U.S. patent application number 09/821887 was filed with the patent office on 2002-02-14 for process for the preparation of matrix metalloproteinase inhibitors.
Invention is credited to Bailey, Anne E., Hill, David R., Hsiao, Chi-Nung W., Kurukulasuriya, Ravi, McDermott, Todd, McLaughlin, Maureen A., Wittenberger, Steve.
Application Number | 20020019539 09/821887 |
Document ID | / |
Family ID | 26889663 |
Filed Date | 2002-02-14 |
United States Patent
Application |
20020019539 |
Kind Code |
A1 |
Bailey, Anne E. ; et
al. |
February 14, 2002 |
Process for the preparation of matrix metalloproteinase
inhibitors
Abstract
The instant invention provides a process for the synthesis of
matrix metalloproteinase inhibitors.
Inventors: |
Bailey, Anne E.; (Beach
Park, IL) ; Hill, David R.; (Gurnee, IL) ;
Hsiao, Chi-Nung W.; (Libertyville, IL) ;
Kurukulasuriya, Ravi; (Gurnee, IL) ; Wittenberger,
Steve; (Mundelein, IL) ; McDermott, Todd; (Oak
Park, IL) ; McLaughlin, Maureen A.; (Gurnee,
IL) |
Correspondence
Address: |
Steven F. Weinstock
Abbott Laboratories
AP6D/D-377
100 Abbott Park Road
Abbott Park
IL
60064-6050
US
|
Family ID: |
26889663 |
Appl. No.: |
09/821887 |
Filed: |
March 30, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60194069 |
Mar 31, 2000 |
|
|
|
Current U.S.
Class: |
548/225 ;
548/323.5 |
Current CPC
Class: |
C07C 239/20 20130101;
C07D 205/08 20130101; C07D 233/78 20130101; C07D 233/38 20130101;
C07D 263/24 20130101; C07C 213/00 20130101; C07C 217/34
20130101 |
Class at
Publication: |
548/225 ;
548/323.5 |
International
Class: |
C07D 263/20; C07D
233/32 |
Claims
What is claimed is:
1. A process for preparing a compound of formula (3) 99wherein
R.sup.1 is selected from the group consisting of hydrogen, an amino
protecting group, and --OR.sup.2; R.sup.2 is hydrogen or a hydroxy
protecting group; L.sup.1 is --O-- or --N(R.sup.3)--, wherein
R.sup.3 is hydrogen or an amino protecting group; and X is O or S,
the process comprising: (a) reacting a compound of formula (2)
100wherein R.sup.4 is a carboxyl protecting group, with a reducing
agent to provide a first reaction mixture; and (b) adjusting the pH
of the first reaction mixture to about 2 to about 6; and (c)
isolating the compound of formula (3).
2. The process of claim 1 further comprising reacting a compound of
formula (1) 101a base, and a reagent selected from the group
consisting of phosgene, thiophosgene, triphosgene,
carbonyldiimidazole, thiocarbonyldiimidazole, and a dialkyl
carbonate.
3. The process of claim 1, wherein the compound of formula (3) is
(4R)-4-(hydroxymethyl)-1,3-oxazolidin-2-one.
4. A process for preparing a compound of formula (5-a) 102or a
compound of formula (5-b) 103wherein Q.sup.1 is selected from the
group consisting of halide, methanesulfonate, and
trifluoromethanesulfonate; Y is nitrogen or C(H); R.sup.6 is
selected from the group consisting of alkoxy, alkoxyalkyl, alkyl,
aminosulfonyl, aminosulfonylalkyl, aryl, arylalkyl, cyano,
cyanoalkyl, halo, haloalkyl, (heterocycle)oxy,
(heterocycle)oxyalkyl, hydroxy, hydroxyalkyl, phenylalkoxy,
phenylalkoxyalkyl phenoxy, phenoxyalkyl, perfluoroalkoxy,
perfluoroalkoxyalkyl, perfluorothioalkoxy,
perfluorothioalkoxyalkyl, sulfinyl, sulfinylalkylsulfonyl,
sulfonylalkyl, thioalkoxy, and thioalkoxyalkyl; and L.sup.2 is
--O-- or --S--, the process comprising: (a) activating the hydroxyl
of the compound of formula (3) 104(b) reacting the product of step
(a), a compound of formula (4) 105and base to provide the compound
of formula (5-a) 106(c) optionally oxidizing the product of step
(b); and (d) optionally reacting the product of step (b) or step
(c) and a compound of formula (6) 107wherein Q.sup.2 is selected
from the group consisting of trialkylstannanes, boronic acid,
boronic esters, magnesium halides, zinc halides, and
silyl(alkyl)cyclobutanes, and a coupling catalyst.
5. The process of claim 4, wherein the compound of formula (5-a) is
(4R)-4-((4-bromophenoxy)methyl)-1,3-oxazolidin-2-one and the
compound of formula (5-b) is
(4R)-4-(((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)oxy)-
methyl)-1,3-oxazolidin-2-one.
6. A process for preparing a compound of formula (5-c) 108the
process comprising: (a) reacting a compound of formula (7)
109wherein R.sup.4 is alkyl, a compound of formula (4) 110and base
to provide a compound of formula (8) 111(b) optionally reacting the
product from step (a) and an oxidant; (c) reacting the product of
step (a) or step (b), hydrogen, and a hydrogenation catalyst to
provide a compound of formula (9) 112(d) reacting the product from
step (c) and base to provide a compound of formula (10) 113(e)
reacting the product from step (d) and a compound of formula
H.sub.2NOR.sup.2, or a salt thereof, wherein R.sup.2 is a hydroxyl
protecting group, under dehydrating conditions to provide a
compound of formula (11) 114(f) reacting the product of step (e)
under Mitsunobu conditions to provide a compound of formula (12)
115(g) reacting the product from step (f) and base to provide a
compound of formula (13) 116and (h) reacting the product from step
(g) and azide under dehydrating conditions.
7. The process of claim 6, wherein the compound of formula (5-c) is
(5R)-1-(benzyloxy)-5-((4-bromophenoxy)methyl)-2-imidazolidinone.
8. A process for preparing a compound of formula (15) 117wherein
R.sup.5 is Q.sup.1 or 118the process comprising: (a) reacting a
compound of formula (5) 119and base.
9. The process of claim 8, wherein the compound of formula (15) is
selected from the group consisting of
(2S)-2-amino-3-((4'-(trifluorometho-
xy)(1,1'-biphenyl)-4-yl)oxy)-1-propanol,
(2S)-2-amino-3-(4-bromophenoxy)-1- -propanol, and
(2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)-1-propanamine.
10. A process for preparing of a compound of formula (20), 120or a
salt thereof, wherein R.sup.7 and R.sup.8, together with the atoms
to which they are attached, form a heterocycle selected from the
group consisting of 5,5-dimethyl-1,3-oxazolidine-2,4-dionyl;
1-methyl-2,4-imidazolidinedio- nyl;
1,5,5-trimethyl-2,4-imidazolidinedionyl; 2,4-imidazolidinedionyl;
5,5-dimethyl-2,4-imidazolidinedionyl;
1,2-dimethyl-1,2,4-triazolidine-3,5- -dionyl;
4,4-dimethyl-2,6-piperidinedione; 8-azaspiro(4.5)decane-7,9-diony-
l; 3a,6-dihydro-1H-benzo(de)isoquinoline-1,3(2H)-dionyl;
2,4(1H,3H)-quinazolinedionyl; 1-methyl-2,4(1H,3H)-pyrimidinedionyl;
and 1,1-dioxo-1,2-benzisothiazol-3(2H)-onyl, the process
comprising: (a) reacting a compound of formula (15-a) 121and a
compound of formula R.sup.9--CHO, wherein R.sup.9 is optionally
substituted aryl, to provide a compound of formula (16) 122(b)
reacting the product of step (a) and a compound of formula (17)
under Mitsunobu conditions 123to provide a compound of formula (18)
124(c) reacting the product of step (b) and an oxaziridine forming
agent to provide a compound of formula (19) 125(d) reacting the
product of step (c) and a compound of formula H.sub.2NOR.sup.2, or
a salt thereof, and base; and (e) optionally deprotecting the
product of step (d).
