U.S. patent application number 09/772501 was filed with the patent office on 2002-01-24 for process for the preparation of aminoalcohol derivatives and their further conversion to (1r, 4s)-4-((2-amino-6-chloro-5-formamido-4-pyrimidinyl)-am- ino)-2-cyclopentenyl-1- methanol.
This patent application is currently assigned to Lonza AG. Invention is credited to Berchtold, Katja, Bernegger-Egli, Christine, Breitbach, Holger, Brieden, Walter, Petersen, Michael, Roduit, Jean-Paul, Schroer, Josef, Urban, Eva Maria.
Application Number | 20020010360 09/772501 |
Document ID | / |
Family ID | 27508776 |
Filed Date | 2002-01-24 |
United States Patent
Application |
20020010360 |
Kind Code |
A1 |
Brieden, Walter ; et
al. |
January 24, 2002 |
Process for the preparation of aminoalcohol derivatives and their
further conversion to (1R,
4S)-4-((2-amino-6-chloro-5-formamido-4-pyrimidinyl)-am-
ino)-2-cyclopentenyl-1- methanol
Abstract
The invention relates to a novel process for the preparation of
an aminoalcohol of the formula 1 racemically or optically active,
starting from 2-azabi-cyclo[2.2.1]hept-5-- en-3-one, its further
conversion to give the corresponding acyl derivative and its
further conversion to (1S,4R)- or (1R,4S)-4-(2-amino-6-chloro-9-H-
-purine-9-yl)-2-cyclopentenyl-1-methanol of the formulae 2 In the
latter synthesis, the aminoalcohol is converted into the
corresponding D- or L-tartrate, which is then reacted with
N-(2-amino-4,6-dichloropyrimidin-5-yl) formamide of the formula 3
to give (1S,4R)- or
(1R,4S)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl-
)amino]-2-cyclopentenyl-1-methanol of the formulae 4 and then
cyclized to give the end compounds.
Inventors: |
Brieden, Walter; (Brig,
CH) ; Schroer, Josef; (Susten, CH) ;
Bernegger-Egli, Christine; (Munster, CH) ; Urban, Eva
Maria; (Visp, CH) ; Petersen, Michael; (Visp,
CH) ; Roduit, Jean-Paul; (Grone, CH) ;
Berchtold, Katja; (Baltschieder, CH) ; Breitbach,
Holger; (Baltschieder, CH) |
Correspondence
Address: |
Bert J. Lewen
DARBY & DARBY P.C.
805 Third Avenue
New York
NY
10022
US
|
Assignee: |
Lonza AG
Munchensteinerstrasse 39
Basel
CH
CH-4002
|
Family ID: |
27508776 |
Appl. No.: |
09/772501 |
Filed: |
January 30, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09772501 |
Jan 30, 2001 |
|
|
|
09198427 |
Nov 24, 1998 |
|
|
|
Current U.S.
Class: |
560/115 ;
564/210; 564/444 |
Current CPC
Class: |
C07C 233/23 20130101;
C07C 213/10 20130101; C12P 41/007 20130101; C07C 2601/10 20170501;
C07C 213/08 20130101; C07C 271/24 20130101; C07C 213/00 20130101;
C12P 13/001 20130101; C12P 13/02 20130101; C07C 213/02 20130101;
C07D 473/00 20130101; C07B 2200/07 20130101; C07D 473/40 20130101;
C07C 215/42 20130101; C07C 213/00 20130101; C07C 215/26 20130101;
C07C 213/00 20130101; C07C 215/42 20130101; C07C 213/02 20130101;
C07C 215/26 20130101; C07C 213/02 20130101; C07C 215/42 20130101;
C07C 213/08 20130101; C07C 215/26 20130101; C07C 213/08 20130101;
C07C 215/42 20130101; C07C 213/10 20130101; C07C 215/26 20130101;
C07C 213/10 20130101; C07C 215/42 20130101 |
Class at
Publication: |
560/115 ;
564/210; 564/444 |
International
Class: |
C07C 233/06; C07C
271/24 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 27, 1997 |
CH |
2739/97 |
Dec 3, 1997 |
CH |
2781/97 |
Jan 21, 1998 |
CH |
0133/98 |
Mar 27, 1998 |
CH |
0723/98 |
Oct 7, 1998 |
EP |
98118895.6 |
Claims
1. Process for the preparation of an aminoalcohol of the formula
26in the form of the racemate or one of its optically active
isomers, comprising the reduction of
2-azabicyclo-[2.2.1]hept-5-en-3-one of the formula 27in the form of
the racemate or one of its optically active isomers with a metal
hydride.
2. Process according to claim 1, characterized in that the metal
hydride used is a metal borohydride.
3. Process according to Patent claim 1 or 2, characterized in that
the reduction is carried out at a temperature of from -20 to
200.degree. C.
4. Process according to at least one of Patent claims 1 to 3,
characterized in that the reduction is carried out in an aprotic or
protic organic solvent or in a corresponding solvent mixture.
5. Process according to at least one of Patent claims 1 to 4,
characterized in that the reduction is carried out in the presence
of water or a lower aliphatic alcohol.
6. Process for the preparation of an aminoalcohol of the formula
28in the form of the racemate or one of its optically active
isomers, comprising the hydrolysis of a cyclopentene derivative of
the general formula 29in the form of the racemate or one of its
optically active isomers, in which R is C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, aryl or aryloxy, with an alkali metal
hydroxide
7. Process according to Patent claim 6, characterized in that the
cyclopentene derivative of the general formula 30in the form of the
racemate or one of its optically active isomers, in which R is as
defined above, is prepared by reducing an
acyl-2-azabicyclo[2.2.1]hept-5-en-3-one of the formula 31in the
form of the racemate or one of its optically active isomers, in
which R is as defined above, with a metal hydride in an anhydrous
solvent.
8. Process for the preparation of (1S,4R)- or
(1R,4S)-1-amino-4-(hydroxyme- thyl)-2-cyclopentene of the formulae
32or salts thereof and/or of (1S,4R)- or
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene derivatives of the
general formulae 33or salts thereof, in which X and Y are identical
or different and are an acyl group or H, with the exception of
X=Y=H, comprising the racemate resolution of racemic aminoalcohol
of the formula 34either by chemical means using an optically active
tartaric acid or biotechnological means using a hydrolase in the
presence of an acylating agent.
9. Process according to Patent claim 8, characterized in that the
biotechnological racemate resolution is carried out using a lipase,
and the chemical racemate resolution using D-(-)- or L-(+)-tartaric
acid.
10. Process for the preparation of (1S,4R)- or
(1R,4S)-1-amino-4-(hydroxym- ethyl)-2-cyclopentene of the formulae
35or salts thereof, comprising the chemical hydrolysis of (1S,4R)-
or (1R,4s)-1-amino-4-(hydroxymethyl)-2-cy- clopentene derivatives
of the general formulae 36in which X and Y are as defined
above.
11. Process for the preparation of an (1R,4S)- or
(1S,4R)-1-amino-4-(hydro- xymethyl)-2-cyclopentene derivative of
the general formulae 37in which R is C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, aryl or aryloxy, characterized in that, in a
first stage (.+-.)-2-azabicyclo-[2.2.1]hept-5-en-3-one of the
formula 38in the form of the racemate or one of its optically
active isomers is reduced with a metal hydride into a racemic
aminoalcohol of the formula 39which, in a second stage, is
converted by biotechnological means using a hydrolase in the
presence of an acylating agent, or by chemical means using an
optically active tartaric acid, into (1S,4R)- or
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene of the formula V
or VI, which is acylated to give products of the formula IX or
X.
12. Process for the preparation of (1S,4R)- or
(1R,4S)-4-(2-amino-6-chloro-
-9-H-purine-9-yl)-2-cyclopentenyl-1-methanol, or salts thereof, of
the formulae 40characterized in that (1R,4S)- or
(1S,4R)-1-amino-4-(hydroxym- ethyl)-2-cyclopentene D- or
L-hydrogentartrate is reacted with
N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide of the formula 41to
give
(1S,4R)-4-(1R,4S)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-
-cyclopentenyl-1-methanol of the formulae 42and the latter is then
cyclized in a known manner to give compounds of formula XI or
XII.
13. Process for the preparation of
(1S,4R)-4-(2-amino-6-chloro-9-H-purine--
9-yl)-2-cyclopentenyl-1-methanol, or salts thereof, of the formula
43characterized in that (-)-2-azabicyclo[2.2.1]hept-5-en-3-one or
(-)-acyl-2-azabicyclo[2.2.1]hept-5-en-3-one of the formulae 44in
which R is as defined above, is reduced with a metal hydride to
give an aminoalcohol of the formula 45or to give a cyclopentene
derivative of the general formula 46in which R is as defined above,
which is then converted into the corresponding hydrohalide salts,
then reacted with N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide
of the formula 47to give
(1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopent-
enyl-1-methanol of the formula 48and cyclizing the latter in a
known manner to give the compounds of the formula XII.
14. (1R,4s)-1-Amino-4-(hydroxymethyl)-2-cyclopentene D- or
L-hydrogentartrate.
15. (1S,4R)-1-Amino-4-(hydroxymethyl)-2-cyclopentene L- or
D-hydrogentartrate.
Description
DESCRIPTION
[0001] The present invention relates to a novel process for the
preparation of (1R,4S)- or (1S,4R)-1-amino-4
(hydroxymethyl)-2-cyclopente- ne of the formulae 5
[0002] or salts thereof, or the D- or L-hydrogentartrates thereof
and also their further conversion to give (1S,4R)- or
(1R,4S)-4-(2-amino-6-chloro-- 9-H-purine-9-yl)-2-cyclopentene.
(1R,4S)-1-Amino-4-(hydroxymethyl)-2-cyclo- pentene of the formula
IV is an important intermediate for the preparation of carbocyclic
nucleosides such as, for example, Carbovir.RTM. (Campbell et al.,
J. Org. Chem. 1995, 60, 4602-4616).
[0003] A process for the preparation of
(1R,4S)-1-amino-4-(hydroxymethyl)-- 2-cyclopentene is described,
for example, by Campbell et al. (ibid) and by Park K. H. &
Rapoport H. (J. Org. Chem. 1994, 59, 394-399). In this process, the
starting material is either D-glucono-6-lactone or D-serine,
approximately 15 synthesis stages being required to form
(1R,4S)-N-tert-butoxy-carbonyl-4-hydroxymethyl-2-cyclopentene, and
the protecting group is removed to give
(1R,4S)-1-amino-4-(hydroxy-methyl)-2-- cyclopentene.
