the
following reactions according to reductive amination with
2,5-difluoro-benzaldehyde (example 4a) and subsequent trityl
cleavage (method 3) yielding
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-merca-
pto-pyrrolidine-1-carboxylic acid butylamide as colorless oil, MS:
358 (MH.sup.+).
[0323] Analogously, the following compounds were prepared from
(2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine and
2-fluorophenyl isocyanate or benzylisocyanate and
2,5-difluorobenzaldehyde.
[0324]
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidin-
e-1-carboxylic acid (2-fluoro-phenyl)-amide as white solid, mp
126.degree. C., MS: 396 (MH.sup.+).
[0325]
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidin-
e-1-carboxylic acid benzylamide as colorless oil, MS: 392
(MH.sup.+).
Example 5
Second Substituent on Methylamine (Y=N)
[0326] 6.94 g (14.5 mmol)
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4--
(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl
ester were dissolved in 170 ml acetonitrile and treated with 3 ml
(20.3 mmol, 1.4 eq) t-butyl bromoacetate and 18.6 g (134.9 mmol,
9.3 mmol) K.sub.2CO.sub.3 at RT for 2d. The solid was removed by
filtration, and the organic phase was washed with water and brine,
dried over Na.sub.2SO.sub.4 and evaporated, yielding 9.02 g (quant)
(2S,4R)-2-[[tert-butoxycarbonylmethyl-(2,5-difluoro-benzyl)-amino]-methyl-
]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid
tert-butyl ester as orange oil, MS: 593 (MH.sup.+).
[0327] 397 mg (0.67 mmol)
(2S,4R)-2-[[tert-butoxycarbonylmethyl-(2,5-diflu-
oro-benzyl)-amino]-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carb-
oxylic acid tert-butyl ester were treated with 4.2 ml 1N HCl in
EtOAc at RT. The reaction mixture was concentrated and tituration
with ether yielded 250 mg (76%)
(2S,4R)-[(2,5-difluoro-benzyl)-[4-(4-methoxy-benzyls-
ulfanyl)-pyrrolidin-2-ylmethyl]-amino]-acetic acid tert-butyl ester
as light brown solid, which was transformed to
(2S,4R)-2-[[tert-butoxycarbon-
ylmethyl-(2,5-difluoro-benzyl)-amino]-methyl]-4-(4-methoxy-benzylsulfanyl)-
-pyrrolidine-1-carboxylic acid butyl ester according to example 4b
by treatment with butyl chloroformate.
[0328] 250 mg (0.42 mmol)
(2S,4R)-2-[[tert-butoxycarbonylmethyl-(2,5-diflu-
oro-benzyl)-amino]-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carb-
oxylic acid butyl ester were treated with 670 .mu.l (4.2 mmol, 10
eq) triethyl silane in 7.5 ml TFA at 80.degree. C. for 1.5 h. The
solvent was evaporated and the residue was redissolved in toluene
and evaporated. The crude material was purified by flash
chromatography yielding 85 mg (49%)
(2S,4R)-2-[[carboxymethyl-(2,5-difluoro-benzyl)-amino]-methyl]-4-mercapto-
-pyrrolidine-1-carboxylic acid butyl ester as light brown oil, MS:
417 (MH.sup.+).
[0329] Analogously,
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-trityl-
sulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester was treated
with 2,5-difluoro-benzylbromide to give
(2S,4R)-2-{[bis-(2,5-difluoro-benzyl)--
amino]-methyl}-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid
tert-butyl ester which was treated with TFA according to general
method B (variation 0.degree. C. to RT) to give
(2S,4R)-bis-(2,5-difluoro-benzyl)-(4-tritylsu-
lfanyl-pyrrolidin-2-ylmethyl)-amine yellow oil, MS: 627
(MH.sup.+).
[0330] Using the procedures described for the reactions in 4a and
4c the following compounds were prepared from
(2S,4R)-bis-(2,5-difluoro-benzyl)--
(4-tritylsulfanyl-pyrrolidin-2-ylmethyl)-amine and 2-naphthalene
sulfonylchloride, N-butyl chloroformate, N-benzyl chloroformate,
p-methoxyphenyl chloroformate, isopropyl chloroformate:
[0331]
(2S,4R)-5-[[Bis-(2,5-difluoro-benzyl)-amino]-methyl]-1-(naphthalene-
-2-sulfonyl)-pyrrolidine-3-thiol as colorless oil, MS: 575
(MH.sup.+).
[0332]
(2S,4R)2-[[Bis-(2,5-difluoro-benzyl)-amino]-methyl]-4-mercapto-pyrr-
olidine-1-carboxylic acid butyl ester as colorless oil, MS: 485
(MH.sup.+).
[0333]
(2S,4R)-2-[[Bis-(2,5-difluoro-benzyl)-amino]-methyl]-4-mercapto-pyr-
rolidine-1-carboxylic acid benzyl ester as colorless oil, MS: 519
(MH.sup.+).
[0334]
(2S,4R)-2-[[Bis-(2,5-difluoro-benzyl)-amino]-methyl]-4-mercapto-pyr-
rolidine-1-carboxylic acid 4-methoxy-phenyl ester as colorless oil,
MS: 535 (MH.sup.+).
[0335]
(2S,4R)-2-[[Bis-(2,5-difluoro-benzyl)-amino]-methyl]-4-mercapto-pyr-
rolidine-1-carboxylic acid isopropyl ester as colorless oil, MS:
471 (MH.sup.+).
[0336]
(2S,4R)-2-[[benzyloxycarbonyl-(2,5-difluoro-benzyl)-amino]-methyl]--
4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester was
treated according to trityl cleavage (method 5) to give
(2S,4R)-2-[[benzyloxycarbonyl-(2,5-difluoro-benzyl)-amino]-methyl]-4-merc-
apto-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless
oil, MS: 493 (MH.sup.+).
Example 6
Methylamine: Amides and Sulfonamides
[0337] 11 g (83.9 mmol) L-Hydroxyproline were dissolved in 110 ml
hexamethyldisilazane and heated to 120.degree. C. overnight, cooled
to room temperature and evaporated. The oily residue was dissolved
in 110 ml THF, 16.5 ml (79.7 mmol, 0.95 eq) N-ethyl-morpholine was
added, followed by 18.25 g (79.7 mmol, 0.95 eq)
2-naphthalenesulfonyl chloride in 130 ml THF over a period of 60
min. The solution was stirred at RT for 50h, 15 ml ethanol were
added and the solution was stirred for 15 min. At that time 400 ml
of Et.sub.2O and 250 ml of aqueous saturated NaHCO.sub.3 solution
were added and the phases were separated. The aqueous layer was
acidified and extracted with EtOAc, the combined organic layers
were washed with brine, dried over MgSO.sub.4 and concentrated.
17.39 g (65%)
(2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic
acid isolated as yellow solid, mp 140.degree. C., MS: 321
(MH.sup.+).
[0338] 38.97 g (121.4 mmol)
(2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-p-
yrrolidine-2-carboxylic acid were dissolved in 97 ml MeOH and 64.5
ml 1.75 M (112.8 mmol) HCl in MeOH were added and the solution
heated to reflux for 3 h and concentrated. Trituration with hexane
yielded 41.4 g (quant.)
(2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic
acid methyl ester as brown solid, MS: 335 (MH.sup.+).
[0339] 29 ml (194 mmol, 1.6 eq) DBU were added to a suspension of
41.4 g (121.4 mmol)
(2S,4R)-4-Hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-c-
arboxylic acid methyl ester in 150 ml acetonitrile at 0.degree. C.
To the resulting solution 29.25 g (194 mmol, 1.6 eq) TBDMSCl were
added in portions and the reaction was stirred at RT overnight.
After concentrating the crude oil was purified by column
chromatography with EtOAc/hexane 1:2 on silica gel to give 49.2 g
(90%)
(2S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-1-(naphthalene-2-sulfonyl)-pyr-
rolidine-2-carboxylic acid methyl ester.
[0340] 3.4 g (148 mmol, 95%, 2.7 eq) LiBH.sub.4 were added in small
portions to a solution of 24.5 g (54.6 mmol)
(2S,4R)-4-(tert-Butyl-dimeth-
yl-silanyloxy)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic
acid methyl ester in 11 THF at 0.degree. C. The solution was
stirred overnight, further 1.8 g (78 mmol, 95%, 1.4 eq) LiBH.sub.4
were added and stirred for additional 48 h, before 10 ml acetic
acid in 30 ml THF were added under cooling. 650 ml 5% NaHCO.sub.3
solution were added slowly, the phases were separated, and the
inorganic one was extracted with EtOAc. The combined organic ones
were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated
yielding 22.3 g of a light yellow oil. An analytical sample was
purified on silica gel with EtOAc/hexane 1:2 as solvent,
(2S,4R)-[4-(tert-butyl-dimethyl-silanyloxy)-1-(naphthalene-2-sul-
fonyl)-pyrrolidin-2-yl]-methanol as white powder, MS: 422
(MH.sup.+).
[0341] 24.34 g (57.73 mmol)
(2S,4R)-[4-(tert-butyl-dimethyl-silanyloxy)-1--
(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-methanol in 380 ml
toluene were treated with 17.57 g (0.67 mmol, 1.16 eq)
triphenylphosphine, 10.02 g (68.12 mmol, 1.18 eq) phthalimide. 13.8
ml (88.9 mmol, 1.5 eq) DEAD in 65 ml toluene were added to the
solution over a period of 2.5 h, keeping the temperature below
3.degree. C. The mixture was stirred at room temperature for 48 h,
and recooled to 3.degree. C. for further addition of 8.79 g (33.5
mmol, 0.58 eq) triphenyl-phosphine, 5.01 g (34 mmol, 0.59 eq)
phthalimide and 6.9 ml (44.5 mmol, 0.75 eq) DEAD in 35 ml toluene.
After stirring at 80.degree. C. for 4h and at room temperature for
3d, additional 8.79 g (33.5 mmol, 0.58 eq) triphenyl phosphine,
5.01 g (34 mmol, 0.59 eq) phthalimide and 6.9 ml (44.5 mmol, 0.75
eq) DEAD in 35 ml toluene were added, and the reaction heated to
80.degree. C. for 3 h, recooled and diluted with EtOAc, extracted
with 2M NaOH, aqueous saturated NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4 and evaporated. The crude product was purified by
column chromatography on silica gel yielding 15.6 g (50%)
(2S,4R)-2-[4-(tert-butyl-dimethyl-silanyloxy)-1-(na-
phthalene-2-sulfonyl)-pyrrolidin-2-ylmethyl]-isoindole-1,3-dione
and 6.0 g (25%) recovered starting material.
[0342] 14.5 g (26.3 mmol)
(2S,4R)-2-[4-(tert-butyl-dimethyl-silanyloxy)-1--
(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethyl]-isoindole-1,3-dione
in 145 ml THF were treated with 10.3 g (31.7 mmol, 1.2 eq) TBAF
3H.sub.2O at RT for 1.5 h, the solvent was evaporated and the crude
product purified by column chromatography on silica gel with a
gradient EtOAc/hexane 4:1, EtOAc/CH.sub.2Cl.sub.2 1:1,
CH.sub.2Cl.sub.2 /MeOH 9:1 yielding 5.5 g (45%)
(2S,4R)-2-[4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmeth-
yl]-isoindole-1,3-dione as white crystalline, MS: 437
(MH.sup.+).
[0343] 3.0 ml (21.7 mmol, 1.2 eq) triethylamine and 6.05 g (22.6
mmol, 1.2 eq) triphenylphosphine were added to a solution of 1.42
ml (21.7 mmol, 1.25 eq) methanesulfonic acid in 60 ml toluene,
successively followed by a solution of 7.9 g (18.1 mmol)
(2S,4R)-2-[4-hydroxy-1-(naphthalene-2-sul-
fonyl)-pyrrolidin-2-ylmethyl]-isoindole-1,3-dione in 80 ml
toluene/THF (5/3) and 5.06 ml (23.6 mmol, 1.3 eq) DIAD. The
suspension was heated to 80.degree. C. for 6 h and stirred at room
temperature overnight. After diluting the mixture with EtOAc and
water, the phases were separated, and the inorganic one was
extracted with EtOAc and CH.sub.2Cl.sub.2, the combined organic
phases were washed with 1M KHSO.sub.4 and brine, dried over
Na.sub.2SO.sub.4 and evaporated. Column chromatography with a
gradient of CH.sub.2Cl.sub.2: EtOAc 4:1 to 1:1 yielded 8.3 g (90%)
of (3R,5S)-methanesulfonic acid
5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl-
)-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl ester as white
crystals.
[0344] To 8.3 g (16.1 mmol) (3R,5S)-methanesulfonic acid
5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1-(naphthalene-2-sulfonyl)--
pyrrolidin-3-yl ester in 210 ml DMF were added 2.82 g (24.2 mmol,
1.5 eq) potassium thioacetate and heated to 100.degree. C. for 2.5
h. The mixture was concentrated under vacuum and the residue was
redissolved in EtOAc and water, the layers were separated and the
inorganic one was extracted with EtOAc (3.times.). The combined
organic phases were extracted with saturated NaHCO.sub.3 solution
and brine, dried over Na.sub.2SO.sub.4 and evaporated. Purification
with column chromatography on silica gel with EtOAc/hexane 1:1 as
eluent yielded 6.8 g (85%) Thioacetic acid
(2S,4R)-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1-(naphthalene-2-su-
lfonyl)-pyrrolidin-3-yl as off white crystalline, mp 159.degree.
C., MS: 495 (MH.sup.+).
[0345] 6.35 g (12.85 mmol) Thioacetic acid
(2S,4R)-5-(1,3-dioxo-1,3-dihydr-
o-isoindol-2-ylmethyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl
ester treated with 320 ml 33% methylamine in ethanol (8.03 M, 2.57
mol) at room temperature for 2 days. The solvent was evaporated and
the residue was purified on silica gel by column chromatography
with CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 90:10:1 yielding 2.26 g (55%)
of
C-[(2S,4R)-4-[(3R,5S)-5-aminomethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-
-3-yldisulfanyl]-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-methylamine
as off white foam, MS: 643 (MH.sup.+).
[0346] To a suspension of 127 mg (0.68 mmol, 1.05 eq)
mono-methylterephthalate in 11 ml CH.sub.2Cl.sub.2 were added 77
.mu.l (0.68 mmol, 1.05 eq) 4-methyl morpholine, 222 mg (0.75 mmol,
1.2 Eq) TPTU and 200 mg (0.31 mmol)
C-[(2S,4R)-4-[(3R,5S)-5-aminomethyl-1-(naphthalene-
-2-sulfonyl)-pyrrolidin-3-yldisulfanyl]-1-(naphthalene-2-sulfonyl)-pyrroli-
din-2-yl]-methylamine. The solution was stirred at room temperature
overnight, evaporated and the residue was purified on silica gel
with a gradient of EtOAc/hexane 2:1 to 4:1 yielding 248 mg (82%)
N-[(2S,4R)-4-[(5S,3R)-5-[(4-methoxycarbonyl-benzoylamino)-methyl]-1-(naph-
thalene-1-sulfonyl)-pyrrolidin-3-yldisulfanyl]-1-(naphthalene-1-sulfonyl)--
pyrrolidin-2-ylmethyl]-terephthalamic acid methyl ester as white
foam, which was directly subjected to the next reaction.
[0347] 238 mg (0.25 mmol) of
N-[(2S,4R)-4-[(5S,3R)-5-[(4-methoxycarbonyl-b-
enzoylamino)-methyl]-1-(naphthalene-1-sulfonyl)-pyrrolidin-3-yldisulfanyl]-
-1-(naphthalene-1-sulfonyl)-pyrrolidin-2-ylmethyl]-terephthalamic
acid methyl ester were suspended in 7 ml 2,2,2-trifluoro ethanol
and 38 .mu.l H.sub.2O and cooled to 0.degree. C. 87 .mu.l (0.3
mmol) tri-n-butylphosphine were added. The mixture was diluted with
1 ml CH.sub.2Cl.sub.2 after 1 h at 0.degree. C., and stirring was
continued for another 1 h. Evaporation under vacuum and
purification on silica gel with EtOAc/hexane 1:1 gave 198 mg (83%)
(2S,4R)-N-[4-Mercapto-1-(naphthal-
ene-2-sulfonyl)-pyrrolidin-2-ylmethyl]-terephthalamic acid methyl
ester as white solid, MS: 485 (MH.sup.+).
[0348] In a similar manner, but replacing mono-methylterephthalate
with cyclohexane carbonic acid, BOC-glycine, BOC-L-tyrosine,
BOC-L-leucine and
4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-butyric acid [Puhl et
al. PCT Int. Appl. WO 9856770] and successive cleavage of the
disulfide bond (analogously to the example described above) the
following compounds were prepared:
[0349] (2S,4R)-cyclohexanecarboxylic acid
[4-mercapto-1-(naphthalene-2-sul-
fonyl)-pyrrolidin-2-ylmethyl]-amide as white foam, MS: 433
(MH.sup.+);
[0350]
(2S,4R)-[[[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmet-
hyl]-carbamoyl]-methyl]-carbamic acid tert-butyl ester as white
foam, MS: 480 (MH.sup.+);
[0351]
(S)-[2-(4-hydroxy-phenyl)-1-[[(2S,4R)-4-mercapto-1-(naphthalene-2-s-
ulfonyl)-pyrrolidin-2-ylmethyl]-carbamoyl]-ethyl]-carbamic acid
tert-butyl ester as white foam, MS: 586 (MH.sup.+);
[0352]
(S)-[1-[[(2S,4R)-4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-
-ylmethyl]-carbamoyl]-3-methyl-butyl]-carbamic acid tert-butyl
ester as beige foam, MS: 536 (MH.sup.+);
[0353]
(2S,4R)-4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-N-[4-mercapto--
1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethyl]-butyramide as
white crystalline, MS: 553 (MH.sup.+).
[0354] A degassed solution of 102 mg (0.21 mmol)
(2S,4R)-N-[4-mercapto-1-(-
naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethyl]-terephthalamic acid
methyl ester in 12.6 ml THF was treated with 12.6 ml 0.1 M aqueous
LiOH (1.26 mmol, 6 eq) at 0.degree. C. and was stirred at room
temperature for 1.5 h. 1 M KHSO.sub.4 solution was added (pH 2),
the layers were separated and the inorganic one was extracted with
EtOAc. The combined organic ones were washed with water and brine,
dried over Na.sub.2SO.sub.4 and evaporated, yielding
(2S,4R)-N-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyr-
rolidin-2-ylmethyl]-terephthalamic acid as white foam, MS: 471
(MH.sup.+).
[0355] Reaction with Sulfonyl- or Acid-chlorides:
[0356] To 100 mg (0.16 mmol)
C-[(2S,4R)-4-[(3R,5S)-5-aminomethyl-1-(naphth-
alene-2-sulfonyl)-pyrrolidin-3-yldisulfanyl]-1-(naphthalene-2-
sulfonyl)-pyrrolidin-2-yl]-methylamine in 8 ml CH.sub.2Cl.sub.2
were added 58 mg (0.47 mmol, 2.9 eq) DMAP and 80 mg (0.47 mmol, 2.9
eq) toluene sulfonylchloride. The solution was stirred at room
temperature for 2 h and was evaporated. The crude oil was purified
on silica gel with CH.sub.2Cl.sub.2: EtOAc 9:1 yielding 129 mg
(87%) 4-methyl-N-[(2S,4R)-4-[-
(3R,5S)-5-[(4-methyl-benzenesulfonylamino)-methyl]-1-(naphthalene-2-sulfon-
yl)-pyrrolidin-3-yldisulfanyl]-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylm-
ethyl]-benzenesulfonamide as white crystalls.
[0357] Cleavage of the disulfide bond analogously to the example
described above yielded 120 mg (94%)
(2S,4R)-N-[4-mercapto-1-(naphthalene-2-sulfony-
l)-pyrrolidin-2-ylmethyl]-4-methyl-benzenesulfonamide as white
crystalline, mp 175.degree. C., MS: 477 (MH.sup.+).
[0358] In a similar manner, but replacing toluene sulfonylchloride
with 2-naphthalene sulfonylchloride, methyl sulfonylchloride,
acetyl chloride, benzoyl chloride and successive cleavage of the
disulfide bond (analogously to example described above) the
following compounds were prepared:
[0359] Naphthalene-2-sulfonic acid
(2S,4R)-[4-mercapto-1-(naphthalene-2-su-
lfonyl)-pyrrolidin-2-ylmethyl]-amide as white crystalline, mp
156.degree. C., MS: 513 (MH.sup.+);
[0360]
(2S,4R)-N-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmet-
hyl]-methanesulfonamide as beige crystalline, mp 136.degree. C.,
MS: 401 (MH.sup.+);
[0361]
(2S,4R)-N-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmet-
hyl]-acetamide as white crystalline, mp 145.degree. C., MS: 365
(MH.sup.+);
[0362]
(2S,4R)-N-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmet-
hyl]-benzamide as white crystalline, MS: 427 (MH.sup.+).
[0363] In analogy Z-L-hydroxyproline benzylester hydrochloride gave
(2S,4R)-4-mercapto-2-[(naphthalene-2-sulfonylamino)-methyl]-pyrrolidine-1-
-carboxylic acid benzyl ester as white solid, MS: 457
(MH.sup.+);
Example 7
Heteroaromates
[0364] (The heteroaromatic compounds were prepared according to
Cottrell, Ian F.; Hands, David; Houghton, Peter G.; Humphrey, Guy
R., J. Heterocyclic Chem., 28, 301-304 (1991))
[0365] To a suspension of 281 mg (2.0 mmol, 4 eq.) potassium
carbonate in 2 ml DMSO were added 300 mg (0.51 mmol)
(2S,4R)-2-azidomethyl-1-(naphthal-
ene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine and 72 .mu.l (0.7
mmol, 1.38 eq) acetyl acetone. The reaction mixture was stirred at
40.degree. C. for 3 d, diluted with water and extracted with
Et.sub.2O, the layers were separated and the inorganic one was
extracted with EtOAc, the combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was
purified by column chromatography on silica gel with EtOAc/hexane
1:1 yielding 249 mg (73%) (2S,4R)-1-{5-methyl-1-[1--
(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl]-1H-[1,2,3-
]triazol-4-yl}-ethanone as white foam, MS: 673 (MH.sup.+). 150 mg
(0.2 mmol)
(2S,4R)-1-{5-methyl-1-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl--
pyrrolidin-2-ylmethyl]-1H-[1,2,3]triazol-4-yl}-ethanone were
dissolved in 6.5 ml acetonitrile and 3 ml TFA and were treated with
0.5 ml triethylsilane at 40.degree. C. for 4 h. The reaction
mixture was added to a aqueous saturated NaHCO.sub.3 solution
carefully, extracted, and the organic layer was washed with water
and brine, dried over Na.sub.2SO.sub.4 and evaporated. Purification
by column chromatography on silica gel with EtOAc/hexane 1:1 gave
63 mg (66%) (2S,4R)-1-[1-[4-mercapt-
o-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethyl]-5-methyl-1H-[1,2,3]tri-
azol-4-yl]-ethanone as white solid, mp 145.degree. C., MS: 431
(MH.sup.+).
[0366] In a similar manner the following compounds were
prepared:
[0367] From
(2S,4R)-2-azidomethyl-4-(4-methoxy-benzylsulfanyl)-1-(naphthal-
ene-2-sulfonyl)-pyrrolidine
[0368] b) and ethyl acetoacetate
(2S,4R)-1-[4-(4-methoxy-benzylsulfanyl)-1-
-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethyl]-5-methyl-1H-[1,2,3]triazo-
le-4-carboxylic acid ethyl ester as white solid, mp 121.degree. C.,
MS: 581 (MH.sup.+);
[0369] c) and cyano acetamide
(2S,4R)-5-amino-1-[4-(4-methoxy-benzylsulfan-
yl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethyl]-1H-[1,2,3]triazole-4-
-carboxylic acid amide as off-white solid, mp 190.degree. C., MS:
553 (MH.sup.+);
[0370] From
(2S,4R)-2-azidomethyl-1-methanesulfonyl-4-(4-methoxy-benzylsul-
fanyl)-pyrrolidine
[0371] d) and acetyl acetone
(2S,4R)-1-{1-[1-methanesulfonyl-4-(4-methoxy--
benzylsulfanyl)-pyrrolidin-2-ylmethyl]-5-methyl-1H-[1,2,3]triazol-4-yl}-et-
hanone as white foam, MS: 439 (MH.sup.+);
[0372] e) and ethyl acetoacetate
(2S,4R)-1-[1-methanesulfonyl-4-(4-methoxy-
-benzylsulfanyl)-pyrrolidin-2-ylmethyl]-5-methyl-1H-[1,2,3]triazole-4-carb-
oxylic acid ethyl ester as white foam, MS: 469 (MH.sup.+);
[0373] f) and phenyl acetone
(2S,4R)-1-[1-methanesulfonyl-4-(4-methoxy-ben-
zylsulfanyl)-pyrrolidin-2-ylmethyl]-5-methyl-4-phenyl-1H-[1,2,3]triazole
as white foam, MS: 473 (MH.sup.+).
[0374] g) and cyano acetamide
(2S,4R)-5-amino-1-[1-methanesulfonyl-4-(4-me-
thoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl]-1H-[1,2,3]triazole-4-carboxyl-
ic acid amide as white foam, MS: 441 (MH.sup.+);
[0375] h) and benzyl cyanide
(2S,4R)-3-[1-methanesulfonyl-4-(4-methoxy-ben-
zylsulfanyl)-pyrrolidin-2-ylmethyl]-5-phenyl-3H-[1,2,3]triazol-4-ylamine
as white foam, MS: 473 (MH.sup.+);
[0376] From
(2S,4R)-2-(2-azido-ethyl)-1-methanesulfonyl-4-tritylsulfanyl-p-
yrrolidine
[0377] i) and acetyl acetone
(2S,4R)-1-[1-[2-(1-methanesulfonyl-4-tritylsu-
lfanyl-pyrrolidin-2-yl)-ethyl]-5-methyl-1H-[1,2,3]triazol-4-yl]-ethanone
as white foam, MS: 575 (MH.sup.+);
[0378] j) and ethyl acetoacetate
(2S,4R)-1-[2-(1-methanesulfonyl-4-trityls-
ulfanyl-pyrrolidin-2-yl)-ethyl]-5-methyl-1H-[1,2,3]triazole-4-carboxylic
acid ethyl ester as white foam, MS: 605 (MH.sup.+);
[0379]
k)andphenylacetone(2S,4R)-1-[2-(1-methanesulfonyl-4-tritylsulfanyl--
pyrrolidin-2-yl)-ethyl]-5-methyl-4-phenyl-1H-[1,2,3]triazole as
white foam, MS: 609 (MH.sup.+);
[0380] Cleavage of the protecting group analogously (for Trityl:
see example a) above, for methoxy-benzylsulfanyl: Method 2) to
yield:
[0381] a)
(2S,4R)-1-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl-
methyl]-5-methyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester
as white solid, mp 95.degree. C., MS: 459 (M-H.sup.+);
[0382] b)
(3R,5S)-5-(5-methyl-4-phenyl-[1,2,3]triazol-1-ylmethyl)-1-(napht-
halene-2-sulfonyl)-pyrrolidine-3-thiol as light yellow solid, mp
146.degree. C., MS: 465 (MH.sup.+);
[0383] c)
(3R,5S)-5-(5-amino-4-phenyl-[1,2,3]triazol-1-ylmethyl)-1-(naphth-
alene-2-sulfonyl)-pyrrolidine-3-thiol as white solid, mp 70.degree.