11. The process of claim 10, wherein the compound of formula (20)
is selected from the group consisting of
3-((2S)-2-(hydroxyamino)-3-((4'-(tr-
ifluoromethoxy)(1,1'-biphenyl)-4-yl)oxy)propyl)-5,5-dimethyl-2,4-imidazoli-
dinedione and
3-((2S)-3-(4-bromophenoxy)-2-(hydroxyamino)propyl)-5,5-dimet-
hyl-2,4-imidazolidinedione.
12. A process for preparing of a compound of formula (20-b) 126or a
salt thereof the process comprising: (a) reacting the compound of
formula (20-a) 127the coupling catalyst, and the compound of
formula (6) 128
13. The process of claim 12, wherein the compound of formula (20-b)
is
3-((2S)-2-(hydroxyamino)-3-((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)ox-
y)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
14. A process for preparing of a compound of formula (20-c) 129or a
salt thereof, the process comprising: (a) reacting a compound of
formula (15-b) 130and a compound of formula (21) 131to provide a
compound of formula (22) 132and (b) reacting the product from step
(a) and acid.
15. The process of claim 14, wherein the compound of formula (20-c)
is
3-((2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)propyl)-5,5-dimethyl-2,4-i-
midazolidinedione.
16. A process for preparing a compound of formula (23) 133the
process comprising: (a) N-formylating the compound of formula (20);
and (b) optionally deprotecting the product of step (a).
17. The process of claim 16, wherein the compound of formula (23)
is selected from the group consisting of
(1S)-2-(4,4-dimethyl-2,5-dioxo-1-im-
idazolidinyl)-1-(((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)oxy)methyl)et-
hyl(hydroxy)formamide and
benzyloxy((1R)-2-(4-bromophenoxy)-1-((4,4-dimeth-
yl-2,5-dioxo-1-imidazolidinyl)methyl)-ethyl)formamide.
18. A process for preparing a compound of formula (23-b) 134the
process comprising: (a) reacting a compound of formula (23-a)
135the coupling catalyst, and the compound of formula (6) 136and
(b) optionally deprotecting the product of step (a).
19. The process of claim 18, wherein the compound of formula (23-b)
is
4-(((2R)-2-((benzyloxy)(formyl)amino)-3-(4,4-dimethyl-2,5-dioxo-1-imidazo-
lidinyl)-propyl)oxy)-4'-(trifluoromethoxy)-1,1'-biphenyl.
20. A process for preparing a compound of formula (23-b) 137the
process comprising: (a) reacting a compound of formula (1) 138a
base, and a reagent selected from the group consisting of phosgene,
thiophosgene, triphosgene, carbonyldiimidazole,
thiocarbonyldiimidazole, and a dialkyl carbonate to provide a
compound of formula (2); 139(b) reacting the product of step (a)
with a reducing agent to provide a compound of formula (3); 140(c)
activating the hydroxyl of the product of step (b); (d) reacting
the product of step (c) with base and a compound of formula (4)
141to provide a compound of formula (5-a), 142(e) optionally
oxidizing the product of step (d); (f) reacting the product of step
(d) or step (e), a coupling catalyst, and a compound of formula (6)
143to provide a compound of formula (5-b), 144(g) reacting the
product of step (f) with base to provide a compound of formula
(15), 145(h) reacting the product of step (g) with a compound of
formula R.sup.9--CHO, to provide a compound of formula (16), 146(i)
reacting the product of step (h) with a compound of formula (17)
147to provide a compound of formula (18) 148(j) reacting the
product of step (i) and an oxaziridine forming agent to provide a
compound of formula (19) 149(k) reacting the product of step (j)
with H.sub.2NOR.sup.2, or a salt thereof, and base to provide a
compound of formula (20-b); 150(l) N-formylating the product from
step (k) to provide a compound of formula (23-b); 151and (m)
optionally deprotecting the product of step (l).
21. A process for the preparation of a compound of formula (23-b)
152the process comprising: (a) reacting a compound of formula (1)
153a base, and a reagent selected from the group consisting of
phosgene, thiophosgene, triphosgene, carbonyldiimidazole,
thiocarbonyldiimidazole, and a dialkyl carbonate, to provide a
compound of formula (2); 154(b) reacting the product of step (a)
with a reducing agent to provide a compound of formula (3); 155(c)
activating the hydroxyl of the product of step (b); (d) reacting
the product of step (c) with base and a compound of formula (4)
156to provide a compound of formula (5-a), 157(e) optionally
oxidizing the product of step (d); (f) reacting the product of step
(e) with base to provide a compound of formula (15), 158wherein
R.sup.5 is Q.sup.1; (g) reacting the product of step (f) with a
compound of formula R.sup.9--CHO to provide a compound of formula
(16), 159wherein R.sup.5 is Q.sup.1; (h) reacting the product of
step (g) with a compound of formula (17) 160to provide a compound
of formula (18) 161wherein R.sup.5 is Q.sup.1; (i) reacting the
product of step (h) with an oxaziridine forming agent to provide a
compound of formula (19) 162wherein R.sup.5 is Q.sup.1; (j)
reacting the product of step (i) with H.sub.2NOR.sup.2, or a salt
thereof, and base to provide a compound of formula (20); 163wherein
R.sup.5 is Q.sup.1; (k) reacting the product of step (j) with a
coupling catalyst and a compound of formula (6) 164to provide a
compound of formula (20), 165wherein R.sup.5 is 166(l)
N-formylating the product from step (k) to provide a compound of
formula (23) 167wherein R.sup.5 is 168and (m) optionally
deprotecting the product of step (l).
22. A process for the preparation of a compound of formula (23)
169wherein R.sup.2 is hydrogen; and 170R.sup.5 is the process
comprising: (a) reacting a compound of formula (7) 171a compound of
formula (4) 172and base to provide a compound of formula (8) 173(b)
optionally oxidizing the product from step (a); (c) hydrogenating
the product of step (a) or step (b) to provide a compound of
formula (9) 174(d) reacting the product from step (c) with base to
provide a compound of formula (10) 175(e) reacting the product from
step (d) with H.sub.2NOR.sup.2 or a salt thereof, wherein R.sup.2
is a a hydroxyl protecting group, under dehydrating conditions to
provide a compound of formula (11) 176wherein R.sup.2 is a hydroxyl
protecting group; (f) reacting the product of step (e) under
Mitsunobu conditions to provide a compound of formula (12)
177wherein R.sup.2 is a hydroxyl protecting group; (g) reacting the
product from step (f) with base to provide a compound of formula
(13) 178(h) activating the product from step (g) with azide to
provide a compound of formula (5-c); 179wherein R.sup.2 is a
hydroxyl protecting group; (i) reacting the product from step (h)
with base to provide a compound of formula (15) 180wherein R.sup.1
is --OR.sup.2; R.sup.2 is a hydroxyl protecting group; R.sup.5 is
Q.sup.1; and L.sup.1 is --NH--; (j) reacting the product from step
(i) with a compound of formula (21) 181to provide a compound of
formula (22) 182wherein R.sup.2 is a hydroxyl protecting group; (k)
reacting the product from step (j) with acid to provide a compound
of formula (20-c) 183wherein R.sup.2 is a hydroxyl protecting
group; (l) N-formylating the product from step (k) to provide a
compound of formula (23) 184wherein R.sup.2 is a hydroxyl
protecting group; (m) reacting the product from step (l) with a
coupling catalyst and a compound of formula (6) 185to provide a
compound of formula (23) 186wherein R.sup.2 is a hydroxyl
protecting group R.sup.5 is 187and (n) deprotecting the product of
step (m).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of the U.S. Provisional
Patent Application Serial No. 60/194,069, filed Mar. 31, 2000.
TECHNICAL FIELD
[0002] This invention relates to a process for the preparation of
matrix metalloproteinase inhibitors and to intermediates useful in
the process.
BACKGROUND OF THE INVENTION
[0003] Matrix metalloproteinases are a class of extracellular
enzymes such as collagenase, stromelysin, and gelatinase which are
believed to be involved in tissue destruction which accompanies a
number of diseases including arthritis and cancer. There is,
therefore, a continuing need for compounds which are inhibitors of
matrix matalloproteinase.
[0004] The instant invention discloses a synthesis of
metalloproteinase inhibitors from
((4S)-2-oxo-1,3-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate
(Sibi, M. P., Rutherford, D., Sharma, R. J. Chem. Soc. Perkin
Trans. 1994, 13, 1, 1675). Although an efficient synthesis of this
compound has been reported, racemization occurs during the
sequence, causing a reduction in the enantiomeric excess of the
final product. This invention discloses a method for the
preparation of ((4S)-2-oxo-1,3-oxazolidin-4-yl)methyl
4-methylbenzenesulfonate which significantly reduces
racemization.