[0004] Both these processes are costly, complex and not practicable
industrially. WO 93/17020 describes a process for the preparation
of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene, in which
(1R,4S)-4-amino-2-cyclopentene-1-carboxylic acid is reduced to the
desired product using lithium aluminium hydride.
[0005] Disadvantages of this process are firstly that the double
bond of the cyclopentene ring is also reduced, the poor handling
properties of lithium aluminium hydride and secondly that it is too
costly.
[0006] Taylor S. J. et al. (Tetrahetron: Asymmetry Vol. 4, No. 6,
1993, 1117-1128) desribe a process for the preparation of
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene starting from
(.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-one as starting material. In
this process, the starting material is converted, using
microorganisms of the species Pseudomonas solanacearum or
Pseudomonas fluorescens, into
(1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one, which is then reacted
with di-tert-butyl dicarbonate to give (1R,
4S)-N-tert-butoxycarbonyl-2-azabic- yclo[2.2.1]hept-5-en-3-one, and
the latter is reduced using sodium borohydride and trifluoroacetic
acid to give the desired product. This process is far too
costly.
[0007] In addition, Martinez et al. (J. Org. Chem. 1996, 61,
7963-7966) describe a 10-stage synthesis of
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cycl- opentene starting from
diethyl dialkylmalonate. This process too has the disadvantage that
it is complex and not practicable industrially.
[0008] It is also known that N-substituted
(.+-.)-2-azabicyclo-[2.2.1]hept- -5-en-3-ones, which carry an
electron-withdrawing substituent, can be reduced to the
corresponding N-substituted aminoalcohols using a metal hydride
(Katagiri et al., Tetrahedron Letters, 1989, 30, 1645-1648; Taylor
et al., ibid).
[0009] In contrast to this, it is known that unsubstituted
(.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-one of the formula 6
[0010] is reduced with lithium aluminium hydride to give
(.+-.)-2-azabicyclo[2.2.2]octene (Malpass & Tweedle, J. Chem.
Soc., Perkin Trans 1, 1977, 874-884), and that the direct reduction
of (.+-.)-2-azabicyclo[2.2.2]hept-5-en-3-one to give the
corresponding aminoalcohol has to date been impossible (Katagiri et
al., ibid; Taylor et al., ibid).
[0011] It is also known to resolve racemic
1-amino-4-(hydroxymethyl)-2-cyc- lopentene using
(-)-dibenzoyl-tartaric acid (U.S. Pat. No. 5,034,394). On the one
hand, this reaction has the disadvantage that (-)-dibenzoyltartaric
acid is expensive, and, on the other hand, that the separation must
take place in the presence of an exactly defined mixture of
acetonitrile and ethanol. This solvent mixture cannot be removed
and must be fed to the combustion.
[0012] The object of the present invention was to provide a simple,
economical and cost-effective process for the preparation of a
(1R,4S)-1-amino-4-(hydroxy-methyl)-2-cyclopentene.
[0013] Surprisingly, it has now been found that when
(.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-one of the formula 7
[0014] in the form of the racemate or one of its optically active
isomers, is reduced with a metal hydride, the aminoalcohol of the
formula 8
[0015] in the form of the racemate or one of its optically active
isomers is obtained in a simple manner.
[0016] As the person skilled in the art is aware, the aminoalcohol
of the formula I can be converted using an acid into the
corresponding salts, such as, for example, into hydrohalide salts.
Suitable hydrohalide salts are hydrobromides and
hydrochlorides.
[0017] The starting material, the
(.+-.)-2-azabicyclo-[2.2.1]hept-5-en-3-o- ne can be prepared
according to EP-A 0 508 352.
[0018] Metal hydrides which may be used are alkali metal or
alkaline earth metal hydrides and also binary or complex metal
hydrides of the boron or aluminium group, such as alkali metal and
alkaline earth metal borohydrides, alkali metal and alkaline earth
metal aluminium hydrides. Suitable alkali metal or alkaline earth
metal hydrides are LiH, NaH, KH, BeH.sub.2, MgH.sub.2 or
CaH.sub.2.
[0019] Binary alkali metal or alkaline earth metal borohydrides
which may be used are NaBH.sub.4, LIBH.sub.4, KBH.sub.4,
NaAlH.sub.4, LiAlH.sub.4, KAlH.sub.4, Mg(BH.sub.4).sub.2,
Ca(BH.sub.4).sub.2, Mg(AlH.sub.4).sub.2 and Ca(AlH.sub.4).sub.2
Complex metal hydrides of the boron or aluminium group may have the
general formula M.sup.1M.sup.2H.sub.nL.sub.m, in which n is an
integer from 1 to 4, and m is an integer from 4 to 4 minus the
corresponding number n, M.sup.1 is an alkali metal atom, M.sup.2 is
boron or aluminium, and L is C.sub.1-4-alkyl, C.sub.1-4-alkenyl,
C.sub.1-4-alkoxy, CN or an amine, or the complex metal hydrides may
have the general formula M.sup.2H.sub.OL.sub.p, in which M.sup.2 is
as defined above and O is an integer from 0 to 3, and p is an
integer from 3 to 3 minus the corresponding number p. Possible
M.sup.1M.sup.2M.sub.nL.sub.m compounds are
LiBH(C.sub.2H.sub.5).sub.3, LiBH.sub.x(OCH.sub.3).sub.4-x,
LiAlH(OC(CH.sub.3).sup.-.sub.3).sub.3,
NaAlH.sub.2(OC.sub.2H.sub.4OCH.sub- .3).sub.2,
NaAlH.sub.2(C.sub.2H.sub.5).sub.2 or NaBH.sub.3CN. Preferably, the
reduction is carried out using a metal borohydride. As an expert in
the art is aware, the metal hydrides mentioned such as, for
example, LiBH.sub.4, can also be produced "in situ". Common
preparation methods for LiBH.sub.4 are, for example, the reaction
of an alkali metal borohydride with a lithium halide (H. C. Brown
et al., Inorg. Chem. 20, 1981, 4456-4457), the reaction of LiH with
B.sub.2O.sub.3 in the presence of hydrogen and a hydrogenation
catalyst (EP-A 0 512 895), the reaction of LiH with
(H.sub.5C.sub.2)OBF.sub.3 (DE-A 94 77 02) and that of LiH with
B(OCH.sub.3).sub.3 (U.S. Pat. No. 2,534,533).
[0020] The metal hydrides are expediently used in a molar ratio of
from 1 to 5 per mole of
(.+-.)-2-azabicyclo-[2.2.1]hept-5-en-3-one.
[0021] The metal hydrides, in particular NaBH.sub.4, are preferably
used with lithium salt additives. Lithium salts which may be used
are LiCl, LiF, LiBr, LiI, Li.sub.2SO.sub.4, LiHSO.sub.4,
Li.sub.2CO.sub.3, Li(OCH.sub.3) and LiCO.sub.3.
[0022] The reduction is expediently carried out in an inert-gas
atmosphere, such as, for example, in an argon or nitrogen
atmosphere.
[0023] The reduction can be carried out at a temperature of from
-20 to 200.degree. C., preferably at a temperature of from 60 to
150.degree. C.
[0024] Suitable solvents are aprotic or protic organic solvents.
Suitable aprotic organic solvents may be ethers or glycol ethers,
such as, for example, diethyl ether, dibutyl ether, ethyl methyl
ether, dilsopropyl ether, tert-butyl methyl ether, anisole,
dioxane, tetrahydrofuran, monoglyme, diglyme and formaldehyde
dimethyl-acetal. Suitable protic organic solvents are
C.sub.1-6-alcohols, such as methanol, ethanol, propanol,
isopropanol, butanol, tert-butanol, pentanol, tert-amyl alcohol or
hexanol and also mixtures of these with water. Suitable protic
organic solvents are also mixtures of one of said ethers, glycol
ether with water or with one of said alcohols, such as a mixture of
a C.sub.1-6-alcohol with an ether or glycol ether, in particular a
mixture of methanol, ethanol or water with diethyl ether,
tetrahydrofuran, dioxane, glyme or diglyme. The solvent used is
preferably a protic organic one, such as a mixture of a
C.sub.1-6-alcohol or water with an ether or glycol ether.
[0025] In a preferred embodiment, the reduction is carried out in
the presence of an additive, such as in the presence of water or of
a lower aliphatic alcohol. The lower aliphatic alcohol may be
methanol, ethanol, methoxyethanol, n-propanol, isopropanol,
isobutanol, tert-butanol, n-butanol, diols such as butanediol, and
triols such as glycerol. In particular, the lower aliphatic alcohol
is methanol or ethanol. Here, the lower aliphatic alcohol is
expediently used in a molar ratio of from 2 to 15 per mol of
(.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-one.
[0026] If the reaction is carried out in the presence of said
alcohol, the corresponding amino acid ester can be formed in situ
(intermediate). I.e. if the starting material used is
(.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-on- e, according to the
invention the corresponding (.+-.)-amino acid ester can be formed.
If the starting material used is (-)-2-azabicyclo[2.2.1]he-
pt-5-en-3-one, according to the invention the (-)-amino acid ester
can correspondingly be formed as intermediate.
[0027] Surprisingly, it has also been found that when a
cyclopentene derivative of the general formula 9
[0028] in the form of the racemate or one of its optically active
isomers, in which R is C.sub.1-4-alkyl, C.sub.1-4-alkoxy, aryl or
aryloxy, is hydrolyzed with an alkali metal hydroxide, the
aminoalcohol of the formula 10
[0029] in the form of the racemate or one of its optically active
isomers is obtained in a simple manner.