C., MS: 466 (MH.sup.+);
[0384] d)
(2S,4R)-1-(4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethyl)-5-
-methyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester as white
solid, mp 123.degree. C., MS: 469(MH.sup.+);
[0385] e)
(3R,5S)-1-methanesulfonyl-5-(5-methyl-4-phenyl-[1,2,3]triazol-1--
ylmethyl)-pyrrolidine-3-thiol as white solid, mp 150.degree. C.,
MS: 473(MH.sup.+);
[0386] f)
(2S,4R)-5-amino-1-(4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylm-
ethyl)-1H-[1,2,3]triazole-4-carboxylic acid amide as white solid,
mp 189.degree. C., MS: 321(MH.sup.+);
[0387] g)
(3R,5S)-5-(5-amino-4-phenyl-[1,2,3]triazol-1-ylmethyl)-1-methane-
sulfonyl-pyrrolidine-3-thiol as white foam, MS: 354(MH.sup.+);
[0388] h)
(2S,4R)-1-[1-[2-(4-mercapto-1-methanesulfonyl-pyrrolidin-2-yl)-e-
thyl]-5-methyl-1H-[1,2,3]triazol-4-yl]-ethanone as colorless oil,
MS: 317 (M-CH.sub.3.sup.+);
[0389] i)
(2S,4R)-1-[2-(4-mercapto-1-methanesulfonyl-pyrrolidin-2-yl)-ethy-
l]-5-methyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester as
colorless oil, MS: 363 (MH.sup.+);
[0390] j)
(3R,5S)-1-methanesulfonyl-5-[2-(5-methyl-4-phenyl-[1,2,3]triazol-
-1-yl)-ethyl]-pyrrolidine-3-thiol as colorless oil, MS: 366
(MH.sup.+);
[0391] Saponification of the ethyl ester analogously to (see above:
General method for hydrolysis of an ester) yielded:
[0392]
(2S,4R)-1-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmet-
hyl]-5-methyl-1H-[1,2,3]triazole-4-carboxylic acid as white solid,
mp 218.degree. C., MS: 431(M-H.sup.-).
[0393] In a similar manner, but without isolation of intermediates
the following compounds were prepared:
[0394]
(2S,4R)-2-azidomethyl-4-(4-methoxy-benzylsulfanyl)-1-(naphthalene-2-
-sulfonyl)-pyrrolidine and methyl benzyl ketone and removal of the
PMB protecting group (Method 2)
(2S,4R)-1-[4-mercapto-1-(naphthalene-2-sulfon-
yl)-pyrrolidin-2-ylmethyl]-5-methyl-1H-[1,2,3]triazole-4-carboxylic
acid as white solid, mp 218.degree. C., MS: 431(M-H.sup.-);
[0395] From
(2S,4R)-2-azidomethyl-4-(4-methoxy-benzylsulfanyl)-1-(naphthal-
ene-2-sulfonyl)-pyrrolidine and benzyl cyanide and and removal of
the PMB protecting group (Method 2)
(2S,4R)-5-amino-1-[4-mercapto-1-(naphthalene--
2-sulfonyl)-pyrrolidin-2-ylmethyl]-1H-[1,2,3]triazole-4-carboxylic
acid amide as white solid, mp 1300 C, MS: 433 (MH.sup.+);
[0396] From (2R,
4R)-2-(2-azido-ethyl)-1-(naphthalene-2-sulfonyl)-4-trityl-
sulfanyl-pyrrolidine and phenyl acetone and removal of the
protecting group
(3R,5R)-5-[2-(5-methyl-4-phenyl-[1,2,3]triazol-1-yl)-ethyl]-1-(naph-
thalene-2-sulfonyl)-pyrrolidine-3-thiol as light yellow foam, MS:
479 (MH.sup.+).
Example 8
N-Pyrrolidine-optimization, Heteroaromates
[0397] In analogy to above Example 7:
(2S,4R)-2-azidomethyl-4-tritylsulfan- yl-pyrrolidine-1-carboxylic
acid tert-butyl ester and phenyl acetone gave
(2S,4R)-2-(5-methyl-4-phenyl-[1,2,3]triazol-1-ylmethyl)-4-tritylsulfanyl--
pyrrolidine-1-carboxylic acid tert-butyl ester as yellow crystals,
MS: 616 (MH.sup.+).
[0398]
(2S,4R)-2-(5-methyl-4-phenyl-[1,2,3]triazol-1-ylmethyl)-4-tritylsul-
fanyl-pyrrolidine-1-carboxylic acid tert-butyl ester gave by
treatment with TFA in methylene chloride (following the general
method for a selective BOC-deprotection)
(2S,4R)-5-methyl-4-phenyl-1-(4-tritylsulfanyl-
-pyrrolidin-2-ylmethyl)-1H-[1,2,3]triazole as yellow foam, MS: 517
(MH.sup.+);
[0399]
(2S,4R)-5-methyl-4-phenyl-1-(4-tritylsulfanyl-pyrrolidin-2-ylmethyl-
)-1H-[1,2,3]triazole and benzyl chloroformate,
N-ethyldiisopropylamine in CH.sub.2Cl.sub.2 (see carbamate
synthesis, Method A) followed by the removal of the
trityl-protecting group (see Method 3) gave
(2S,4R)-4-mercapto-2-(5-methyl-4-phenyl-[1,2,3]triazol-1-ylmethyl)-pyrrol-
idine-1-carboxylic acid benzyl ester as white foam, MS:
409(MH.sup.+).
[0400] In a similar manner but replacing benzyl chloroformate with
isopropyl chloroformate, phenyl chloroformate, chloroformic acid
2-naphtyl ester, 1,4-benzodioxan-5-yl chloroformate [Eitel, A.
& Hammann, I. S. African, ZA 6800512 680627] and butyl
chloroformate the following compounds were prepared:
[0401]
(2S,4R)-4-mercapto-2-(5-methyl-4-phenyl-[1,2,3]triazol-1-ylmethyl)--
pyrrolidine-1-carboxylic acid isopropyl ester as colorless oil, MS:
361 (MH.sup.+);
[0402]
(2S,4R)-4-mercapto-2-(5-methyl-4-phenyl-(1,2,3)triazol-1-ylmethyl)--
pyrrolidine-1-carboxylic acid phenyl ester as white foam, MS: 395
(MH.sup.+);
[0403]
(2S,4R)-4-mercapto-2-(5-methyl-4-phenyl-[1,2,3]triazol-1-ylmethyl)--
pyrrolidine-1-carboxylic acid naphthalen-2-yl ester as colorless
oil, MS: 445 (MH.sup.+);
[0404]
(2S,4R)-4-mercapto-2-(5-methyl-4-phenyl-[1,2,3]triazol-1-ylmethyl)--
pyrrolidine-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl
ester as colorless oil, MS: 453(MH.sup.+);
[0405]
(2S,4R)-4-mercapto-2-(5-methyl-4-phenyl-[1,2,3]triazol-1-ylmethyl)--
pyrrolidine-1-carboxylic acid butyl ester as colorless oil, MS:
375(MH.sup.+).
Example 9
Ether, Phenolethers
[0406] 0.37 ml (2.25 mmol) DEAD was added at -15.degree. C. to 590
mg (2.25 mmol) triphenylphosphine in 3 ml THF. Then a solution of
497 mg (1.5 mmol)
(2S,4R)-[1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrol-
idin-2-yl]-methanol and 146 mg (1.5 mmol) phenol in 2 ml THF was
added. The reaction was stirred at 0.degree. C. over night, heated
to reflux and evaporated under reduced pressure. Flash silica gel
column (hexane/EtOAc 4:1) gave 240 mg (39%) of
(2S,4R)-1-methanesulfonyl-4-(4-methoxy-benzylsu-
lfanyl)-2-phenoxymethyl-pyrrolidine, mp 92-94.degree. C., MS: 408
(MH.sup.+).
[0407] (Method 2): A solution of 102 mg (0.25 mmol)
(2S,4R)-1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-2-phenoxymethyl-py-
rrolidine and 0.4 ml (2.5 mmol) triethylsilane was heated for 1 min
at 80.degree. C., cooled to room temperature and evaporated.
Crystallization from Et.sub.2O/pentane gave 39 mg (54%) of
(3R,5S)-1-methanesulfonyl-5-ph- enoxymethyl-pyrrolidine-3-thiol, mp
78-79.degree. C., MS: 288 (MH.sup.+).
[0408] In analogy:
(2R,4R)-2-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidi-
n-2-yl)-ethanol gave after TFA/triethylsilane trityl deprotection
(Method 3)
(3R,5R)-1-methanesulfonyl-5-(2-phenoxy-ethyl)-pyrrolidine-3-thiol,
mp 82.5-83.5.degree. C., MS: 302 (MH.sup.+).
Example 10
Ether, O-carbamate
[0409] A solution of 497 mg (1.5 mmol)
(2S,4R)-[1-methanesulfonyl-4-(4-met-
hoxy-benzylsulfanyl)-pyrrolidin-2-yl]-methanol in 9 ml toluene was
treated with 0.18 ml (1.65 mmol) phenylisocyanate and 0.18 ml (1.65
mmol) 4-methylmorpholine. The reaction was stirred over night at
room temperature and extracted with aqueous 10% KHSO.sub.4/EtOAc
(3.times.). The organic phase was washed with aqueous saturated
NaHCO.sub.3 dried over Na.sub.2SO.sub.4 and evaporated. Flash
column chromatography on silica gel with hexane/EtOAc (4:1 to 2:1)
gave 426 mg (63%) of phenyl-carbamic acid
(2S,4R)-1-methanesulfonyl-4-(4-methoxy-benyzlsulfany-
l)-pyrrolidin-2-ylmethyl ester, mp 141.5-142.5.degree. C., MS: 451
(MH.sup.+).
[0410] TFA/triethylsilane deprotection (Method 2, 8 min refluxed)
gave phenyl-carbamic acid
(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-yl- methyl ester
in 55% yield, mp 147.5-148.5.degree. C., MS: 331 (MH.sup.+).
[0411] In analogy:
(2R,4R)-2-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidi-
n-2-yl)-ethanol gave phenyl-carbamic acid
(2R,4R)-2-[4-mercapto-1-(naphtha-
lene-2-sulfonyl)-pyrrolidin-2-yl]-ethyl ester, MS: 456 (M).
[0412] A solution of 150 mg (0.33 mmol) phenyl-carbamic acid
(2S,4R)-1-methane-sulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylme-
thyl ester in 1.3 ml DMF was treated at 0.degree. C. with 23.2 mg
(0.53 mmol) 55% NaH and 30 min later with 0.2 ml (1.33 mmol)
tert-butyl bromoacetate. Over night it was warmed up to room
temperature, then extracted with aqueous saturated NH.sub.4Cl/EtOAc
(3.times.). The organic phases were washed with aqueous 10% NaCl,
dried (Na.sub.2SO.sub.4) and evaporated. Flash chromatography on
silica gel (EtOAc/hexane 1/2) gave 179 mg (95%) of
(2S,4R)-{[1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)--
pyrrolidin-2-ylmethoxycarbonyl]-phenyl-amino}-acetic acid
tert-butyl ester, MS: 565 (MH.sup.+).
[0413] TFA/triethylsilane-deprotection (Method 2, 1 min refluxed)
gave
(2S,4R)-[(4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxycarbonyl)-ph-
enyl-amino]-acetic acid was received in 50% yield, MS: 389
(MH.sup.+).
[0414] In analogy:
(2R,4R)-2-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidi-
n-2-yl)-ethanol gave via phenyl-carbamic acid
(2R,4R)-2-[1-(naphthalene-2--
sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-yl]-ethyl ester with methyl
bromoacetate
(2R,4R)-({2-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidi-
n-2-yl]-ethoxycarbonyl}-phenyl-amino)-acetic acid methyl ester, MS:
529 (MH.sup.+).
Example 11
Ether (Table 1 and Table 2)
[0415] Method A: 9.07 g (20 mmol) of
(2S,4R)-(1-methanesulfonyl-4-tritylsu-
lfanyl-pyrrolidin-2-yl)-methanol and 9.5 ml (80 mmol) of
benzylbromide were dissolved in 660 ml DMF, cooled to 0.degree. C.
and treated with 1.4 g (32 mmol) of 55% NaH over 15 min in 4
portions. The reaction was warmed up over night and treated with
4.75 ml (40 mmol) benzylbromide/700 mg (16 mmol) 55% NaH and 6 h
later again with the same amount of benzylbromide/NaH. After
further 16 h at room temperature the reaction was quenched with
saturated NH.sub.4Cl solution/EtOAc (3.times.). The organic phase
was washed with aqueous 10% NaCl soution, dried over
Na.sub.2SO.sub.4 and evaporated to give 25 g crude product.
Flash-chromatography on silica gel (Hexane/EtOAc 4:1 to 1:4) gave
6.43 g (59%) of (2S,4R)-2-b
enzyloxymethyl-1-methanesulfonyl-4-tritylsulfanyl-py- rrolidine,
MS: 544 (MH.sup.+). 6.4 g (11.77 mmol) (2S,4R)-2-benzyloxymethy-
l-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidine were dissolved in
170 ml TFA and treated at 0.degree. C. with 18.75 ml (117.7 mmol)
of triethylsilane. After 18 h at 0.degree. C., the mixture was
evaporated and purified by flash-chromatography on silica gel
(Hexane/EtOAc 4:1 to 1:4) to give 2.66 g (72%) of
(3R,5S)-5-benzyloxymethyl-1-methanesulfonyl-- pyrrolidine-3-thiol,
MS: 302 (MH.sup.+).
[0416] In analogy:
(2S,4R)-2-hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-- carboxylic
acid butyl ester with benzyl bromide gave
(2S,4R)-2-benzyloxymethyl-4-mercapto-pyrrolidine-1-carboxylic acid
butyl ester, MS: 324 (MH.sup.+).
[0417]
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-methan-
ol with 3-bromo-1-phenyl-1-propene, followed by hydrogenation (17
h) and TFA/triethylsilane deprotection (Method 3) gave
(3R,5S)-1-methanesulfonyl-
-5-(3-phenyl-propoxymethyl)-pyrrolidine-3-thiol, MS: 329 (M).
[0418] Method B: A solution of 0.41 g (0.91 mmol) in 20 ml
(bromomethyl)cyclohexane was mixed with 20 ml aqueous 50% NaOH and
a catalytic amount of tetrabutyl-ammonium hydrogen sulfate and
stirred vigorously over night. The organic phase was separated, and
evaporated on the Kugelrohr. Flash-chromatography on silica gel
(hexane/EtOAc 95:5) gave 0.3 g (60%) of
(2S,4R)-2-cyclohexylmethoxymethyl-1-methanesulfonyl-4-
-tritylsulfanyl-pyrrolidine, MS: 550 (MH.sup.+).
[0419] In analogy to Method 3:
(2S,4R)-2-cyclohexylmethoxymethyl-1-methane-
sulfonyl-4-tritylsulfanyl-pyrrolidine gave
(3R,5S)-5-cyclohexylmethoxymeth-
yl-1-methanesulfonyl-pyrrolidine-3-thiol, mp 68-69.degree. C., MS:
308 (MH.sup.+).
[0420] Following Method A:
(2S,4R)-[4-(4-methoxy-benzylsulfanyl)-1-(naphth-
alene-2-sulfonyl)-pyrrolidin-2-yl]-methanol and iodomethane gave
after PMB deprotection (Method 1)
(3R,5S)-5-methoxymethyl-1-(naphthalene-2-sulfonyl-
)-pyrrolidine-3-thiol as colorless solid, 68-69.degree. C., MS: 338
(MH.sup.+).
[0421] According to an analogous method the following compounds
were prepared via reacton of
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrro-
lidin-2-yl)-methanol and the 2. educt. mentioned in the following
table 1. With chlorides one equivalent of Nal was added:
1 TABLE 1 PHYSICAL Name 2. Educt Method MS COLOR MP FORM 1
(3R,5S)-5-Benzyloxymeth- yl-1- BENZYL BROMIDE A 302 M + H+ white
waxy solid methanesulfonyl-pyrrolidine-3-thiol 2
(2S,4R)-3-(4-Mercapto-1-meth- anesulfonyl- 3-CARBOMETHOXY- A 356 M
+ H+ white waxy solid pyrrolidin-2-ylmethoxymethyl)-benzoic acid
BENZYL BROMIDE methyl ester 3
(3R,5S)-1-Methanesulfonyl-5-(pyridin-2- 2-PICOLYL CHLORIDE A 302 M
+ H+ color- oil ylmethoxy-methyl)-pyrrolidine-3-thiol) HYDROCHLORID
less trifluoro-acetate (1:1) 4
(3R,5S)-1-Methanesulfonyl-5-(pyridin-4- 4-PICOLYL CHLORIDE A 302 M
+ H+ yellow oil ylmethoxymethyl)-pyrrolidine-3-thiol HYDROCHLORID
trifluoro-acetate (1:1) 5 (3R,5S)-1-Methanesulfonyl-5-prop-2-
PROPARGYL A 248 M-H- brown oil ynyloxymethyl-pyrrolidine-3-thiol
BROMIDE 6 (3R,5S)-1-Methanesulfonyl-5-(pyridin-3- 3-PICOLYL
CHLORIDE A 302 M + H+ color- oil ylmethoxy-methyl)-pyrrolidine-3-
-thiol) HYDROCHLORID less trifluoro-acetate (1:1) 7
(3R,5S)-1-Methanesulfonyl-5-(naphthalen- 2-(BROMOMETHYL)- A 352 M +
H+ white 104-106.degree. C. powder
2-ylmethoxymethyl)-pyrrolidine-3-- thiol NAPHTHALENE 8
(3R,5S)-1-Methanesulfonyl-5-(naphthalen- 1-(BROMOMETHYL)- A 352 M +
H+ white 93-95.degree. C. crystalline
1-ylmethoxymethyl)-pyrrolidine-3-thiol NAPHTHALENE 9
(3R,5S)-1-Methanesulfonyl-5-(3-methoxy- 3-METHOXYBENZYL A 332 M +
H+ benzyloxymethyl)-pyrrolidine-3-thiol BROMIDE 10
(3R,5S)-5-(4-tert-Butyl-benzyloxymethyl)- 4-TERT-BUTYLBENZYL A 358
M + H+ 1-methanesulfonyl-pyrrolidine-3-thiol BROMIDE 11
(3R,5S)-1-Methanesulfonyl-5- PENTAFLUOROBENZYL A 392 M + H+
pentafluorophenylmethoxymethyl- BROMIDE pyrrolidine-3-thiol 12
(3R,5S)-5-(3-Bromo-benzyloxymethyl)-1- 3-BROMO BENZYL A 380 M + H+
methanesulfonyl-pyrrolidine-3-thiol BROMIDE 1 Br 13
(2S,4R)-3-(4-Mercapto-1-methanesulfonyl- 3-CYANO BENZYL A 327 M +
H+ pyrrolidin-2-ylmethoxymethyl)-benzonitrile BROMIDE 14
(3R,5S)-1-Methanesulfonyl-5-(4-methyl- 4-METHYL BENZYL A 316 M + H+
benzyloxymethyl)-pyrrolidine-3-thiol BROMIDE 15
(3R,5S)-1-Methanesulfonyl-5-(2-methyl- 2-METHYL BENZYL A 316 M + H+
benzyloxymethyl)-pyrrolidine-3-thiol BROMIDE 16
(3R,5S)-1-Methanesulfonyl-5-(3-methyl- 3-METHYL BENZYL A 316 M + H+
benzyloxymethyl)-pyrrolidine-3-thiol BROMIDE 17
(3R,5S)-5-(2-Fluoro-benzyloxymethyl)-1- 2-FLUORO BENZYL A 320 M +
H+ methanesulfonyl-pyrrolidine-3-thiol BROMIDE 18
(3R,5S)-5-(3-Fluoro-benzyloxymethyl)-1- 3-FLUORO BENZYL A 320 M +
H+ methanesulfonyl-pyrrolidine-3-thiol BROMIDE 19 Mixture of
(3R,5S)-1-methanesulfonyl-5- (1-BROMOETHYL) A 338 M + Na+ [(R)- and
-[(S)-1-phenyl-ethoxymethyl)- BENZENE pyrrolidi 20
(3R,5S)-5-(2-Chloro-benzyloxymethyl)-1- 3-CHLOROO BENZYL A 336 M +
H+ methanesulfonyl-pyrrolidine-3-thiol BROMIDE 21
(3R,5S)-5-(2,4-Difluoro-benzyloxymethyl)- 2,4-DIFLUORO BENZYL A 338
M + H+ 1-methanesulfonyl-pyrrolidine-3-thiol BROMIDE 22
(3R,5S)-5-(3-Chloro-benzyloxymethyl)-1- 3-CHLORO BENZYL A 336 M +
H+ methanesulfonyl-pyrrolidine-3-thiol BROMIDE 23
(3R,5S)-5-(3,5-Dimethyl-benzyloxymethyl)- 3,5-DIMETHYLBENZYL A 330
M + H+ 1-methanesulfonyl-pyrrolidine-3-thiol BROMIDE 24
(3R,5S)-5-(4-Fluoro-benzyloxymethyl)-1- 4-FLUORO BENZYL A 320 M +
H+ methanesulfonyl-pyrrolidine-3-thiol BROMIDE 25
(3R,5S)-1-Methanesulfonyl-5-(2,3,6- 2,3,5-TRIFLUORO A 356 M + H+
trifluoro-benzyloxymethyl)-pyrrolidine-3 BENZYL BROMIDE thiol 26
(3R,5S)-5-(3,5-Difluoro-benzyloxymethyl)- 3,5-DIFLUORO BENZYL A 338
M + H+ 1-methanesulfonyl-pyrrolidine-3-thiol BROMIDE 27
(3R,5S)-5-(Biphenyl-4-ylmethoxymethyl)-1- 4-BIPHENYLMETHYL A 400 M
+ Na+ methanesulfonyl-pyrrolidine-3-thiol CHLORIDE 28
(3R,5S)-1-Methanesulfonyl-5-(3-phenoxy- 3-PHENOXYBENZYL A 416 M +
Na+ benzyloxymethyl)-pyrrolidine-3-thiol CHLORIDE 29
(3R,5S)-5-(2,5-Difluoro-benzyloxymethyl)- 2,5-DIFLUORO BENZYL A 338
M + H+ 1-methanesulfonyl-pyrrolidine-3-thiol BROMIDE 30
(3R,5S)-5-(3,4-Difluoro-benzyloxymethyl)- 3,4-DIFLUORO BENZYL A 338
M + H+ 1-methanesulfonyl-pyrrolidine-3-thiol BROMIDE 31
(3R,5S)-5-(Benzo[1,3]dioxol-5- 3,4-METHYLENE- A 368 M + Na+
ylmethoxymethyl)-1-methanesulfonyl- DIOXYBENZYL pyrrolidine-3-thiol
CHLORIDE 32 (3R,5S)-1-Methanesulfonyl-5- 2-PHENYLETHYL B 316 M + H+
brown oil phenethyloxymethyl-pyrrolid- ine-3-thiol BROMIDE 33
(3R,5S)-1-Methanesulfonyl-5-(3-phenyl- CINNAMYL BROMIDE A 329 M
brown oil propoxymethyl)-pyrrolidine-3-- thiol 34
(3R,5S)-5-(2-Fluoro-3-trifluoromethyl- 2-FLUORO-3- A 388 M + H+
benzyloxymethyl)-1-methanesulfonyl- TRIFLUORO-BENZYL
pyrrolidine-3-thiol BROMIDE 35 (3R,5S)-5-(2-Chloro-6-fluoro-
2-CHLORO-6-FLUORO A 354 M + H+ benzyloxymethyl)-1-methanesulfonyl-
- BENZYL BROMIDE pyrrolidine-3-thiol 36
(3R,5S)-5-(2,3-Difluoro-4-trifluoromethyl- 2,3-DIFLUORO-4- A 406 M
+ H+ benzyloxymethyl)-1-methanesulfonyl- TRIFLUOROMETHYL-
pyrrolidine-3-thiol BENZYL BROMIDE 37 (3R,5S)-1-Methanesulfonyl-5--
(2- 2-(TRIFLUORO- A 386 M + H+ trifluoromethoxy-benzyloxymethyl)-
METHOXY)-BENZYL pyrrolidine-3-thiol BROMIDE 38
(3R,5S)-5-(2-Fluoro-5-trifluoromethyl- 2-FLUORO-5- A 388 M + H+
benzyloxymethyl)-1-methanesulfonyl- TRIFLUOROBENZYL
pyrrolidine-3-thiol BROMIDE 39 (3R,5S)-5-(2-Fluoro-4-trifluorometh-
yl- 2-FLUORO-4- A 388 M + H+ benzyloxymethyl)-1-methanesulfonyl-
TRIFLUOROBENZYL pyrrolidine-3-thiol BROMIDE 40
(3R,5S)-5-(2-Fluoro-6-trifluoromethyl- 2-FLUORO-6- A 388 M + H+
benzyloxymethyl)-1-methanesulfonyl- TRIFLUOROBENZYL
pyrrolidine-3-thiol BROMIDE 41 (3R,5S)-1-Methanesulfonyl-5-(2,4,5-
2,4,5-TRIFLUORO A 356 M + H+ trifluoro-benzyloxymethyl)-pyrrolidi-
ne-3- BENZYL BROMIDE thiol 42 (3R,5S)-5-(2,6-Difluoro-benzy-
loxymethyl)- 2,6-DIFLUORO BENZYL A 338 M + H+
1-methanesulfonyl-pyrrolidine-3-thiol BROMIDE 43
(3R,5S)-1-Methanesulfonyl-5-(2,3,4- 2,3,4-TRIFLUORO A 356 M + H+
trifluoro-benzyloxymethyl)-pyrrolidine-3- BENZYL BROMIDE thiol 44
(3R,5S)-5-(2,3-Difluoro-benzyloxymethyl)- 2,3-DIFLUORO BENZYL A 338
M + H+ 1-methanesulfonyl-pyrrolidine-3-thiol BROMIDE 45
(3R,5S)-1-Methanesulfonyl-5-(2- 2-TRIFLUOROBENZYL A 370 M + H+
trifluoromethyl-benzyloxymethyl)- BROMIDE pyrrolidine-3-thiol 46
(3R,5S)-5-(2-Bromo-benzyloxymethyl)-1- 2-BROMO BENZYL A 380 M + H+,
methanesulfonyl-pyrrolidine-3-thiol BROMIDE 1 Br 47
(3R,5S)-5-(Biphenyl-2-ylmethoxymethyl)-1- 2-PHENYLBENZYL A 400 M +
Na+ methanesulfonyl-pyrrolidine-3-thiol BROMIDE 48
(2S,4R)-2-(4-Mercapto-1-methanesulfonyl- 2-CYANO BENZYL A 327 M +
H+ pyrrolidin-2-ylmethoxymethyl)-benzonitrile BROMIDE 49
(3R,5S)-1-Methanesulfonyl-5-(3,4,5- 3,4,5-TRIFLUORO A 356 M + H+
trifluoro-benzyloxymethyl)-pyrrolidine-3- BENZYL BROMIDE thiol 50
(3R,5S)-1-Methanesulfonyl-5-(2,3,5- 2,3,5-TRIFLUORO A 356 M + H+
trifluoro-benzyloxymethyl)-pyrrolidine-3- BENZYL BROMIDE thiol 51
(3R,5S)-1-Methanesulfonyl-5-(2,4,6- 2,4,6-TRIFLUORO A 356 M + H+
trifluoro-benzyloxymethyl)-pyrrolidine-3- BENZYL BROMIDE thiol 52
(3R,5S)-5-Cyclohexylmethoxymethyl-1- (BROMOMETHYL) B 308 M + H+
white 68-69.degree. C. crystalline
methanesulfonyl-pyrrolidine-3-thiol CYCLOHEXANE 53
(3R,5S)-5-(5-Chloro-thiophen-2- 2-CHLORO-5- A 341.9 M + H+ color-
oil ylmethoxymethyl)-1-methanesulfonyl- (CHLOROMETHYL) less
pyrrolidine-3-thiol THIOPHENE 54 (3R,5S)-1-Methanesulfonyl-5-(5-me-
thyl- 3-CHLOROMETHYL-5- A 307 M + H+ white 74-75.degree. C.