SUMMARY OF THE INVENTION
[0005] In one embodiment of the instant invention is disclosed a
process for preparing a compound of formula (3) 1
[0006] wherein
[0007] R.sup.1 is selected from the group consisting of hydrogen,
an amino protecting group, and --OR.sup.2;
[0008] R.sup.2 is hydrogen or a hydroxy protecting group;
[0009] L.sup.1 is --O-- or --N(R.sup.3)--, wherein R.sup.3 is
hydrogen or an amino protecting group;
[0010] and
[0011] X is O or S,
[0012] the process comprising:
[0013] (a) reacting a compound of formula (2) 2
[0014] wherein
[0015] R.sup.4 is a carboxyl protecting group,
[0016] with a reducing agent to provide a first reaction mixture;
and
[0017] (b) adjusting the pH of the first reaction mixture to about
2 to about 6; and
[0018] (c) isolating the compound of formula (3).
[0019] In a preferred embodiment the compound of formula (3) is
(4R)-4-(hydroxymethyl)-1,3-oxazolidin-2-one.
[0020] Another embodiment of the instant invention comprises
reacting a compound of formula (1) 3
[0021] a base, and a reagent selected from the group consisting of
phosgene, thiophosgene, triphosgene, carbonyldiimidazole,
thiocarbonyldiimidazole, and a dialkyl carbonate.
[0022] Another embodiment of the instant invention comprises a
process for preparing a compound of formula (5-a) 4
[0023] or
[0024] a compound of formula (5-b) 5
[0025] wherein
[0026] Q.sup.1 is selected from the group consisting of halide,
methanesulfonate, and trifluoromethanesulfonate;
[0027] Y is nitrogen or C(H);
[0028] R.sup.6 is selected from the group consisting of alkoxy,
alkoxyalkyl, alkyl, aminosulfonyl, aminosulfonylalkyl, aryl,
arylalkyl, cyano, cyanoalkyl, halo, haloalkyl, (heterocycle)oxy,
(heterocycle)oxyalkyl, hydroxy, hydroxyalkyl, phenylalkoxy,
phenylalkoxyalkyl phenoxy, phenoxyalkyl, perfluoroalkoxy,
perfluoroalkoxyalkyl, perfluorothioalkoxy,
perfluorothioalkoxyalkyl, sulfinyl, sulfinylalkylsulfonyl,
sulfonylalkyl, thioalkoxy, and thioalkoxyalkyl;
[0029] and
[0030] L.sup.2 is --O-- or --S--,
[0031] the process comprising:
[0032] (a) activating the hydroxyl of the compound of formula (3)
6
[0033] (b) reacting the product of step (a), a compound of formula
(4) 7
[0034] and base to provide the compound of formula (5-a) 8
[0035] (c) optionally oxidizing the product of step (b);
[0036] and
[0037] (d) optionally reacting the product of step (b) or step (c)
and a compound of formula (6) 9
[0038] wherein
[0039] Q.sup.2 is selected from the group consisting of
trialkylstannanes, boronic acid, boronic esters, magnesium halides,
zinc halides, and silyl(alkyl)cyclobutanes,
[0040] and a coupling catalyst.
[0041] In a preferred embodiment the compound of formula (5-a) is
(4R)-4-((4-bromophenoxy)methyl)-1,3-oxazolidin-2-one and the
compound of formula (5-b) is
(4R)-4-(((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)oxy)-
methyl)-1,3-oxazolidin-2-one.
[0042] Another embodiment of the instant invention comprises a
process for preparing a compound of formula (5-c) 10
[0043] the process comprising:
[0044] (a) reacting a compound of formula (7) 11
[0045] wherein
[0046] R.sup.4 is alkyl,
[0047] a compound of formula (4) 12
[0048] and base to provide a compound of formula (8) 13
[0049] (b) optionally reacting the product from step (a) and an
oxidant;
[0050] (c) reacting the product of step (a) or step (b), hydrogen,
and a hydrogenation catalyst to provide a compound of formula (9)
14
[0051] (d) reacting the product from step (c) and base to provide a
compound of formula (10) 15
[0052] (e) reacting the product from step (d) and a compound of
formula H.sub.2NOR.sup.2, or a salt thereof,
[0053] wherein
[0054] R.sup.2 is a hydroxyl protecting group,
[0055] under dehydrating conditions to provide a compound of
formula (11) 16
[0056] (f) reacting the product of step (e) under Mitsunobu
conditions to provide a compound of formula (12) 17
[0057] (g) reacting the product from step (f) and base to provide a
compound of formula (13) 18
[0058] and
[0059] (h) reacting the product from step (g) and azide under
dehydrating conditions.
[0060] In a preferred embodiment the compound of formula (5-c) is
(5R)-1-(benzyloxy)-5-((4-bromophenoxy)methyl)-2-imidazolidinone.
[0061] Another embodiment of the instant invention comprises a
process for preparing a compound of formula (15) 19
[0062] the process comprising:
[0063] (a) reacting a compound of formula (5) 20
[0064] and base.
[0065] In a preferred embodiment the compound of formula (15) is
selected from the group consisting of
[0066]
(2S)-2-amino-3-((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)oxy)-1-p-
ropanol,
[0067] (2S)-2-amino-3-(4-bromophenoxy)-1-propanol, and
[0068]
(2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)-1-propanamine.
[0069] Another embodiment of the instant invention comprises a
process for preparing of a compound of formula (20), 21
[0070] or a salt thereof,
[0071] wherein
[0072] R.sup.7 and R.sup.8, together with the atoms to which they
are attached, form a heterocycle selected from the group consisting
of 5,5-dimethyl-1,3-oxazolidine-2,4-dionyl;
1-methyl-2,4-imidazolidinedionyl- ;
1,5,5-trimethyl-2,4-imidazolidinedionyl; 2,4-imidazolidinedionyl;
5,5-dimethyl-2,4-imidazolidinedionyl;
1,2-dimethyl-1,2,4-triazolidine-3,5- -dionyl;
4,4-dimethyl-2,6-piperidinedione; 8-azaspiro(4.5)decane-7,9-diony-
l; 3a,6-dihydro-1H-benzo(de)isoquinoline-1,3(2H)-dionyl;
2,4(1H,3H)-quinazolinedionyl;
1-methyl-2,4(1H,3H)-pyrimidinedionyl;
[0073] and 1,1-dioxo-1,2-benzisothiazol-3(2H)-onyl,
[0074] the process comprising:
[0075] (a) reacting a compound of formula (15-a) 22
[0076] and a compound of formula R.sup.9--CHO,
[0077] wherein
[0078] R.sup.9 is optionally substituted aryl,
[0079] to provide a compound of formula (16) 23
[0080] (b) reacting the product of step (a) and a compound of
formula (17) under Mitsunobu conditions 24
[0081] to provide a compound of formula (18) 25
[0082] (c) reacting the product of step (b) and an oxaziridine
forming agent to provide a compound of formula (19) 26
[0083] (d) reacting the product of step (c) and a compound of
formula H.sub.2NOR.sup.2, or a salt thereof, and base;
[0084] and
[0085] (e) optionally deprotecting the product of step (d).
[0086] In a preferred embodiment the compound of formula (20) is
selected from the group consisting of
[0087]
3-((2S)-2-(hydroxyamino)-3-((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-
-yl)oxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione
[0088] and
[0089]
3-((2S)-3-(4-bromophenoxy)-2-(hydroxyamino)propyl)-5,5-dimethyl-2,4-
-imidazolidinedione.
[0090] Another embodiment of the instant invention comprises a
process for preparing of a compound of formula (20-b) 27
[0091] or a salt thereof,
[0092] the process comprising:
[0093] (a) reacting the compound of formula (20-a) 28
[0094] the coupling catalyst, and the compound of formula (6)
29
[0095] In a preferred embodiment the compound of formula (20-b) is
3-((2S)-2-(hydroxyamino)-3-((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)ox-
y)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
[0096] Another embodiment of the instant invention comprises a
process for preparing of a compound of formula (20-c) 30
[0097] or a salt thereof,
[0098] the process comprising:
[0099] (a) reacting a compound of formula (15-b) 31
[0100] and a compound of formula (21) 32
[0101] to provide a compound of formula (22) 33
[0102] and
[0103] (b) reacting the product from step (a) and acid.