[0030] C.sub.1-4-Alkyl can be substituted or unsubstituted. In the
text below substituted C.sub.1-4-alkyl is taken to mean C.sub.1-4
-alkyl substituted by a halogen atom. The halogen atom may be F,
Cl, Br or I. Examples of C.sub.1-4-alkyl are methyl, ethyl, propyl,
butyl, isobutyl, tert-butyl, isopropyl, chloromethyl, bromomethyl,
dichloromethyl and dibromomethyl. The C.sub.1-4-alkyl is preferably
methyl, ethyl, propyl, butyl, isobutyl or chloromethyl.
[0031] The C.sub.1-4-alkoxy used may be, for example, methoxy,
ethoxy, propoxy or butoxy. The aryl used can be, for example,
phenyl or benzyl, substituted or unsubstituted. The aryloxy used
can be, for example, benzyloxy or phenoxy, substituted or
unsubstituted.
[0032] The alkali metal hydroxide used may be sodium or potassium
hydroxide.
[0033] For this process variant, the cyclopentene derivative of the
general formula III is preferably prepared by reduction of the
corresponding acyl-2-azabicyclo[2.2.1]hept-5-en-3-one of the
general formula 11
[0034] in the form of the racemate or one of its optically active
isomers, in which R is as defined above, using one of the metal
hydrides already mentioned in an anhydrous solvent.
[0035] The anhydrous solvent may be protic or aprotic organic
solvents, in particular an anhydrous protic organic solvent such as
a tertiary alcohol. The tertiary alcohol may be tert-butyl alcohol
or tert-amyl alcohol.
[0036] As already mentioned above, this reduction is also
preferably carried out in the presence of an addition, such as in
the presence of a lower aliphatic alcohol such as methanol, in
particular in the presence of 2 mol of methanol per mole of
acyl-2-azabicyclo-[2.2.1]hept-5-en-3-one (formula IV).
[0037] The reaction is expediently carried out at a temperature of
from 0 to 50.degree. C., preferably from 15 to 30.degree. C.
[0038] The racemic aminoalcohol of the formula I is then converted
according to the invention either by chemical means using an
optically active tartaric acid or by biotechnological means using a
hydrolase in the presence of an acylating agent to give (1R,4S)- or
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene of the formula
12
[0039] or salts thereof and/or to give (1S,4R)- or
(1R,4S)-1-amino-4-(hydr- oxymethyl)-2-cyclopentene derivative of
the general formulae 13
[0040] or salts thereof, in which X and Y are identical or
different and are an acyl group or H, with the exception of
X=Y=H.
[0041] The hydrolases used may be lipases, proteases, amidases or
esterases, lipases being expediently used.
[0042] In the text below, salts are taken to mean hydrohalide salts
such as hydrochlorides, hydrobromides or tartrates.
[0043] As the person skilled in the art is aware,
hydrolase-catalyzed acylations in which optically active compounds
are formed are carried out in the presence of a suitable acylating
agent (Balkenhohl et al., 1997, J. Prakt. Chem. 339, 381-384; K.
Faber, "Biotransformation in Organic Chemistry", 2nd ed., Berlin
1995, 270-305). Suitable acylating agents are generally carboxylic
acid derivatives such as carboxamides, carboxylic anhydrides or
carboxylic esters. The carboxylic esters may, for example, be
alkoxycarboxylic esters, such as ethyl methoxyacetate and isopropyl
methoxyacetate, C.sub.1-6-carboxylic esters, such as butyl acetate,
ethyl butyrate and ethyl hexanoate, glyceryl esters, such as
tributyrin (glyceryl tributyrate), glycol esters, such as glycol
dibutyrate and diethyl diglycolate, dicarboxylic esters, such as
diethyl fumarate and malonate, cyanocarboxylic esters, such as
ethyl cyanoacetate, or cyclic esters, such as, for example,
6-caprolactone. Accordingly, the acyl group in the formulae VII and
VIII corresponds to the acid component of the carboxylic acid
derivative used.
[0044] The lipases used may be standard commercial lipases, such
as, for example: Novo lipase SP523 from Aspergillus oryzae (Novozym
398), Novo lipase SP524 from Aspergillus oryzae (lipase=Palatase
20000 L from Novo), Novo lipase SP525 from Candida antarctica
(lipase B Navozym 435, immobilized), Novo lipase SP526 from Candida
antarctica (lipase A=Novozym 73S, immobilized), lipase kits from
Fluka (1 & 2), Amano P lipase, lipase from Pseudomonas sp. ,
lipase from Candida cylindracea, lipase from Candida lypolytica,
lipase from Mucor miehei, lipase from Aspergillus niger, lipase
from Bacillus thermocatenulatus, lipase from Candida antarctica,
lipase AH (Amano; immobilized), lipase P (Nagase), lipase AY from
Candida rugosa, lipase G (Amano 50), lipase F (Amano FAP15), lipase
PS (Amano), lipase AH (Amano), lipase D (Amano), lipase AK from
Pseudomonas fluorescens, lipase PS from Pseudomonas cepacia,
newlase I from Rhizopus niveus, lipase PS-CI (immobilized lipase
from Pseudomonas cepacia). These lipases may, as the person skilled
in the art is aware, be used as cell-free enzyme extracts or else
in the corresponding microorganism cell.
[0045] The proteases may also be commercially available, such as,
for example, serine proteases such as subtilisins. The subtilisin
may be savinase from Bacillus sp., alcalase, subtilisin from
Bacillus licheniformis and also proteases from Aspergillus,
Rhizopus, Streptomyces or Bacillus sp.
[0046] The biotechnological racemate resolution is expediently
carried out at a temperature of from 10 to 80.degree. C. and at a
pH of from 4 to 9.
[0047] The biotechnological racemate resolution is expediently
carried out in a protic or aprotic organic solvent. Suitable
aprotic organic solvents are ethers such as tert-butyl methyl
ether, diisopropyl ether, dibutyl ether, dioxane and
tetrahydrofuran, aliphatic hydrocarbons such as hexane, organic
bases such as pyridine, and carboxylic esters such as ethyl
acetate, and suitable protic organic solvents are the
C.sub.1-6-alcohols already described, such as, for example,
pentanol.
[0048] The (1S,4R)- or
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene derivatives of the
general formulae VII and VIII formed in accordance with the
invention during the biotechnological racemate resolution are,
depending on the desired target compound (aminoalcohol of the
formula V or VI), hydrolyzed by chemical means to give the
aminoalcohol of the formula V or VI. The chemical hydrolysis is
expediently carried out in an aqueous basic solution or using a
basic ion exchanger. The aqueous basic solution is preferably, as
for the hydrolysis of the cyclopentene derivatives of the general
formula III described above, an alkali metal hydroxide. The basic
ion exchangers can, for example, be Dowex 1.times.8(OH-) and
Duolite A147.
[0049] The chemical racemate resolution is carried out using an
optically active tartaric acid such as using D-(-)-tartaric acid or
L-(+)-tartaric acid.
[0050] The racemate resolution with D-(-)-tartaric acid is
expediently carried out by firstly reacting the racemic
1-amino-4-(hydroxymethyl)-2-c- yclopentene with the D-(-)-tartaric
acid in the presence of a lower aliphatic alcohol.
[0051] Suitable lower aliphatic alcohols are the same as those
described above. Preference is given to using methanol. The
reaction which leads to formation of the salt is usually carried
out at temperature between 20.degree. C. and the reflux temperature
of the solvent, preferably at the reflux temperature.
[0052] If desired, the 1-amino-4-(hydroxymethyl)-2-cyclopentene
D-tartrate formed during the reaction can be further purified by
recrystallization from a lower aliphatic alcohol such as
methanol.
[0053] The racemate resolution with L-(+)-tartaric acid is
expediently carried out as that with D-(-)-tartaric acid. I.e. the
racemate resoluton with L-(+)-tartaric acid is likewise carried out
in the presence of a lower aliphatic alcohol and at a temperature
between 20.degree. C. and the reflux temperature of the solvent,
preferably at the reflux temperature. After cooling, the
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclo- pentene
L-hydrogentartrate crystallizes out.
[0054] The (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene
L-hydrogentartrate is present, in particular, in dissolved form in
the mother liquor.
[0055] Isolation, further purification (liberation) and conversion
to the corresponding salt of (1R,4S)- or
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cyc- lopentene takes place with
a base and subsequent acid treatment. Suitable bases are alkali
metal alkoxides, alkali metal or alkaline earth metal carbonates,
or alkali metal or alkaline earth metal hydroxides. The alkali
metal alkoxides may be sodium or potassium alkoxides. The alkali
metal carbonate may be potassium or sodium carbonate, potassium or
sodium hydrogencarbonate, and the alkaline earth metal carbonate
may be magnesium or calcium carbonate. The alkali metal hydroxide
may be sodium or potassium hydroxide, and the alkaline earth metal
hydroxide may be calcium hydroxide. Conversion to the corresponding
salt usually takes place with a mineral acid such as with sulphuric
acid, hydrochloric acid or phosphoric acid, preferably with
hydrochloric acid.
[0056] (1R,4S)- or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene
D-hydrogentartrate and (1R,4S)- or
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cy- clopentene
L-hydrogen-tartrate are compounds unknown in the literature and are
likewise provided by the invention.
[0057] Preference is given to carrying out the chemical racemate
resolution with D-(.+-.)-tartaric acid due to the higher
performance, technical facility and more efficient racemate
resolution.
[0058] As for the racemic aminoalcohol, it is of course also
possible to react the optically active (1R,4S)- or
(1S,4R)-1-amino-4-(hydroxymethyl)-- 2-cyclopentenes with D-(-)- or
L-(+)-tartaric acid to give the corresponding tartrates.
[0059] A further constituent of the present invention is the
further conversion, the acylation, of the (1R,4S)- or
(1S,4R)-1-amino-4-(hydroxym- ethyl)-2-cyclopentenes to give the
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyc- lopentene derivative of
the general formula 14
[0060] Here, the substituent R is as defined in the cyclopenten
derivative of the general formula III.
[0061] The acylation can be carried out using a carbonyl halide of
the general formula 15
[0062] in which X is a halogen atom, and R is as defined above, or
using a carboxylic anhydride of the general formula 16
[0063] in which R is as defined above.
[0064] The halogen atom X may be F, Cl, Br or I. Preference is
given to Cl or F.