crystalline isoxazol-3-ylmethoxymethyl)-pyrrolidine-3-
METHYLISOXAZOLE thiol 55 (3R,5S)-1-Methanesulfonyl-5-(2-methyl-
4-CHLOROMETHYL-2- A 437 M + H+ color- oil
thiazol-4-ylmethoxymethyl)-pyrrolidine-3- - METHYLTHIAZOLE less
thiol trifluoro-acetate (1:1) HYDROCHLORIDE
[0422] Further compounds were prepared by reaction of
(2S,4R)-2-hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic
acid butyl ester with the second educt mentioned in table 2:
2 TABLE 2 Name 2. Educt Method MS 1
(2S,4R)-2-Benzyloxymethyl-4-mercapto- BENZYL BROMIDE A M + H+ 324
pyrrolidine-1-carboxylic acid butyl ester 2
(2S,4R)-2-(3-Chloro-benzyloxymethyl)-4- 3-CHLORO BENZYL A M + H+
358 mercapto-pyrrolidine-1-carboxylic acid BROMIDE butyl ester 3
(2S,4R)-2-(3-Cyano-benzyloxymethyl)-4- 3-CYANO BENZYL A M + H+ 349
mercapto-pyrrolidine-1-carboxylic acid BROMIDE butyl ester 4
(2S,4R)-2-(3-Bromo-benzyloxymethyl)-4- 3-BROMO BENZYL A M + H+, 402
mercapto-pyrrolidine-1-carboxylic acid BROMIDE 1 Br butyl ester 5
(2S,4R)-2-(3-Fluoro-benzyloxymethyl)-4- 3-FLUORO BENZYL A M + H+
342 mercapto-pyrrolidine-1-carboxylic acid BROMIDE butyl ester 6
(2S,4R)-2-(2-Fluoro-benzyloxymethyl)- -4- 2-FLUORO BENZYL A M + H+
342 mercapto-pyrrolidine-1-carboxylic acid BROMIDE butyl ester 7
(2S,4R)-2-(2,4-Difluoro-benzylo- xymethyl)- 2,4-DIFLUORO A M + H+
360 4-mercapto-pyrrolidine-1-carb- oxylic acid BENZYL BROMIDE butyl
ester 8 (2S,4R)-2-(2-Chloro-benzyloxymethyl)-4- 2-CHLORO BENZYL A M
+ H+ 358 mercapto-pyrrolidine-1-carboxylic acid BROMIDE butyl ester
9 (2S,4R)-2-(4-Bromo-2-fluoro- 4-BROMO-2-FLUORO A M + H+, 420
benzyloxymethyl)-4-mercapto-pyrrolidine- BENZYL BROMIDE 1 Br
1-carboxylic acid butyl ester 10 (2S,4R)-4-Mercapto-2-(3-methyl-
3-METHYL BENZYL A M + H+ 338 benzyloxymethyl)-pyrrolidine-1-carbo-
xylic BROMIDE acid butyl ester 11 (2S,4R)-4-Mercapto-2-(2,3-
,6-trifluoro- 2,3,6-TRIFLUORO A M + H+ 378 benzyloxymethyl)-pyrrol-
idine-1-carboxylic BENZYL BROMIDE acid butyl ester 12
(2S,4R)-2-(3,4-Difluoro-benzyloxymethyl)- 3,4-DIFLUORO A M + H+ 360
4-mercapto-pyrrolidine-1-carboxylic acid BENZYL BROMIDE butyl ester
13 (2S,4R)-2-(4-Fluoro-benzyloxymethyl)-4- 4-FLUORO BENZYL A M + H+
342 mercapto-pyrrolidine-1-carboxylic acid BROMIDE butyl ester 14
(2S,4R)-2-(2,5-Difluoro-benzyloxymethyl)- 2,5-DIFLUORO A M + H+ 360
4-mercapto-pyrrolidine-1-carboxylic acid BENZYL BROMIDE butyl ester
15 (2S,4R)-2-(3-Chloro-2-f- luoro-benzyloxymethyl)-4-
3-CHLORO-2FLUORO A M + H+ 376 mercapto-pyrrolidine-1-carboxylic
acid butyl BENZYL BROMIDE ester 16
(2S,4R)-2-(2-Cyano-benzyloxymethyl)-4-mercapto- 2-CYANO BENZYL A M
+ H+ 349 pyrrolidine-1-carboxylic acid butyl ester BROMIDE 17
(2S,4R)-2-(2-Bromo-benzyloxymethyl)-4-mercapto- 2-BROMO BENZYL A M
+ H+, 402 pyrrolidine-1-carboxylic acid butyl ester BROMIDE 1 Br 18
(2S,4R)-2-(2,3-Difluoro-benzyloxymethyl)-4- 2,3-DIFLUORO A M + H+
360 mercapto-pyrrolidine-1-carboxylic acid butyl BENZYL BROMIDE
ester 19 (2S,4R)-2-(2-Fluoro-4-trifluoromethyl- 2-FLUORO-4- A M +
H+ 410 benzyloxymethyl)-4-mercapto-pyrrolidine-- 1- TRIFLUOROMETHYL
carboxylic acid butyl ester BENZYL BROMIDE 20
(2S,4R)-4-Mercapto-2-(2,3,5-trifluoro- 2,3,5-TRIFLUORO A M + H+ 378
benzyloxymethyl)-pyrrolidine-1-carboxylic acid BENZYL BROMIDE butyl
ester 21 (2S,4R)-4-Mercapto-2-(2,3,4-trifluoro- 2,3,4-TRIFLUORO A M
+ H+ 378 benzyloxymethyl)-pyrrolidine-1-carbo- xylic acid BENZYL
BROMIDE butyl ester 22 (2S,4R)-4-Mercapto-2-(3,4,5-trifluoro-
3,4,5-TRIFLUORO A M + H+ 378
benzyloxymethyl)-pyrrolidine-1-carboxylic acid BENZYL BROMIDE butyl
ester
Example 12
Ether, Sugar Replacement
[0423] To a solution of
(2S,4R)-(4-mercapto-1-methanesulfonyl-pyrrolidin-2- -yl)-methanol
(0.28 g) in dichloromethane (10 ml) were added pyridine (0.131 g)
and acetic anhydride (0.160 g). The reaction mixture was stirred
for 4 h at room temperature, treated with ice/water and extracted
with EtOAc. The organic phase was washed with a saturated solution
of sodium bicarbonate and brine, dried over magnesium sulphate and
concentrated. The residue was chromatographed on silica gel using
EtOAc/hexane 1:2 as eluent to obtain thioacetic acid
(3R,5S)-S-(5-hydroxymethyl-1-methanesulfonyl-pyrrolidin-3-yl) ester
(0.080 g) as a viscous oil.
[0424] A solution of thioacetic acid
(3R,5S)-S-(5-hydroxymethyl-1-methanes- ulfonyl-pyrrolidin-3-yl)
ester (0.070 g) and 1,2,3,4-tetra-O-acetyl-6-deox-
y-beta-L-mannopyranose [G. Hodosi and P. Kovc, Carbohydr. Res.,
303, 239-243 (1997)] (0.138 g) in dichloromethane (10.0 ml) was
treated with trimethylsilyl trifluoromethanesulphonate (0.075 ml)
at 0.degree. C. The reaction mixture was stirred at 0.degree. C.
for 1 h, poured into a sodium bicarbonate solution, and extracted
with EtOAc. The organic phase was washed with brine, dried over
magnesium sulphate and concentrated. The residue was
chromatographed on silica gel using EtOAc/hexane 1:1 as eluent to
obtain acetic acid (2S,3R,4R,5S,6S)-4,5-diacetoxy-2-[(2S,4R)-4--
acetylsulfanyl-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahyd-
ro-pyran-3-yl ester (0.105 g) as a syrup, MS: 543 (M+NH.sub.4+).
Acetic acid
(2S,3R,4R,5S,6S)-4,5-diacetoxy-2-[(2S,4R)-4-acetylsulfanyl-1-methane-
sulfonyl-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahydro-pyran-3-yl
ester (0.080 g) was reacted as described for the S-Acetyl
deprotection (see below) to obtain
(2S,3R,4R,5R,6S)-2-[(2S,4R)-4-mercapto-1-methanesulfonyl-
-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahydro-pyran-3,4,5-triol
(0.035 g) as a colourless foam, MS: 358 (MH.sup.+).
Example 13
Ether, O-Nonbenzylether
[0425] Following Method A,
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyr-
rolidin-2-yl)-methanol and tert-butyl bromoacetate gave
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy)-aceti-
c acid tert-butyl ester, mp 98.degree. C., slow dec., MS: 568
(MH.sup.+).
[0426] In analogy:
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin--
2-yl)-methanol and methyl (+/-)-2-bromo-4-methylvalerate gave after
flash-chromatography on silica gel (Hexane/EtOAc 9:1 to 3:1) (R)-
or
(S)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy]-
-4-methyl-pentanoic acid methyl ester, MS: 582 (MH.sup.+) and (S)-
or
(R)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy]-
-4-methyl-pentanoic acid methyl ester, MS: 582 (MH.sup.+).
[0427] BOC-deprotection (see General Method for a Selective
BOC-deprotection):
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-
-2-ylmethoxy)-acetic acid tert-butyl ester gave
(2S,4R)-(1-methanesulfonyl-
-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy)-acetic acid, MS: 512
(MH.sup.+).
[0428] Hydrolysis in EtOH/THF (see General Method for Hydrolysis of
an Ester): (R)- or
(S)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrroli-
din-2-ylmethoxy]-4-methyl-pentanoic acid methyl ester gave (R)- or
(S)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy]-
-4-methyl-pentanoic acid, MS: 568 (MH.sup.+); and (S)- or
(R)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy]-
-4-methyl-pentanoic acid methyl ester gave (R)- or
(S)-2-[(2S,4R)-1-Methan-
esulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy]-4-methyl-pentanoic
acid, MS: 568 (MH.sup.+).
[0429] EDCI-coupling (see General Method for EDCI-coupling) of
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy)-aceti-
c acid with N-methylbenzylamine gave
(2S,4R)-N-benzyl-2-(1-methanesulfonyl-
-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy)-N-methyl-acetamide, MS:
615 (MH.sup.+).
[0430] Following the TFA/triethylsilane trityl deprotection (Method
3),
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy)-aceti-
c acid tert-butyl ester gave
(2S,4R)-(4-mercapto-1-methanesulfonyl-pyrroli-
din-2-ylmethoxy)-acetic acid, MS: 268 (M-H).sup.-;
[0431] (R)- or
(S)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidi-
n-2-ylmethoxy]-4-methyl-pentanoic acid methyl ester gave (R)- or
(S)-2-[(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-4meth-
yl-pentanoic acid methyl ester, MS: 340 (MH.sup.+);
[0432] (S)- or
(R)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidi-
n-2-ylmethoxy]-4-methyl-pentanoic acid methyl ester gave (S)- or
(R)-2-[(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-4-met-
hyl-pentanoic acid methyl ester, MS: 340 (MH.sup.+);
[0433] (R)- or
(S)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidi-
n-2-ylmethoxy]-4-methyl-pentanoic acid gave (R)- or
(S)-2-[(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-4-met-
hyl-pentanoic acid, MS: 324 (M-H).sup.-;
[0434] (R)- or
(S)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidi-
n-2-ylmethoxy]-4-methyl-pentanoic acid gave (S)- or
(R)-2-[(2S,4R)-4-Mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-4-met-
hyl-pentanoic acid, MS: 324 (M-H).sup.-;
[0435]
(2S,4R)-N-benzyl-2-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-
-ylmethoxy)-N-methyl-acetamide gave
(2S,4R)-N-Benzyl-2-(4-mercapto-1-metha-
nesulfonyl-pyrrolidin-2-ylmethoxy)-N-methyl-acetamide, MS: 373
(MH.sup.+).
[0436] In analogy:
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin--
2-yl)-methanol and methyl (+/-)-alpha-bromophenylacetate gave after
the separation of the diastereomers and deprotection of the trityl
group (Method 3) (R)- or
(S)-[(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-
-ylmethoxy]-phenyl-acetic acid methyl ester, MS: 359 (M); and (S)-
or
(R)-[(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-phenyl--
acetic acid methyl ester, MS: 359 (M).
Example 14
N-Pyrrolidin-derivatisation of the Ethers
[0437] Starting Materials:
[0438] A solution of 15.5 g (32.59 mmol)
(2S,4R)-2-hydroxymethyl-4-trityls- ulfanyl-pyrrolidine-1-carboxylic
acid tert-butyl ester and 24.7 g (109.77 mmol)
2,4,5-trifluorobenzylbromide in 700 ml DMF at 0.degree. C. was
treated with 2.28 g (52.14 mmol) of 55% NaH in 4 portions and
warmed up to room temperature during 7 h. The reaction was cooled
to 0.degree. C. and treated with 500 ml aqueous saturated
NH.sub.4Cl solution, extracted with EtOAc (3.times.). The organic
phase was washed with 10% NaCl dried over Na.sub.2SO.sub.4 and
evaporated. Flash column chromatography on silica gel with
hexane/EtOAc (9:1 to 8.5:1.5) gave 9.37 g (46%) of
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine--
1-carboxylic acid tert-butyl ester, MS: 620 (MH.sup.+).
[0439] In analogy:
(2S,4S)-4-chloro-2-hydroxymethyl-pyrrolidine-1-carboxyl- ic acid
tert-butyl ester gave (2S,4S)-4-chloro-2-(2,4,5-trifluoro-benzylox-
ymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 379
(M).
[0440] A solution of 9.37 g (15.11 mmol)
(2S,4R)-2-(2,4,5-trifluoro-benzyl-
oxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid
tert-butyl ester in 30 ml CH.sub.2Cl.sub.2 was treated at
-20.degree. C. with 34 ml TFA and warmed up to room temperature
during 5.5 h. The reaction was evaporated and treated with aqueous
saturated NaHCO.sub.3 solution/EtOAc (3.times.) to give 7.77 g
(quantitative) (2S,4R)-2-(2,4,5-trifluoro-benzy-
loxymethyl)-4-tritylsulfanyl-pyrrolidine, MS: 520 (M).
[0441] In analogy: The reaction of
(2S,4R)-2-hydroxymethyl-4-tritylsulfany- l-pyrrolidine-1-carboxylic
acid tert-butyl ester with benzylbromide gave
(2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine, MS: 466
(MH.sup.+).
Example 14.a:
Ether, Carbamates (Table 3 and Table 4)
[0442] Carbamate, Method A: A solution of 1.9 g (4.1 mmol)
(2S,4R)-2-benzyloxy-methyl-4-tritylsulfanyl-pyrrolidine in 25 ml
THF at 0.degree. C. was treated with 0.57 ml (4.5 mmol) phenyl
chloroformate and 0.41 ml (5.1 mmol) pyridine. After 2 h at room
temperature the reaction was worked up with 1N HCl/EtOAc
(3.times.), the organic phases were washed with H.sub.2O, aqueous
saturated NaHCO.sub.3, dried and evaporated to give 2.6 g
(quantitative) (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-p-
yrrolidine-1-carboxylic acid phenyl ester, MS: 586 (MH.sup.+).
[0443] Trityl deprotection (Method 3) (7 h at 0.degree. C.) gave
(2S,4R)-2-benzyloxymethyl-4-mercapto-pyrrolidine-1-carboxylic acid
phenyl ester, MS: 343 (M).
[0444] Carbamate, Method B: A solution of 0.19 ml (1.58 mmol)
trichloromethyl-chloroformate in 20 ml CH.sub.2Cl.sub.2 was treated
at 0.degree. C. with 0.28 ml (3 mmol) 2-fluorophenol and 0.35 ml (3
mmol) quinoline and then stirred for 3 h at room temperature. The
reaction was then cooled (0.degree. C.) and a solution of 0.52 g (1
mmol)
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine
and 0.2 ml (2.5 mmol) pyridine in 3 ml CH.sub.2Cl.sub.2 was added,
followed by 122 mg (1 mmol) DMAP. After 3 h at 0.degree. C. the
reaction was evaporated and poured into aqueous 10%
KHSO.sub.4/Et.sub.2O (3.times.). The organic phases were washed
with aqueous 10% NaCl solution, dried over Na.sub.2SO.sub.4 and
evaporated. Flash chromatography on silica gel (hexane/EtOAc 9:1)
gave 0.39 g (60%)
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine--
1-carboxylic acid 2-fluoro-phenyl ester, MS: 658 (MH.sup.+).
[0445] Trityl deprotection (Method 3) gave
(2S,4R)-4-mercapto-2-(2,4,5-tri-
fluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid
2-fluoro-phenyl ester, MS: 416 (MH.sup.+).
[0446] In analogy: a)
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-trityl-
sulfanyl-pyrrolidine and DL-Leucyc acid isopropyl ester gave after
separation on silica gel with hexane/EtOAc 9:1
(2S,4R)-2-(2,4,5-trifluoro-
-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid
(S)- or (R)-1-isopropoxycarbonyl-3-methyl-butyl ester, MS: 720
(MH.sup.+) and
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine--
1-carboxylic acid (R)- or (S)-1-isopropoxycarbonyl-3-methyl-butyl
ester, MS: 720 (MH.sup.+).
[0447]
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrol-
idine and ethyl-3-hydroxy-benzoate gave
(2S,4R)-2-(2,4,5-trifluoro-benzylo-
xymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid
3-ethoxycarbonyl-phenyl ester, MS: 712 (MH.sup.+).
[0448]
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrol-
idine and ethylglycolate gave
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)--
4-tritylsulfanyl-pyrrolidine-1-carboxylic acid ethoxycarbonylmethyl
ester, MS: 650 (MH.sup.+).
[0449] Trityl deprotection (Method 3) of
(2S,4R)-2-(2,4,5-trifluoro-benzyl-
oxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid (S)- and
(R)-1-isopropoxycarbonyl-3-methyl-butyl ester gave
(2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carb-
oxylic acid (S)- and (R)-1-isopropoxycarbonyl-3-methyl-butyl ester,
MS: 478 (MH.sup.+).
[0450] In analogy:
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsul-
fanyl-pyrrolidine-1-carboxylic acid 3-ethoxycarbonyl-phenyl ester
gave
(2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carb-
oxylic acid 3-ethoxycarbonyl-phenyl ester, MS: 470 (MH.sup.+).
[0451] b) Hydrolysis with 1 N NaOH (see General method for
hydrolysis of an ester) in dioxane of
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tri-
tylsulfanyl-pyrrolidine-1-carboxylic acid (S)- or
(R)-1-isopropoxycarbonyl- -3-methyl-butyl ester gave
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-t-
ritylsulfanyl-pyrrolidine-1-carboxylic acid (S)- or
(R)-1-carboxy-3-methyl-butyl ester, MS: 678 (MH.sup.+) and
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine--
1-carboxylic acid (R)- or (S)-1-isopropoxycarbonyl-3-methyl-butyl
ester gave
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrroli-
dine-1-carboxylic acid (R)- or (S)-1-carboxy-3-methyl-butyl ester,
MS: 678 (MH.sup.+).
[0452] In analogy:
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsul-
fanyl-pyrrolidine-1-carboxylic acid 3-ethoxycarbonyl-phenyl ester
gave
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine--
1-carboxylic acid 3-carboxy-phenyl ester, MS: 684 (MH.sup.+).
[0453]
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrol-
idine-1-carboxylic acid ethoxycarbonylmethyl ester gave
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine--
1-carboxylic acid carboxymethyl ester, MS: 620 (M-H).sup.-.
[0454] Trityl deprotection (Method 3):
(2S,4R)-2-(2,4,5-trifluoro-benzylox-
ymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid (S)- or
(R)-1-carboxy-3-methyl-butyl ester gave
(2S,4R)-4-mercapto-2-(2,4,5-trifl-
uoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid (S)- or
(R)-1-carboxy-3-methyl-butyl ester, MS: 434 (M-H.sup.-) and
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine--
1-carboxylic acid (R)- or (S)-1-carboxy-3-methyl-butyl ester gave
(2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carb-
oxylic acid (R)- or (S)-1-carboxy-3-methyl-butyl ester, MS: 434
(M-H.sup.-).
[0455]
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrol-
idine-1-carboxylic acid 3-carboxy-phenyl ester gave
(2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carb-
oxylic acid (S)- or (R)-1-carboxy-3-methyl-butyl ester, MS: 440
(M-H.sup.-).
[0456]
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrol-
idine-1-carboxylic acid carboxymethyl ester gave
(2S,4R)-4-Mercapto-2-(2,4-
,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid
carboxymethyl ester, MS: 380 (MH.sup.+).
[0457] Carbamate, Method C: A solution of 0.07 ml (0.55 mmol)
trichloromethyl-chloroformate in 7 ml CH.sub.2Cl.sub.2 was treated
at 0.degree. C. with 0.13 ml (1.1 mmol) quinoline and after 15 min
with 0.52 g (1 mmol)
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-p-
yrrolidine in 7 ml CH.sub.2Cl.sub.2. After 2 h at 0.degree. C. the
CH.sub.2Cl.sub.2 was evaporated. The residue was dissolved in 15 ml
THF , treated at 0.degree. C. with 0.27 ml (2.1 mmol) methyl
salicylate, 96 mg (2.4 mmol) of 55% NaH and 166 mg (1 mmol) of KI.
The reaction was stirred at room temperature over night, cooled
(0.degree. C.) and after the addition of 44 mg (1 mmol) of 55% NaH
refluxed for 3 h. The reaction was partitioned between aqueous 10%
KHSO.sub.4/EtOAc (3.times.300). The organic phases were washed with
aqueous 10% NaCl, dried (Na.sub.2SO.sub.4) and evaporated. Flash
chromatography on silica gel (Hexane/EtOAc 9:1) gave 0.48 g (69%)
(2S,4R)-2-(2,4,5-trifluoro-benzyloxy-
methyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid
2-methoxycarbonyl-phenyl ester, MS: 698 (MH.sup.+).
[0458] (Method 3): A solution of 0.4 g (0.58 mmol)
(2S,4R)-2-(2,4,5-triflu-
oro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid
2-methoxycarbonyl-phenyl ester in 5.8 ml TFA was treated at
0.degree. C. with 0.92 ml (5.78 mmol) triethylsilane and after 10
min at room temperature evaporated and purified by flash
chromatography on silica gel (Hexane/EtOAc 4:1) to give 0.22 (82%)
(2S,4R)-4-mercapto-2-(2,4,5-trifluo-
ro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid
2-methoxycarbonyl-phenyl ester, MS: 456 (MH.sup.+).
[0459] (Method 4): A solution of 0.32 mmol trityl-protected
compound was dissolved in 1.5 ml acetonitril/0.4 ml TFA/0.1 ml
triethylsilane and after 1 night at RT purified by prep HPLC (RP18,
CH.sub.3CN/H.sub.2O 80:20 to 95:5) to give the free thiols.