[0104] In a preferred embodiment the compound of formula (20-c) is
3-((2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)propyl)-5,5-dimethyl-2,4-i-
midazolidinedione.
[0105] Another embodiment of the instant invention comprises a
process for preparing a compound of formula (23) 34
[0106] the process comprising:
[0107] (a) N-formylating the compound of formula (20);
[0108] and
[0109] (b) optionally deprotecting the product of step (a).
[0110] In a preferred embodiment the compound of formula (23) is
selected from the group consisting of
[0111]
(1S)-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-1-(((4'-(trifluoro-
methoxy)(1,1'-biphenyl)-4-yl)oxy)methyl)ethyl(hydroxy)formamide
[0112] and
[0113]
benzyloxy((1R)-2-(4-bromophenoxy)-1-((4,4-dimethyl-2,5-dioxo-1-imid-
azolidinyl)methyl)-ethyl)formamide.
[0114] Another embodiment of the instant invention comprises a
process for preparing a compound of formula (23-b) 35
[0115] the process comprising:
[0116] (a) reacting a compound of formula (23-a) 36
[0117] the coupling catalyst, and the compound of formula (6)
37
[0118] and
[0119] (b) optionally deprotecting the product of step (a).
[0120] In a preferred embodiment the compound of formula (23-b) is
selected from the group consisting of
[0121]
4-(((2R)-2-((benzyloxy)(formyl)amino)-3-(4,4-dimethyl-2,5-dioxo-l-i-
midazolidinyl)-propyl)oxy)-4'-(trifluoromethoxy)-1,1'-biphenyl.
[0122] Another embodiment of the instant invention comprises a
process for preparing a compound of formula (23-b) 38
[0123] the process comprising:
[0124] (a) reacting a compound of formula (1) 39
[0125] a base, and a reagent selected from the group consisting of
phosgene, thiophosgene, triphosgene, carbonyldiimidazole,
thiocarbonyldiimidazole, and a dialkyl carbonate to provide a
compound of formula (2); 40
[0126] (b) reacting the product of step (a) with a reducing agent
to provide a compound of formula (3); 41
[0127] (c) activating the hydroxyl of the product of step (b);
[0128] (d) reacting the product of step (c) with base and a
compound of formula (4) 42
[0129] to provide a compound of formula (5-a), 43
[0130] (e) optionally oxidizing the product of step (d);
[0131] (f) reacting the product of step (d) or step (e), a coupling
catalyst, and a compound of formula (6) 44
[0132] to provide a compound of formula (5-b), 45
[0133] (g) reacting the product of step (f) with base to provide a
compound of formula (15), 46
[0134] (h) reacting the product of step (g) with a compound of
formula R.sup.9--CHO, to provide a compound of formula (16), 47
[0135] (i) reacting the product of step (h) with a compound of
formula (17) 48
[0136] to provide a compound of formula (18) 49
[0137] (j) reacting the product of step (i) and an oxaziridine
forming agent to provide a compound of formula (19) 50
[0138] (k) reacting the product of step (j) with H.sub.2NOR.sup.2,
or a salt thereof, and base to provide a compound of formula
(20-b); 51
[0139] (l) N-formylating the product from step (k) to provide a
compound of formula (23-b); 52
[0140] and
[0141] (m) optionally deprotecting the product of step (l).
[0142] Another embodiment of the instant invention comprises a
process for the preparation of a compound of formula (23-b) 53
[0143] the process comprising:
[0144] (a) reacting a compound of formula (l) 54
[0145] a base, and a reagent selected from the group consisting of
phosgene, thiophosgene, triphosgene, carbonyldiimidazole,
thiocarbonyldiimidazole, and a dialkyl carbonate, to provide a
compound of formula (2); 55
[0146] (b) reacting the product of step (a) with a reducing agent
to provide a compound of formula (3); 56
[0147] (c) activating the hydroxyl of the product of step (b);
[0148] (d) reacting the product of step (c) with base and a
compound of formula (4) 57
[0149] to provide a compound of formula (5-a), 58
[0150] (e) optionally oxidizing the product of step (d);
[0151] (f) reacting the product of step (e) with base to provide a
compound of formula (15), 59
[0152] wherein
[0153] R.sup.5is Q.sup.1;
[0154] (g) reacting the product of step (f) with a compound of
formula R.sup.9--CHO to provide a compound of formula (16), 60
[0155] wherein
[0156] R.sup.5 is Q.sup.1;
[0157] (h) reacting the product of step (g) with a compound of
formula (17) 61
[0158] to provide a compound of formula (18) 62
[0159] wherein R.sup.5 is Q.sup.1;
[0160] (i) reacting the product of step (h) with an oxaziridine
forming agent to provide a compound of formula (19) 63
[0161] wherein
[0162] R.sup.5 is Q.sup.1;
[0163] (j) reacting the product of step (i) with H.sub.2NOR.sup.2,
or a salt thereof, and base to provide a compound of formula (20);
64
[0164] wherein
[0165] R.sup.5 is Q.sup.1;
[0166] (k) reacting the product of step (j) with a coupling
catalyst and a compound of formula (6) 65
[0167] to provide a compound of formula (20), 66
[0168] wherein 67
[0169] R.sup.5 is
[0170] (l) N-formylating the product from step (k) to provide a
compound of formula (23) 68
[0171] wherein
[0172] R.sup.5 is 69
[0173] and
[0174] (m) optionally deprotecting the product of step (l).
[0175] Another embodiment of the instant invention comprises a
process for the preparation of a compound of formula (23) 70
[0176] wherein
[0177] R.sup.2 is hydrogen;
[0178] and
[0179] R.sup.5 is 71
[0180] the process comprising:
[0181] (a) reacting a compound of formula (7) 72
[0182] a compound of formula (4) 73
[0183] and base to provide a compound of formula (8) 74
[0184] (b) optionally oxidizing the product from step (a);
[0185] (c) hydrogenating the product of step (a) or step (b) to
provide a compound of formula (9) 75
[0186] (d) reacting the product from step (c) with base to provide
a compound of formula (10) 76
[0187] (e) reacting the product from step (d) with H.sub.2NOR.sup.2
or a salt thereof, wherein R.sup.2 is a a hydroxyl protecting
group, under dehydrating conditions to provide a compound of
formula (11) 77
[0188] wherein
[0189] R.sup.2 is a hydroxyl protecting group;
[0190] (f) reacting the product of step (e) under Mitsunobu
conditions to provide a compound of formula (12) 78
[0191] wherein
[0192] R.sup.2 is a hydroxyl protecting group;
[0193] (g) reacting the product from step (f) with base to provide
a compound of formula (13) 79
[0194] (h) activating the product from step (g) with azide to
provide a compound of formula (5-c); 80
[0195] wherein
[0196] R.sup.2 is a hydroxyl protecting group;
[0197] (i) reacting the product from step (h) with base to provide
a compound of formula (15) 81
[0198] wherein
[0199] R.sup.1 is --OR.sup.2;
[0200] R.sup.2 is a hydroxyl protecting group;
[0201] R.sup.5 is Q.sup.1;
[0202] and
[0203] L.sup.1 is --NH--;
[0204] (j) reacting the product from step (i) with a compound of
formula (21) 82
[0205] to provide a compound of formula (22) 83
[0206] wherein
[0207] R.sup.2 is a hydroxyl protecting group;
[0208] (k) reacting the product from step 0) with acid to provide a
compound of formula (20-c) 84
[0209] wherein
[0210] R.sup.2 is a hydroxyl protecting group;
[0211] (l) N-formylating the product from step (k) to provide a
compound of formula (23) 85
[0212] wherein
[0213] R.sup.2 is a hydroxyl protecting group;
[0214] (m) reacting the product from step (l) with a coupling
catalyst and a compound of formula (6) 86
[0215] to provide a compound of formula (23) 87
[0216] wherein
[0217] R.sup.2 is a hydroxyl protecting group R.sup.5 is 88
[0218] and
[0219] (n) deprotecting the product of step (m).
DETAILED DESCRIPTION OF THE INVENTION
[0220] This invention relates to processes for the preparation of
matrix metalloproteinase inhibitors and to intermediates which are
ueful in these processes of preparation. The following terms have
the meanings specified.
[0221] The term "alkoxy," as used herein, refers to an alkyl group
connected to the parent group through an oxygen atom.
[0222] The term "alkoxyalkyl," as used herein, refers to an alkyl
group to which is attached at least one alkoxy group.