[0065] Examples of carbonyl halides are: acetyl chloride,
chloroacetyl chloride, butyryl chloride, isobutyryl chloride,
phenylacetyl chloride, benzyl chloroformate, propionyl chloride,
benzoyl chloride, alkyl chloroformate or tert-butyloxycarbonyl
fluoride.
[0066] Examples of carboxylic anhydrides are: tert-butoxycarbonyl
anhydride, butyric anhydride, acetic anhydride or propionic
anhydride. The acylation is preferably carried out using a
carboxylic anhydride, in particular using tert-butoxycarbonyl
anhydride.
[0067] The acylation can be carried out without solvent or using an
aprotic organic solvent. The acylation is expediently carried out
in an aprotic organic solvent. Suitable aprotic organic solvents
are, for example, pyridine, acetonitrile, dimethylformamide,
diisopropyl ether, tetrahydrofuran, toluene, methylene chloride,
N-methylpyrrolidone, triethylamine, chloroform, ethyl acetate,
acetic anhydride and mixtures thereof.
[0068] The acylation is expediently carried out at a temperature of
from -20 to 100.degree. C., preferably from 0 to 80.degree. C.
[0069] The further conversion according to the invention of
(1R,4S)- or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene D- or
L-hydrogentartrate to (1S,4R)- or
(1R,4S)-4-(2-amino-6-chloro-9-H-purine-9-yl)-2-cyclopenten-
yl-1-methanol, or a salt thereof, of the formulae 17
[0070] is carried out by reacting (1R,4S)- or (1S,4R)
1-amino-4-(hydroxymethyl)-2-cyclopentene D- or L-hydrogentartrate
with N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide of the formula
18
[0071] to give (1S,4R)- or
(1R,4S)-4-[(2-amino-6-chloro-5-formamido-4-pyri-
midinyl)amino]-2-cyclopentenyl-1-methanol of the formulae 19
[0072] and then cyclizing the latter in a known manner to give the
compounds according to formula VIII and IX.
[0073] N-(2-Amino-4,6-dichloropyrlmidin-5-yl)formamide can be
prepared according to WO 95/21 161.
[0074] The reaction is expediently carried out in the presence of a
base. Suitable bases are the same as those previously described for
liberating (1R,4S)- or
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentenes from the
corresponding tartrate.
[0075] The reaction is expediently carried out in a protic solvent.
The protic solvent may be lower aliphatic alcohols such as
methanol, ethanol, propanol, isopropanol, butanol or
isobutanol.
[0076] The (1S,4R)- or
(1R,4S)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidi-
nyl)amino]-2-cyclopentenyl-1-methanol of the formula XI or XII is
then cyclized in a known manner according to WO 95/21 161 to give
the end product according to Pormula VIII or IX.
[0077] The cyclization is usually carried out dissolved in trialkyl
orthoformate in the presence of a concentrated aqueous acid. The
trialkyl orthoformates used may be, for example, trimethyl or
triethyl orthoformate.
[0078] The aqueous acid may be, for example, hydrogen fluoride,
sulphuric acid or methanesulphonic acid.
[0079] A further constituent of the invention is the overall
process for the preparation of
(1S,4R)-4-(2-amino-6-chloro-9-H-purine-9-yl)-2-cyclope-
ntenyl-1-methanol, or salts thereof, of the formula XII starting
from (-)-2-azabicyclo[2.2.1]hept-5-en-3-one or
(-)-acyl-2-azabicyclo[2.2.1]hep- t-5-en-3-one of the formulae
20
[0080] in which R is as defined above, by reduction with a metal
hydride to give an aminoalcohol of the formula 21
[0081] or to give a cyclopentene derivative of the general formula
22
[0082] in which R is as defined above, which are then converted
into the corresponding hydrohalide salts, and then reacted with
N-(2-amino-4,6-dichloropyrimidin-5-yl)-formamide of the formula
23
[0083] to give
(1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amin-
o]-2-cyclopentenyl-1-methanol of the 24
[0084] and then the latter is cyclized in a known manner to give
the compound of the formula 25
[0085] This process variant has the advantage that the hydrohalide
salts formed therein may be used as a crude mixture in the
preparation of the product of the formula XII.
EXAMPLES
Example 1
[0086] Reduction of acyl- or
unsubstituted-2-azabicyclo[2.2.1]-hept-5-en-3- -one
[0087] 1.1. Preparation of
(.+-.)-acetyl-1-amino-4-(hydroxymethyl)-2-cyclo- pentene in an
anhydrous protic organic solvent using sodium borohydride
[0088] 280 g of 2-methyl-2-butanol (amyl alcohol) and 15.2 g of
sodium borohydride (0.4 mol) were charged into a sulphonation flask
at 20.degree. C. A mixture of 907 g of
(.+-.)-acetyl-2-azabicyclo[2.2.1]hept- -5-en-3-one (0.6 mol) and
37.5 g of methanol (2 equivalents based on
(.+-.)-acetyl-2-azabicyclo[2.2.1]hept-5-en-3-one was metered into
this suspension over the course of 2 h at 20.degree. C. The
reaction mixture was then stirred for a further 3 h at 20.degree.
C. The solvent was distilled as far as possible (40.degree. C.).
Boron was removed by adding 280 g of methanol and 27.2 g of formic
acid, warming the mixture to 25-30.degree. C. and distilling off
the methyl borate/methanol azeotrope at this temperature (130 to 80
mbar). The precipitated sodium formate was filtered off, and the
filtrate was reduced by evaporation to give 93.4 g of crude product
as a clear viscous oil; crude yield: about 84-85%
[0089] 1.2. Preparation of
cis-1-amino-4-(hydroxymethyl)-2-cyclopentene
[0090] A suspension of (.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-one
(10.00 g, 91.6 mmol) and lithium borohydride (4.00 g, 183.7 mmol)
in dry dioxane (100 ml) was heated in an inert-gas atmosphere
(argon) for 4 h at 110.degree. C. below the reflux temperature.
After this time, about 20-25%; of the starting material had reacted
to give the product (GC analysis with internal standard
benzophenone after work-up of the reaction mixture; work-up: 0.05
ml of the reaction mixture were quenched with 0.1 ml of 1M HCl and
immediately rendered basic using 0.2 ml of 1M NaOH) The structural
detection of the product was carried out by H-NMR, GC and
GC-MS.
[0091] 1.3. Preparation of
(+)-1-amino-4-(hydroxymethyl)-2-cyclopentene
[0092] A 25 ml round-bottom flask was charged with 1.0 g (9.2
mmol)of (+)-2-azabicyclo[2.2.1]hept-5-en-3-one and 0.4 g (18.4
mmol) of lithium borohydride, under an inert-gas atmosphere, in 10
ml of dioxane, and the mixture was refluxed for 3 h at 110.degree.
C. Excess reducing agent was destroyed by adding about 5 ml of
semi-concentrated HCl (adjusted to pH 3). The mixture was then
immediately buffered by adding about 1 ml of saturated NaHCO.sub.3
solution at pH 8. GC analysis indicated the formation of the
product. The entire reaction mixture was then evaporated to dryness
and purified by means of column chromatography (gradient:
hexane/ethyl acetate/MeOH 1:1:1.fwdarw.MeOH). In this way
(+)-2-azabicyclo-[2.2.1]hept-5-en-3-one and the corresponding
(+)-aminoalcohol were obtained.
[0093] 1.4. Preparation of
(-)-1-amino-4-(hydroxymethyl)-2-cyclopentene
[0094] A 25 ml round-bottom flask was charged with 1.0 g (9.2
mmol)of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one and 0.4 g (18.4
mmol) of lithium borohydride, under an inert-gas atmosphere, in 10
ml of dioxane, and the mixture was refluxed for 3 h at 110.degree.
C. Excess reducing agent was destroyed by adding about 5 ml of
semi-concentrated HCl (adjusted to pH 3). The mixture was then
immediately buffered by adding about 1 ml of saturated NaHCO.sub.3
solution at pH 8. GC analysis indicated the formation of the
product in 18% yield (GC standard is benzophenone). The entire
reaction mixture was then evaporated to dryness and purified by
means of column chromatography (gradeent: hexane/ethyl
acetate/MeOH=1:1:1.fwdarw.MeOH). In this way, 0.43 g (43%) of
(-)-2-azabicyclo[2.2.1]-hept-5-en-3-one was reisolated and 0.04 g
(4%) of the corresponding (-)-aminoalcohol was obtained.
[0095] By HPLC, only the (-)-enantiomer of the aminoalcohol was
detectable. The ee of the product is thus >98%.
[0096] 1.5. Preparation of
(.+-.)-1-amino-4-(hydroxymethyl)-2-cyclopentene in an alcohol
[0097] A 100 ml round-bottom flask fitted with magnetic stirrer was
charged with 3.0 g (27.5 mmol) of
(.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-o- ne and 1.2 g (28.3 mmol)
of lithium borohydride, under an inert-gas atmosphere, in 35 g of
2-butanol, and the mixture was stirred for 3 h at 60.degree. C. GC
analysis of a sample (work-up: 0.1 g sample rendered acidic using
0.2 ml of 1M HCl, then quickly rendered basic using 0.1 ml of
saturated NaHCO.sub.3) indicated the formation of the product in
12% yield after this time. (GC standard is benzophenone.)
[0098] 1.6. Preparation of a
(.+-.)-1-amino-4-(hydroxymethyl)-2-cyclopente- ne in an
alcohol/ether mixture
[0099] A 10 ml round-bottom flask was charged under at inert-gas
atmosphere with 0.5 g (4.6 mmol) of
(.+-.)-2-azabicyclo[2.2.1]hept-5-en-3- -one and 0.59 g (18.4 mmol)
of methanol in 7.5 ml of dioxane (abs.). 0.21 g (9.2 mmol) of
lithium borohydride were added, and the mixture was heated for 4 h
at 60.degree. C. The mixture was then cooled to 5.degree. C. using
an ice/waterbath, and about 10 ml of semi-concentrated HCl was
carefully added to the reaction mixture (vigorous reaction, gas
evolution), as a result of which a yellowish clear solution formed.