[0460] By the reaction of
(2S,4R)-2-Benzyloxymethyl-4-tritylsulfanyl-pyrro- lidine with the
second educt in table 3 the following compounds were obtained:
3 TABLE 3 Name 2. Educt Method MS 1
(2S,4R)-2-Benzyloxymethyl-4-mercapto- PHENYL CHLOROFORMATE A M 343
pyrrolidine-1-carboxylic acid phenyl ester 2
(2S,4R)-2-Benzyloxymethyl-4-mercapto- ISOPROPYL CHLOROFORMATE A M +
H+ 310 pyrrolidine-1-carboxylic acid isopropyl ester 3
(2S,4R)-2-Benzyloxymethyl-4-mercapto- 2-CHLOROETHYL A M + H+ 330
pyrrolidine-1-carboxylic acid 2-chloro-ethyl ester CHLOROFORMATE 4
(2S,4R)-2-Benzyloxymethyl-4-mercapto- BENZYL CHLOROFORMATE A M + H+
358 pyrrolidine-1-carboxylic acid benzyl ester 5
(2S,4R)-2-Benzyloxymethyl-4-mercapto- CHLOROFORMIC ACID 2- A M + H+
394 pyrrolidine-1-carboxylic acid naphthalen-2-yl ester NAPHTHYL
ESTER 6 (2S,4R)-2-Benzyloxymethyl-4-mercapto- CHLOROFORMIC ACID N-
A M + H+ 338 pyrrolidine-1-carboxylic acid pentyl ester AMYL ESTER
7 (2S,4R)-2-Benzyloxymethyl-4-mercapto- ISOBUTYL CHLOROFORMATE A M
+ H+ 324 pyrrolidine-1-carboxylic acid isobutyl ester 8
(2S,4R)-2-Benzyloxymethyl-4-mercapto- METHYL CHLOROFORMATE A M 281
pyrrolidine-1-carboxylic acid methyl ester 9
(2S,4R)-2-Benzyloxymethyl-4-mercapto- BUTYL CHLOROFORMATE A M + H+
324 pyrrolidine-1-carboxylic acid butyl ester
[0461] By the reaction of
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tr-
itylsulfanyl-pyrrolidine with the second educt mentioned in table 4
the following compounds were obtained:
4 TABLE 4 Name 2. Educt Method MS 1
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- ISOPROPYL A M + H+ 364
benzyloxymethyl)-pyrrolidine-1-carboxylic acid CHLOROFORMATE
isopropyl ester 2 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- PHENYL
CHLOROFORMATE A M + H+ 398 benzyloxymethyl)-pyrrolidine-1-carboxy-
lic acid phenyl ester 3 (2S,4R)-4-Mercapto-2-(2,4,5-trifluo- ro-
2-CHLOROETHYL A M + H+ 384 benzyloxymethyl)-pyrrolidine-1-carb-
oxylic acid 2- CHLOROFORMATE chloro-ethyl ester 4
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- BENZYL CHLOROFORMATE A M +
H+ 412 benzyloxymethyl)-pyrrolidine-1-carboxylic acid benzyl ester
5 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- CHLOROFORMIC ACID 2- A M +
H+ 448 benzyloxymethyl)-pyrrolidine-1-carboxylic acid NAPHTHYL
ESTER naphthalen-2-yl ester 6
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- CHLOROFORMIC ACID N- A M +
H+ 392 benzyloxymethyl)-pyrrolidine-1-carboxylic acid AMYL ESTER
pentyl ester 7 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- ISOBUTYL
CHLOROFORMATE A M + H+ 378 benzyloxymethyl)-pyrrolidine-1-carboxy-
lic acid isobutyl ester 8 (2S,4R)-4-Mercapto-2-(2,4,5-trifl- uoro-
METHYL CHLOROFORMATE A M + H+ 336 benzyloxymethyl)-pyrrolidi-
ne-1-carboxylic acid methyl ester 9 (2S,4R)-4-Mercapto-2-(2-
,4,5-trifluoro- 4-FLUOROPHENYL A M + H+ 416
benzyloxymethyl)-pyrrolidine-1-carboxylic acid 4- CHLOROFORMATE
fluoro-phenyl ester 10 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- Lit
(1) A M + H+ 456 benzyloxymethyl)-pyrrolidine-1-carboxylic acid
2,3- dihydro-benzo[1,4]dioxin-5-yl ester 11
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 4-METHOXYCARBONYL- A M + H+
456 benzyloxymethyl)-pyrrolidine-1-carboxylic acid 4- PHENYL
CHLOROFORMATE methoxycarbonyl-phenyl ester 12
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 4-CHLOROPHENYL A M + H+ 432
benzyloxymethyl)-pyrrolidine-1-carboxylic acid 4- CHLOROFORMATE
chloro-phenyl ester 13 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-
P-TOLYL CHLOROFORMATE A M + H+ 412 benzyloxymethyl)-pyrrolidine-1-
-carboxylic acid p- tolyl ester 14 (2S,4R)-4-Mercapto-2-(2,-
4,5-trifluoro- 4-BROMOPHENYL A M + H+, 476 benzyloxymethyl)-pyrrol-
idine-1-carboxylic acid 4- CHLOROFORMATE 1 Br bromo-phenyl ester 15
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- PROPARGYL A M + H+ 36
benzyloxymethyl)-pyrrolidine-1-carboxylic acid CHLOROFORMATE
prop-2-ynyl ester 16 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-
3-BUTENYL A M + H+ 376 benzyloxymethyl)-pyrrolidine-1-carboxylic
acid but- CHLOROFORMATE 3-enyl ester 17
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- (-)-MENTHYL A M + H+ 460
benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2- CHLOROFORMATE
isopropyl-5-methyl-cyclohexyl ester 18 (2S,4R)-4-Mercapto-2-(2,4,5-
-trifluoro- PHENETHYLALCOHOL B M + H+ 426 benzyloxymethyl)-pyrroli-
dine-1-carboxylic acid phenethyl ester 19
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 2,2,2-TRIFLUORETHANOL B M
403 benzyloxymethyl)-pyrrolidine-1-carboxylic acid
2,2,2-trifluoro-ethyl ester 20 (2S,4R)-4-Mercapto-2-(2,4,5-trifluo-
ro- 4-METHOXYPHENYL A M + H+ 428 benzyloxymethyl)-pyrrolidine-1-ca-
rboxylic acid 4- CHLOROFORMATE methoxy-phenyl ester 21
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- CHLOROFORMIC ACID 2- A M +
H+ 380 benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-
METHOXYETHYL ESTER methoxy-ethyl ester 22
(2S,4R)-4-Mercapto-2-(2,4,5-t- rifluoro- BUTYL CHLOROFORMATE A M +
H+ 370 benzyloxymethyl)-pyrrol- idine-1-carboxylic acid butyl ester
23 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- ETHYL CHLOROFORMATE A M +
H+ 350 benzyloxymethyl)-pyrrolidine-1-carboxylic acid ethyl ester
24 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- PROPYL CHLOROFORMATE A M
+ H+ 364 benzyloxymethyl)-pyrrolidine-1-carboxylic acid propyl
ester 25 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- ETHYLGLYCOLATE B M
+ H+ 408 benzyloxymethyl)-pyrrolidine-1-carbox- ylic acid
ethoxycarbonylmethyl ester 26
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- CHLOROFORMIC ACID N- A M +
H+ 406 benzyloxymethyl)-pyrrolidine-1-carboxylic acid HEXYL ESTER
hexyl ester 27 (2S)4R)-4-Mercapto-2-(2,4,5-trifluoro-
2-FLUOROBENZYL ALCOHOL B M + H+ 430 benzyloxymethyl)-pyrrolidine--
1-carboxylic acid 2- fluoro-benzyl ester 28
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 2-FLUOROPHENOL B, de- M + H+
416 benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2- scribed
fluoro-phenyl ester 29 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-
BOC-AMINOETHANOL C M + H+ 365 benzyloxymethyl)-pyrrolidine-1-carb-
oxylic acid 2- amino-ethyl ester; compound with trifluoro-acetic
acid 30 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 4-(HYDROXYMETHYL) B
M + H+ 413 benzyloxymethyl)-pyrrolidine-1-car- boxylic acid
PYRIDINE pyridin-4-ylmethyl ester; compound with trifluoro- acetic
acid 31 (2S,4R)-4-Mercapto-2-(2,4,5-trif- luoro- 2-METHYLPHENOL B M
+ H+ 412 benzyloxymethyl)-pyrrolidine-1-- carboxylic acid o- tolyl
ester 32 (2S,4R).4-Mercapto-2-(2,4- ,5-trifluoro- 2-METHOXYPHENOL B
M + H+ 428 benzyloxymethyl)-pyrrol- idine-1-carboxylic acid 2-
methoxy-phenyl ester 33 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-
METHYL SALICYLATE C, de- M + H+ 456
benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2- scribed
methoxycarbonyl-phenyl ester 34 (2S,4R)-4-Mercapto-2-(2,4,5-t-
rifluoro- 2-DIMETHYLAMINOETHANOL B M + H+ 393
benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-
dimethylamino-ethyl ester; compound with trifluoro-acetic acid 35
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 2-HYDROXYBENZONITRILE B M +
H+ 423 benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-
cyano-phenyl ester 36 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-
3-FLUOROPHENOL B M + H+ 416 benzyloxymethyl)-pyrrolidine-1-carbox-
ylic acid 3- fluoro-phenyl ester 37 (2S,4R)-4-Mercapto-2-(2-
,4,5-trifluoro- 2-BROMOPHENOL B M + H+ 477 benzyloxymethyl)-pyrrol-
idine-1-carboxylic acid 2- bromo-phenyl ester 38
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 1-NAPHTHALENEMETHANOL B M +
H+ 462 benzyloxymethyl)-pyrrolidine-1-carboxylic acid
naphthalen-1-ylmethyl ester 39 (2S,4R)-4-Mercapto-2-(2,4,5-trifluo-
ro- 2-NAPHTHALENEETHANOL B M + H+ 476 benzyloxymethyl)-pyrrolidine-
-1-carboxylic acid 2- naphthalen-2-yl-ethyl ester 40
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 1-NAPHTHALENEETHANOL B M+ H+
476 benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-
naphthalen-1-yl-ethyl ester 41 (2S,4R)-4-Mercapto-2-(2,4,5-trifluo-
ro- 3-PHENOXYPHENOL B M + H+ 490 benzyloxymethyl)-pyrrolidine-1-ca-
rboxylic acid 3- phenoxy-phenyl ester 42
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 3-PHENYLPHENOL B M + H+ 474
benzyloxymethyl)-pyrrolidine-1-carboxylic acid biphenyl-3-yl ester
43 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 4-CYCLOHEXYLPHENOL B M +
H+ 480 benzyloxymethyl)-pyrrolidine-1-carboxylic acid 4-
cyclohexyl-phenyl ester 44 (2S,4R)-4-Mercapto-2-(2,4,5-triflu- oro-
2-PHENYLPHENOL B M + H+ 474 benzyloxymethyl)-pyrrolidine
1-carboxylic acid biphenyl-2-yl ester 45
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 5,6,7,8-TETRAHYDRO-1- B M +
H+ 452 benzyloxymethyl)-pyrrolidine-1-carboxylic acid NAPHTHOL
5,6,7,8-tetrahydro-naphthalen-1-yl ester 46
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 2-NAPHTHALENEMETHANOL B M +
H+ 462 benzyloxymethyl)-pyrrolidine-1-carboxylic acid
naphthalen-2-ylmethyl ester 47 (2S,4R)-4-Mercapto-2-(2,4,5-trifluo-
ro- 4-PHENYLPHENOL B M + H+ 474 benzyloxymethyl)-pyrrolidine-1-car-
boxylic acid biphenyl-4-yl ester 48 (2S,4R)-4-Mercapto-2-(2-
,4,5-trifluoro- 2CHLOROPHENOL B M + H+ 432 benzyloxymethyl)-pyrrol-
idine-1-carboxylic acid 2- chloro-phenyl ester 49
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 5-HYDROXYISOQUINOLINE B M +
H+ 563 benzyloxymethyl)-pyrrolidine-1-carboxylic acid
isoquinolin-5-yl ester; compound with trifluoro- acetic acid 50
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 4-HYDROXYQUINOLINE B M + H+
563 benzyloxymethyl)-pyrrolidine-1-carboxylic acid quinolin-4-yl
ester trifluoroacetate (1:1) 51
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 8-HYDROXYQUINOLINE B M + H+
563 benzyloxymethyl)-pyrrolidine-1-carboxylic acid quinolin-8-yl
ester trifluoroacetate (1:1) 52 (2S,4R)-4-Mercapto-2-(2,4,5-triflu-
oro- 5-HYDROXYQUINOLINE B M + H+ 563 benzyloxymethyl)-pyrrolidine--
1-carboxylic acid quinolin-5-yl ester trifluoroacetate (1:1) 53
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- ISOCARBOSTYRIL B M + H+ 563
benzyloxymethyl)-pyrrolidine-1-carboxylic acid isoquinolin-1-yl
ester trifluoroacetate (1:1) 54
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- Lit [2] B M + H+ 442
benzyloxymethyl)-pyrrolidine-1-carboxylic acid
benzo[1,3]dioxol-4-yl ester 55 (2S,4R)-4-Mercapto-2-(2,4,5-trifluo-
ro- 1-NAPHTOL B M + H+ 448 benzyloxymethyl)-pyrrolidine-1-carboxyl-
ic acid naphthalen-1-yl ester 56 (2S,4R)-4-Mercapto-2-(2,4,-
5-trifluoro- 3-HYDROXYPYRIDINE B M + H+ 513
benzyloxymethyl)-pyrrolidine-1-carboxylic acid pyridin-3-yl ester
trifluoroacetate (1:1) 57 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-
2-HYDROXYPYRIDINE B M + H+ 513 benzyloxymethyl)-pyrrolidine-1-car-
boxylic acid pyridin-2-yl ester trifluoroacetate (1:1) 58
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 6-HYDROXYQUINOLINE B M + H+
563 benzyloxymethyl)-pyrrolidine-1-carboxylic acid quinolin-6-yl
ester trifluoroacetate (1:1) 59 (2S,4R)-4-Mercapto-2-(2,4,5-triflu-
oro- 5-(2-HYDROXYETHYL)-4- B M + H+ 561 benzyloxymethyl)-pyrrolidi-
ne-1-carboxylic acid 2- METHYLTHIAZOLE (4-methyl-thiazol-5-yl)-eth-
yl ester trifluoroacetate (1:1) 60 (2S,4R)-4-Mercapto-2-(2,-
4,5-trifluoro- 4-PYRIDINEPROPANOL B M + H+ 555
benzyloxymethyl)-pyrrolidine-1-carboxylic acid 3-
pyridin-4-yl-propyl ester trifluoroacetate (1:1) 61
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- PYRIDINE-2-METHANOL B M + H+
527 benzyloxymethyl)-pyrrolidine 1-carboxylic acid
pyridin-2-ylmethyl ester 62 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-
2-CHLOROOPHENOL B M + H+ 432 benzyloxymethyl)-pyrrolidine-1-carbo-
xylic acid 3- chloro-phenyl ester 63
(2S,4R,3R)-4-Mercapto-2-(2,4,5-trifluoro- Lit [3] B M + H+ 526
benzyloxymethyl)-pyrrolidine-1-carboxylic acid
(R)-1-benzyloxycarbonyl-3-methyl-butyl ester 64
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 5,7-DICHLORO-8- B M + H+ 632
benzyloxymethyl)-pyrrolidine-1-carboxylic acid 5,7-
HYDROXYQUINOLINE dichloro-quinolin-8-yl ester; compound with
trifluoro-acetic acid 65 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-
CYCLOHEXYL A M + H+ 404 benzyloxymethyl)-pyrrolidine-1-carboxylic
acid CHLOROFORMATE cyclohexyl ester 66
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- 3-Methoxy-phenol B M + H+
428 benzyloxymethyl)-pyrrolidine-1-carb- oxylic acid 3-
methoxy-phenyl ester 67 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-
3,4-Dimethoxy-phenol C M + H+ 458
benzyloxymethyl)-pyrrolidine-1-carboxylic acid 3,4-
dimethoxy-phenyl ester 68 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- C
M-H- 440 benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-
carboxy-phenyl ester
[0462] [1] 5-(1,4-benzodioxan)-chloroformate: Eitel, Alfred;
Hammann, Ingeborg. Benzodioxan-N-methylcarbamates useful as
insecticides or acaricides. S. African, 14 pp. CODEN: SFXXAB. ZA
6800512 680627. CAN 70:57861 CAPLUS
[0463] [2] Benzo[1,3]dioxol-4-ol: Dallacker, Franz; Holschbach,
Markus; Holschbach, Ute; Konings, A. W. T. 1,3-Benzo-dioxole
derivatives as radioprotectants. 5. Preparation of 4- and
5-hydroxy-1,3-benzodioxole derivatives. Chem.-Ztg. (1990),
114(7-8), 225-8.
[0464] [3] (2R)-2-Hydroxy-4-methyl-pentanoic acid benzyl ester:
Brown, Frank K.; Brown, Peter J.; Bickett, D. Mark; Chambers, C.
Lynn; Davies, H. Geoff; Deaton, David N.; Drewry, David; Foley,
Michael; McElroy, Andrew B.; et al. Matrix Metalloproteinase
Inhibit
[0465] [4] 2-Hydroxy-benzoic acid tert-butyl ester: Widmer, Ulrich.
A convenient preparation of tert-butyl esters. Synthesis (1983),
Issue 2, 135-6.
Example 14.b
Ether, Carbamate Via Thioacetate
[0466] A solution of 0.873 mg (2 mmol)
(2S,4S)-4-chloro-2-(2,4,5-trifluoro-
-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester
was dissolved in 20 ml DMF and after the addition of 0.343 mg (3
mmol) potassium thioacetate heated for 2.5 h at 100.degree. C.
Evaporation and flash-chromatography on silica gel
(toluene/CH.sub.3CN 95:5) gave 0.745 g (89%) of
(2R,4S)-4-acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyr-
rolidine-1-carboxylic acid tert-butyl ester, MS: 420
(MH.sup.+).
Example 14.c
Deprotection of Thioacetate
[0467] A solution of 0.126 g (0.3 mmol)
(2R,4S)-4-acetylsulfanyl-2-(2,4,5--
trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl
ester in 12 ml EtOH (degased with Ar) was treated at 0.degree. C.
with 0.9 ml 1N LiOH, warmed up to room temperature and stirred for
4.5 h. The reaction was recooled to 0.degree. C. and quenched with
aqueous 10% KHSO.sub.4. The reaction was extracted with aqueous 10%
KHSO.sub.4/EtOAc (3.times.) and the organic phase was washed with
aqueous 10% NaCl, dried over Na.sub.2SO.sub.4 and evaporated to
give 0.11 g (97%)
(2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carb-
oxylic acid tert-butyl ester, MS: 378 (MH.sup.+).
Example 14.d
Ether, Sulfonamides (see Table 5 and Table 6)
[0468] General procedure for the synthesis of sulfonamides: A
solution of 0.32 mmol
(2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine or
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine,
65 .mu.l (0.38 mmol) diisopropylethylamine and a catalytic amount
of DMAP in 2 ml dichloroethane was added to 1.2 eq
sulfonylchloride. After a night, the reaction was evaporated,
redissolved in DMF and purified by preparative HPLC.
[0469] Trityl deprotection following Method 4 gave the free
thiol.
[0470] In analogy:
(2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine and
2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-sulfonyl chloride
[Ferrini et al. Eur. Pat. Appl. No. 800220] gave
(2S,4R)-6-(2-benzyloxyme-
thyl-4-tritylsulfanyl-pyrrolidine-1-sulfonyl)-1H-benzo[d][1,3]oxazine-2,4--
dione, MS: 689(M-H.sup.-), which was deprotected (following Method
3) to give
(2S,4R)-6-(2-benzyloxymethyl-4-mercapto-pyrrolidine-1-sulfonyl)-1H-b-
enzo[d][1,3]oxazine-2,4-dione, MS: 447 (M-H.sup.-).
[0471] A solution of 0.72 g (1.05 mmol)
(2S,4R)-6-(2-benzyloxymethyl-4-tri-
tylsulfanyl-pyrrolidine-1-sulfonyl)-1H-benzo[d][1,3]oxazine-2,4-dione
in 40 ml CH.sub.2Cl.sub.2 was treated at room temperature with 0.42
ml (10.5 mmol) MeOH and 0.31 ml (2.09 mmol) DBU and stirred for 6
h. Flash chromatography on silica gel (Hexane/EtOAc 9:1) gave
(2S,4R)-2-amino-5-[2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-sulfo-
nyl]-benzoic acid methyl ester which was deprotected (following
Method 3) to give
(2S,4R)-2-amino-5-[2-benzyloxymethyl-4-mercapto-pyrrolidine-1-sul-
fonyl]-benzoic acid methyl ester, MS: 437 (M+H.sup.+).
[0472] A solution of 0.70 g (1.05 mmol)
(2S,4R)-6-(2-benzyloxymethyl-4-tri-
tylsulfanyl-pyrrolidine-1-sulfonyl)-1H-benzo[d][1,3]oxazine-2,4-dione
in 30 ml dioxane was treated at 8.degree. C. with 2.1 ml (2.09
mmol) aqueous LiOH and stirred for 16 h at room temperature. The
reaction was evaporated, extracted with aqueous 10%
KHSO.sub.4/EtOAc (3.times.) and the organic phase was dried over
Na.sub.2SO.sub.4 to give after evaporation and trityl deprotection
(following Method 3) 96 mg mg (21%) of
(2S,4R)-2-Amino-5-[2-benzyloxymethyl-4-mercapto-pyrrolidine-1-sulfonyl-
]-benzoic acid, MS: 423 (M+H.sup.+).
[0473] In analogy to the general procedure:
(2S,4R)-2-Benzyloxymethyl-4-tr- itylsulfanyl-pyrrolidine and
alpha-bromophenylacetic acid gave a 1:1 mixture of (R)- and
(S)-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrro- lidin-2-yl
which was esterified with MeOH (see general method for
EDCI-coupling taking DMAP instead of HOBT) to give after flash
chromatography on silica gel (hexane/EtOAc) (R)- or
(S)-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy]-p-
henyl-acetic acid methyl ester, MS: 602 (MH.sup.+) and (S)- or
(R)-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy]-p-
henyl-acetic acid methyl ester, MS: 602 (MH.sup.+).
[0474] Trityl deprotection (following Method 3) gave: (R)- or
(S)-[(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-phenyl--
acetic acid methyl ester, MS: 359 (M) and (S)- or
(R)-[(2S,4R)-4-mercapto--
1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-phenyl-acetic acid methyl
ester, MS: 359 (M).
[0475] By the reaction of
(2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrro- lidine with the
second educt mentioned in table 5 the following compounds were
obtained:
5 TABLE 5 Name 2. Educt MS 1
(2S,4R)-N-[4-(2-Benzyloxymethyl-4-mercapto-
4-ACETAMIDOBENZENESULFONY- L M + H + 421
pyrrolidine-1-sulfonyl)-phenyl]-acetamide CHLORIDE 2
(3R,5S)-5-Benzyloxymethyl-1-(3-nitro- 3-NITROBENZENESULFONYL M + Na
+ 431 benzenesulfonyl)-pyrrolidine-3-thiol CHLORIDE 3
(3R,5S)-5-Benzyloxymethyl-1-(2-nitro- 2-NITROBENZENESULFONYL M + H
+ 409 benzenesulfonyl)-pyrrolidine-3-thiol CHLORIDE 4
(3R,5S)-5-Benzyloxymethyl-1-(4- 4-METHYLSULPHONYL- M + Na + 464
methanesulfonyl-benzenesulfonyl)-pyrrolidine-3- BENZENESULPHONYL
CHLORIDE thiol 5 (3R,5S)-5-Benzyloxymethyl-1-(biphenyl-4-
4-BIPHENYLSULFONYL CHLORIDE M + H + 440 sulfonyl)-pyrrolidine-3-t-
hiol 6 (3R,5S)-5-Benzyloxymethyl-1-(2-naphthalen-1-
2-(1-NAPHTHYL)ETHANESULFONYL 442 M + H + yl-ethanesulfonyl)-pyrro-
lidine-3-thiol CHLORIDE 7
(3R,5S)-5-Benzyloxymethyl-1-(3,5-dimethyl- -
3,5-DIMETHYLISOXAZOLE-4- 383 M + H+ isoxazole-4-sulfonyl)-pyrrol-
idine-3-thiol SULFONYL CHLORIDE 8
(3R,5S)-5-Benzyloxymethyl-1-(thio- phene-2- THIOPHENE-2-SULFONYL
CHLORIDE 370 M + H+ sulfonyl)-pyrrolidine-3-thiol 9
(3R,5S)-1-Benzenesulfonyl-5-benzyl- oxymethyl- BENZENESULFONYL
CHLORIDE 364 M + H + pyrrolidine-3-thiol 10
(3R,5S)-5-Benzyloxymethyl-1-(3-chloro- 2-CHLOROBENZENESULFONYL 398
M + H + benzenesulfonyl)-pyrrolidine-- 3-thiol CHLORIDE 11
(3R,5S)-5-Benzyloxymethyl-1-(2-phenyl- TRANS-BETA-STYRENESULFONYL
390 M + H + ethenesulfonyl)-pyrrolidin- e-3-thiol CHLORIDE 12
(3R,5S)-5-Benzylozymethyl-1-(propane-2- ISOPROPYLSULFONYL CHLORIDE
352 M + Na + sulfonyl)-pyrrolidine-3-t- hiol 13
(3R,5S)-5-Benzyloxymethyl-1-(4-fluoro- 4-FLUOROBENZENESULFONYL 382
M + H + benzenesulfonyl)-pyrrolidine-- 3-thiol CHLORIDE 14
(3R,5S)-5-Benzyloxymethyl-1-(quinoline-8- 8-QUINOLINESULFONYL
CHLORIDE 415 M + H + sulfonyl)-pyrrolidine-3-- thiol 15 Mixture of
(3R,5S)-1-methanesulfonyl-5-[(R)- (1-BROMOETHYL)BENZENE 338 M + Na
+ and -[(S)-1-phenyl-ethoxymethy- l)-pyrrolidi 16
(2S,4R)-6-(2-Benzyloxymethyl-4-mercapto- Lit [1] described 447 M -
H - pyrrolidine-1-sulfonyl)-1H-benzo[d][1,3]oxa- zine-
2,4-dione
[0476] [1] 2,4-Dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-sulfonyl
chloride: Ferrini, Pier Giorgio; Rossi, Alberto; Haas, Georges.
Substituted anthranilic acid amides. Eur. Pat. Appl., 40 pp. CODEN:
EPXXDW. EP 8072 800220. CAN 93:71808 CAPLUS.
[0477] By the reaction of
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tr-
itylsulfanyl-pyrrolidine 66-7030 with the second educt mentioned in
table 6 the following comounds were obtained:
6 TABLE 6 Name 2. Educt MS 1
(3R,5S)-1-(Thiophene-2-sulfonyl)-5-(2,4,5- THIOPHENE-2-SULFONYL
CHLORIDE M + H + 424 trifluoro-benzyloxymethyl)-pyrrolidine-3-thi-
o 2 (3R,5S)-1-(2-Naphthalen-1-yl-ethanesulfonyl)-5-
2-(1-NAPHTHYL)ETHANESULFONYL M + H + 496 (2,4,5-trifluoro-benzylo-
xymethyl)-pyrrolidine-3- CHLORIDE thiol 3
(3R,5S)-1-(2-Phenyl-ethenesulfonyl)-5-(2,4,5-
TRANS-BETA-STYRENESULFONYL M + H + 444
trifluoro-benzyloxymethyl)-pyrrolidine-3-t CHLORIDE 4
(3R,5S)-1-(Naphthalene-1-sulfonyl)-5-(2,4,5- 1-NAPHTHALENESULFONYL
M + H + 468 trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol CHLORIDE
5 (3R,5S)-1-(2-Phenyl-ethanesulfonyl)-5-(2,4,5- Lit [1] M + H + 446
trifluoro-benzyloxymethyl)-pyrrolidine-3-t 6
(3R,5S)-1-(3-Phenyl-propane-1-sulfonyl)-5-
3-PHENYL-PROPANE-1-SULFONYL M + H + 460
(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine CHLORIDE 7
(3R,5S)-1-Ethanesulfonyl-5-(2,4,5-triflouro- ETHANESULFONYL
CHLORIDE M + H + 370 benzyloxymethyl)-pyrrolidine-3-thiol 8
(3R,5S)-1-(Propane-1-sulfonyl)-5-(2,4,5- 1-PROPANESULFONYL CHLORIDE
M + H + 384 trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol 9
(3R,5S)-1-(Butane-1-sulfonyl)-5-(2,4,5-trifluoro- 1-BUTANESULFONYL
CHLORIDE M + H + 398 benzyloxymethyl)-pyrrolidine-3-thiol 10
(3R,5S)-1-(Quinoline-8-sulfonyl)-5-(2,4,5- 8-QUINOLINESULFONYL
CHLORIDE M + H + 469 trifluoro-benzyloxymethyl)-pyrrolidine-3-thi-
o 11 (2S,4R)-N-{4-[-Mercapto-2-(2,4,5-trifluoro-
4-ACETAMIDOBENZENESULFONYL M + H + 475 benzyloxymethyl)-pyrrolidi-
ne-1-sulfonyl]-phenyl}- CHLORIDE acetamide 12
(2S,4R)-2-Ethoxy-5-[4-mercapto-2-(2,4,5- Lit [2] M + H + 506
trifluoro-benzyloxymethyl)-pyrrolidine-1- sulfonyl]-benzoic
acid
[0478] [1] 2-Phenyl-ethanesulfonyl chloride: Zhong, Ziyang; Bibbs,
Jeffrey A.; Yuan, Wei; Wong, Chi Huey. Active-site-directed
modification of subtilisin. J. Am. Chem. Soc. (1991), 113(6),
2259-63. CODEN: JACSAT; ISSN: 0002-7863. CAN 114:123036 CAPLUS.
[0479] [2] 5-Chlorosulfonyl-2-ethoxy-benzoic acid: Dunn, Peter
James; Wood, Albert Shaw. Process for preparation of Sildenafil by
cyclization. Eur. Pat. Appl., 18 pp. CODEN: EPXXDW. EP 812845 Al
971217. CAN 128:75412 CAPLUS.
Example 14.e
Ether: Ureas (Table 7 and Table 8)
[0480] A solution of 50 mg (0.11 mmol) amine in 0.5 ml EtOH was
treated with 0.21 mmol of the appropriate isocyanate, the reaction
was kept 30 min at room temperature and purified by preparative
HPLC (RP18, CH.sub.3CN/H.sub.2O 80:20 to 95:5). Trityl deprotection
following Method 4 gave the free thiol.