[0223] The term "alkyl," as used herein, refers to a monovalent
straight or branched chain saturated hydrocarbon having one to six
carbons.
[0224] The term "alkylsulfinyl," as used herein, refers to an alkyl
group connected to the parent group through a sulfinyl group.
[0225] The term "alkylsulfonyl," as used herein, refers to an alkyl
group connected to the parent group through a sulfonyl group.
[0226] The term "amino," as used herein, refers to -NH.sub.2 or a
derivative thereof formed by independent replacement of one or both
hydrogens thereon by a substituent selected from the group
consisting of alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,
and an amino protecting group.
[0227] The term "amino protecting group," as used herein, refers to
selectively removable groups which protect amino groups against
undesirable side reactions during synthetic procedures and includes
all conventional amino protecting groups. Examples of amino groups
include optionally substituted acyl groups such as
trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,
para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl,
chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl,
phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl,
tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl,
2-furfuryloxycarbonyl, diphenylmethoxycarbonyl,
1,1-dimethylpropoxycarbon- yl, isopropoxycarbonyl, phthaloyl,
succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, and
8-quinolyloxycarbonyl; optionally substituted arylalkyl groups such
as benzyl, diphenylmethyl, and triphenylmethyl; optionally
substituted arylthio groups such as 2-nitrophenylthio and
2,4-dinitrophenylthio; optionally substituted alkyl sulfonyl and
optionally substituted arylsulfonyl groups such as methanesulfonyl,
and para-toluenesulfonyl; optionally substituted
dialkylaminoalkylidene groups such as N,N-dimethylaminomethylene;
optionally substituted arylalkylidene groups such as benzylidene,
2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, and
2-hydroxy-1-naphthylmethylene; optionally substituted
nitrogen-containing heterocyclic alkylidene groups such as
3-hydroxy-4-pyridylmethylene; optionally substituted
cycloalkylidene groups such as cyclohexylidene,
2-ethoxycarbonylcyclohexy- lidene,
2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, and
3,3-dimethyl-5-oxycyclohexylidene; optionally substituted
diarylalkylphosphoryl and optionally substituted
diarylalkylphosphoryl groups such as diphenylphosphoryl and
dibenzylphosphoryl; optionally substituted oxygen-containing
heterocyclic alkyl groups such as
5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl; and optionally
substituted silyl groups such as trimethylsilyl, triethylsilyl, and
triphenylsilyl.
[0228] The term "aminosulfonyl as used herein, refers to an amino
group connected to the parent group through a sulfonyl group.
[0229] The term "aryl," as used herein, refers to a mono or
bicyclic carbocyclic ring system having at least one aromatic ring.
Aryl groups are exemplified by phenyl, naphthyl,
1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl,
indanyl, and indenyl.
[0230] The term "aryl," as used herein, also includes compounds of
formula 89
[0231] wherein Y* is --C(O)-- or --(CH.sub.2).sub.v--, wherein v is
1 or 2; and Z* is --CH.sub.2-- or --O--. The aryl groups of this
invention can be optionally substituted with one, two, or three
substituents independently selected from the group consisting of
alkoxy, alkyl, halo, and thioalkoxy.
[0232] The term "arylalkyl," as used herein, refers to an alkyl
group to which is attached at least one aryl group.
[0233] The term "base," as used herein, refers to a reagent capable
of accepting protons during the course of a reaction. Examples of
bases include carbonates such as potassium carbonate, potassium
bicarbonate sodium carbonate, sodium bicarbonate, and cesium
carbonate; halides such as cesium fluoride; phosphates such as
potassium phosphate, potassium dihydrogen phosphate, and potassium
hydrogen phosphate; hydroxides such as lithium hydroxide, sodium
hydroxide, and potassium hydroxide; trialkylamines such as
triethylamine and diisopropylamine; heterocyclic amines such as
imidazole, pyridine, pyridazine, pyrimidine, and pyrazine; bicyclic
amines such as DBN and DBU; and hydrides such as lithium hydride,
sodium hydride, and potassium hydride. The base chosen for a
particular conversion depends on the nature of the starting
materials, the solvent or solvents in which the reaction is
conducted, and the temperature at which the reaction is
conducted.
[0234] The term "carbonyl," as used herein, refers to
--C(.dbd.O)--.
[0235] The term "carboxaldehyde," as used herein, refers to
--CHO.
[0236] The term "carboxy," as used herein, refers to
--CO.sub.2H.
[0237] The term "carboxyl protecting group," as used herein, refers
to selectively removable groups which protect hydroxyl groups
against undesirable side reactions during synthetic procedures and
includes all conventional carboxyl protecting groups. Examples of
carboxyl groups include optionally substituted alkyl groups such as
methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl,
and tert-butyl; aryl groups such as phenyl, and naphthyl;
optionally substituted arylalkyl groups such as benzyl,
diphenylmethyl, triphenylmethyl, para-nitrobenzyl,
para-methoxybenzyl, and bis(para-methoxyphenyl)methyl; optionally
substituted acylalkyl groups such as acetylmethyl, benzoylmethyl,
para-nitrobenzoylmethyl, para-bromobenzoylmethyl, and
para-methanesulfonylbenzoylmethyl; optionally substituted
oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl
and 2-tetrahydrofuranyl; optionally substituted haloalkyl groups
such as 2,2,2-trichloroethyl; optionally substituted
alkylsilylalkyl groups such as 2-(trimethylsilyl)ethyl; optionally
substituted acyloxyalkyl groups such as acetoxymethyl,
propionyloxymethyl, and pivaloyloxymethyl; optionally substituted
nitrogen-containing heterocyclic groups such as phthalimidomethyl
and succinimidomethyl; optionally substituted cycloalkyl groups
such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
optionally substituted alkoxyalkyl groups such as methoxymethyl,
methoxyethoxymethyl, and 2-(trimethylsilyl)ethoxymethyl; optionally
substituted arylalkoxyalkyl groups such as benzyloxymethyl;
optionally substituted alkylthioalkyl groups such as
methylthiomethyl and 2-methylthioethyl; optionally substituted
arylthioalkyl groups such as phenylthiomethyl; optionally
substituted alkenyl groups such as 1,1-dimethyl-2-propenyl,
3-methyl-3-butenyl, and allyl; and optionally substituted silyl
groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl,
diethylisopropylsilyl, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl, diphenylmethylsilyl, and
tert-butylmethoxyphenyl- silyl.
[0238] The term "coupling catalyst," as used herein, refers to
palladium complexes which enhance the rate of biaryl couplings.
Examples of catalysts include palladium(II) acetate,
tetrakis(triphenylphosphine)pall- adium(O), Pd.sub.2Cl.sub.2(dba),
and PdCl.sub.2.CH.sub.2Cl.sub.2. Each of these catalysts can be
used with an additive such as triphenylphosphine, triphenylarsine,
or a trialkylphosphine such as tributylphosphine optionally
present.
[0239] The term "cyano," as used herein, refers to -CN.
[0240] The term "cyanoalkyl," as used herein, refers to an alkyl
group to which is attached at least one cyano group.
[0241] The term "cycloalkyl," as used herein, refers to a saturated
cyclic alkyl group having three to six carbons.
[0242] The term "cycloalkylalkoxy," as used herein, refers to an
alkoxy group to which is attached at least one cycloalkyl
group.
[0243] The term "cycloalkylalkyl," as used herein, refers to an
alkyl group to which is attached at least one cycloalkyl group.
[0244] The terms "halo" or "halide," as used herein, refer to F,
Cl, Br, or I.
[0245] The term "haloalkyl," as used herein, refers to an alkyl
group to which is attached at least one halide.
[0246] The term "heterocycle," as used herein, refers to five- or
six-membered saturated or unsaturated rings having one, two, or
three heteroatoms independently selected from the group consisting
of nitrogen, oxygen, and sulfur. The nitrogen and sulfur
heteroatoms can be optionally oxidized, and the nitrogen
heteroatoms can be optionally quaternized. The heterocycles of the
instant invention are attached through a carbon atom in the ring.
Representative heterocycles include pyrrolidinyl, piperidinyl,
pyrazinyl, pyrazolyl, pyridazinyl morpholinyl, piperazinyl,
thiomorpholinyl, pyridyl, pyrimidinyl, quinolyl, furyl, benzofuryl,
thienyl, thiazolyl, pyrimidyl, indolyl, imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, 1,2,3-oxadiazolyl, thienyl,
triazolyl, 1,3,4-thiadiazolyl, and tetrazolyl.