This solution was analyzed directly by a quantitative
ion-chromatographic method It contained 0.60 mmol (13.1%) of
(.+-.)-2-azabicyclo[2.2.1]hept-5- -en-3-one (determined as HCl salt
of the corresponding amino acid, which is the acidic hydrolysis
product of (.+-.)-2-azabicyclo-[2.2.1]hept-5-en-- 3-one) and 3.06
mmol of product, corresponding to a yield of 66.8%,
aminoalcohol
[0100] 1.7. Preparation of
(.+-.)-1-amino-4-(hydroxymethyl)-2-cyclopentene in the presence of
additives such as water or various alcohols
[0101] A 10 ml round-bottom flask was charged with 0.50 g (4.66
mmol) of (.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-one and 0.30 g (13.7
mmol) of lithium borohydride in 7.5 ml of abs. dioxane, and the
mixture was heated to 60.degree. C.
[0102] At this temperature, over the course of 30 min, X mmol of
alcohol Y was added dropwise using a syringe. The mixture is then
stirred for 2 h at 60.degree. C., cooled to about 20.degree. C. and
poured into about 10 ml of semi-concentrated HCl. The content was
then determined directly using a quantitative ion-chromatographic
method (cf. Table 1).
1TABLE 1 (.+-.)-2-Aza- bicyclo- [2.2.1]- X hept-5-en- Ex- Addi- X
equiva- 3-one Amino- ample tive Y mmol lents % yield alcohol 1.7.1
-- -- -- 15 52 1.7.2 water 17.1 1.25 23.3 67.5 1.7.3 water 34.3 2.5
32.3 58.3 1.7.4 meth- 34.3 2.5 4.5 83.1 anol 1.7.5 eth- 34.3 2.5
6.5 74.7 anol 1.7.6 isopro- 34.3 2.5 28.1 52.3 panol 1.8.
Preparation of (.+-.)-1-amino-4-(hydroxymethyl)-2-cyclopentene with
various amounts of methanol
[0103] Using the procedure of Example 1.7, the reaction was carried
out in a variety of methanol concentrations. The results are given
in Table 2.
2TABLE 2 (.+-.)-2-Azabi- cyclo [2.2.1]- Methanol hept-5-en-3-
Methanol equiva- one Amino- Example mmol lents % yield alcohol
1.8.1 9.2 1 27.5 44.8 1.8.2 18.3 2 13.1 66.8 1.8.3 27.5 3 24.7 54.8
1.8.4 36.6 4 5.7 56.8 1.8.5 45.8 5 12.0 58.3 1.8.6 55.0 6 7.2 33.0
1.9 Preparation of (.+-.)-1-amino-4-(hydroxymethyl)-2-cyclopentene
with various solvents
[0104] Using the procedure of Example 1.7, the reaction was carried
out in a variety of solvents (7.5 ml) and the content was
determined. The results are given in Table 3.
3TABLE 3 (.+-.)-2-Aza- bicyclo- [2.2.1]- hept-5- en-3-one Amino-
Example Solvent X % Yield alcohol 1.9.1 dioxane 13.6 79.8 1.9.2
diethyl ether 10.8 68.6 1.9.3 tetrahydrofuran 22.4 67.6 1.9.4
diisopropyl ether 12.6 51.3 1.9.5 tert-butyl methyl 10.0 71.3 ether
1.9.6 monoglyme 15.5 75.3 1.9.7 formaldehyde 12.0 74.2 dimethyl
acetal 1.10 Preparation of
(.+-.)-1-amino-4-(hydroxymethyl)-2-cyclopentene with various
additions of LiBH.sub.4
[0105] Following the procedure of Example 1.7, the reaction was
carried out using a variety of LIBH.sub.4 concentrations, and the
content was determined. The results are given in Table 4.
4TABLE 4 (.+-.)-2-Aza- bicyclo- [2.2.1]- LiBH.sub.4 hept-5-en- Ex-
LiBH.sub.4 equiva- 3-one Amino- ample mmol lents % yield alcohol
1.10.1 4.6 1 11.9 47.9 1.10.2 6.9 1.5 9.6 45.6 1.10.3 9.2 2 12.7
71.3 1.10.4 11.5 2.5 13.3 74.5 1.10.5 13.8 3 12.8 77.1 1.10.6 16.1
3.5 12.7 62.4 1.11 Preparation (1R,4S).- and
(1S,4R)-1-amino-4-(hydroxy-methyl)-2-cyclopente- ne in the presence
of various alcohols and in the presence of water in a variety of
solvents
[0106] A 10 ml round-bottom flask fitted with magnetic stirrer was
charged with 0.50 g (4.6 mmol) of
(.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-one and 0.30 g (13.7 mmol) of
lithium borohydride in 6 ml of a variety of solvents, and the
mixture was heated to 60.degree. C. At this temperature, over the
course of 30 min, 34.3 mmol of the additive Y were added dropwise
using a syringe. The mixture was then stirred for 2 h at 60.degree.
C., cooled to about 20.degree. C. and poured onto about 10 ml of
semi-condentrated HCl
[0107] The content is determined directly using a quantitative
ion-chromatographic method (cf. Table 5). The ee value of the
product was determined by means of HPLC. The results are given
Table 5.
5TABLE 5 (-)-2-Azabi- cyclo- (+)-2-Azabi- [2.2.1]hept- cyclo-
5-en-3-one [2.2.1]hept- Aminoalcohol Example ee value 5-en-3-one
Solvent Additive Y Yield (IC) ee value (HPLC) 1 98.0 dioxane water
64.3 >99.0 2 98.0 glyme water 68.0 >99.0 3 75.9 dioxane water
65.1 76.0 4 75.9 glyme water 63.5 75.6 5 50.2 dioxane water 74.8
51.4 6 51.6 glyme water 64.1 53.0 7 25.3 dioxane water 61.1 30.4 8
25.6 glyme water 61.0 29.6 9 98.0 dioxane methanol 83.1 98.2 10
98.0 glyme methanol 81.5 99.2 11 75.9 dioxane methanol 81.4 78.0 12
76.2 glyme methanol 79.9 78.6 13 50.4 dioxane methanol 81.3 54.4 14
51.5 glyme methanol 82.0 55.2 15 24.8 dioxane methanol 65.2 27.4 16
27.8 glyme methanol 81.7 32.2 17 98.0 dioxane ethanol 80.8 80.8 18
98.0 glyme ethanol 85.1 85.1 19 75.5 dioxane ethanol 85.3 78.2 20
75.6 glyme ethanol 83.6 78.4 21 50.7 dioxane ethanol 76.3 54.4 22
51.1 glyme ethanol 71.3 55.2 23 25.4 dioxane ethanol 73.0 28.6 24
25.5 glyme ethanol 75.0 28.6 25 98.0 dioxane water 62.0 >99.0 26
98.0 glyme water 59.5 >99.0 27 51.3 dioxane water 79.0 52.2 28
49.0 glyme water 61.3 52.0 29 98.0 dioxane methanol 77.2 >99.0
30 98.0 glyme methanol 80.0 >99.0 31 49.0 dioxane methanol 80.8
46.8 32 49.5 glyme methanol 80.9 48.8
[0108] 1.12 Preparation of
(.+-.)-1-amino-4-(hydroxymethyl)-2-cyclopentene using sodium
borohydride in various alcohols
[0109] Following the procedure of Example 17, the reaction was
carried out in a variety of alcohols. In contrast to Example 1.7,
however, sodium borohydride (0.51 g, 13.7 mmol) was used as
reducing agent. The results are given in Table 6.
6TABLE 6 (.+-.)-2-Aza- bicyclo- [2.2.1]- X hept-5- Amino- Ex- Addi-
X equiva- en-3-one alco- ample tive Y mmol valents Yield % y hol
1.12.1 water 17.1 1.25 75.4 20.1 1.12.2 watex 34.3 2.5 71.9 26.7
1.12.3 methanol 34.3 2.5 39.2 22.2 1.12.4 ethanol 34.3 2.5 67.8 8.6
1.12.5 -- -- -- 62.2 3.5 1.13 Preparation of
(.+-.)-1-amino-4-(hydroxymethyl)-2-cyclopentene using
NaBH.sub.3CN
[0110] 60 ml of dioxane and 8.6 g (137 mmol) of sodium
cyanoborohydride and 11.9 g (137 mmol) of lithium bromide were
refluxed overnight for 15 h at 110.degree. C. in a 100 ml
sulphonation flask. The mixture was then cooled to 60.degree. C.,
and a solution of 5.0 g (45.8 mmol) of
(.+-.)-2-azabicyclo[2.2.]hept-5-en-3-one containing 15 ml of
methanol were added dropwise over the course of 30 min. The white
suspension was stirred for 3 h at 60.degree. C., cooled to about
5.degree. C. and poured into about 100 ml of semi-concentrated HCl.
The content was then determined directly using a quantitative
ion-chromatographic method. The yield of amino-alcohol was about
4%.
Example 2
[0111] Alkaline hydrolysis of
acetyl-(.+-.)-1-amino-4-(hydroxymethyl)-2-cy- clopentene
[0112] 88.9 g of racemic
acetyl-1-amino-4-(hydroxymethyl)-2-cyclopentene (content 77.2%)
were suspended (partially dissolved) in 70 g of water. 84 g of 30%
NaOH (1.1 equivalents) were added thereto, and the solution was
refluxed for 3 h. According to TLC, the hydrolysis was complete.
The resulting acetate was removed by electrodialysis. The obtained
aqueous solution was reduced by evaporation and dried by azeotropic
distillation with butanol. The residue was taken up in methanol for
racemate resolution. Yield of hydrolysis to
(.+-.)-1-amino-4-(hydroxymethyl)-2-cyc- lopentene was 90%.
Example 3
[0113] Preparation of (1R,4S)- or
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cycl- opentene
[0114] 3.1 Racemate resolution using hydrolases
[0115] 3.1.1 Preparation of
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopente- ne using
lipases
[0116] 3.1.1.1 25 mM of racemic
1-amino-4-(hydroxymethyl)-2-cyclopentene were suspended with 1000
units of Novozym 435 in 5 ml of dioxane at room temperature. 25 mM
of ethyl methoxyacetate were added as acetylating agent. The
formation of N-methoxyacetylaminoalcohol was unambiguously detected
by TLC. The conversion was 50% (according to estimation of the
TLC). This reaction produced
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopen- tene.