[0481] A solution of 0.02 ml (0.18 mmol)
trichloromethylchloroformate in 3 ml CH.sub.2Cl.sub.2 was treated
at 0.degree. C. with 0.04 ml (0.37 mmol) quinoline and after 15 min
with 0.17 g (0.33 mmol)
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine
in 2 ml CH.sub.2Cl.sub.2. After 2 h, the reaction was evaporated
and redissolved in 15 ml CH.sub.2Cl.sub.2 and treated at 0.degree.
C. with 0.14 ml (1.65 mmol) pyrrolidine and stirred for 30 min. The
reaction was extracted with aqueous 10% KHSO.sub.4/Et.sub.2O
(3.times.) and the organic phase was dried over Na.sub.2SO.sub.4.
Evaporation and precipitation from Et.sub.2O/pentane gave 121 mg
(59 %)
(2S,4R)-Pyrrolidin-1-yl-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulf-
anyl-pyrrolidin-1-yl]-methanone, MS: 617 (M+H.sup.+).
[0482] Trityl deprotection (following Method 3) gave
(2S,4R)-[4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidin-1-yl]--
pyrrolidin-1-yl-methanone, MS: 374 (M).
[0483] By the reaction of
(2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrro- lidine with the
second educt of table 7 the following compound have been
obtained:
7 TABLE 7 Name 2. Educt MS 1
(2S,4R)-[(2-Benzyloxymethyl-4-mercapto- ETHYL ISOCYANATOACETATE M +
H + 353 pyrrolidine-1-carbonyl)-amino]-acetic acid ethyl ester 2
(2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrrolidine- 'PHENYL
ISOCYANATE M + H + 343 1-carboxylic acid phenylamide 3
(2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrrolidine- 2-FLUOROPHENYL
ISOCYANATE M + H + 361 1-carboxylic acid (2-fluoro-phenyl)-amide 4
(2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrrolidine-
2,4-DIFLUOROPHENYL M + H + 379 1-carboxylic acid
(2,4-difluoro-phenyl)-amide ISOCYANATE 5 (2S,4R)-(2-Benzyloxymethy-
l-4-mercapto- 'ETHOXYCARBONYL ISOCYANAT M + Na + 361
pyrrolidine-1-carbonyl)-carbamic acid ethyl ester 6
(2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrrolidine- 3-CYANOROPHENYL
ISOCYANATE M + H + 368 1-carboxylic acid (3-cyano-phenyl)-amide 7
(2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrrolidine- '4-ACETYLPHENYL
ISOCYANATE M + H + 385 1-carboxylic acid (4-acetyl-phenyl)-amide 8
1:1 Mixture of (R)- and (S)-2-[[(2S,4R)-2- ETHYL 2-ISOCYANATO-3- M
+ Na + 465 benzyloxymethyl-4-mercapto-pyrrolidine-1-
PHENYLPROPIONATE carbonyl)-amino]-3-phenyl-propionic acid ethyl
ester 9 (2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrrolidine- 'BENZYL
ISOCYANATE M + H + 357 1-carboxylic acid benzylamide 10
(2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrrolidine- 3-TRIFLUOROPHENYL
M + H + 411 1-carboxylic acid (3-trifluoromethyl-phenyl)-amide
ISOCYANATE 11 (2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrrolidine-
'PHENETHYL ISOCYANATE M + H + 371 1-carboxylic acid phenethyl-amide
12 (2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrrolidin- e- '2-NAPHTHYL
ISOCYANATE M + H + 393 1-carboxylic acid naphthalen-2-ylamide 13
(2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrro- lidine- 1-NAPHTHYL
ISOCYANATE M + H + 393 1-carboxylic acid naphthalen-1-ylamide
[0484] By the reaction of
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tr-
itylsulfanyl-pyrrolidine with the second educt mentioned in table 8
the following compound were obtained:
8 TABLE 8 Name 2. Educt MS 1
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-
2-FLUOROPHENYL M + H + 415 pyrrolidine-1-carboxylic acid
(2-fluoro-phenyl)-amide ISOCYANATE 2 (2S,4R)-4-Mercapto-2-(2,4,5-t-
rifluoro-benzyloxymethyl)- '2-NAPHTHYL ISOCYANATE M + H + 447
pyrrolidine-1-carboxylic acid naphthalen-2-ylamide 3
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)- 1-NAPHTHYL
ISOCYANATE M + H + 447 pyrrolidine-1-carboxylic acid
naphthalen-1-ylamide 4 (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzy-
loxymethyl)- 'PHENETHYL ISOCYANATE M + H + 425
pyrrolidine-1-carboxylic acid phenethyl-amide 5
(2S,4R)-[4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-
'ETHOXYCARBONYL M + H + 393 pyrrolidine-1-carbonyl]-carbamic acid
ethyl ester ISOCYANAT 7
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)- - 'PHENYL
ISOCYANATE M + H + 397 pyrrolidine-1-carboxylic acid phenylamide 8
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethy- l)- N-BUTYL
ISOCYANATE M + H + 377 pyrrolidine-1-carboxylic acid butylamide 6
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl- )- 'BENZYL
ISOCYANATE M + H + 411 pyrrolidine-1-carboxylic acid
benzylamide
Example 14.f
Alkylation of Ureas
[0485] A solution of the urea in DMF (20 ml/mmol) was placed in an
ice bath. KOtBu (1.2 eq.) was added and stirred for 15 min. MeI
(1.1 eq.) was added and stirred overnight at room temperature. If
required, a further 1 eq. of KOtBu and MeI was added and stirred
overnight at room temperature. Water was added and the mixture was
extracted with dichloromethane. The organic phase was dried
(Na.sub.2SO.sub.4), filtered and evaporated. The product was
purified by chromatography (SiO.sub.2, EtOAc/hexane
9:1=>hexane/EtOAc 1:1).
[0486] Benzyl-methyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-trityl-
sulfanyl-pyrrolidine-1-carboxylic acid benzyl-methyl-amide; yield:
53%;
[0487] Butyl-methyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-trityls-
ulfanyl-pyrrolidine-1-carboxylic acid butyl-methyl-amide; yield:
52%.
[0488] Trityl deprotection (Method 3):
[0489] Butyl-methyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl-
)-pyrrolidine-1-carboxylic acid butyl-methyl-amide; colorless oil;
yield: 76%, MS: 391 (MH.sup.+);
[0490] Benzyl-methyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethy-
l)-pyrrolidine-1-carboxylic acid benzyl-methyl-amide; colorless
oil; yield: 87%, MS: 425 (MH.sup.+).
[0491] A solution of 400 mg (0.86 mmol)
(2S,4R)-2-benzyloxymethyl-4-trityl- sulfanyl-pyrrolidine in 15 ml
CH.sub.2Cl.sub.2 with 0.3 ml (2.2 mmol) trimethylsilylisocyanate
and a catalytic amount of DMAP was stirred over night. The reaction
was extracted with aqueous 10% KHSO.sub.4/EtOAc (3.times.) and the
organic phase was dried over Na.sub.2SO.sub.4. Crystallization
(CH.sub.2Cl.sub.2/MeOH/Et.sub.2O) gave 205 mg (47%)
(2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic
acid amide, MS: 509 (MH.sup.+).
[0492] Trityl deprotection (Method 3)
(2S,4R)-2-benzyloxymethyl-4-mercapto- -pyrrolidine-1-carboxylic
acid amide, MS: 267 (MH.sup.+).
Example 14.g
Ether, Amides (Table 9 and Table 10)
[0493] General procedure Method A: 2 equivalents of an acid (0.996
mmol) in 1.7 ml THF at -10.degree. C. were treated with 75 .mu.l
(0.48 mmol) diisopropyl carbodiimide and a catalytic amount of DMAP
and warmed up to room temperature over night. 150 mg (0.32 mmol)
(2S,4R)-2-benzyloxymethyl- -4-tritylsulfanyl-pyrrolidine were then
added and after 5 h filtered and purified by prep HPLC (RP18,
CH.sub.3CN/H.sub.2O 80:20 to 95:5).
[0494] General procedure Method B: A solution of 0.25 mmol
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine
and 0.375 mmol acid in 1 ml dioxane was treated with 0.375 mmol
EDCI in 1 ml CH.sub.2Cl.sub.2 and a catalytic amount of DMAP and
stirred at room temperature over night. After evaporation and
purification by prep HPLC (RP18, CH.sub.3CN/H.sub.2O 80:20 to 95:5)
the amide was received.
[0495] Trityl deprotection following Method 4 gave the free
thiol.
[0496] By the reaction of
(2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrro- lidine with the
second educt metioned in table 9 the compounds mentioned in table 9
were obtained.
[0497] By the reaction of
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tr-
itylsulfanylpyrrolidine with the second educt metioned in table 10
the compounds mentioned in table 10 were obtained.
9 TABLE 9 Name 2. Educt MS 1
(2S,4R)-1-(2-Benzyloxymethyl-4-mercapto- ISOBUTYRIC ACID M + H +
294 pyrrolidin-1-yl)-2-methyl-propan-1-one 2
(2S,4R)-1-(2-Benzyloxymethyl-4-mercapto- ACETIC ACID M + H + 266
pyrrolidin-1-yl)-ethanone 3 ((2S,4R)-2-Benzyloxymethyl-4-mercapto--
pyrrolidin- BENZOIC ACID M + H + 328 1-yl)-phenyl-methanone 4
((2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrrolidin- P-ANISIC ACID M +
H + 358 1-yl)-(4-methoxy-phenyl)-methanone 5
((2S,4R)-2-Benzyloxymethyl-4-mercapto-pyrrolidin- 3-BROMOBENZOIC
ACID M + H +, 1Br 406 1-yl)-(3-bromo-phenyl)-methanone 6
(2S,4R)-(2-Benzyloxymethyl-4-mercapto-pyrrolidin-
2,4-DIFLUOROBENZOIC ACID M + H + 364
1-yl)-(2,4-difluoro-phenyl)-methanone 7
(2S,4R)-(2-Benzyloxymethyl-4-mercapto-pyrrolidin-
4-BIPHENYLCARBOXYLIC ACID M + H + 404 1-yl)-biphenyl-4-yl-methanone
8 (2S,4R)-(2-Benzyloxymethyl-4-mercapto-pyrrolidin- 4-BROMOBENZOIC
ACID M + H +, 1Br 406 1-yl)-(4-bromo-phenyl)-methanone 9
(2S,4R)-(2-Benzyloxymethyl-4-mercapto-pyrrolidin-
2,4-DIMETHOXYBENZOIC ACID M + H + 388
1-yl)-(2,4-dimethoxy-phenyl)-methanone 10
(2S,4R)-1-(2-Benzyloxymethyl-4-mercapto- 4-BIPHENYLACETIC ACID M +
H + 418 pyrrolidin-1-yl)-2-biphenyl-4-yl-ethanone
[0498]
10 TABLE 10 Name 2. Educt Method MS 1.
(2S,4R)-[4-Mercapto-2-(2,4,5-trifluoro- BENZOIC ACID B M + H + 382
benzyloxymethyl)-pyrrolidin-1-yl]-phenyl- methanone 2.
(2S,4R)-1-[4-Mercapto-2-(2,4,5-trifluoro- PHENYLACETIC ACID B M + H
+ 396 benzyloxymethyl)-pyrrolidin-1-yl]- -2-phenyl- ethanone 3
(2S,4R)-Biphenyl-4-yl-[4-mercapto-2-(- 2,4,5- 4-BIPHENYL-CARBOXYLIC
ACID B M + H + 458 trifluoro-benzyloxymethyl)-pyrrolidin-1-yl]-
methanone 4. (2S,4R)-2-Biphenyl-4-yl-1-[4-mercapto-2-(2,4,5-
4-BIPHENYLACETIC ACID B M + H + 472
trifluoro-benzyloxymethyl)-pyrrolidin-1- 5.
(2S,4R)-2-(1H-Indol-3-yl)-1-[4-mercapto-2-(2,4,5- INDOLE-3-ACETIC
ACID B M + H + 435
trifluoro-benzyloxymethyl)-pyrrolidin-1-yl]-ethanone 6.
(2S,4R)-(1H-Indol-2-yl)-[4-mercapto-2-(2,4,5- INDOLE-2-CARBOXYLIC
ACID B M + H + 421 trifluoro-benzyloxymethyl)- -pyrrolidin-1-yl]-
methanone 7. (2S,4R)-(1H-Indol-3-yl)-[4-- mercapto-2-(2,4,5-
INDOLE-3-CARBOXYLIC ACID B M + H + 421
trifluoro-benzyloxymethyl)-pyrrolidin-1-yl]- methanone 8.
(2S,4R)-(1H-Indol-5-yl)-[4-mercapto-2-(2,4,5- INDOLE-5-CARBOXYLIC
ACID B M + H + 421 trifluoro-benzyloxymethyl)-pyrrolidin-1-yl]-
methanone 9. (2S,4R)-(1H-Indol-6-yl)-[4-mercapto-2-(2,4,5-
INDOLE-6-CARBOXYLIC ACID B M + H + 421 trifluoro-benzyloxymethyl)-
-pyrrolidin-1-yl]- methanone 10. (2S,4R)-(1H-Indol-7-yl)-[4-
-mercapto-2-(2,4,5- INDOLE-7-CARBOXYLIC ACID B M + H + 421
trifluoro-benzyloxymethyl)-pyrrolidin-1-yl]- methanone 11. Mixture
of (R)- and (S)-N-[1-(1H-Indol-3-ylmethyl)- N-ACETYL-DL-TRYPHOPHAN
B M + H + .sub.-- 506 2-[(2S,4R)-4-mercapto-2-(2,4,5-trifl 12.
(2S,4R)-3-(1H-Indol-3-yl)- -1-[4-mercapto-2-(2,4,5-
3-INDOLEPROPIONIC ACID B M + H + 449
trifluoro-benzyloxymethyl)-pyrrolidin-1-yl]-propan-1- one 13.
(2S,4R)-4-(1H-Indol-3-yl)-1-[4-mercapto-2-(2,4,5- 3-INDOLEBUTYRIC
ACID B M + H + 463 trifluoro-benzyloxymethyl)-pyrrolidin-1-yl]-bu-
than-1- one 14. (2S,4R)-3-Indol-1-yl-1-[4-mercapto-2-(2,4,5- -
BETA-N-INDOLEPROPIONIC B M + H + 449 trifluoro-benzyloxymethyl)--
pyrrolidin-1-yl]-propan-1- ACID one 15.
(1S)-N-[1-[(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-
N-ACETYL-L-LEUCINE B M + H + 433
benzyloxymethyl)-pyrrolidine-1-carbonyl]-3-methyl- butyl}-acetamide
16. (2S,4R)-1-[4-Mercapto-2-(2,4,5-trifluoro- 3-methyl-1-butanoic
acid B M + H + 362 benzyloxymethyl)-pyrrolidi-
n-1-yl]-3-methyl-butan-1- one 17. (2S,4R)-1-[4-Mercapto-2-(-
2,4,5-trifluoro- 4-methyl-1-pentanoic acid B M + H + 376
benzyloxymethyl)-pyrrolidin-1-yl]-4-methyl-pentan- 1-one 18.
(2S,4R)-1-[4-Mercapto-2-(2,4,5-trifluoro- 1-butanoic acid B M + H +
348 benzyloxymethyl)-pyrrolidin-1-yl]-butan-1-one 19.
(2S,4R)-1-[4-Mercapto-2-(2,4,5-trifluoro- 5-methyl-1-hexanoic acid
B M + H + 390 benzyloxymethyl)-pyrrolidin-1-yl]-5-methyl-hexan-1-
one 20. (2S,4R)-1-[4-Mercapto-2-(2,4,5-trifluoro- 1-hexanoic acid B
M + H + 376 benzyloxymethyl)-pyrrolidin-1-yl]-hexan-1-one 21.
(2-Hydroxy-phenyl)-[(2S,4R)-4-mercapto-2-(2,4,5- SALICYLIC ACID B M
+ H + 398 trifluoro-benzyloxymethyl)-pyrrolidin-1-yl]- methanone
22. 1-[(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro- ACETIC ACID B M + H +
320 benzyloxymethyl)-pyrrolidin-1-yl]-ethan- one
Example 14.h
Ether, Sulfamides
[0499] Sulfamides, Method A: SO.sub.2NH.sub.2: A solution of 567 mg
(1.09 mmol)
(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrol-
idine, 302 mg (1.09 mmol) sulfamic acid 2,4,6-trichloro-phenyl
ester [Hedayatullah, M. & Hugueny, J. Phosphorus, Sulfur
Silicon Relat. Elem. (1991), 61(1-2), 19-25.] and 0.15 ml
triethylamine in 2 ml CH.sub.2Cl.sub.2 was heated for 1 h at
reflux, evaporated and purified by flash column chromatography on
silica gel with hexane/EtOAc (9:1 to 1:1) to give 286 mg (44%)
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-trityl-
sulfanyl-pyrrolidine-1-sulfonic acid amide. [Hedayatullah, M. &
Hugueny, J. Phosphorus Sulfur (1985), 25(1), 33-8.] MS: 621
(M+Na.sup.+).
[0500] Trityl deprotection (Method 3)
(2S,4R)-4-mercapto-2-(2,4,5-trifluor-
o-benzyloxymethyl)-pyrrolidine-1-sulfonic acid amide, MS: 355
(M-H).sup.-.
[0501] In analogy:
(2S,4R)-2-Benzyloxymethyl-4-tritylsulfanyl-pyrrolidine, gave
(2S,4R)-2-benzyloxymethyl-4-mercapto-pyrrolidine-1-sulfonic acid
amide, MS: 303 (M+H).
[0502] Sulfamide, Method B: SO.sub.2NHR (via NSO.sub.2Cl) Following
a procedure described in U.S. Pat. No. 4,868,308: 2.12 ml (21.5
mmol) Alpha-picoline and 0.19 ml (2.8 mmol) chloro sulfonic acid
were added at -10.degree. C. to 30 ml 1,2-dimethoxyethane, warmed
up to 10.degree. C. and treated with 431 mg (0.93 mmol) of
(2S,4R)-2-benzyloxymethyl-4-trityl- sulfanyl-pyrrolidine. The
reaction was stirred at room temperature over night, treated with
0.32 ml (3.5 mmol) POCl.sub.3 and after 4 h at room temperature
with 5 ml 8.03 M MeNH.sub.2 in EtOH. The reaction was stirred over
night and extracted with aqueous 10% KHSO.sub.4/EtOAc (3.times.),
the organic phases were washed with 10% NaCl. The crude product was
crystallized from CH.sub.2Cl.sub.2/Et.sub.2O at -20.degree. C. to
give 147 mg (28%) of
(2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-- sulfonic
acid methylamide, mp 140-142.degree. C., MS: 581 (M+Na.sup.+).
[0503] Trityl deprotection (Method 3) gave
(2S,4R)-2-benzyloxymethyl-4-mer- capto-pyrrolidine-1-sulfonic acid
methylamide, MS: 315 (M-H).sup.-.
[0504] Sulfamide, Method C:
[0505] Preparation of sulfamoyl chlorides
[0506] Method C1:
[0507] The amine (3 eq.) was dissolved in CH.sub.2Cl.sub.2 (1
ml/mmol) and placed in an ice bath. A solution of chlorosulfonic
acid (1 eq.) in CH.sub.2Cl.sub.2 (0.5 ml/mmol) was added slowly (30
min). The reaction mixture was stirred at 0.degree. C. for a
further 30 min. Afterward, the ice bath was removed and the
stirring was continued for 1 h at room temperature. The precipitate
was collected by filtration and dried under high vacuum. This salt
was suspended in toluene (1 ml/mmol amine) and PCl.sub.5 (1 eq) was
added. The mixture was stirred at 75.degree. C. for 2 h, cooled to
room temperature and filtered. The solid residue was washed with
toluene. The filtrate was evaporated and dried under high vacuum.
The crude sulfamoyl chloride was used in the next step without
further purification.
[0508] Benzylsulfamoyl chloride (75%)
[0509] Phenylsulfamoyl chloride (72%)
[0510] Butylsulfamoyl chloride (45%)
[0511] Phenethylsulfamoyl chloride (52%)
[0512] 2-Phenoxyethylsulfamoyl chloride (20%)
[0513] Cyclohexylmethylsulfamoyl chloride (74%)
[0514] Cyclopropylmethylsulfamoyl chloride (100%)
[0515] Cyclopropylsulfamoyl chloride (82%)
[0516] 2,2,2-Trifluoroethylsulfamoyl chloride (74%)
[0517] 4-Fluoro-benzylsulfamoyl chloride (39%)
[0518] Method C2:
[0519] The amine hydrochloride (1 eq.) was dissolved in CH.sub.3CN
and placed in an ice bath. Sulfuryl chloride (3 eq.) was added
slowly (20 min). The reaction mixture was stirred at room
temperature for 15 min and at 65.degree. C. for 20 h. The solvent
was evaporated and the residue was dried under high vacuum. The
crude sulfamoyl chloride was used in the next step without further
purification.
[0520] 3-Chlorosulfonylamino-propionic acid ethyl ester
[0521] 4-(Chlorosulfonylamino-methyl)-benzoic acid methyl ester
[0522] Preparation of sulfamides:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxym
ethyl)-4-tritylsulfanyl-pyrrolidine (1 eq) was dissolved in
CH.sub.2Cl.sub.2 (2 ml/mmol) and placed in an ice bath.
Diisopropylethyl amine (1.4 eq) was added and stirred for 5 min. A
solution of the crude sulfamoyl chloride (1.4 eq) in
CH.sub.2Cl.sub.2 (1 ml/mmol) was added. The ice bath was removed
and the stirring was continued at RT overnight. A aqueous saturated
solution of KHSO.sub.4 was added and extracted with EtOAc. The
organic phase was washed with water, dried over Na.sub.2SO.sub.4
and evaporated. The product was purified by chromatography
(SiO.sub.2, hexane=>hexane/EtOAc 70:30)
[0523] Benzyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfany-
l-pyrrolidine-1-sulfonic acid benzylamide; yield: 75%, MS: 687
(M-H).sup.-;
[0524] Phenyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfany-
l-pyrrolidine-1-sulfonic acid phenylamide; yield: 72%;
[0525] Butyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-
-pyrrolidine-1-sulfonic acid butylamide; yield: 45%, MS: 653
(M-H).sup.-;
[0526] Phenethyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulf-
anyl-pyrrolidine-1-sulfonic acid phenethylamide; yield: 52%;
[0527] Phenoxyethyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-trityls-
ulfanyl-pyrrolidine-1-sulfonic acid (2-phenoxy-ethyl)-amide; yield:
20%, MS: 717 (M-H).sup.-;
[0528] Cyclohexylmethyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tri-
tylsulfanyl-pyrrolidine-1-sulfonic acid cyclohexylmethyl-amide;
yield: 74%, MS: 694 (M-H).sup.-;
[0529] Cyclopropylmethyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tr-
itylsulfanyl-pyrrolidine-1-sulfonic acid cyclopropylmethyl-amide;
yield: quant., MS: 651 (M-H).sup.-;
[0530] Cyclopropyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsu-
lfanyl-pyrrolidine-1-sulfonic acid cyclopropyl-amide; yield: 82%,
MS: 637 (M-H).sup.-;
[0531] 2,2,2-Trifluoro-ethyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)--
4-tritylsulfanyl-pyrrolidine-1-sulfonic acid
(2,2,2-trifluoro-ethyl)-amide- ; yield: 78%, MS: 679
(M-H).sup.-;
[0532] 4-Fluoro-benzyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-trit-
ylsulfanyl-pyrrolidine-1-sulfonic acid 4-fluoro-benzylamide; yield:
39%, MS: 705 (M-H).sup.-;
[0533] Acetic acid ethyl ester:
(2S,4R)-[2-(2,4,5-Trifluoro-benzyloxymethy-
l)-4-tritylsulfanyl-pyrrolidine-1-sulfonylamino]-acetic acid ethyl
ester; yield: 85%, MS: 682 (M-H).sup.-;
[0534] 4-Methoxycarbonyl-benzyl:
(2S,4R)-[4-{[2-(2,4,5-Trifluoro-benzyloxy-
methyl)-4-tritylsulfanyl-pyrrolidine-1-sulfonylamino]-methyl}-benzoic
acid methyl ester; yield: 63%;
[0535] Dimethyl:
(2S,4R)-2-Benzyloxymethyl-4-tritylsulfanyl-pyrrolidine and
dimethylsulphamoyl chloride gave
(2S,4R)-2-Benzyloxymethyl-4-tritylsu- lfanyl-pyrrolidine-1-sulfonic
acid dimethylamide, MS: 573 (MH.sup.+).
Example 14.i
Ether, Alkylation of Sulfamides
[0536] A solution of the sulfamide in DMF (20 ml/mmol) was placed
in an ice bath. NaH (55% in mineral oil, 1.2 eq.) was added and
stirred for 30 min. The alkylating agent (MeI or
t-butylbromoacetate, 1.2 eq.) was added and stirred overnight at
room temperature. A aqueous saturated solution of NH.sub.4Cl was
added and the mixture was extracted with dichloromethane. The
organic phase was dried (Na.sub.2SO.sub.4), filtered and
evaporated. The product was purified by chromatography (SiO.sub.2,
EtOAc I hexane 95:5=>hexane/EtOAc 70:30.
[0537] Benzyl-methyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-trityl-
sulfanyl-pyrrolidine-1-sulfonic acid benzyl-methyl-amide; yield:
36%, MS: 703 (M+H).sup.+;
[0538] Methyl-phenyl:
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-trityl-
sulfanyl-pyrrolidine-1-sulfonic acid methyl-phenyl-amide; yield:
84%;
[0539] Benzyl-acetic acid t-butyl ester:
{Benzyl-[2-(2,4,5-trifluoro-benzy-
loxymethyl)-4-tritylsulfanyl-pyrrolidine-1-sulfonyl]-amino}-acetic
acid-tert-butyl ester; yield: 77%;
[0540] Deprotection (Method 3): Triethylsilane (10 eq.) was added
to a solution of the trityl-protected thiol (1 eq.) in
trifluoroacetic acid (200 eq.) at 0.degree. C. The reaction mixture
was stirred for 30 min at 0.degree. C. The solvent was evaporated
under vacuum at 0.degree. C. The product was purified by
chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2=>CH.sub.2Cl.sub.2/MeOH 9:1).