[0247] The term "(heterocycle)oxy," as used herein, refers to a
heterocycle attached to the parent group through an oxygen
atom.
[0248] The term "(heterocycle)oxyalkyl," as used herein, refers to
an alkyl group to which is attached at least one (heterocycle)oxy
group.
[0249] The term "hydroxy," as used herein, refers to --OH.
[0250] The term "hydroxy protecting group," as used herein, refers
to selectively introducible and movable groups which protect
hydroxyl groups against undesirable side reactions during synthetic
procedures. Examples of hydroxyl protecting groups include
optionally substituted acyl groups such as benzyloxycarbonyl,
4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,
methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,
1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl,
isobutyloxycarbonyl, diphenylmethoxycarbonyl,
2,2,2-trichloroethoxycarbon- yl, 2,2,2-tribromoethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl,
1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl,
S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,
8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl,
dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl,
phenoxyacetyl, pivaloyl, and benzoyl; optionally substituted alkyl
groups such as methyl, tert-butyl, 2,2,2-trichloroethyl, and
2-trimethylsilylethyl; optionally substituted alkenyl groups such
as as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, and allyl;
optionally substituted arylalkyl groups such as benzyl,
para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, and
triphenylmethyl; oxygen-containing and sulfur-containing
heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, and
tetrahydrothiopyranyl; optionally substituted alkoxy and optionally
substituted alkylthioalkyl groups such as methoxymethyl,
methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl,
2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, and
1-ethoxyethyl; alkylsulfonyl; optionally substituted arylsulfonyl
groups such as methanesulfonyl, and para-toluenesulfonyl; and
optionally substituted silyl groups such as trimethylsilyl,
triethylsilyl, triisopropylsilyl, diethylisopropylsilyl,
tert-butyldimethylsilyl, tert-butyldiphenylsilyl,
diphenylmethylsilyl, and tert-butylmethoxyphenyl- silyl.
[0251] The term "hydroxyalkyl," as used herein, refers to an alkyl
group to which is attached at least one hydroxy group.
[0252] The term "methine," as used herein, refers to
.dbd.C(H)--.
[0253] The term "Mitsunobu conditions," as used herein, refers to
treatment of an alcohol with a diazo compound such as DIAD or DEAD
and a triarylphosphine such as triphenylphosphine or a
trialkylphosphine such as tributylphosphine.
[0254] The term "pharmaceutically acceptable salt," as used herein,
refers to salts which are suitable for use in contact with tissue
without undue toxicity, irritation, or allergic response and are
commensurate with a reasonable benefit/risk ratio. The salts can be
prepared during the final isolation and purification of the
compounds or separately by reacting a basic group with a suitable
acid. Representative acid addition salts include acetate, adipate,
alginate, citrate, aspartate, benzoate, benzenesulfonate, sulfate,
bisulfate, butyrate, camphorate, camphorsufonate, digluconate,
glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate
(isethionate), lactate, maleate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
para-toluenesulfonate and undecanoate. Basic nitrogen-containing
groups can also be quaternized with alkyl halides such as methyl,
ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl
sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates;
long chain halides such as decyl, lauryl, myristyl, and stearyl
chlorides, bromides, and iodides; and arylalkyl halides such as
benzyl and phenethyl bromides. Examples of acids employed to form
pharmaceutically acceptable acid addition salts include inorganic
acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric
and organic acids as oxalic, maleic succinic, and citric.
[0255] Basic addition salts can be prepared during the final
isolation and purification of the compounds by reacting a
carboxylic acid-containing group with a suitable base such as the
hydroxide, carbonate, or bicarbonate of a pharmaceutically
acceptable metal cation or with ammonia or an organic primary,
secondary, or tertiary amine. Pharmaceutically acceptable salts
include cations based on alkali metals or alkaline earth metals
such as lithium, sodium, potassium, calcium, magnesium, and
aluminum salts and nontoxic quaternary ammonia and amine cations
such as ammonium, tetramethylammonium, tetraethylammonium,
methylamine, dimethylamine, trimethylamine, triethylamine,
diethylamine, and ethylamine. Other representative organic amines
useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, and
piperazine.
[0256] The term "pharmaceutically acceptable prodrugs," as used
herein, refers to prodrugs and zwitterionic forms of the compounds
which are suitable for contact with tissue without undue toxicity,
irritation, allergic response, are commensurate with a reasonable
benefit/risk ratio, and are effective for their intended use.
[0257] The term "phenoxy," as used herein, refers to a phenyl group
connected to the parent group through an oxygen atom.
[0258] The term "phenoxyalkyl," as used herein, refers to an alkyl
group to which is attached at least one phenoxy group.
[0259] The term "phenylalkoxy," as used herein, refers to to an
alkoxy group to which is attached at least one phenyl group.
[0260] The term "phenylalkoxyalkyl," as used herein, refers to an
alkyl group to which is attached at least one phenylalkoxy
group.
[0261] The term "perfluoroalkoxy," as used herein, refers to a
perfluoroalkyl group attached to the parent group through an oxygen
atom.
[0262] The term "perfluoroalkyl," as used herein, refers to an
alkyl group in which all of the hydrogen atoms have been replaced
with fluoride atoms.
[0263] The term "perfluoroalkoxyalkyl," as used herein, refers to
an alkyl group to which is attached at least one perfluoroalkoxy
group.
[0264] The term "perfluorothioalkoxy," as used herein, refers to a
perfluoroalkyl group attached to the parent group through a sulfur
atom.
[0265] The term "perfluorothioalkoxyalkyl," as used herein, refers
to an alkyl group to which is attached at least one
perfluorothioalkoxy group.
[0266] The term "prodrug," as used herein, refers to compounds
which are rapidly transformed in vivo to parent compounds such as,
for example, by hydrolysis in blood.
[0267] The term "reducing agent," as used herein, refers to
reagents capable of converting protected carboxylic acids to
alcohols. Examples of reducing agents include
borane-dimethylsulfide, borane-tetrahydrofuran, and sodium
borohydride.
[0268] The term "sulfinyl," as used herein, refers to --S(O)--.
[0269] The term "sulfonyl," as used herein, refers to
--SO.sub.2--.
[0270] The term "thioalkoxy," as used herein, refers to an alkyl
group attached to the parent molecular group through a sulfur
atom.
[0271] The term "thioalkoxyalkyl," as used herein, refers to an
alkyl group to which is attached at least one thioalkoxy group.
[0272] Asymmetric centers exist in the compounds of the invention.
The invention contemplates stereoisomers and mixtures thereof.
Individual stereoisomers of compounds are prepared by synthesis
from starting materials containing the chiral centers or by
preparation of mixtures of enantiomeric products followed by
separation such as conversion to a mixture of diastereomers
followed by separation or recrystallization, chromatographic
techniques, or direct separation of the enantiomers on chiral
chromatographic columns. Starting compounds of particular
stereochemistry are either commercially available or are made by
the processes described herein and resolved by techniques
well-known in the art.
[0273] Chiral purity (percent enantiomeric excess (ee)) was
determined by chiral HPLC (Chiralcel OD) by comparing the
enantiomeric purity of a compound from a reaction mixture to a
mixture of the same enantiomer in known enantiomeric excess.
[0274] Yields of compounds in solution were determined by HPLC by
comparing the amount of product in solution to solutions of known
concentrations of that product.
[0275] Percentages obtained by HPLC analyses were determined by
peak area calculations.
[0276] All of the processes of the invention can be conducted as
continuous processes. The term "continuous process," as used
herein, refers to the conduction of steps in without isolation of
intermediates.
[0277] The formylation process used in the synthesis of Example 1N
is that described in pending U.S. application Ser. No. ______,
filed on the same day herewith, incorporated herein by
reference.
[0278] Abbreviations
[0279] Abbreviations which have been used in the descriptions of
the scheme and the examples that follow are: DBN for
1,5-diazabicyclo[4.3.0]n- on-5-ene; DBU for
1,8-diazabicyclo[5.4.0]undec-7-ene; dba for dibenzylideneacetone;
DIAD for diisopropyl azodicarboxylate; DEAD for diethyl
azodicarboxylate; THF for tetrahydrofuran; dppf for
diphenylphosphinoferrocene; DMF for dimethylformamide; DME for
dimethoxyethane; DMSO for dimethylsulfoxide; BINAP for
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; DCC for
1,3-dicyclohexylcarbodiimide; DIC for 1,3-diisoprpylcarbodiimide;
HOBT for 1-hydroxybenzotriazole hydrate; EDCI for
1-(3-dimethylaminopropyl)-3-- ethylcarbodiimide hydrochloride;
PyBOP benzotriazol-1-yloxytripyrrolidinop- hosphonium
hexafluorophosphate; NMM for N-methylmorpholine; NMP for
1-methyl-2-pyrrolidinone; MTBE for methyl tert-butyl ether; m-CPBA
for 3-chloroperoxybenzoic acid; and DPPA for diphenylphosphoryl
azide.