[0117] 3.1.1.2 50 mM of racemic
1-amino-4-(hydroxymethyl)-2-cyclopenLene were suspended with 1000
units (U) of Novozym 435 in 5 ml of tetrahydrofuran 50 mM of NaOH
and 50 mM of ethyl methoxyacetate were added, and the mixture was
incubated at 30.degree. C. N-Methoxyacetylaminoaicohol was detected
using TLC. The estimated conversion was 50% This reaction produced
(1R,4S)-1-amino-4-(hydroxymethy- l)-2-cyclopentene.
[0118] 3.1.1.3 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of methyl tert-butyl ether, 0.06 ml of tributyrin (glyceryl
tributyrate) and 20 U of Novozym 435 (immob. lipase from Candida
antarctica) at room temperature. After 3 days, enantiomerically
pure, according to HPLC, (1R,4S)-1-amino-4-(hydroxymethy-
l)-2-cyclopentene was obtained in 43% yield.
[0119] 3.1.1.4 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of methyl tert-butyl ether. 0.02 ml of 6-caprolactone and 20 U
of Novozym 435 (immob. lipase from Candida antarctica) at room
temperature. After 4 days, (1R,4S)-1-amino-4-(hydroxy-
methyl)-2-cyclopentene with 87% ee was obtained in 49% yield
(HPLC).
[0120] 3.1.1.5 100 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopent- ene were stirred with 1
ml of hexane, 0.3 ml of tributyrin and 20 U of Novozym 435 (immob.
lipase from Candida antarctica) at room temperature. After 1 week,
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 77% ee was
obtained in 28% yield (HPLC).
[0121] 3.1.1.6 100 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopent- ene were stirred with 1
ml of tert-butanol, 0.3 ml of tributyrin and 20 U of Novozym 435
(immob. lipase from Candida antarctica) at 30.degree. C. After 1
week, (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentenewith78% ee
was obtained in 15% yield (HPLC)
[0122] 3.1.1.7 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of methyl tert-butyl ether, 0.2 mmol of methyl caproate and 20 U
of Novozym 435 (immob. lipase from Candida antarctica) at room
temperature. After 4 days (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyc-
lopentene with 68% ee was obtained in 52% yield (HPLC).
[0123] 3.1.1.8 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of methyl tert-butyl ether, 0.2 mmol of glycol dibutyrate and 40
U of Novozym 435 (immob. lipase from Candida antarctica) at room
temperature. After 4 days, (1R,4S)-1-amino-4-(hydroxy-
methyl)-2-cyclopentene with 89% ee was obtained in 31% yield
(HPLC).
[0124] 3.1.1.9 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of methyl tert-butyl ether, 0.2 mmol of diethyl fumarate and 40
U of Novozym 435 (immob. lipase from Candida antarctica) at room
temperature. After 4 days, (1R,4S)-1-amino-4-(hydroxymethyl)-2-cy-
clopentene with 86% ee was obtained in 36% yield (HPLC).
[0125] 3.1.1.10 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopent- ene were stirred with 1
ml of methyl tert-butyl ether, 0.2 mmol of diethyl malonate and 40
U of Novozym 435 (immob. lipase from Candida antarctica) at room
temperature. After 4 days, (1R,4S)-1-amino-4-(hydroxymethyl)-2
cyclopentene with 86% ee was obtained in 21% yield (HPLC)
[0126] 3.1.1.11 11 mg of racemic cis-1-amino-4-(hydroxymethyl)
2-cyclopentene were stirred with 1 ml of diisopropyl ether, 0.2
mmol of tributyrin and 40 U of Novozym 435 (immob. lipase from
Candida antarctica) at room temperature. After 4 days,
enantiomerically pure
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene was obtained in
15% yield (HPLC).
[0127] 3.1.1.12 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopent- ene were stirred with 1
ml of diisopropyl ether, 0.2 mmol of diethyl fumarate and 40 U of
Novozym 435 (immob. lipase from Candida antarctica) at room
temperature. After 4 days, (1R,4S)-1-amino-4-(hydroxymethyl)-2-cy-
clopentene with 88% ee was obtained in 24% yield (HPLC).
[0128] 3.1.1.13 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopent- ene were stirred with 1
ml of diisopropyl ether, 0.2 mmol of diethyl malonate and 40 U of
Novozym 435 (immob. lipase from Candida antarctica) at room
temperature. After 4 days, (1R,4S)-1-amino-4-(hydroxymethyl)-2-cy-
clopentene with 82% ee was obtained in 14% yield (HPLC).
[0129] 3.1.1.14 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopent- ene were stirred with 1
ml of diisopropyl ether, 0.2 mmol of diethyl diglycolate and 40 U
of Novozym 435 (immob. lipase from Candida antarctica) at room
temperature. After 4 days, (1R,4S)-1-amino-4-(hydroxy-
methyl)-2-cyclopentene with 88% ee was obtained in 7% yield
(HPLC).
[0130] 3.1.1.15 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopent- ene were stirred with 1
ml of dibutyl ether, 0.2 mmol of tributyrin and 40 U of Novozym 435
(immobilized lipase from Candida antarctica) at room temperature.
After 4 days, (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopente- ne
with 95% ee was obtained in 13% yield (HPLC).
[0131] 3.1.1.16 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopent- ene were stirred with 1
ml of pyridine, 0.02 ml of ethyl 2-methoxyacetate and 20 mg of
lipase AK (lipase from Pseudomonas fluorescens) at room
temperature. After 4 days,
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopente- ne with 84% ee was
obtained in 18% yield (HPLC).
[0132] 3.1.1.17 11 mg of racemic cls-1-amino-4-(hydroxymethyl)
2-cyclopentene were stirred with 1 ml of methyl tert-butyl ether,
0.2 mmol of ethyl cyanoacetate and 10 mg of lipase PS (lipase from
Pseudomonas cepacia) at room temperature. After 4 days,
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 67% ee was
obtained in 40% yield (HPLC).
[0133] 3.1.1.18 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopent- ene were stirred with 1
ml of methyl tert-butyl ether, 0.2 mmol of diethyl fumarate and 10
mg of lipase PS (lipase from Pseudomonas cepacia) at room
temperature. After 4 days,
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopente- ne with 86% ee was
obtained in 18% yield (HPLC).
[0134] 3.1.2 Preparation of (1R,4S)-1-amino-4-(hydroxy
methyl)-2-cyclopentene using proteases
[0135] 3.1.2.1 11 mg of racemic cis-1-amino-4-(hydroxymethyl)
2-cyclopentene were stirred with 1 ml of 2-methyl-2-butanol, 0.2
mmol of diethyl maleate and 40 mg of Alcalase (protease from
Bacillus licheniformis) at room temperature. After 4 days,
(1R,4S)-1-amino-4-(hydr- oxymethyl)-2-cyclopentene with 28% ee was
obtained in 39% yield (HPLC).
[0136] 3.1.2.2 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of 2-methyl-2-butanol, 0.2 mmol of diethyl fumarate and 40 mg of
Savinase (protease from Bacillus sp.) at room temperature. After 4
days, (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopente- ne with 32%
ee was obtained in 42% yield (HPLC).
[0137] 3.1.2.3 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of 2-methyl-2-butanol, 0.06 ml of tributyrin and 20 mg of
Savinase (protease from Bacillus sp.) at room temperature. After 4
days, (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentenewith22% ee
was obtained in 39% yield (HPLC).
[0138] 3.1.2.4 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of 2-methyl-2-butanol, 0.06 ml of tributyrin and 20 mg of
subtilisin (protease from Bacillus licheniformis) at room
temperature. After 4 days,
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopente- ne with 23% ee was
obtained in 36% yield (HPLC).
[0139] 3.1.3 Preparation of
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopente- ne using
proteases
[0140] 3.1.3.1 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of hexane, 0.06 ml of tributyrin and 120 U of Savinase (protease
from Bacillus sp.) at room temperature. After 3-6 days,
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 44% ee was
obtained in 46% yield (HPLC).
[0141] 3.1.3.2 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of hexane, 0.06 ml of tributyrin and 20 mg of Alcalase (protease
from Bacillus licheniformis) at room temperature. After 3-6 days,
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentenewith44% ee was
obtained in 35% yield (HPLC).
[0142] 3.1.4 Preparation of
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopente- ne using
lipases
[0143] 3.1.4.1 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of 2-methyl-2-butanol, 0.03 ml of ethyl butyrate and 20 mg of
Newlase F (lipase from Rhizopus niveus) at room temperature. After
1 week, (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 39%
ee was obtained in 37% yield (HPLC).
[0144] 3.1.4.2 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of pyridine, 0.06 ml of tributyrin and 20 mg of lipase AK
(lipase from Pseudomonas fluorescens) at room temperature. After 1
week, (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentenewith 30% ee
was obtained in 10% yield (HPLC)
[0145] 3.1.4.3 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of 2-methyl-2-butanol, 0.06 ml of tributyrin and 20 mg of lipase
AY (lipase from Candida rugosa) at room temperature. After 1 week,
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentenewith32% ee was
obtained in 13% yield (HPLC).
[0146] 3.1.4.4 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of methyl t-butyl ether, 0.06 ml of tributyrin and 20 mg of
lipase PS-CI (immobilized lipase from Pseudomonas cepacia) at room
temperature. After 1 week, (1S,4R)-1-amino-4-(hydroxymethyl)-2-cy-
clopentene with 29% ee was obtained in 16% yield (HPLC).
[0147] 3.1.4.5 11 mg of racemic
cis-1-amino-4-(hydroxymethyl)-2-cyclopente- ne were stirred with 1
ml of methyl t-butyl ether, 0.06 ml of tributyrin and 20 mg of
lipase PS (lipase from Pseudomonas cepacia) at room temperature.
After 1 week, (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopente-
newith24% ee was obtained in 22% yield (HPLC).