[0541] Benzyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrr-
olidine-1-sulfonic acid benzylamide; colorless oil; yield: 85%, MS:
445 (M-H).sup.-;
[0542] Phenyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrr-
olidine-1-sulfonic acid phenylamide; yellowish oil; yield: quant.,
MS: 431 (M-H).sup.-;
[0543] Butyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrro-
lidine-1-sulfonic acid butylamide; colorless solid; yield: 69%, MS:
411 (M-H).sup.-;
[0544] Phenethyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-p-
yrrolidine-1-sulfonic acid phenethylamide; colorless oil; yield:
53%, MS: 459 (M-H).sup.-;
[0545] Phenoxyethyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl-
)-pyrrolidine-1-sulfonic acid (2-phenoxy-ethyl)-amide; colorless
oil; yield: quant., MS: 475 (M-H).sup.-;
[0546] Cyclohexylmethyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxyme-
thyl)-pyrrolidine-1-sulfonic acid cyclohexylmethyl-amide; colorless
solid; yield: 87%, MS: 451 (M-H).sup.-;
[0547] Cyclopropylmethyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxym-
ethyl)-pyrrolidine-1-sulfonic acid cyclopropylmethyl-amide;
colorless solid; yield: 94%, MS: 409 (M-H).sup.-;
[0548] Cyclopropyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-
-pyrrolidine-1-sulfonic acid cyclopropyl-amide; colorless oil;
yield: 75%, MS: 395 (M-H).sup.-;
[0549] 2,2,2-Trifluoro-ethyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyl-
oxymethyl)-pyrrolidine-1-sulfonic acid
(2,2,2-trifluoro-ethyl)-amide; colorless oil; yield: 88%, MS: 437
(M-H).sup.-;
[0550] 4-Fluoro-benzyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymet-
hyl)-pyrrolidine-1-sulfonic acid 4-fluoro-benzylamide; colorless
oil; yield: 86%, MS: 463 (M-H).sup.-;
[0551] Benzyl-methyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethy-
l)-pyrrolidine-1-sulfonic acid benzyl-methyl-amide; colorless oil;
yield: 87%, MS: 425 (M+H).sup.+;
[0552] Methyl-phenyl:
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethy-
l)-pyrrolidine-1-sulfonic acid methyl-phenyl-amide; light green
oil; yield: 86%, MS: 447 (M+H).sup.+;
[0553] Benzyl-acetic acid:
{Benzyl-[4-mercapto-2-(2,4,5-trifluoro-benzylox-
ymethyl)-pyrrolidine-1-sulfonyl]-amino}-acetic acid; colorless oil;
yield: 88%, MS: 503 (M-H).sup.-;
[0554] Acetic acid ethyl ester:
(2S,4R)-[4-Mercapto-2-(2,4,5-trifluoro-ben-
zyloxymethyl)-pyrrolidine-1-sulfonylamino]-acetic acid ethyl ester;
colorless oil; yield: 96%, MS: 443 (M+H).sup.+;
[0555] 4-Methoxycarbonyl-benzyl:
(2S,4R)-4-{[4-Mercapto-2-(2,4,5-trifluoro-
-benzyloxymethyl)-pyrrolidine-1-sulfonylamino]-methyl}-benzoic acid
methyl ester; colorless oil; yield: 70%, MS: 503 (M-H).sup.-;
[0556] Dimethyl:
(2S,4R)-2-Benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-- sulfonic
acid dimethylamide gave, MS: 331 (MH.sup.+);
[0557]
(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrol-
idine gave over two steps
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxym-
ethyl)-pyrrolidine-1-sulfonic acid dimethylamide, MS: 385
(MH.sup.+).
Example 14.k
Ether, Sulfonic Acid
[0558] A solution of 2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine
(0.435 g) in dichloromethane (30.0 ml) was treated with 2-picoline
(2.11 ml) and chlorosulphonic acid (0.186 ml). The reaction mixture
was stirred for 5 h at room temperature and evaporated to dryness.
The residue was quenched with ice/water and extracted with EtOAc.
The aqueous layer was saturated with sodium chloride and acidified
with 1 molar HCl to pH 3.4 and extracted again with EtOAc. The
organic phase was washed with brine, dried over magnesium sulphate
and concentrated to obtain
(2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-sulfonic
acid (0.26 g) as an oil, MS: 544 (M-H).sup.-.
[0559] To a solution of
(2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrroli- dine-1-sulfonic
acid (0.24 g) in dichloromethane (2.0 ml) was added triethylsilane
(0.51 g) and trifluoroacetic acid (8.0 ml) at -10.degree. C. The
reaction mixture was stirred at -5.degree. C. for 0.5 h and
concentrated without heating. The residue was treated with water,
acidified to pH 3-4 with HCl, and extracted with EtOAc. The organic
phase was washed with brine, dried over magnesium sulphate and
evaporated to dryness without heating. The residue was dissolved in
a solution of water (3 ml) and sodium acetate (0.165 g) and
chromatographed on MCI using water/methanol 1:1 as eluent to obtain
2-benzyloxymethyl-4-mercapto-pyrro- lidine-1-sulfonic acid sodium
salt (0.105 g) as a colourless powder after lyophillisation, MS:
302 (M-H).sup.-.
Example 15
Synthesis of C-analogues
[0560]
(2R,4R)-4-(4-Methoxy-benzylsulfanyl)-2-(2-methoxycarbonyl-ethyl)-py-
rrolidine-1-carboxylic acid tert-butyl ester gave after hydrolysis
(General method for hydrolysis of an ester) and Weinreb-amide
formation (General method for EDCI-coupling)
(2R,4R)-4-(4-methoxy-benzylsulfanyl)-2-
-[2-(methoxy-methyl-carbamoyl)-ethyl]-pyrrolidine-1-carboxylic acid
tert-butyl ester, MS: 439 (MH.sup.+).
[0561] A solution of 200 mg (0.456 mmol)
(2R,4R)-4-(4-Methoxy-benzylsulfan-
yl)-2-[2-(methoxy-methyl-carbamoyl)-ethyl]-pyrrolidine-1-carboxylic
acid tert-butyl ester in 3 ml THF was treated at 0.degree. C. with
1.14 ml (1.14 mmol, 1M THF solution) of a 4-fluorophenyl-magnesium
bromide solution and after 10 min warmed up to room temperature.
The reaction was partitioned between aqueous aqueous 10%
KHSO.sub.4/t-butyl methyl ether (3.times.). The organic phases were
washed with aqueous 10% NaHCO.sub.3 and saturated NaCl solution,
dried over MgSO.sub.4 and evaporated to give 144 mg (68%) of
(2R,4R)-2-[3-(4-fluoro-phenyl)-3-oxo-propyl]-4-(4-methoxy-
-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester,
MS: 474 (MH.sup.+).
[0562] A solution of 0.539 g (1.14 mmol)
(2R,4R)-2-[3-(4-Fluoro-phenyl)-3--
oxo-propyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic
acid tert-butyl ester in 10 ml CH.sub.2Cl.sub.2 was treated at
0.degree. C. with 0.43 ml TFA. After 30 min the reaction was warmed
up to room temperature (2 h) and evaporated to give
(2R,4R)-1-(4-fluoro-phenyl)-3-[4-
-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-yl]-propan-1-one; compound
with trifluoro-acetic acid, MS: 374 (MH.sup.+).
[0563] The crude mixture was dissolved in 20 ml CH.sub.2Cl.sub.2
and treated with 0.68 ml (6.2 mmol) N-methylmorpholine and 0.24 ml
(1.86 mmol) n-butyl chloroformate. The reaction was stirred over
night and partitioned between aqueous aqueous 10%
KHSO.sub.4/CH.sub.2Cl.sub.2 (3.times.). The organic phases were
washed with aqueous 10% NaHCO.sub.3 and saturated NaCl solution,
dried over MgSO.sub.4 and evaporated to give 72 mg (12%)
(2R,4R)-2-[3-(4-fluoro-phenyl)-3-oxo-propyl]-4-(4-methoxy-ben-
zylsulfanyl)-pyrrolidine-1-carboxylic acid butyl ester, MS: 474
(MH.sup.+) and 36 mg (6%)
(2R,4R)-1-(4-fluoro-phenyl)-3-[4-(4-methoxy-benzylsulfanyl-
)-1-trifluoroacetyl-pyrrolidin-2-yl]-propan-1-one, MS: 470
(MH.sup.+).
[0564] In analogy:
(2R,4R)-4-(4-Methoxy-benzylsulfanyl)-2-[2-(methoxy-meth-
yl-carbamoyl)-ethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester
was:
[0565] 1. TFA deprotected (see above) to give
(2R,4R)-N-methoxy-3-[4-(4-me-
thoxy-benzylsulfanyl)-pyrrolidin-2-yl]-N-methyl-propionamide;
compound with trifluoro-acetic acid, MS: 339 (MH.sup.+);
[0566] 2. Sulfonylated (see above) with methanesulfonyl chloride to
give
(2R,4R)-3-[1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-yl-
]-N-methoxy-N-methyl-propionamide, MS: 417 (MH.sup.+) and with
2-naphthylsulfonyl chloride
(2R,4R)-N-methoxy-3-[4-(4-methoxy-benzylsulfa-
nyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-N-methyl-propionamide,
MS: 529 (MH.sup.+);
[0567] 3. Reacted with a 1M THF solution of 4-fluorophenylmagnesium
bromide (see above) to give
(2R,4R)-1-(4-fluoro-phenyl)-3-[1-methanesulfo-
nyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-yl]-propan-1-one, MS:
452 (MH.sup.+) and
(2R,4R)-1-(4-fluoro-phenyl)-3-[4-(4-methoxy-benzylsulfanyl-
)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-propan-1-one, MS: 564
(MH.sup.+).
[0568] A solution of 72 mg (0.152 mmol)
(2R,4R)-2-[3-(4-fluoro-phenyl)-3-o-
xo-propyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic
acidbutyl ester and 0.12 (1.4 mmol) triethylsilane in 2.7 ml TFA
was heated for 18 h at 80.degree. C. Evaporation followed by flash
chromatography on silica gel (EtOAc/hexane 7:3) gave 8 mg (15%)
(2R,4R)-2-[3-(4-fluoro-phenyl)-pro-
pyl]-4-mercapto-pyrrolidine-1-carboxylic acid butyl ester, MS: 340
(MH.sup.+).
[0569] In analogy:
(2R,4R)-1-(4-fluoro-phenyl)-3-[4-(4-methoxy-benzylsulfa-
nyl)-1-trifluoroacetyl-pyrrolidin-2-yl]-propan-1-one gave
(2R,4R)-2,2,2-trifluoro-1-{2-[3-(4-fluoro-phenyl)-propyl]-4-mercapto-pyrr-
olidin-1-yl}-ethanone, MS: 336 (MH.sup.+).
[0570]
(2R,4R)-1-(4-Fluoro-phenyl)-3-[1-methanesulfonyl-4-(4-methoxy-benzy-
lsulfanyl)-pyrrolidin-2-yl]-propan-1-one gave
(2R,4R)-5-[3-(4-fluoro-pheny-
l)-propyl]-1-methanesulfonyl-pyrrolidine-3-thiol, MS: 318
(MH.sup.+).
[0571]
(2R,4R)-1-(4-fluoro-phenyl)-3-[4-(4-methoxy-benzylsulfanyl)-1-(naph-
thalene-2-sulfonyl)-pyrrolidin-2-yl]-propan-1-one gave
(2R,4R)-5-[3-(4-fluoro-phenyl)-propyl]-1-(naphthalene-2-sulfonyl)-pyrroli-
dine-3-thiol, MS: 336 (MH.sup.+).
Example 16
5-ring Ether Synthesis with the Final Introduction of Thiol
[0572] Cis-compound:
[0573] Tert-Butyletherification: To a solution of
(2S,4R)-4-hydroxy-1-(nap-
hthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester
(14.8 g) in dichloromethane (140 ml) were added boron trifluoride
ethyl etherate (3 ml) and isobutylene (cooled and liquefied at
-30.degree. C., 170 ml) at -30.degree. C. The turbid reaction
mixture was stirred at -20 .degree. C. for 2 h, poured onto a
saturated sodium bicarbonate solution, and extracted with
dichloromethane. The organic phases were washed with water, dried
over magnesium sulphate and concentrated. The residue was
chromatographed on silica gel using EtOAc/hexane 1:4 and 1:2 as
eluents to obtain
(2S,4R)-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2--
carboxylic acid benzyl ester (16.4 g) as a glassy syrup, MS: 467
(M).
[0574] In analogy (6-ring):
(2RS,5RS)-5-Hydroxymethyl-1-methanesulfonyl-pi-
peridine-2-carboxylic acid methyl ester (3.85 g) gave
(2RS,5RS)-5-tert-butoxymethyl-1-methanesulfonyl-piperidine-2-carboxylic
acid methyl ester (4.40 g) as a syrup, MS: 250 (M-57).
[0575] LAH reduction: To a slurry of lithium aluminium hydride
(0.72 g) in Et.sub.2O (120 ml) was added a solution of
(2S,4R)-4-tert-butoxy-1-(napht-
halene-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester (9.0
g) in Et.sub.2O (80 ml) dropwise at -15.degree. C. within 0.5 h.
The suspension was stirred for 2 h at the same temperature, then a
saturated solution of potassium-sodium tartrate (10 ml) was added
dropwise. The slurry was filtered through a pad of filter aid and
was washed with Et.sub.2O. The combined filtrates were washed with
brine, dried over magnesium sulphate and concentrated. The residue
was crystallized from acetone/Et.sub.2O/hexane to obtain
(2S,4R)-[4-tert-butoxy-1-(naphthalene--
2-sulfonyl)-pyrrolidin-2-yl]-methanol (6.1 g) as a colorless solid,
mp 124-125.degree. C.; MS 363 (M).
[0576] In analogy (6-ring):
(2RS,5RS)-5-tert-Butoxymethyl-1-methanesulfony-
l-piperidine-2-carboxylic acid methyl ester (4.20 g) gave
(2RS,5RS)-(5-tert-butoxymethyl-1-methanesulfonyl-piperidin-2-yl)-methanol
(3.67 g) as a colourless solid: mp 100-102.degree. C., MS: 280
(MH.sup.+).
[0577] R.sup.2-ether formation: To a slurry of sodium hydride (60%
in mineral oil, 2.75 g) in DMSO (100 ml) were added
(2S,4R)-[4-tert-butoxy-1-
-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-methanol (11.2 g) in
portions within 0.5 h and benzyl bromide (7.2 ml) dropwise within
0.5 h at 20.degree. C. The reaction mixture was stirred at room
temperature for 1.5 h, poured onto ice/water and extracted with
EtOAc. The organic phases were washed with water and brine, dried
over magnesium sulphate and concentrated. The residue was
crystallized from acetone/Et.sub.2O/hexane to obtain
(2S,4R)-2-benzyloxymethyl-4-tert-butoxy-1-(naphthalene-2-sulfon-
yl)-pyrrolidine (10.05 g) as a colorless solid, mp 101-103.degree.
C., MS: 454 (MH.sup.+).
[0578] In analogy:
(2S,4R)-[4-tert-Butoxy-1-(naphthalene-2-sulfonyl)-pyrro-
lidin-2-yl]-methanol (2.18 g) and 3-bromomethylbenzoic acid methyl
ester gave
(3S,5R)-3-[4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylm-
ethoxymethyl]-benzoic acid methyl ester (2.08 g) as a colourless
solid: mp 126-127.degree. C.; MS: 480 (M-OCH.sub.3).
[0579]
(2S,4R)-[4-tert-Butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]--
methanol (7.26 g) and cinnamyl bromide gave after chromatography on
silica gel using EtOAc/hexane 1:3 as eluent
(E)-(2S,4R)-4-tert-butoxy-1-(naphtha-
lene-2-sulfonyl)-2-(3-phenyl-allyloxymethyl)-pyrrolidine (7.2 g) as
a solid, MS: 480 (MH.sup.+).
[0580] Hydrogenation: A solution of
(E)-(2S,4R)-4-tert-butoxy-1-(naphthale-
ne-2-sulfonyl)-2-(3-phenyl-allyloxymethyl)-pyrrolidine (2.3 g) in
ethanol/dioxane 1:2 (75 ml) was hydrogenated in the presence of 10%
palladium on charcoal (0.50 g) at 1.1 bar and room temperature for
4 h. The reaction mixture was filtered over a pad of celite and
washed with ethanol. The filtrate was concentrated, and the residue
was chromatographed on silica gel using EtOAc/hexane 1:4 as eluent
to obtain
(2S,4R)-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-2-(3-phenyl-propoxymethy-
l)-pyrrolidine (2.16 g) as a gum, MS: 482 (MH.sup.+).
[0581] Mitsunobu reaction: To a solution of
(2S,4R)-[4-tert-butoxy-1-(naph-
thalene-2-sulfonyl)-pyrrolidin-2-yl]-methanol (1.81 g) in THF (15
ml) were added phenol (0.495 g) and triphenylphosphine (1.38 g) in
one portion at room temperature and diisopropyl azodicarboxylate
(1.0 ml) dropwise in 2 minutes. The reaction mixture was stirred
over night at room temperature and concentrated. The residue was
treated with water and extracted with EtOAc. The organic phase was
washed with 1N sodium hydroxide, saturated sodium bicarbonate
solution and brine, dried over magnesium sulphate and concentrated.
The residue was chromatographed on silica gel using EtOAc/hexane
1:3 as eluent to obtain (3S,5R)-4-tert-butoxy-1-(naphthalene-
-2-sulfonyl)-2-phenoxymethyl-pyrrolidine as a colourless powder,
MS: 439 (M).
[0582] (6-ring): To a solution of
(2RS,5RS)-(5-tert-butoxymethyl-1-methane-
sulfonyl-piperidin-2-yl)-methanol (2.80 g) in dichloromethane (20
ml) and cyclohexane (30 ml) was added benzyl
2,2,2-trichloroacetimidate (3.03 g) and trifluoromethanesulphonic
acid (0.2 ml). The reaction mixture was stirred 1 h at room
temperature, poured onto a saturated sodium bicarbonate solution
and extracted with EtOAc. The organic phase was washed with brine,
dried over magnesium sulphate and concentrated. The residue was
chromatographed on silica gel using EtOAc/hexane 1:3 and 1:2 as
eluents to obtain
(2RS,5RS)-2-benzyloxymethyl-5-tert-butoxymethyl-1-me-
thanesulfonyl-piperidine (3,6 g) as a syrup, MS: 369 (M.sup.+).
[0583] Trifluoroacetic acid (100 ml) was cooled to 0.degree. C.,
then
(2S,4R)-2-benzyloxymethyl-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrol-
idine (7.0 g) was added in one portion. The reaction mixture was
stirred for 3 h at the same temperature and then concentrated
without heating under vacuum. The residue crystallized from
Et.sub.2O/hexane to obtain
(3R,5S)-5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-ol
(5.07 g) as a colorless solid, mp 124-126.degree. C., MS: 398
(MH.sup.+).
[0584] In analogy:
(3S,5R)-3-[4-tert-Butoxy-1-(naphthalene-2-sulfonyl)-pyr-
rolidin-2-ylmethoxymethyl]-benzoic acid methyl ester (2.00 g) gave
(3S,5R)-3-[4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethoxymet-
hyl]-benzoic acid methyl ester (0.98 g) as a colourless powder: MS:
456 (MH.sup.+).
[0585]
(2S,4R)-4-tert-Butoxy-1-(naphthalene-2-sulfonyl)-2-(3-phenyl-propox-
ymethyl)-pyrrolidine gave
(3R,5S)-1-(naphthalene-2-sulfonyl)-5-(3-phenyl-p-
ropoxymethyl)-pyrrolidin-3-ol (1.36 g) as a foam: MS: 426
(MH.sup.+).
[0586]
(3S,5R)-4-tert-Butoxy-1-(naphthalene-2-sulfonyl)-2-phenoxymethyl-py-
rrolidine (1.5 g) gave
(3S,5R)-1-(naphthalene-2-sulfonyl)-5-phenoxymethyl--
pyrrolidin-3-ol (0.82 g) as a white powder: MS: 384 (MH.sup.+).
[0587] (6-ring)
(2RS,5RS)-2-Benzyloxymethyl-5-tert-butoxymethyl-1-methanes-
ulfonyl-piperidine (3.4 g) gave
(3RS,6RS)-(6-benzyloxymethyl-1-methanesulf-
onyl-piperidin-3-yl)-methanol (1.75 g) as a colourless syrup, MS:
313 (M.sup.+).
[0588] To a solution of triphenylphosphine (2.92 g) in
tetrahydrofuran (30 ml) was added diisopropylazodicarboxylate (2.20
ml) within 5 minutes at 0.degree. C. The solution was stirred for
0.5 h at 0.degree. C., then a solution of
(3R,5S)-5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolid-
in-3-ol (2.2 g) and thioacetic acid (0.81 ml) in tetrahydrofurane
(10 ml) were added to the suspension within 0.5 h at 0.degree. C.
Stirring was continued for 1 h at 0.degree. C. and 1 h at room
temperature. The reaction mixture was concentrated, and the residue
was chromatographed on silica gel using EtOAc/hexane 1:4 and 1:3 as
eluents to obtain (3S,5S)-thioacetic acid
S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-p-
yrrolidin-3-yl]ester (2.1 g) as a syrup, MS: 456 (MH.sup.+).
[0589] In analogy:
(3S,5R)-3-[4-Hydroxy-1-(naphthalene-2-sulfonyl)-pyrroli-
din-2-ylmethoxymethyl]-benzoic acid methyl ester (0.78 g) was
reacted as described above to obtain
(2S,4S)-3-[4-acetylsulfanyl-1-(naphthalene-2-su-
lfonyl)-pyrrolidin-2-ylmethoxymethyl]-benzoic acid methyl ester
(0.34 g) as a thick syrup, MS: 514 (MH.sup.+).
[0590]
(3R,5S)-1-(Naphthalene-2-sulfonyl)-5-(3-phenyl-propoxymethyl)-pyrro-
lidin-3-ol (0.48 g) gave thioacetic acid
(3S,5S)-S-[1-(naphthalene-2-sulfo-
nyl)-5-(3-phenyl-propoxymethyl)-pyrrolidin-3-yl]ester (0.41 g) as a
syrup, MS: 484 (MH.sup.+).
(3S,5R)-1-(naphthalene-2-sulfonyl)-5-phenoxymethyl-py-
rrolidin-3-ol (0.54 g) gave (3S,5S)-thioacetic acid
S-[1-(naphthalene-2-sulfonyl)-5-phenoxymethyl-pyrrolidin-3-yl]ester
(0.54 g) as a glassy syrup, MS: 442 (MH.sup.+).
[0591] (6-ring)
(3RS,6RS)-(6-Benzyloxymethyl-1-methanesulfonyl-piperidin-3-
-yl)-methanol (0.94 g) gave thioacetic acid
(3RS,6RS)-S-(6-benzyloxymethyl-
-1-methanesulfonyl-piperidin-3-ylmethyl) ester as a colorless
syrup, MS: 371 (M.sup.+).
[0592] S-Acetyl deprotection: To a solution of (3S,5S)-thioacetic
acid
S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl]ester
(1.2 g) in methanol (17 ml) was added sodium methanolate
(28%-solution in methanol, 0.55 ml) at 0.degree. C.
[0593] The reaction mixture was stirred at 0.degree. C. for 1.5 h,
and acetic acid (0.17 ml) was added. The reaction mixture was
concentrated, and the residue was extracted with EtOAc. The organic
phases were washed with water, dried over magnesium sulphate and
concentrated. The residue was chromatographed on silica gel using
EtOAc/hexane 1:3 and 1:2 as eluents to obtain
(3S,5S)-5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-py-
rrolidine-3-thiol (0.59 g) as a slightly coloured syrup, MS: 414
(MH.sup.+).
[0594] In analogy:
(2S,4S)-3-[4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)--
pyrrolidin-2-ylmethoxymethyl]-benzoic acid methyl ester (0.30 g)
gave
(2S,4S)-3-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethoxyme-
thyl]-benzoic acid methyl ester (0.21 g) as a colourless amorphous
powder, MS: 440 (M-OCH.sub.3).
[0595] Thioacetic acid
(3S,5S)-S-[1-(naphthalene-2-sulfonyl)-5-(3-phenyl-p-
ropoxymethyl)-pyrrolidin-3-yl]ester (0.33 g) gave
(3S,5S)-1-(naphthalene-2-
-sulfonyl)-5-(3-phenyl-propoxymethyl)-pyrrolidine-3-thiol (0.23 g)
as a syrup, MS: 407 (M-H.sub.2S). (3S,5S)-Thioacetic acid
S-[1-(naphthalene-2-sulfonyl)-5-phenoxymethyl-pyrrolidin-3-yl]ester
(0.5 g) gave
(3S,5S)-1-(naphthalene-2-sulfonyl)-5-phenoxymethyl-pyrrolidine-3--
thiol (0.27 g) as a colourless powder, MS: 399 (M).
[0596] 6-ring: Thioacetic acid
(3RS,6RS)-S-(6-benzyloxymethyl-1-methanesul-
fonyl-piperidin-3-ylmethyl) ester (0.78 g) gave
(3RS,6RS)-(6-benzyloxymeth-
yl-1-methanesulfonyl-piperidin-3-yl)-methanethiol (0.52 g) as a
syrup, MS: 329 (M.sup.+).
[0597] To solution of
(2S,4S)-3-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyr-
rolidin-2-ylmethoxymethyl]-benzoic acid methyl ester (0.48 g) in
methanol (14 ml) was added a 0.1 molar sodium carbonate solution
(25 ml). The reaction mixture was refluxed for 5 h and
concentrated. The residue was treated with 1 eq 1N HCl, water and
extracted with EtOAc.
[0598] The organic phase was washed with brine, dried over
magnesium sulphate and concentrated. The residue was
chromatographed on silica gel using EtOAc/methanol/water 93:5:2 as
eluent to obtain
(2S,4S)-3-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethoxyme-
thyl]-benzoic acid (0.34 g) as a colourless thick syrup, MS: 458
(MH.sup.+).
Example 17
5-Ring Ether Synthesis with the Final Introduction of Thiol
[0599] Trans Compound:
[0600] To a suspension of methanesulphonic acid (0.96 g) in toluene
(30 ml) was added triethylamine (1.40 ml) and triphenylphosphine
(2.72 g) at 0-5.degree. C. The suspension was stirred for 5
minutes, and
(3R,5S)-5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-ol
(3.46 g) dissolved in toluene (20 ml) was added dropwise in 5
minutes, followed by diisipropyl azodicarboxylate (2.0 ml). The
reaction mixture was stirred for 3 h at 85.degree. C., poured onto
ice/water and extracted with ethy acetate. The organic phase was
washed with 10% KHSO.sub.4- and NaCl solutions, dried over
magnesium sulphate and concentrated. The residue was
chromatographed on silica gel using EtOAc/hexane 1:2 and 1:1 as
eluents to obtain (3S,5S)-methanesulfonic acid
5-benzyloxymethyl-1-(na- phthalene-2-sulfonyl)-pyrrolidin-3-yl
ester (3.35 g) as a slightly yellow syrup, MS: 476 (MH.sup.+)
[0601] In analogy:
(3S,5R)-3-[4-Hydroxy-1-(naphthalene-2-sulfonyl)-pyrroli-
din-2-ylmethoxymethyl]-benzoic acid methyl ester (1.10 g) gave
(2S,4S)-3-[4-methanesulfonyloxy-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-y-
lmethoxymethyl]-benzoic acid methyl ester (0.32 g) as a colourless
solid, MS: 534 (MH.sup.+).
[0602]
(3R,5S)-1-(Naphthalene-2-sulfonyl)-5-(3-phenyl-propoxymethyl)-pyrro-
lidin-3-ol (0.88 g) gave methanesulfonic acid
(3S,5S)-1-(naphthalene-2-sul-
fonyl)-5-(3-phenyl-propoxymethyl)-pyrrolidin-3-yl ester (0.68 g) as
a foam. The compound was used in the next step without
purification.