[0280] Synthetic Processes
[0281] The processes and compounds and of the instant invention
will be better understood in connection with the following
synthetic schemes. The compounds can be prepared by a variety of
processes, and representative processes are shown in Schemes 1-9.
The groups R.sup.1-R.sup.9, L.sup.1, L.sup.2, X, and Q.sup.1 are
defined previously. It will be readily apparent to one skilled in
the art that the selective protection and deprotection steps, as
well as the order of the steps themselves, can be carried out in
varying order, depending on the nature of R.sup.1-R.sup.9, L.sup.1,
L.sup.2, X, and Q.sup.1, to successfully complete the syntheses
shown below. 90
[0282] As shown in Scheme 1, compounds of formula (1) can be
converted to compounds of formula (2) (X is O or S) by treatment of
the former with an acylating agent and base. Representative
acylating agents include phosgene, triphosgene,
carbonyldiimidazole, dialkyl carbonates (for X is O), thiophosgene
and thiocarbonyldiimidazole (for X is S). Representative bases
include triethylamine, diisopropylethylamine, pyridine, and
imidazole.
[0283] Solvents used in these reactions include dichloromethane,
carbon tetrachloride, 1,2-dichloroethane, and chloroform, although
dialkyl carbonates can themselves be used as solvents. The reaction
temperature is about -10.degree. C. to about 100.degree. C. and
depends on the method chosen. Reaction times are typically about
0.5 to about 24 hours. In a preferred embodiment, compounds of
formula (1) in dichloromethane at 0.degree. C. are treated with
triphosgene and triethylamine and stirred for 7 hours to provide
compounds of formula (2).
[0284] Conversion of compounds of formula (2) to compounds of
formula (3) can be accomplished by treatment of the former with a
reducing agent such as sodium borohydride, lithium aluminum
hydride, sodium triacetoxy-borohydride, and lithium
tri-tert-butoxyaluminum hydride. Solvents used in these reactions
include ethanol, methanol, THF, and diethyl ether. The reaction
temperature is about -78.degree. C. to about 35.degree. C. and
depends on the process chosen. Reaction times are typically 1 to 24
hours. In a preferred embodiment, compounds of formula (2) in
ethanol at 0.degree. C. are treated with sodium borohydride and
stirred for 5 hours. The reaction is quenched to a pH of between to
provide compounds of formula (3). 91
[0285] As shown in Scheme 2, compounds of formula (3) can be
converted to compounds of formula (5-a) by activation of the
hydroxyl group of the former followed by treatment with compounds
of formula (4) and base. Activation of the hydroxyl group can be
accomplished by treatment with an acylating or sulfonating agent
and base. Representative acylating and sulfonating agents include
para-toluenesulfonyl chloride, benzenesulfonyl chloride,
trifluoroacetic anhydride, and methanesulfonyl chloride. Examples
of bases include pyridine, imidazole, diisopropylethylamine, and
triethylamine. Solvents used in these reactions include
dichloromethane, chloroform, THF, and methyl tert-butyl ether. The
reaction temperature is about -10.degree. C. to about 50.degree. C.
and depends on the process chosen. Reaction times are typically
about 1 to about 24 hours. The products can then be treated with
compounds of formula (4) (L.sup.2 is O or S; Q.sup.1 is halide,
methanesulfonate, or para-toluenesulfonate) and base to provide
compounds of formula (5-a). Representative bases include potassium
carbonate, sodium carbonate, lithium hexamethyldisilazide, and
lithium diisopropylamide. Examples of solvents used in these
reactions include acetonitrile, water, THF, diethyl ether, and
mixtures thereof. The reaction temperature is about 25.degree. C.
to about 100.degree. C. and depends on the process chosen. Reaction
times are typically about 2 to about 36 hours. In a preferred
embodiment, compounds of formula (3) in pyridine at 5.degree. C.
are treated with para-toluenesulfonyl chloride, warmed to room
temperature, and stirred for 16 hours. The products in acetonitrile
at 70.degree. C. are treated with compounds of formula (4) and
potassium carbonate to provide compounds of formula (5-a).
[0286] Conversion of compounds of formula (5-a) to compounds of
formula (5-b) can be accomplished by treatment of the former with a
compound of formula (6) (Y is nitrogen or 2 methine; Q is
trialkylstannane, boronic acid, boronic ester, magnesium halide,
zinc halide, or silyl(alkyl)cyclobutane) and a coupling catalyst.
Representative coupling catalysts include Pd(PPh.sub.3).sub.4,
Pd(PPh.sub.3).sub.2Cl.sub.2, Pd(dppf)Cl.sub.2, Ni(PPh.sub.3).sub.4,
and Pd(OAc).sub.2. Examples of solvents used in these reactions
include THF, water, acetonitrile, dichloromethane, DMF, DME, and
mixtures thereof. The reaction temperature is about 25.degree. C.
to about 120.degree. C. and depends on the process chosen. Reaction
times are typically about 0.5 to about 36 hours. In a preferred
embodiment, compounds of formula (5-a) in THF and water are treated
with 2 potassium phosphate and a compound of formula (6) (Y is CH;
Q.sup.2 is boronic acid), heated to 65.degree. C., and stirred for
1 hour to provide compounds of formula (5-b). 92
[0287] As shown in Scheme 3, compounds of formula (7) can be
treated with compounds of formula (4) and base to provide compounds
of formula (8). Representative bases include sodium hydroxide,
sodium carbonate, potassium carbonate, and lithium
hexamethyldisilazide. Examples of solvents used in these reactions
include DMSO, water, acetonitrile, THF, and mixtures thereof. The
reaction temperature is about -10.degree. C. to 50.degree. C. and
depends on the process chosen. Reaction times are typically 0.5 to
12 hours. In a preferred embodiment, compounds of formula (7)
(Q.sup.1 is Cl, R.sup.4 is alkyl) in DMSO and water at room
temperature are treated with a compound of formula (4) (L.sup.2 is
O and Q.sup.1 is Br) and NaOH for 1 hour to provide compounds of
formula (8).
[0288] Conversion of compounds of formula (8) to compounds of
formula (9) can be accomplished by hydrogenation and
(Ru.sub.2Cl.sub.5(R)BINAP.sub.2)- .sup.-Et.sub.2NH.sub.2.sup.+.
Examples of solvents used in this reaction include ethanol,
methanol, propanol, and tert-butanol. The reaction temperature is
about 50.degree. C. to 150.degree. C. and depends on the process
chosen. Reaction times are about 1-24 hours. In a preferred
embodiment, compounds of formula (8) in ethanol are treated with
(Ru.sub.2Cl.sub.5(R)BINAP.sub.2).sup.-Et.sub.2NH.sub.2.sup.+ and 2M
HCl and heated to 100.degree. C. under hydrogen for 8 hours to
provide compounds of formula (9).
[0289] Compounds of formula (9) (R.sup.4 is alkyl) can be converted
to compounds of formula (10) (R.sup.4 is H) by treatment with
aqueous base, followed by treatment with aqueous acid.
Representative bases include sodium hydroxide, potassiym hydroxide,
and lithium hydroxide. Examples of acids used in these reactions
are hydrochloric acid, acetic acid, nitric acid, and sulfuric acid.
Solvents used in these reactions include isopropanol, isopropanol
acetate, ethyl acetate, ethanol, methanol, and mixtures thereof.
The reaction temperature is about 0.degree. C. to 25.degree. C. and
depends on the process chosen. Reaction times are typically 10
minutes to 24 hours. In a preferred embodiment, compounds of
formula (9) in ethanol at 5.degree. C. are treated with aqueous
potassium hydroxide over 10 minutes, warmed to room temperature,
treated with water and isopropyl acetate, cooled to 5.degree. C.,
and treated with 6M hydrochloric acid to provide compounds of
formula (10).