[0148] 3.2 Racemate resolution using D-(-)-tartaric acid
[0149] 3.2.1 A mixture of 8 g (70.6 mmol) of racemic
1-amino-4-(hydroxymethyl)-2-cyclopentene and 10.6 g (70.6 mmol) of
D-(-)-tartaric acid in 186 g of methanol were dissolved at the
reflux temperature. The mixture was then cooled to 20.degree. C.
over 2 h. At 43.degree. C., seed crystals of the pure
(1R,4S)-1-amino-4-(hydroxymethyl- )-2-cyclopentene
D-hydrogentartrate were added. The crystallized product was
filtered off and dried. Yield: 8.49 g (45.6% based on racemic
starting material) of
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene
D-hydrogentartrate, ee value: 91.1%. For purification, 8.49 g
(32.25 mmol) of the hydrogentartrate were suspended in 30 ml of
methanol, and 2 equivalents of 30% sodium methoxide were added. The
sodium tartrate was filtered off and the methanol was distilled
off.
[0150] The residue was taken up in 35 ml of pentanol. Then, at
55.degree. C., 1.5 g of HCl were introduced, and the solution was
slowly cooled. At 40.degree. C., the solution was seeded with
(1R,4S)-1-amino-4-(hydroxymet- hyl)-2-cyclopentene hydrochloride.
45 ml of acetone were then metered in, and the suspension was
slowly cooled to 0.degree. C. and filtered, and the residue was
dried. 3.91 g of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cycl- opentene
hydrochloride having an ee value of >98% were obtained,
corresponding to a yield, based on racemic
(1R,4S)-1-amino-4-(hydroxymeth- yl)-2-cyclopentene used, of
37%.
[0151] 3.2.2 A mixture of 64 g of racemic
1-amino-4-(hydroxymethyl)-2-cycl- opentene (0.5 mol) and 75.2 g of
D-(-)-tartaric acid in 1330 g of methanol was dissolved at the
reflux temperature and then cooled to 20.degree. C. over 2 h. At
43.degree. C., seed crystals of the pure 1R,4S-enantiomer were
added. The crystallized product was filtered off and dried. Yield:
63.2 g (48.0% based on racemic
1-amino-4-(hydroxymethyl)-2-cyclopentene) of
(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene hydrogentartrate,
ee value: 91.1%. The ee value in the mother liquor was 76.0%.
[0152] 3.2.3 Recrystallization of
1R,4S-(4-amino-2-cyclopenten-1-yl)methan- ol D-hydrogentartrate
[0153] 61.84 g of 1R,4S-(4-amino-2-cyclopenten-1-yl)-methanol
D-hydrogentartrate (0.235 mol, ee value 91.1%) were dissolved in
752 g of methanol under reflux. The solution was cooled to
20.degree. C. within 90 min, then the product was filtered off and
washed with 64 g of cold methanol. Drying gave 54.56 g of
1R,4S-(4-amino-2-cyclopenten-1-yl)-metha- nol D-hydrogentartrate
were obtained, ee value 99.4% (yield 88.2%, 42.3% based on racemic
1-amino-4-(hydroxymethyl)-2-cyclopentene). This was used tel quel
in the chloropurine synthesis.
[0154] 3.2.4 Following the procedure of Example 3.2.2, but using
223 g of methanol and seeding at 50.degree. C., the racemate was
separated. The yield was 7.98 g (42.9% based on racemic
(1R,4S)-1-amino-4-(hydroxymethyl- )-2-cyclopentene used).
[0155] 3.3 Racemate resolution using L-(+)-tartaric acid
[0156] 3.3.1 A mixture of 8 g (70.6 mmol) of racemic
1-amino-4-(hydroxymethyl)-2-cyclopentene and 10.6 g (70.6 mmol) of
L-(.+-.)-tartaric acid in 186 g of methanol were dissolved at the
reflux temperature. The mixture was then cooled to 20.degree. C.
over 2 h. At 43.degree. C., seed crystals of the pure
(1S,4R)-1-amino-4-(hydroxymethyl- )-2-cyclopentene
L-hydrogentartrate were added. The crystallized
(1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene L-hydrogentartrate
was filtered off and dried. (ee value: 91.1%). 14 g of 30%
methanolic sodium methoxide were added to the mother liquor, then
the methanol was evaporated. The residue was taken up in 35 ml of
isobutanol, and the insoluble sodium tartrate was filtered off. At
55.degree. C., 2 g of gaseous HCl were introduced into the
filtrate. 38 ml of acetone were then added, and the mixture was
left to cool to 10.degree. C. over the course of 1 h. After 1 h,
the (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene hydrochloride
was filtered off with suction and washed with 8 ml of acetone.
Drying under reduced pressure gave the (1R,4S)-1-amino-4-(hydrox-
ymethyl)-2-cyclopentene hydrochloride in a yield of 34 g, 31.6%
based on racemic 1-amino-4-(hydroxymethyl)-2-cyclopentene with an
ee value of >98%.
Example 4
[0157] Preparation of
(1R,4S)-amino-4-(hydroxymethyl)-2-cyclopentene hydrochloride
[0158] 4.1 Reduction of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one
[0159] A 2 l autoclave (stainless steel type V4A) rendered inert
with N.sub.2, was charged with 61.4 g of sodium borohydride 97.5%
(1.623 mol), 70.2 g of lithium chloride 98.5% (1.656 mol), 13.2 g
of Celite and 1410 g of tetrahydrofuran. The autoclave was closed
and heated to an internal temperature of 130.degree. C. and the
contents stirred for 4.5 hours at this temperature (max. 8.0
bar).
[0160] After the autoclave had been cooled to about 60.degree. C.,
the sodium salts insoluble in tetrahydrofuran (NaCl, NaBH.sub.4)
were filtered off. These were washed with 353 g of tetrahydrofuran,
and the combined filtrates were reduced to about half in a stirred
1 l glass vessel by distillation at atmospheric pressure
(distillate 1: about 710 g of tetrahydrofuran). Further
distillation, alternating with the portionwise addition of a total
of 936 g of dioxane then completed the solvent exchange (distillate
2: about 1289 g of tetrahydrofuran/dioxane).
[0161] The LiBH.sub.4 suspension was cooled to about 60.degree. C.,
and 56.7 g of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (97.5%) were
added.
[0162] Starting at about 60.degree. C., 132.5 g of methanol were
metered in in exactly one hour at a rate such that a temperature
range of 58-62.degree. C. was maintained. The mixture was then
allowed to react for a further hour at 60.degree. C. A further
397.0 g of methanol were then added (sample comprises an analytical
yield of 70.5%), and the contents of the stirred vessel were cooled
to 0.degree. C. At this temperature, 90.0 g of HCl were introduced
into the reaction mixture (slightly exothermic) and stirring was
continued for a further hour at about 0.degree. C. Distillation at
atmospheric pressure (up to a head temperature of 75.degree. C.)
removed the low-boiling fractions (methanol, borate) and about 70%
of the dioxane (distillate 3: about 1093 g). Distillation under
reduced pressure (about 30 mbar), alternating with the portionwise
addition of a total of 282 g of 1-pentanol then completed the
solvent exchange (distillate 4: about 240 g of
dioxane/pentanol).
[0163] After a further 302 g of 1-pentanol had been added, the
mixture was stirred for 1 hour at 50.degree. C., and precipitated
salts, about 39 g moist weight, were filtered off and washed with
200 g of 1-pentanol. The combined filtrates were reduced by
redistillation under reduced pressure (about 20 mbar) (distillate
5: 235 g of 1-pentanol). Then, at about 50.degree. C., 236 g of
acetone were metered in, and the reaction mixture was seeded with a
few crystals of (1R,4S)-amino-4-(hydroxymethyl)-2-cyclo- pentene.
The mixture was cooled to 5.degree. C. over the course of 1 hour,
and crystallization was completed by stirring the mixture for a
further 6 h at 5.degree. C.
[0164] The crystals were filtered off, washed with 63 g of acetone
and dried at a max. 50.degree. C. in a vacuum drying cabinet (10
mbar). This gave 83.5 g of crude product* (content: 56.5%).
[0165] This corresponded to a yield of 61.4% based on
(-)-2-azabicyclo[2.2.1]hept-5-en-3-one used.
[0166] 4.2 Reduction of
(.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-one
[0167] A 2 l autoclave (stainless steel type V4A) rendered inert
with N.sub.2, was charged with 41.56 g of sodium borohydride 97.5%
(1.071 mol), 51.48 g of lithium chloride 98.5% (1.196 mol), 9.30 g
of Celite and 955.0 g of tetrahydrofuran. The autoclave was closed
and heated to an internal temperature of 130.degree. C. and the
contents stirred for 6 hours at this temperature (max. 6.3
bar).
[0168] After the autoclave had been cooled to about 60.degree. C.,
the sodium salts insoluble in tetrahydrofuran (Nacl, NaBH.sub.4)
were filtered off. These were washed with 239.0 g of
tetrahydrofuran, and the combined filtrates were reduced to about
half in a stirred 1 l glass vessel by distillation at atmospheric
pressure (distillate 1: about 590 g of THF). Further distillation,
alternating with the portionwise addition of a total of 661.0 g of
dioxane then completed the solvent exchange (distillate 2: about
685 g of tetrahydrofuran/dioxane).
[0169] The LiBH.sub.4 suspension was cooled to about 60.degree. C.,
and 36.0 g of 2-azabicyclo[2.2.1]hept-5-en-3-one (97.5%) were
added.
[0170] Starting at about 60.degree. C., 77.6 g of methanol were
metered in in exactly one hour at a rate such that a temperature
range of 58-62.degree. C. was maintained. The mixture was then
allowed to react for a further hour at 60.degree. C. A further
233.0 g of methanol were then added, and the contents of the
stirred vessel were cooled to 0.degree. C. At this temperature,
52.9 g of HCl were introduced into the reaction mixture (slightly
exothermic) and stirring was continued for a further hour at about
0.degree. C. Distillation at atmospheric pressure (up to a head
temperature of 75.degree. C.) removed the low-boiling fractions
(methanol, borate) and about 70% of the dioxane (distillate 3:
about 700 g). Distillation under reduced pressure (about 30 mmol),
alternating with the portionwise addition of a total of 169.4 g of
1-pentanol then completed the solvent exchange (distillate 4: about
183 g of dioxane/pentanol). After a further 127.1 g of 1-pentanol
had been added, the mixture was stirred for 1 hour at 50.degree.