[0603]
(3S,5R)-1-(Naphthalene-2-sulfonyl)-5-phenoxymethyl-pyrrolidin-3-ol
(0.75 g) gave (3S,5S)-methanesulfonic acid
1-(naphthalene-2-sulfonyl)-5-p- henoxymethyl-pyrrolidin-3-yl ester
(0.65 g) as a syrup, MS: 462 (MH.sup.+).
[0604] To a solution of (3S,5S)-methanesulfonic acid
5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl ester
(3.0 g) in abs DMF (60 ml) was added potassium thioacetate (1.08
g). The reaction mixture was stirred for 1 h at 100.degree. C. and
concentrated under oil pump vacuum. The residue was treated with
ice/water and extracted with EtOAc. The organic phase was washed
with water and brine, dried over magnesium sulphate and
concentrated. The residue was chromatographed on silica gel using
EtOAc/hexane 1:3 as eluent to obtain (3S,5R)-thioacetic acid
S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-p-
yrrolidin-3-yl]ester (2.16 g) as a slightly yellow powder, MS: 334
(M-121).
[0605] In analogy:
(2S,4S)-3-[4-Methanesulfonyloxy-1-(naphthalene-2-sulfon-
yl)-pyrrolidin-2-ylmethoxymethyl]-benzoic acid methyl ester (0.30
g) was reacted as described above to obtain
(2S,4R)-3-[4-acetylsulfanyl-1-(napht-
halene-2-sulfonyl)-pyrrolidin-2-ylmethoxymethyl]-benzoic acid
methyl ester (0.23 g) as a thick syrup, MS: 514 (MH.sup.+). Crude
methanesulfonic acid
(3S,5S)-1-(naphthalene-2-sulfonyl)-5-(3-phenyl-propoxymethyl)-pyrrolidin--
3-yl este (0.64 g) gave thioacetic acid
(3R,5S)-S-[1-(naphthalene-2-sulfon-
yl)-5-(3-phenyl-propoxymethyl)-pyrrolidin-3-yl]ester (0.26 g) as a
syrup, MS: 484 (MH.sup.+)
[0606] (3S,5S)-Methanesulfonic acid
1-(naphthalene-2-sulfonyl)-5-phenoxyme- thyl-pyrrolidin-3-yl ester
(0.62 gave (3R,5S)-thioacetic acid
S-[1-(naphthalene-2-sulfonyl)-5-phenoxymethyl-pyrrolidin-3-yl]ester
(0.52 g) as a slightly coloured powder, MS: 442 (MH.sup.+).
[0607] (3S,5R)-Thioacetic acid
S-[5-benzyloxymethyl-1-(naphthalene-2-sulfo-
nyl)-pyrrolidin-3-yl]ester (1.91 g) was reacted as described above
in S-Acetyl deprotection to obtain
(3S,5R)-5-benzyloxymethyl-1-(naphthalene--
2-sulfonyl)-pyrrolidine-3-thiol (1.15 g) as an off-white solid, mp
79-80.degree. C., MS: 413 (M).
[0608] In analogy:
(2S,4R)-3-[4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)--
pyrrolidin-2-ylmethoxymethyl]-benzoic acid methyl ester (0.53 g)
was reacted as described above in S-Acetyl deprotection to obtain
(2S,4R)-3-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethoxyme-
thyl]-benzoic acid methyl ester (0.23 g) as a thick syrup, MS: 471
(M).
[0609] Thioacetic acid
(3R,5S)-S-[1-(naphthalene-2-sulfonyl)-5-(3-phenyl-p-
ropoxymethyl)-pyrrolidin-3-yl]ester (0.20 g) was reacted as
described above in S-Acetyl deprotection to obtain
(3R,5S)-1-(naphthalene-2-sulfony-
l)-5-(3-phenyl-propoxymethyl)-pyrrolidine-3-thiol (0.17 g) as a
syrup, MS: 442 (MH.sup.+).
[0610] (3R,5S)-Thioacetic acid
S-[1-(naphthalene-2-sulfonyl)-5-phenoxymeth-
yl-pyrrolidin-3-yl]ester (0.35 g) was reacted as described above in
S-Acetyl deprotection to obtain
(3R,5S)-1-(naphthalene-2-sulfonyl)-5-phen-
oxymethyl-pyrrolidine-3-thiol (0.21 g) as a thick syrup, MS: 399
(M).
[0611] 6-ring: To rac-cis-Piperidine-2,5-dicarboxylic acid dimethyl
ester [Frank J., J. Heterocyclic Chem. 32, 857-861 (1995)] (36.2 g)
dissolved in dichloromethane (720 ml) were added
4-dimethylaminopyridine (33.0 g) and, dropwise, methanesulphonyl
chloride (28.6 g) within 10 minutes and room temperature. The
temperature rose to 35.degree. C. The reaction mixture was stirred
1 h at room temperature, washed with 2 molar HCl, sodium
carbonate-solution and brine, dried over magnesium sulphate and
concentrated to dryness to obtain
(2RS,5RS)-1-methanesulfonyl-piperidine-- 2,5-dicarboxylic acid
dimethyl ester (46.8 g) as a syrup, MS: 220 (M.sup.+-59).
[0612] In analogy: rac-cis-Piperidine-2,5-dicarboxylic acid
dimethyl ester with naphthalene-2-sulphonyl chloride gave
(2RS,5RS)-1-(naphthalene-2-sul- fonyl)-piperidine-2,5-dicarboxylic
acid dimethyl ester (36.3 g) as a colourless solid, mp
94-96.degree. C., MS: 392 (MH.sup.+).
[0613] To a solution of a 16:9 mixture of meso- and
(3RS,5RS)-piperidine-3,5-dicarboxylic acid dimethyl ester [Stetter,
H. & Henning, H., Chem. Ber. 88, 789-795 (1955)] (23.0 g) in
dichloromethane (460 ml) and triethylamine (30 ml) was added
naphthalene-2-sulphonyl chloride (24.5 g) in dichloromethane (50
ml) in 15 minutes at room temperature. The reaction mixture was
boiled under reflux for 4 h, cooled down and washed with water and
sodium bicarbonate solution, dried over magnesium sulphate and
concentrated. The residue was chromatographed on silica gel using
EtOAc/hexane 1:3, 1:2 and 1:1 as eluents to obtain a racemic
mixture of meso-1-(naphthalene-2-sulfonyl)-piperidine-3,5-dicarbo-
xylic acid dimethyl ester (22.6 g) as a colourless solid, mp
123-125.degree. C., MS: 360 (M+-31).
[0614] To a solution of
(2RS,5RS)-1-methanesulfonyl-piperidine-2,5-dicarbo- xylic acid
dimethyl ester (46.5 g) in methanol (850 ml) and water (85 ml) was
added 1 molar sodium hydroxide (166 ml) within 20 minutes at reflux
temperature. The reaction mixture was stirred for 45 minutes at
reflux, cooled and concentrated. The residue was taken up in water
(300 ml) and washed with Et.sub.2O. The aqueous phase was acidified
with 1 molar HCl (166 ml) and extracted with EtOAc. The organic
phase was washed with brine, dried over magnesium sulphate and
concentrated. The residue was crystallized from acetone/Et.sub.2O
to obtain (2RS,5RS)-1-methanesulfonyl- -piperidine-2,5-dicarboxylic
acid 2-methyl ester (16.8 g) as a colourless solid, mp
130-133.degree. C., MS: 206 (M.sup.+-59).
[0615] In analogy:
(2RS,5RS)-1-(Naphthalene-2-sulfonyl)-piperidine-2,5-dic- arboxylic
acid dimethyl ester (16.0 g) gave (2RS,5RS)-1-(naphthalene-2-sul-
fonyl)-piperidine-2,5-dicarboxylic acid 2-methyl ester (6.25 g) as
a colourless solid, MS: 377 (M.sup.+).
[0616] Meso-1-(naphthalene-2-sulfonyl)-piperidine-3,5-dicarboxylic
acid dimethyl ester (3.0 g) gave
(3RS,5SR)-1-(naphthalene-2-sulfonyl)-piperidi- ne-3,5-dicarboxylic
acid monomethyl ester (1.58 g) as a colourless amorphous powder,
MS: 378 (MH.sup.+).
[0617] To a solution of
(2RS,5RS)-1-methanesulfonyl-piperidine-2,5-dicarbo- xylic acid
2-methyl ester (10.7 g) in tetrahydrofuran was added a 1 M borane
solution in tetrahydrofuran (215 ml) within 0.5 h at 0.degree. C.
The reaction mixture was stirred for 4 h at 0.degree. C., poured
onto ice/saturated sodium bicarbonate solution and concentrated.
The aqueous residue was extracted with EtOAc. The organic phase was
washed with brine, dried over magnesium sulphate and concentrated.
The residue was chromatographed on silica gel using EtOAc/hexane
1:1 and 3:2 as eluents to obtain
(2RS,5RS)-5-hydroxymethyl-1-methanesulfonyl-piperidine-2-carbox-
ylic acid methyl ester (8.1 g) as a colourless solid, MS: 206
(100%, M+-59).
[0618] In analogy:
(2RS,5RS)-1-(Naphthalene-2-sulfonyl)-piperidine-2,5-dic- arboxylic
acid 2-methyl ester (1.80 g) gave (2RS,5RS)-5-hydroxymethyl-1-(n-
aphthalene-2-sulfonyl)-piperidine-2-carboxylic acid methyl ester
(1.45 g) as a colourless foam, MS: 364 (MH.sup.+).
[0619]
(3RS,5SR)-1-(Naphthalene-2-sulfonyl)-piperidine-3,5-dicarboxylic
acid monomethyl ester (1.50 g) gave
(3SR,5RS)-5-hydroxymethyl-1-(naphthal-
ene-2-sulfonyl)-piperidine-3-carboxylic acid methyl ester (0.86 g)
as a syrup, MS: 364 (MH.sup.+).
[0620]
(3SR,5RS)-5-Hydroxymethyl-1-(naphthalene-2-sulfonyl)-piperidine-3-c-
arboxylic acid methyl ester (4.8 g) was reacted as described in
Example 16 (R.sup.2-ether formation) to obtain
(3SR,5RS)-5-benzyloxymethyl-1-(naphth-
alene-2-sulfonyl)-piperidine-3-carboxylic acid methyl ester (5.4 g)
as a colourless gum, MS: 454 (MH.sup.+).
[0621] In analogy:
(2RS,5RS)-5-Hydroxymethyl-1-(naphthalene-2-sulfonyl)-pi-
peridine-2-carboxylic acid methyl ester (1.82 g) gave
(2RS,5RS)-5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidine-2-carbo-
xylic acid methyl ester (1.60 g) as a light yellow gum, MS: 454
(MH.sup.+).
[0622]
(2RS,5RS)-5-Hydroxymethyl-1-methanesulfonyl-piperidine-2-carboxylic
acid methyl ester (3.01 g) gave
(2RS,5RS)-5-benzyloxymethyl-1-methanesulf-
onyl-piperidine-2-carboxylic acid methyl ester (2.80 g) as a
colourless gum, MS: 282 (M-59).
[0623]
(3SR,5RS)-5-Benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidine-3-
-carboxylic acid methyl ester (2.70 g) was reduced with lithium
aluminium hydride as described in Example 17 to obtain
(3SR,5RS)-[5-benzyloxymethyl-
-1-(naphthalene-2-sulfonyl)-piperidin-3-yl]-methanol (1.54 g) as a
syrup, MS: 426 (MH.sup.+).
[0624] In analogy:
(2RS,5RS)-5-Benzyloxymethyl-1-(naphthalene-2-sulfonyl)--
piperidine-2-carboxylic acid methyl ester (1.30 g) gave
(2RS,5RS)-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidin-2-yl]-m-
ethanol (0.67 g) as a light yellow viscous oil, MS: 426
(MH.sup.+).
[0625]
(2RS,5RS)-5-Benzyloxymethyl-1-methanesulfonyl-piperidine-2-carboxyl-
ic acid methyl ester (2.70 g) gave
(2RS,5RS)-(5-benzyloxymethyl-1-methanes-
ulfonyl-piperidin-2-yl)-methanol (1.70 g) as a light yellow syrup,
MS: 282 (M-31).
[0626]
(3SR,5RS)-[5-Benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidin-3-
-yl]-methanol (1.35 g) was reacted with thioacetic acid (see
Mitsunobu reaction described in Example 17) to obtain thioacetic
acid
(3SR,5RS)-S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidin-3-ylm-
ethyl]ester (0.92 g) as a syrup, MS: 484 (MH.sup.+).
[0627] In analogy:
(2RS,5RS)-[5-Benzyloxymethyl-1-(naphthalene-2-sulfonyl)-
-piperidin-2-yl]-methanol (0.64 g) gave thioacetic acid
(2RS,5RS)-S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidin-2-ylm-
ethyl]ester (0.48 g) as a light yellow syrup, MS: 484
(MH.sup.+).
[0628]
(2RS,5RS)-(5-Benzyloxymethyl-1-methanesulfonyl-piperidin-2-yl)-meth-
anol (1.41 g) gave thioacetic acid
(2RS,5RS)-S-(5-benzyloxymethyl-1-methan-
esulfonyl-piperidin-2-ylmethyl) ester (0.95 g) as a light brown
gum, MS: 372 (MH.sup.+).
[0629] Thioacetic acid
(3SR,5RS)-S-[5-benzyloxymethyl-1-(naphthalene-2-sul-
fonyl)-piperidin-3-ylmethyl]ester (0.88 g) gave
(3SR,5RS)-[5-benzyloxymeth-
yl-1-(naphthalene-2-sulfonyl)-piperidin-3-yl]-methanethiol (0.92 g)
as a syrup, MS: 442 (MH.sup.+).
[0630] In analogy: Thioacetic acid
(2RS,5RS)-S-[5-benzyloxymethyl-1-(napht-
halene-2-sulfonyl)-piperidin-2-ylmethyl]ester (0.34 g) gave
(2RS,5RS)-5-Benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidin-2-yl]-me-
thanethiol (0.23 g) as a colourless syrup, MS: 442 (MH.sup.+).
[0631] Thioacetic acid
(2RS,5RS)-S-(5-benzyloxymethyl-1-methanesulfonyl-pi-
peridin-2-ylmethyl) ester (0.78 g) gave
(2RS,5RS)-(5-benzyloxymethyl-1-met-
hanesulfonyl-piperidin-2-yl)-methanethiol (0.54 g) as a colourless
syrup, MS: 330 (MH.sup.+).
Example 18
Ethers, 3,4-substituted Pyrrolidine-ethers
[0632] To a solution of (3RS,4RS)-pyrrolidine-3,4-dicarboxylic acid
diethyl ester (2.04 g, 9.48 mmol) [Bull. Soc. Chim. Fr. 1988, 579]
in dichloromethane (30 ml) was added pyridine (1.12 g, 14.22 mmol),
N,N-dimethylaminopyridine (10 mg) and methanesulfonyl chloride
(1.30 g, 11.38 mmol) and stirred for 2 h at RT The solution was
washed with 0.5 M aqueous HCl and water, dried and evaporated.
Flash chromatography (EtOAc/hexane 1:1) gave 1.6 g (42%) of
(3RS,4RS)-1-methanesulfonyl-pyrrol- idine-3,4-dicarboxylic acid
diethyl ester as a colorless solid, MS: 310 (M+NH.sub.4).sup.+.
[0633] In analogy:
(3RS,4RS)-1-(Naphthalene-2-sulfonyl)-pyrrolidine-3,4-di- carboxylic
acid diethyl ester was obtained (44%) as a colorless solid, MS: 410
(MH.sup.+).
[0634] To a solution of
(3RS,4RS)-1-methanesulfonyl-pyrrolidine-3,4-dicarb- oxylic acid
diethyl ester (1.13 g, 3.85 mmol) in THF (40 ml) was slowly added a
1 M solution of LiAlH.sub.4 in THF (11.55 ml. 11.55 mmol) at
0.degree. C. The mixture was stirred for 1.5 h at 0.degree. C.
Water (0.44 ml), 1 M aqueous NaOH (0.44 ml) and water (1.31 ml)
were added subsequently at 0.degree. C. MgSO.sub.4 was added and
filtered. The solid was washed with EtOAc (4.times.). The filtrate
was evaporated to leave a colorless solid that was washed with hot
dichloromethane to give
([3RS,4RS]-4-hydroxymethyl-1-methanesulfonyl-pyrrolidin-3-yl)-methanol
as a colorless solid, MS: 268 (M+OAc).sup.-.
[0635] In analogy:
(3RS,4RS)-[4-Hydroxymethyl-1-(naphthalene-2-sulfonyl)-p-
yrrolidin-3-yl]-methanol was obtained (74%) from
(3RS,4RS)-1-(naphthalene-- 2-sulfonyl)-pyrrolidine-3,4-dicarboxylic
acid diethyl ester as a colorless solid, MS: 321 (M)+.
[0636] To a suspension of 60% NaH (66 mg, 1.64 mmol) in DMF (3 ml)
was added a solution of
([3RS,4RS]-4-hydroxymethyl-1-methanesulfonyl-pyrrolid-
in-3-yl)-methanol (327 mg, 1.56 mmol) in DMF (5 ml) at -12.degree.
C. After 5 min, benzylbromide (286 mg, 1.64 mmol) was added and the
mixture was stirred at -12.degree. C. for 30 min. The mixture was
allowed to warm to room temperature. The solvent was evaporated.
Water was added and extracted with dichloromethane. The organic
phase was dried, filtered and evaporated. Flash chromatography
(hexane/EtOAc 2:1=>1:1) gave 275 mg (58%) of
([3RS,4RS]-4-benzyloxymethyl-1-methanesulfonyl-pyrrolidin-3-yl)--
methanol as a colorless oil, MS: 358 (M+OAc).sup.-.
[0637] To a solution of
([3RS,4RS]-4-benzyloxymethyl-1-methanesulfonyl-pyr-
rolidin-3-yl)-methanol (267 mg, 0.89 mmol) and triethylamine (372
ml, 2.67 mmol) in Et.sub.2O (4 ml) was slowly added methanesulfonyl
chloride (137 ml, 1.78 mmol) at -20.degree. C. After 15 min the
mixture was allowed to warm to room temperature 1 M aqueous HCl
(0.5 ml) was added. The organic phase was washed with water, dried,
filtered and evaporated to give a colorless oil (264 mg). DMF (2.5
ml) and potassium thioacetate (120 mg, 1.05 mmol) were added and
the mixture was heated to 100.degree. C. for 1 h.
[0638] Dichloromethane was added and washed with water. The organic
phase was dried, filtered and evaporated. Flash chromatography
(EtOAc/hexane 1:1) gave 151 mg (48%) of thioacetic acid
(3RS,4RS)-S-(4-benzyloxymethyl--
1-methanesulfonyl-pyrrolidin-3-ylmethyl) ester as a light yellow
solid, MS: 416 (M+OAc).sup.-.
[0639] To a solution of LiAlH.sub.4 (0.23 mmol, 1 M in THF) in
Et.sub.2O (6 ml) was added a suspension of thioacetic acid
(3RS,4RS)-S-(4-benzyloxy-
methyl-1-methanesulfonyl-pyrrolidin-3-ylmethyl) ester (75.5 mg,
0.21 mmol) in Et.sub.2O. The mixture was stirred at RT for 30 min
and refluxed for 2 h. After cooling to r.t., water and 1 M aqueous
HCl were added. The organic phase was dried and evaporated to give
63 mg (95%) of
[(3RS,4RS)-4-benzyloxymethyl-1-methanesulfonyl-pyrrolidin-3-yl]-methaneth-
iol as a colorless oil, MS: 333 (M+NH.sub.4).sup.+.
[0640] A solution of
([3RS,4RS]-4-hydroxymethyl-1-methanesulfonyl-pyrrolid-
in-3-yl)-methanol (316 mg, 1.51 mmol), tosylchloride (288 mg, 1.51
mmol), N,N-dimethylaminopyridine (10 mg) and triethylamine (153 mg,
1.51 mmol) in THF (10 ml) was stirred overnight at room temperature
Dichloromethane and 1 M aqueous HCl were added. The organic phase
was separated. The aqueous phase was extracted with
dichloromethane. The combined organic phases were washed with
water, dried and evaporated to give the crude tosylate as a
colorless oil.
[0641] To a solution of triphenylmethane thiol (639 mg, 2.26 mmol)
in DMF (3 ml) was added KotBu (220 mg, 1.96 mmol) at 0.degree. C.
and stirred for 20 min. A solution of the crude tosylate in DMF was
added and stirred for 3 h at room temperature. Water was added and
the mixture was extracted with dichloromethane. The organic phase
was dried, filtered and evaporated. Flash chromatography
(dichloromethane=>dichloromethane/MeO- H 95:5) gave 236 mg (33%)
of [(3RS,4RS)-1-methanesulfonyl-4-tritylsulfanyl-
methyl-pyrrolidin-3-yl]-methanol as a colorless foam, MS: 526
(M+OAc).sup.-.
[0642] In analogy:
(3RS,4RS)-[1-(Naphthalene-2-sulfonyl)-4-tritylsulfanylm-
ethyl-pyrrolidin-3-yl]-methanol was obtained (55%) from
(3RS,4RS)-[4-hydroxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl]-me-
thanol as a colorless foam, MS: 602 (M+Na).sup.+.
[0643] To a solution of
[(3RS,4RS)-1-methanesulfonyl-4-tritylsulfanylmethy-
l-pyrrolidin-3-yl]-methanol (106 mg, 0.226 mmol) in THF (15 ml)
were added triethylamine (47 ml, 0.34 mmol) and methanesulfonyl
chloride (26 ml, 0.34 mmol) at 0.degree. C. The mixture was stirred
at 0.degree. C. for 30 min and at RT for 1 h. Water and 1 M aqueous
HCl were added and the mixture was extracted with EtOAc. The
organic phase was dried, filtered and evaporated to give the crude
mesylate as a colorless oil.
[0644] To a suspension of 60% NaH (14 mg, 0.339 mmol) in DMF (1 ml)
was added phenol (43 mg, 0.452 mmol) and stirred for 15 min. A
solution of the crude mesylate in DMF was added and the mixture was
stirred for 8 h. Water was added and the mixture was extracted with
dichloromethane. The organic phase was dried, filtered and
evaporated. Flash chromatography (hexane/EtOAc 4:1=>1:1) gave 52
mg (43%) of (3RS,4RS)-1-methanesulfony-
l-3-phenoxymethyl-4-tritylsulfanylmethyl-pyrrolidine as a colorless
foam, MS: 566 (M+Na).sup.+.
[0645] In analogy:
(3RS,4RS)-1-(Naphthalene-2-sulfonyl)-3-phenoxymethyl-4--
tritylsulfanylmethyl-pyrrolidine was obtained (43%) from
(3RS,4RS)-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanylmethyl-pyrrolidin-3-
-yl]-methanol as a colorless oil, MS: 656 (MH.sup.+).
[0646] To a solution of
(3RS,4RS)-[1-(naphthalene-2-sulfonyl)-4-tritylsulf-
anylmethyl-pyrrolidin-3-yl]-methanol (200 mg, 0.345 mmol) in DMF (2
ml) was added 60% NaH (15.2 mg, 0.379 mmol) at 0.degree. C. and
stirred for 10 min. Benzyl bromide (45 .mu.l, 0.379 mmol) was added
and stirred for 30 min at 0.degree. C. and for 1 h at room
temperature. Water was added and the mixture was extracted with
dichloromethane. The organic phase was dried, filtered and
evaporated. Flash chromatography (hexane/EtOAc 4:1 =>1:1) gave
140 mg (61%) of (3RS,4RS)-1-(naphthalene-2-sulfonyl)-3-ben-
zyloxymethyl-4-tritylsulfanylmethyl-pyrrolidine as a colorless
foam, MS: 692 (M+Na).sup.+.
[0647] To a solution of
(3RS,4RS)-1-methanesulfonyl-3-phenoxymethyl-4-trit-
ylsulfanyl-methyl-pyrrolidine (50 mg, 0.092 mmol) in
trifluoroacetic acid (1.4 ml, 18.4 mmol) was added triethylsilane
(107 mg, 0.92 mmol) at 0.degree. C. The mixture was stirred for 30
min at 0.degree. C. The solvent was evaporated at room temperature.
Flash chromatography (dichloromethane=>dichloromethane/MeOH
98:2) gave 27 mg (97%) of
[(3RS,4RS)-1-methanesulfonyl-4-phenoxymethyl-pyrrolidin-3-yl]-methanethio-
l as a colorless oil, MS: 301 (M).sup.+.
[0648] In analogy:
(3RS,4RS)-[1-(Naphthalene-2-sulfonyl)-4-phenoxymethyl-p-
yrrolidin-3-yl]-methanethiol was obtained (88%) from
(3RS,4RS)-1-(naphthalene-2-sulfonyl)-3-phenoxymethyl-4-tritylsulfanylmeth-
yl-pyrrolidine as a colorless oil, MS: 414 (MH.sup.+).
[0649]
(3RS,4RS)-[4-Benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin--
3-yl]-methanethiol was obtained (quant.) from
(3RS,4RS)-1-(naphthalene-2-s-
ulfonyl)-3-benzyloxymethyl-4-tritylsulfanylmethyl-pyrrolidine as a
colorless oil, MS: 428 (MH.sup.+).
Example 19
6-Ring Ether
[0650] A suspension of 31.15 g (150 mmol)
3-Ethoxycarbonyl-4-piperidone hydrochloride was suspended in 400 ml
hexamethyldisilazane and heated under reflux (140.degree. C.) for
2.5 h. The solution was evaporated complete, the residue dissolved
in 400 ml THF and treated with 34 g (150 mmol) of
naphthalene-2-sulfonylchloride in 150 ml THF. The reaction was
stirred 16 h at room temperature, evaporated, treated with 400 ml
aqueous 1 0% NaCl, stirred for 10 min and extracted with EtOAc
(3.times.400 ml). The organic phase was dried (Na.sub.2SO.sub.4)
and evaporated and crystallized from Et.sub.2O at 5.degree. C. to
give 53.1 g (90%) of
4-hydroxy-1-(naphthalene-2-sulfonyl)-1,2,5,6-tetrahydro-pyridine-3-carbox-
ylic acid ethyl ester, MS: 362 (MH.sup.+).
[0651] In analogy: 3-Ethoxycarbonyl-4-piperidone hydrochloride and
methanesulfonyl chloride gave
4-hydroxy-1-methanesulfonyl-1,2,5,6-tetrahy-
dro-pyridine-3-carboxylic acid ethyl ester, mp 87-88.degree. C.,
MS: 250 (MH.sup.+).
[0652] A suspension of 28.9 g (80 mmol)
4-hydroxy-1-(naphthalene-2-sulfony-
l)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester in 150
ml MeOH was cooled to room temperature and treated in portion with
3.03 g (80 mmol) of NaBH.sub.4. After 3 h the reaction was adjusted
to pH 4 with AcOH, evaporated and treated with aqueous saturated
NaHCO.sub.3/EtOAc (3.times.). The organic phase was dried
(Na.sub.2SO.sub.4) and evaporated to give 29.3 g (quant.) of 1:1
mixture of (3RS,4RS)- and
(3RS,4SR)-4-hydroxy-1-(naphthalene-2-sulfonyl)-piperidine-3-carboxylic
acid ethyl ester, MS: 364 (MH.sup.+).