C., and precipitated salts, about 41 g moist weight, were filtered
off and washed with 63.5 g of 1-pentanol. The combined filtrates
were reduced by redistillation under reduced pressure (about 20
mbar) (distillate 5: 235 g of 1-pentanol) Then, at about 50.degree.
C., 238.0 g of acetone were metered in, and the reaction mixture
was seeded with a few crystals of aminoalcohol hydrochloride salt.
The mixture was cooled to 5.degree. C. over the course of one hour,
and crystallization was completed by stirring the mixture for a
further 6 hours at 5.degree. C.
[0171] The crystals were filtered off, washed with 61.0 g of
acetone and dried at a max. 50.degree. C. in a vacuum drying
cabinet (10 mbar). This gave 50.0 g of crude product (content:
about 50% of aminoalcohol hydrochloride salt).
[0172] This corresponded to a yield of 52.0% based on
2-azabicyclo[2.2.1]hept-5-en-3-one used.
Example 5
[0173] Preparation of acylated aminoalcohols
[0174] 5.1 Preparation of
(1R,4S)-N-BOC-1-amino-4-(hydroxymethyl)-2-cyclop- entene
(BOC=tert-butoxycarbonyl)
[0175] 75 g of a solution of
(1R,4S)-1-amino-4-hydroxymethyl-2-cyclopenten- e were adjusted to
pH 8 using 30% strength NaOH, and 6 g of NaHCO.sub.3 were added to
the mixture. The mixture was heated to 52.degree. C. Whilst
stirring the mixture thoroughly, 60 ml of diisopropyl ether were
added thereto and then, over the course of 2 h, a solution of 11.12
g of BOC anhydride in 18.2 ml of diisopropyl ether were metered in.
The mixture was filtered over Celite, and the phases were
separated. The aqueous phase was extracted with 65 ml of
diisopropyl ether. The combined organic phases were washed with 45
ml of water, then evaporated to 37.5 g and heated to 5.degree. C.
31 ml of n-hexane were added dropwise to the solution. After the
mixture had been slowly cooled to 0.degree. C. (2 h), the title
compound was filtered, washed with 12 ml of n-hexane/diisopropyl
ether 1/1 and dried. This gave 6.75 g of product The yield was
71%.
[0176] 5.2 Preparation of
(1R,4S)-N-acetyl-1-amino-4-(hydroxymethyl)-2-cyc- lopentene
[0177] 25 g (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene
hydrochloride were dissolved in 182 ml of acetic anhydride, and at
0.degree. C., a solution of 18.25 g of triethylamine in 60 ml of
acetic anhydride were added thereto. The mixture was stirred at
80.degree. C. for 3 h, then cooled to room temperature. The
triethylamine hydrochloride was filtered off and washed with 120 ml
of n-hexane. The filtrate was evaporated. 300 ml of toluene were
added to the residue, and the mixture was stirred at room
temperature in the presence of 5.2 g of activated carbon and 13 g
of Celite for 20 min. The mixture was then filtered, and the filter
cake was washed (3.times.40 ml of toluene), and the solvent was
completely evaporated. 180 ml of methanol and 15.5 g of
K.sub.2CO.sub.3 were added to the residue, and the mixture was
stirred at room temperature for 10 h. The suspension was filtered
off and the filtrate evaporated. The residue was suspended in 750
ml of isopropyl acetate and boiled in the presence of 0.5 g of
activated carbon to reflux for 1.5 h. Following filtration of the
activated carbon (70-80.degree. C.), the filtrate was cooled at
0.degree. C. overnight. The title compound was filtered, washed
with 80 ml of cold isopropyl acetate and dried under reduced
pressure to give 17.2 g of product. The yield was 66%.
[0178] 5.3 Preparationof
(1R,4S)-N-butyryl-1-amino-4-(hydroxymethyl)-2-cyc- lopentene
[0179] 34.7 g of (1R,4S)-1-amino-4-hydroxymethyl-2-cyclopentene
hydrochloride and 2 g of N,N-4-dimethylaminopyridine were dissolved
in 600 ml of methylene chloride. The solution was cooled to
0.degree. C. 52 g of triethylamine were then added dropwise (5
min). The mixture was stirred for a further 30 min. At 0.degree.
C., a solution of 35.2 g of butyryl chloride in 60 ml of methylene
chloride was metered into the mixture over the course of 1 h. The
mixture was stirred for a further 1.5 h at between 0 and 20.degree.
C., and then 600 ml of water were added thereto. Following phase
separation, the aqueous phase was extracted with 600 ml of
methylene chloride. The combined organic phases were washed
3.times.500 ml of 10% strength NaOH, then completely evaporated.
The dried solid was dissolved in 120 ml of methanol. 5 g of
K.sub.2CO.sub.3 were added to the solution, and the mixture was
stirred for a further 2 h at room temperature. The inorganic salts
were filtered off and washed with 20 ml of methanol. The filtrate
was neutralized with 2N HC1. The suspension was filtered off, and
the filter cake was washed with 20 ml of methanol. The filtrate was
completely evaporated. The solid residue was dried and crystallized
in 150 ml of toluene to give 28.5 g of the title compound. The
yield was 67%.
Example 6
[0180] Preparation of
[4(R)-(2-amino-6-chloropurine-9-yl)cyclopent-2-ene-1-
(S)-yl]methanol
[0181] 6.1 Preparation of
[4(R)-(2-amino-6-chloropurine-9-yl)-cyclopent-2--
ene-l(S)-yl]methanol starting from
1R,4S-(4-amino-2-cyclopenten-1-yl)metha- nol D-hydrogentartrate
[0182] 47.4 g of 1R,4S-(4-amino-2-cyclopenten-1-yl)methanol
D-hydrogentartrate (0.18 mol, ee >98%) in 200 ml of ethanol were
introduced initially. At room temperature, 54.6 g of NaHCO.sub.3
(0.65 mol) and 37.3 g (0.18 mol) of
N-(2-amino-4,6-dichloro-4-pyrimidyl) formamide were added, boiled
for 9 h under reflux and then cooled to room temperature. The salts
were filtered off and then washed with 50 ml of ethanol. The
filtrate was concentrated to 280 g on a rotary evaporator. 18.4 g
of HCl gas were introduced into the resulting solution at
T<25.degree. C., then 95.5 g (0.9 mol) of trimethyl orthoformate
were added, and the whole was heated to 40.degree. C. (10 min) At
this temperature, the mixture was seeded with chloropurine
hydrochloride. After 2 h at 42.degree. C., the product crystallized
out. The suspension was cooled to 15.degree. C. The product was
filtered and then washed with 3.times.50 ml of ethanol, then dried
at 50.degree. C. under reduced pressure. The yield was 41.9 g
(75.8%). Beige powder, content (HPLC): 95.0%.
[0183] 6.2 Preparation of
[4(R)-(2-amino-6-chloropurine-9-yl)-cyclopent-2--
ene-l(S)-yl]methanol starting from
(-)-2-azabicyclo[2.2.1]hept-5-en-3-one
[0184] A 2 l autoclave (stainless steel type V4A) rendered inert
with N.sub.2, was charged with 61.4 g of sodium borohydride 97.5%
(1.623 mol), 70.2 g of lithium chloride 98.5% (1.656 mol), 13.2 g
of Celite and 1410 g of tetrahydrofuran. The autoclave was closed
and heated to an internal temperature of 130.degree. C. and the
contents stirred for 4.5 hours at this temperature (max. 8.0 bar).
After the autoclave had been cooled to about 60.degree. C., the
sodium salts insoluble in tetrahydrofuran (NaCl, NaBH.sub.4) were
filtered off. These were washed with 353 g of tetrahydrofuran, and
the combined filtrates were reduced to about half in a stirred 1 l
glass vessel by distillation at atmospheric pressure (distillate 1:
about 710 g of tetrahydrofuran). Further distillation, alternating
with the portionwise addition of a total of 936 g of dioxane then
completed the solvent exchange (distillate 2: about 1289 g of
tetrahydrofuran/dioxane).
[0185] The LiBH.sub.4 suspension was cooled to about 60.degree. C.,
and 56.7 g of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (97.5%/0.507
mol) were added.
[0186] Starting at about 60.degree. C., 132.5 g of methanol were
metered in in exactly one hour at a rate such that a temperature
range of 58-62.degree. C. was maintained. The mixture was then
allowed to react for a further hour at 60.degree. C. A further 397.
0 g of methanol were then added (sample comprises an analytical
yield of 70.5%), and the contents of the stirred vessel were cooled
to 0.degree. C. At this temperature, 90.0 g of HCl were introduced
into the reaction mixture (slightly exothermic) and stirring was
continued for a further hour at about 0.degree. C. The solution was
evaporated on a rotary evaporator at 50.degree. C. under reduced
pressure, 200 ml of methanol were added and the methanol was
removed again (filtration with suction of the methyl borate). The
procedure was repeated using a further 200 ml of methanol. 250 ml
of ethanol were added to the oil obtained (253.4 g comprise 3.16%
of aminoalcohol; this corresponded to 0.360 mol), and the mixture
was poured into a 1 l double-jacketed stirred vessel. At room
temperature, 72.6 g of NaHCO.sub.3 (0.86 mol) and 74.6 g (0.360
mol) of N-(2-amino-4,6-dichloro-4-pyrimidyl) formamide were added,
the mixture was refluxed for 9 h and cooled to room temperature,
and the salts were filtered off and then washed with 100 ml of
ethanol. The filtrate on the rotary evaporator was concentrated to
560 g. 63.4 g of HCl gas were introduced into the resulting
solution at T<25.degree. C., then 191.0 g (1.80 mol) of
trimethyl orthoformate were added, and the mixture was heated to
40.degree. C. (10 min). At this temperature, the mixture was seeded
with chloropurine hydrochloride, and left to crystallize for 2 h at
42.degree. C. The suspension was cooled to 15.degree. C. The
product was filtered and then washed with 3.times.50 ml of ethanol,
then dried at 50.degree. C. under reduced pressure. The yield was
66.0 g (59.7%). Beige powder, content (HPLC): 89.3%. This
corresponded to a yield of 42.4% based on the Vince lactam
used.
* * * * *