[0653] In analogy:
4-Hydroxy-1-methanesulfonyl-1,2,5,6-tetrahydro-pyridine-
-3-carboxylic acid ethyl ester gave a 1:1 mixture of (3RS,4RS)- and
(3RS,4SR)-4-hydroxy-1-methanesulfonyl-piperidine-3-carboxylic acid
ethyl ester which was immediately used for the next reaction.
[0654] A solution of 23.8 g (65 mmol) 1:1 mixture of (3RS,4RS)- and
(3RS,4SR)-4-hydroxy-1-(naphthalene-2-sulfonyl)-piperidine-3-carboxylic
acid ethyl ester in 400 ml CH.sub.2Cl.sub.2 was treated at
0.degree. C. with 5.56 ml (71.5 mmol) methanesulfonyl chloride,
7.85 ml (97.5 mmol) pyridine and 7.94 g (65 mmol) DMAP. The
reaction was stirred 24 h at room temperature and partitioned
between aqueous 1 N HCl/Et.sub.2O (3.times.). The organic phases
were washed with aqueous 10% NaCl solution, dried over
Na.sub.2SO.sub.4 and evaporated to give 28.75 g (quantitative) of a
1:1 mixture of (3RS,4RS)- and (3RS,4SR)
4-methanesulfonyloxy-1-(naphthalene-2-
-sulfonyl)-piperidine-3-carboxylic acid ethyl ester.
[0655] 2.76 ml (17.83 mmol) of 4-methoxybenzyl mercaptan was slowly
added at room temperature to a solution of 1.83 g (16.35 mmol) of
potassium tert-butylate in 60 ml DMF and stirred mechanically for
20 min. Then 6.56 g (14.86 mmol) of a 1:1 mixture of (3RS,4RS)- and
(3RS,4SR)
4-methanesulfonyloxy-1-(naphthalene-2-sulfonyl)-piperidine-3-carboxylic
acid ethyl ester in 60 ml DMF were slowly added at 20.degree. C.
The reaction was stirred for 45 min at room temperature, and
partitioned between cooled saturated aqueous NH.sub.4Cl/EtOAc
(3.times.300). The organic phases were washed with aqueous 10%
NaCl, dried (Na.sub.2SO.sub.4) and evaporated. Flash chromatography
on silica gel (toluene/CH.sub.3CN 97.5:2.5 to 95:5) gave 4.00 g
(54%) of 1:1 mixture of (3RS,4RS)- and
(3RS,4SR)-4-(4-methoxy-benzylsulfanyl)-1-(naphthalene-2-su-
lfonyl)-piperidine-3-carboxylic acid ethyl ester, MS: 500
(MH.sup.+).
[0656] In analogy: A 1:1 mixture of (3RS,4RS)- and
(3RS,4SR)-4-hydroxy-1-m- ethanesulfonyl-piperidine-3-carboxylic
acid ethyl ester gave via a 1:1 mixture of (3RS,4RS)- and
(3RS,4SR)-1-methanesulfonyl-4-methanesulfonylox-
y-piperidine-3-carboxylic acid ethyl ester a 1:1 mixture of
(3RS,4RS)- and
(3RS,4SR)-1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-piperidine-3-car-
boxylic acid ethyl ester, MS: 388 (MH.sup.+).
[0657] 1.2 ml (1.2 mmol, 1M THF solution) of LAH was added during 5
min to a cold solution (-20.degree. C.) of 500 mg (1.2 mmol) in 10
ml THF. The reaction was stirred for 20 min, cooled to -78.degree.
C. and quenched with a suspension of 0.3 g silica gel/0.3 g
MgSO.sub.4.7H.sub.2O in 2 ml aqueous 10% KHSO.sub.4. After the
addition of 0.5 ml H.sub.2O, the suspension was stirred for 10 min
at room temperature, filtered and washed with THF. After
evaporation of the THF, the residue was taken up in
CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4, evaporated and oile
out of Et.sub.2O/pentane to give 430 mg (94%) of 1:1 mixture of
(3RS,4RS)- and
(3RS,4SR)-[4-(4-methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pi-
peridin-3-yl]-methanol, MS: 458 (MH.sup.+).
[0658] In analogy: 1:1 Mixture of (3RS,4RS)- and
(3RS,4SR)-1-methanesulfon-
yl-4-(4-methoxy-benzylsulfanyl)-piperidine-3-carboxylic acid ethyl
ester gave a 1:1 mixture of (3RS,4RS)- and
(3RS,4SR)-[1-methanesulfonyl-4-(4-me-
thoxy-benzylsulfanyl)-piperidin-3-yl]-methanol, MS: 345 (M).
[0659] 150 mg (0.3 mmol) of (3RS,4RS)- and
(3RS,4SR)-[4-(4-methoxy-benzyls-
ulfanyl)-1-(naphthalene-2-sulfonyl)-piperidin-3-yl]-methanol and
0.039 ml (0.33 mmol) of benzylbromide were dissolved in 15 ml DMF,
cooled to 0.degree. C. and treated with 14.4 mg (0.33 mmol) of 55%
NaH and a catalytic amount of Nal. The reaction was warmed up over
night and treated with saturated NH.sub.4Cl solution/EtOAc
(3.times.). The organic phase was washed with 10% NaCl solution,
dried over Na.sub.2SO.sub.4 and evaporated. Flash-chromatography on
silica gel (toluene/CH.sub.3CN 98:2) gave 90 mg (20%) of
(3SR,4RS)-3-benzyloxymethyl-4-(4-methoxy-benzylsulfan-
yl)-1-(naphthalene-2-sulfonyl)-piperidine (proven by .sup.1H-NMR,
NOE), MS: 548 (MH.sup.+) and 77 mg (17%) of
(3SR,4SR)-3-benzyloxymethyl-4-(4-me-
thoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-piperidine
(profane by 1H-NMR, NOE), MS: 548 (MH.sup.+) and 110 mg (24%) of a
1:1 mixture of both diastereomers.
[0660] In analogy: 1:1 Mixture of (3RS,4RS)- and
(3RS,4SR)-[1-methanesulfo-
nyl-4-(4-methoxy-benzylsulfanyl)-piperidin-3-yl]-methanol gave
(3RS,4RS)-3-Benzyloxymethyl-1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl-
)-piperidine, MS: 435 (M) and
(3RS,4SR)-3-benzyloxymethyl-1-methanesulfony-
l-4-(4-methoxy-benzylsulfanyl)-piperidine, MS: 435 (M).
[0661] Method 1: 84 mg (0.153 mmol)
(3SR,4RS)-3-Benzyloxymethyl-4-(4-metho-
xy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-piperidine were
dissolved in 2 ml TFA and treated at 0.degree. C. with 0.244 ml
(1.53 mmol) of triethylsilane. After 2 h at 0.degree. C. and 18 h
at room temperature, the mixture was evaporated and purified by
precipitation with Et.sub.2O/pentane to give 40 mg (61%) of
(3SR,4RS)-3-benzyloxymethyl-1-(n-
aphthalene-2-sulfonyl)-piperidine-4-thiol, MS: 427 (M).
[0662] In analogy:
(3SR,4SR)-3-Benzyloxymethyl-4-(4-methoxy-benzylsulfanyl-
)-1-(naphthalene-2-sulfonyl)-piperidine gave
(3SR,4SR)-3-benzyloxymethyl-1-
-(naphthalene-2-sulfonyl)-piperidine-4-thiol, MS: 428
(MH.sup.+).
[0663]
(3RS,4RS)-3-Benzyloxymethyl-1-methanesulfonyl-4-(4-methoxy-benzylsu-
lfanyl)-piperidine gave
(3RS,4RS)-3-benzyloxymethyl-1-methanesulfonyl-pipe- ridine-4-thiol,
MS: 316 (MH.sup.+).
[0664]
(3RS,4SR)-3-Benzyloxymethyl-1-methanesulfonyl-4-(4-methoxy-benzylsu-
lfanyl)-piperidine gave
(3RS,4SR)-3-benzyloxymethyl-1-methanesulfonyl-pipe- ridine-4-thiol,
MS: 316 (MH.sup.+).
Example 20
Synthesis of Tert.Thiols
[0665] Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
were prepared from BOC-Hyp-OH following literature procedure
[Baldwin, Jack E.; Field, Robert A.; Lawrence, Christopher C.;
Merritt, Kristen D.; Schofield, Christopher J.; Tetrahedron Lett.;
34; 1993; 7489-7492; and Herdewijn, Piet; Claes, Paul J.;
Vanderhaeghe, Hubert; Can.J.Chem.; 60; 1982; 2903-2907;]
[0666] To a solution of methylenetriphenyl phosphorane, previously
prepared from 37 g (777 mmol, 50% NaH in mineral oil, 4 eq) and
277.6 g (777 mmol, 4 eq) methyltriphenyl-phosphonium bromide in 1.5
1 THF by stirring at 50.degree. C. for 4 h, were added 44.5 g (194
mmol, 1 eq) (2S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester in 300 ml over a period of 30 min at RT. The
suspension was stirred at 50.degree. C. over night. After cooling
to RT the suspension was added to a 5% NaHCO.sub.3 solution, washed
with ether, the inorganic phase was acidified and extracted with
EtOAc, washed with brine, dried over Na.sub.2SO.sub.4 and
evaporated. 32.1 g (72%) (2S)-4-Methylene-pyrrolidin-
e-1,2-dicarboxylic acid 1-tert-butyl ester were isolated as white
solid.
[0667] To 14.7 g (64.7 mmol)
(2S)-4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl
ester in 80 ml THF were added 7.13 ml (64.7 mmol, 1.0 eq)
N-methylmorpholine and 8.5 ml (64.0 mmol, 1.0 eq) isobutylchloro
formate at -5.degree. C. and the solution was stirred at that
temperature for 1.5 h. The mixture was filtered and added to a
suspension of 3.7 g (97.8 mmol, 1.5 eq) NaBH.sub.4 in 30 ml water
over a period of 25 min at 0.degree. C. The reaction was stirred at
0.degree. C. for 2 h and at RT over night. Ether was added, the
layers were separated and the inorganic layer was extracted with
ether and CH.sub.2Cl.sub.2, the organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered and evaporated,
yielding 9.3 g (68%) (2S)-2-Hydroxymethyl-4-methylene-pyrroli-
dine-1-carboxylic acid tert-butyl ester as light brown oil, MS: 182
(M-CH.sub.2OH.).
[0668] To 9.6 g (45 mmol)
(2S)-2-Hydroxymethyl-4-methylene-pyrrolidine-1-c- arboxylic acid
tert-butyl ester and 25 g (112.5 mmol, 2.5 eq)
2,4,5-trifluorobenzyl bromide in 950 ml THF were added 3.2 g (73.1
mmol, 50% in mineral oil, 1.6 eq) NaH at 0.degree. C. over a period
of 30 min. The reaction was warmed to RT over night, and added to a
cooled mixture of saturated aqueous NH.sub.4Cl solution and EtOAc,
the phases were separated and the inorganic one was extracted with
EtOAc, the combined organic ones were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated. The crude product was
purified by flash chromatography using hexane/EtOAc 4:1 as an
eluent yielding 5.4 g (34%)
(2S)-4-Methylene-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carbox-
ylic acid tert-butyl ester as yellow oil, MS: 358 (MH.sup.+) and
1.7 g (13%) recovered starting material.
[0669] To 3.7 g (10.4 mmol)
(2S)-4-Methylene-2-(2,4,5-trifluoro-benzyloxym-
ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 160 ml
CH.sub.2Cl.sub.2 were added 5.1 g (20.8 mmol, 2 eq)
3-chloroperoxybenzoic acid. The mixture was stirred at RT over
night, Na.sub.2S.sub.2O.sub.3 solution was added and the reaction
was stirred for 1.5h. The phases were separated and the inorganic
one was extracted with ether. The organic phases were washed with
1M NaOH and brine, dried over Na.sub.2SO.sub.4, filtered and
evaporated yielding 3.9 g crude product as a mixture of (3R,6S)-
and (3S,6S)-6-(2,4,5-trifluoro-benzyloxymethyl)-1-oxa-5-aza-spir- o
[2.4]heptane-5-carboxylic acid tert-butyl, MS: 374 (MH.sup.+).
[0670] g (10.4 mmol) crude mixture of (3R,6S)- and
(3S,6S)-6-(2,4,5-triflu- oro-benzyloxymethyl)-1-oxa-5-aza-spiro
[2.4]heptane-5-carboxylic acid tert-butyl were dissolved in 20 ml
EtOH and were treated with 2.07 g (20.8 mmol, 2 eq) potassium
rhodanide in 2 ml H.sub.2O for 16 h at RT. The mixture was
concentrated, redissolved in EtOAc and washed with brine, dried
over Na.sub.2SO.sub.4, filtered and evaporated. The crude material
was purified by flash chromatography yielding 1.84 g (45%,2 steps)
a mixture of (3R,6S)- and
(3S,6S)-6-(2,4,5-trifluoro-benzyloxymethyl)-1-thi-
a-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester in the
ratio 5:1, MS: 390 (MH.sup.+).
[0671] To 70 mg (0.18 mmol) (major diastereomer) in 3 ml THF were
added 1.08 ml (1.08 mmol, 10 eq) 1M lithium triethylborohydride in
THF. After 1h the reaction was stopped by the addition of saturated
aqueous NH.sub.4Cl solution and the temperature was raised to RT.
The mixture was extracted with EtOAc, the organic phases were
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated.
[0672] The material was dissolved in 5.7 ml trifluoro ethanol and
3.8 ml CH.sub.2Cl.sub.2 and treated with 44.3 .mu.l (0.17 mmol)
tri-n-butyl phosphine and 19 .mu.l H.sub.2O at 0.degree. C. The
solution was stirred for 45 min, concentrated and purified by flash
chromatography with hexane/EtOAc 4:1 yielding 23 mg (33%, 2 steps)
(2S,4R)-4-Mercapto-4-methy-
l-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid
tert-butyl ester as yellow oil, MS: 392 (MH.sup.+).
[0673] Analogously, the following compound was prepared from the
minor diastereomer:
(2S,4S)-4-Mercapto-4-methyl-2-(2,4,5-trifluoro-benzyloxymet-
hyl)-pyrrolidine-1-carboxylic acid tert-butyl ester colorless oil,
MS: 392 (MH.sup.+).
Example 21.a
S-acetyl and Benzoyl-compounds
[0674] A solution of 10 g (21.96 mmol)
(2S,4R)-4-Mercapto-2-(2,4,5-trifluo-
ro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid
2,3-dihydro-benzo[1,4]di- oxin-5-yl ester in 130 ml pyridine were
treated at 0.degree. C. with 3.12 ml (43.92 mmol) acetyl chloride
and stirred for 6 h at RT. The reaction was poured on ice water and
extracted wit Et.sub.2O (3.times.). The organic phases were washed
with aqueous 1 N HCl and 10% NaCl, dried (Na.sub.2SO.sub.4) and
evaporated. Flash chromatography on silica gel
(CH.sub.2Cl.sub.2/Et.sub.2O 99.5:0.5 to 98:2) gave 9.94 g (91%)
(2S,4R)-4-Acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine--
1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester, MS: 498
(MH.sup.+).
[0675] In analogy:
(3R,5S)-5-Benzyloxymethyl-1-methanesulfonyl-pyrrolidine- -3-thiol
gave Thioacetic acid (3R,5S)-S-(5-benzyloxymethyl-1-methanesulfon-
yl-pyrrolidin-3-yl) ester, mp: 79-80.degree. C.; MS: 344
(MH.sup.+);
[0676]
(3R,5S)-1-Methanesulfonyl-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrro-
lidine-3-thiol gave Thioacetic acid
(3R,5S)-S-[1-methanesulfonyl-5-(2,4,5--
trifluoro-benzyloxymethyl)-pyrrolidin-3-yl]ester, MS: 398
(MH.sup.+);
[0677]
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine--
1-carboxylic acid 2-methoxycarbonyl-phenyl ester gave
(2S,4R)-4-Acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine--
1-carboxylic acid 2-methoxycarbonyl-phenyl ester, MS: 498
(MH.sup.+);
[0678]
4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfon-
ic acid butylamide gave (3R,5S)-Thioacetic acid
S-[1-butylsulfamoyl-5-(2,4-
,5-trifluoro-benzyloxymethyl)-pyrrolidin-3-yl]ester, MS: 455
(MH.sup.+);
[0679]
(2S,4R)-1-[4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidi-
n-1-yl]-3-methyl-butan-1-one gave (5S,3R)-Thioacetic acid
S-[1-(3-methyl-butyryl)-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidin-3--
yl]ester, MS: 404 (MH.sup.+);
[0680]
(2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine--
1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester and
benzoyl chloride gave
(2S,4R)-4-Benzoylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethy-
l)-pyrrolidine-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl,
MS: 560 (MH.sup.+).
Example 21.b
S-acetyl and Benzoyl-compounds
[0681] 534.1 mg (0.889 mmol)
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-
-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester in
15 ml CH.sub.2Cl.sub.2 were treated with 180 .mu.l (1.08 mmol, 1.27
eq) iPr.sub.2NEt and 80 .mu.l (1.08 mmol, 1.2 eq) acetylchloride at
0.degree. C. 70 mg (0.11 mmol, 0.12 eq) 4-(N-benzyl-N-methylamino)
pyridine, polymer-supported, were added, and the mixture was shaken
for 1 h, before 220 mg (2.0 mmol/g, 0.44 mmol)
polystyrene-divinylbenzene-supported tris(2-aminoethyl)amine
[synthesized according to: Polymer-Supported Quenching Reagents for
Parallel Purification. Booth, R. John; Hodges, John C, J. Am. Chem.
Soc. (1997), 119(21), 4882-4886.] were added.
[0682] After 1h 700 .mu.l (8.9 mmol, 10 eq) TFA were added
carefully to the mixture, followed by additional 700 .mu.l (8.9
mmol, 10 eq) TFA after 1h, the reaction mixture was shaken for 3 h,
and treated carefully with 3.3 ml (20 mmol) iPr.sub.2NEt, followed
by 70 mg (0.11 mmol, 0.12 eq) 4-(N-benzyl-N-methylamino)pyridine,
polymer-supported, and 150 .mu.l (1.16 mmol, 1.3 eq) n-butyl chloro
formate. After 45 min the mixture was filtered and the resin was
washed thoroughly. To the organic phase was added saturated
NaHCO.sub.3 solution, the layers were separated, and the inorganic
one was extracted with CH.sub.2Cl.sub.2, the organic phases were
washed with brine, dried over Na.sub.2SO.sub.4 and evaporated.
Purification by flash chromatography EtOAc/hexane 1:3 yielded 330
mg (57%, 3 steps)
[2S,4R]-2-{[acetyl-(2,5-difluoro-benzyl)-amino]-methyl}-4--
tritylsulfanyl-pyrrolidine-1-carboxylic acid butyl ester as light
yellow oil which was dissolved in 10 ml CH.sub.2Cl.sub.2 and
treated with 400 .mu.l (5.2 mmol, 10 eq) TFA and 1.1 ml (5.2 mmol,
10 eq) triisopropyl silane for 30 min at 0.degree. C. and 1 h at
RT. The solution was added to a saturated solution of NaHCO.sub.3,
and the inorganic phase was extracted with CH.sub.2Cl.sub.2, the
organic phase was washed with brine, and dried over
Na.sub.2SO.sub.4. Column chromatography with EtOAc/hexane 1:1
yielded 156.5 mg (75%)
[2S,4R]-2-{[acetyl-(2,5-difluoro-benzyl)-amino-
]-methyl}-4-mercapto-pyrrolidine-1-carboxylic acid butyl ester as
light yellow oil, MS: 401 (MH.sup.+).
[0683] Analogously, the following compound was prepared from
(2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-tritylsulfanyl-pyrrolidin-
e-1-carboxylic acid tert-butyl ester and benzyl chloro formate:
[0684]
(2S,4R)-2-[[benzyloxycarbonyl-(2,5-difluoro-benzyl)-amino]-methyl]--
4-mercapto-pyrrolidine-1-carboxylic acid butyl ester as colorless
oil, MS: 493 (MH.sup.+), via
(2S,4R)-2-[[benzyloxycarbonyl-(2,5-difluoro-benzyl)-a-
mino]-methyl]-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid
tert-butyl ester as colorless oil MS: 735 (MH.sup.+).
[0685] 130 mg (0.325 mmol)
[2S,4R]-2-{[acetyl-(2,5-difluoro-benzyl)-amino]-
-methyl}-4-mercapto-pyrrolidine-1-carboxylic acid butyl ester in 3
ml pyridine were treated with 120 .mu.l (1.68 mmol, 5.1 eq) acetyl
chloride at 0.degree. C. The resulting suspension was diluted with
8 ml CH.sub.2Cl.sub.2, and the mixture was stirred at RT over
night, concentrated in vacuo and the oil was redissolved in
EtOAc/1M HCl. The inorganic phase was extracted with
CH.sub.2Cl.sub.2 and the organic phases were washed with 1M HCl and
brine, dried over Na.sub.2SO.sub.4. The crude product was purified
by flash column chromatography with EtOAc/hexane 1:1 as eluent
yielding 118.2 mg (82%)
[2S,4R]-2-{[acetyl-(2,5-difluoro-benzyl)-amino]-methyl}-4-acetylsulfanyl--
pyrrolidine-1-carboxylic acid butyl ester as light yellow oil, MS:
443 (MH.sup.+).
[0686] Analogously, the following compounds were prepared from
(2S,4R)-2-{[benzyloxy-carbonyl-(2,5-difluoro-benzyl)-amino]-methyl}-4-mer-
capto-pyrrolidine-1-carboxylic acid butyl ester with acetyl
chloride or benzoyl chloride:
[0687]
(2S,4R)-4-acetylsulfanyl-2-{[benzyloxycarbonyl-(2,5-difluoro-benzyl-
)-amino]-methyl}-pyrrolidine-1-carboxylic acid butyl ester as
colorless oil, MS: 535 (MH.sup.+).
[0688]
(2S,4R)-4-benzoylsulfanyl-2-{[benzyloxycarbonyl-(2,5-difluoro-benzy-
l)-amino]-methyl}-pyrrolidine-1-carboxylic acid butyl ester as
colorless oil, MS: 597 (MH.sup.+).
[0689] 50 mg (0.09 mmol)
(2S,4R)-4-acetylsulfanyl-2-{[benzyloxycarbonyl-(2-
,5-difluoro-benzyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid
butyl ester were dissolved in 130 .mu.l 33%HBr in acetic acid and
stirred at 0.degree. C. for 30 min, and at RT for 1 h. The solution
was diluted with ether and poured on saturated NaHCO.sub.3
solution, carefully. The inorganic layer was extracted with EtOAc,
the combined organic phases were washed with water and brine, dried
over Na.sub.2SO.sub.4 and evaporated. Column chromatography yielded
13 mg (35%)
(2S,4R)-4-acetylsulfanyl-2-[(2,5-difluoro-benzylamino)-methyl]-pyrrolidin-
e-1-carboxylic acid butyl ester as colorless oil, MS: 401
(MH.sup.+).
[0690] Analogously, the following compound was prepared from
(2S,4R)-4-benzoylsulfanyl-2-[[benzyloxycarbonyl-(2,5-difluoro-benzyl)-ami-
no]-methyl]-pyrrolidine-1-carboxylic acid butyl ester and isolated
as hydrobromide:
[0691]
(2S,4R)-4-benzoylsulfanyl-2-[(2,5-difluoro-benzylamino)-methyl]-pyr-
rolidine-1-carboxylic acid butyl ester hydrobromide as light brown
solid, MS: 463 (MH.sup.+).
Example 22a
S-cys-compounds
[0692]
(3R,5S)-1-Methanesulfonyl-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrro-
lidine-3-thiol (100 mg, 0.28 mmol) and Boc-Cys(Npys)-OH (105 mg,
0.28 mmol) were dissolved in argon-degassed DMF (abs. 3 ml) and
degassed 0.1 M phosphate buffer (pH 6.2, 2 ml) was added. The
reaction mixture was magnetically stirred for 2 h under argon.
Ethyl acetate (30 ml), water (20 ml) were added and the organic
phase was washed with water (3.times.20 ml) and concentrated under
reduced pressure to give a yellow oil. The oil was dissolved in 4 M
HCl/1,4-dioxane (5 ml) for 0.5 h. Diethyl ether (30 ml) was added
and the precipitated product was filtered, washed with diethyl
ether and dried. Prep. RP-HPLC purification followed by pooling and
freeze-drying of desired fractions yielded
(R)-2-amino-3-[(3R,5S)-1-methanesulfonyl-5-(2,4,5-trifluoro-benzyloxymeth-
yl)-pyrrolidin-3-yldisulfanyl]-propionic acid TFA salt (148 mg),
MS: 473 (MH.sup.-).1
[0693] Analogously, the following compound was prepared from
(3R,5S)-5-Benzyloxy-methyl-1-methanesulfonyl-pyrrolidine-3-thiol:
(R)-2-amino-3-[(3R,5S)-5-benzyloxy-methyl-1-methanesulfonyl-pyrrolidin-3--
yldisulfanyl]-propionic acid TFA salt, MS: 419 (MH.sup.-).
Example 22b
N-Acetyl-S-Cys-Compounds
[0694]
(3R,5S)-1-Methanesulfonyl-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrro-
lidine-3-thiol (100 mg, 0.28 mmol) and Ac-Cys(Npys)-OH (89 mg, 0.28
mmol) were dissolved in argon-degassed DMF (abs. 2 ml) and degassed
0.1 M phosphate buffer (pH 6.2, 2 ml) was added. The reaction
mixture was magnetically stirred for 2 h under argon. Work-up as
above (Example 22a) yielded
(R)-2-acetylamino-3-[(3R,5S)-1-methanesulfonyl-5-(2,4,5-trifluoro-
-benzyloxymethyl)-pyrrolidin-3-yldisulfanyl]-propionic acid (135
mg), MS: 515 (MH.sup.-).
[0695] Analogously, the following compound was prepared from
(3R,5S)-5-Benzyloxymethyl-1-methanesulfonyl-pyrrolidine-3-thiol:
(R)-2-acetylamino-[(3R,5S)-benzyloxymethyl-1-methanesulfonyl-pyrrolidin-3-
-yldisulfanyl]-propionic acid, MS: 463 (MH.sup.+).
Example A
[0696] Tablets containing the following ingredients can be
manufactured in a conventional manner:
11 Ingredients Per tablet Compound of formula I 10.0-100.0 mg
Lactose 125.0 mg Maize starch 75.0 mg Talc 4.0 mg Magnesium
stearate 1.0 mg
Example B
[0697] Capsules containing the following ingredients can be
manufactured in a conventional manner:
12 Ingredients Per capsule Compound of formula I 25.0 mg Lactose
150.0 mg Maize starch 20.0 mg Talc 5.0 mg
Example C
[0698] Injection solutions can have the following composition:
13 Compound of formula I 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg
Water for injection solutions ad 1.0 ml
Example D
[0699] 500 mg of compound of formula I are suspended in 3.5 ml of
Myglyol 812 and 0.08 g of benzyl alcohol. This suspension is filled
into a container having a dosage valve. 5.0 g of Freon 12 under
pressure are filled into the container through the valve. The Freon
is dissolved in the Myglyol-benzyl alcohol mixture by shaking. This
spray container contains about 100 single dosages which can be
applied individually.
* * * * *