[0290] Conversion of compounds of formula (10) to compounds of
formula (11) can be accomplished by coupling with an appropriately
substituted hydroxylamine and a carbonyl activating group such as
DCC, DIC, HOBT, EDCI, and PyBOP, and base. Representative bases
include NMM, diisopropylethylamine, and DBU. Examples of solvents
used in these reactions include dichloromethane, chloroform, DMF,
THF, and NMP. The reaction temperature is about -10.degree. C. to
60.degree. C. and depends on the process chosen. Reaction times are
typically 0.5-24 hours. In a preferred embodiment, compounds of
formula (10) in DMF at 5.degree. C. are treated with EDCI, HOBT,
NMM, and O-benzylhydroxylamine hydrochloride, warmed to room
temperature, and stirred for 30 minutes to provide compounds of
formula (11).
[0291] Compounds of formula (11) can be converted to compounds of
formula (12) by treatment with a diazo compound and a triaryl- or
trialkylphosphine. Representative diazo compounds include DIAD and
DEAD, while representative phosphines include triphenylphosphine
and tributylphosphine. Examples of solvents used in these reactions
are THF, MTBE, diethyl ether, and DME. The reaction temperature is
about 20.degree. C. to 70.degree. C. and depends on the process
chosen. The reaction time is typically 0.5 to 3 hours. In a
preferred embodiment, compounds of formula (11) in THF at
40.degree. C. are treated with DEAD and triphenylphosphine and
stirred for 2 hours to provide compounds of formula (12).
[0292] Conversion of compounds of formula (12) to compounds of
formula (13) can be accomplished by treatment with an aqueous
hydroxide base. Representative bases include sodium hydroxide,
lithium hydroxide, and potassium hydroxide. Examples of solvents
used in these reactions include toluene, hexanes, benzene, THF,
water, and mixtures thereof. The reaction temperature is about
30.degree. C. to 80.degree. C. and depends on the process chosen.
Reaction times are typically 1 to 24 hours. In a preferred
embodiment, compounds of formula (12) in toluene are treated with
aqueous lithium hydroxide, heated to 60.degree. C. for 3 hours,
cooled to room temperature, and stirred for 16 hours to provide
compounds of formula (13).
[0293] Compounds of formula (13) can be converted to compounds of
formula (14) by treatment with diphenylphosphoryl azide and base.
Representative bases include diisopropylethyl amine, triethylamine,
and pyridine. Examples of solvents used in these reactions include
THF, diethyl ether, MTBE, and dioxane. The reaction temperature is
about 25.degree. C. to 100.degree. C. and depends on the process
chosen. Reaction times are typically 1 to 24 hours. In a preferred
embodiment, compounds of formula (13) in THF are treated with
diphenylphosphoryl azide and diisopropylethyl amine, heated to
reflux, and stirred for 3 hours to provide compounds of formula
(14), which cyclize under the reaction conditions to provide
compounds of formula (5-c). 93
[0294] As shown in Scheme 4, compounds of formula (5) can be
converted to compounds of formula (15) by treatment with base.
Representative bases include potassium hydroxide, sodium hydroxide,
and lithium hydroxide. Examples of solvents used in these reactions
include water, THF, acetonitrile, and mixtures thereof. The
reaction temperature is about 30.degree. C. to 120.degree. C. and
depends on the process chosen. Reaction times are typically 1 to 24
hours. In a preferred embodiment, compounds of formula (5) in water
are treated with potassium hydroxide, heated to reflux, and stirred
for 9 hours to provide compounds of formula (15). 94
[0295] As shown in Scheme 5, compounds of formula (15-a) can be
converted to compounds of formula (16) by treatment with an
appropriately substituted aldehyde (R.sup.9CHO). Examples of
solvents used in this reaction include toluene, hexanes, heptane,
and benzene. The reaction temperature is about 30.degree. C. to
120.degree. C. and depends on the process chosen. Reaction times
are about 1 to 36 hours. In a preferred embodiment, compounds of
formula (15-a) in toluene are treated with an aldehyde (R.sup.9CHO)
and heated to 80.degree. C. for 2 hours to provide compounds of
formula (16).
[0296] Conversion of compounds of formula (16) to compounds of
formula (18) can be accomplished by treatment with compounds of
formula (17) and a diazo compound and a triaryl- or
trialkylphosphine. Representative diazo compounds include DIAD and
DEAD, while representative phosphines include triphenylphosphine
and tributylphosphine. Examples of solvents used in these reactions
are THF, MTBE, diethyl ether, and DME. The reaction temperature is
about -10.degree. C. to 35.degree. C. and depends on the process
chosen. Reaction times are typically 0.5 to 12 hours. In a
preferred embodiment, compounds of formula (16) in THF at 1.degree.
C. are treated with compounds of formula (17), DIAD, and
triphenylphosphine over 1.25 hours to provide compounds of formula
(18).
[0297] Compounds of formula (18) can be converted to compounds of
formula (19) by treatment with an oxidizing agent. Representative
oxidizing agents include m-CPBA, trifluoroperacetic acid, and
2,5-dinitroperoxybenzoic acid. Examples of solvents used in these
reactions include MTBE, THF, and diethyl ether. The reaction
temperature is about -78.degree. C. to 35.degree. C. and depends on
the process chosen. Reaction times are typically 0.5 to 4 hours. In
a preferred embodiment, compounds of formula (18) in THF at
-45.degree. C. are treated with m-CPBA and warmed to 0.degree. C.
over 2 hours to provide compounds of formula (19).
[0298] Conversion of compounds of formula (19) to compounds of
formula (20) can be accomplished by treatment with N-hydroxylamine
followed by treatment with aqueous base. Representative bases
include sodium hydroxide, potassium hydroxide, and lithium
hydroxide. Examples of solvents used in this reaction include
water, THF, dioxane, and mixtures thereof. The reaction temperature
is about -10.degree. C. to 35.degree. C. and depends on the process
chosen. Reaction times are typically 0.5 to 48 hours. In a
preferred embodiment, compounds of formula (19) in THF at 1.degree.
C. are treated with N-hydroxylamine hydrochloride in water over 1
hour, warmed to room temperature, and stirred for 18 hours to
provide compounds of formula (20). 95
[0299] As shown in Scheme 6, compounds of formula (20-a) can be
converted to compounds of formula (20-b) by the procedure described
in Scheme 2. 96
[0300] As shown in Scheme 7, compounds of formula (15-b) can be
converted to compounds of formula (22) by treatment with compounds
of formula (21). Examples of solvents used in this reaction include
THF, diethyl ether, MTBE, and dioxane. The reaction temperature is
about 20.degree. C. to 40.degree. C. and depends on the process
chosen. Reaction times are typically 0.5 to 12 hours. In a
preferred embodiment, compounds of formula (15-b) in THF at room
temperature are treated with compounds of formula (21) and stirred
for 0.5 hours to provide compounds of formula (22).
[0301] Coversion of compounds of formula (22) to compounds of
formula (20-c) can be accomplished by treatment with acid.
Representative acids include hydrochloric acid, sulfuric acid, and
nitric acid. Examples of solvents used in these reactions include
water, THF, dioxane, and mixtures thereof. Reaction times are about
1 to 24 hours. In a preferred embodiment, compounds of formula (22)
in THF are treated with 6M HCl, heated to reflux, and stirred for 6
hours to provide compounds of formula (20-c). 97
[0302] As shown in Scheme 8, compounds of formula (20) can be
converted to compounds of formula (23) by treatment with a
formylating agent. Representative formylating agents include acetic
anhydride/formic acid and 2,2,2-trifluoroethyl formate. Examples of
solvents used in these reactions include formic acid, THF, MTBE,
and mixtures thereof. The reaction temperature is about 25.degree.
C. to 65.degree. C. and depends on the process chosen. Reaction
times are typically 15 minutes to 6 hours. 98
[0303] As shown in Scheme 9, compounds of formula (23-a), can be
converted to compounds of (23-b) by the procedures described in
Scheme 2.
Synthesis of
(1S)-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-1-(((4'-(tri-
fluoromethoxy)(1,1'-biphenyl)
4-yl)oxy)methyl)ethyl(hydroxy)formamide
EXAMPLE 1A
methyl (4S)-2-oxo-1,3-oxazolidine-4-carboxylate
[0304] A solution of L-serine methyl ester hydrochloride (3.063 kg)
in dichloromethane (24.1 L) at 0.degree. C. was treated with
triethylamine (5.908 kg), stirred for 30 minutes, treated with
triphosgene (1.949 kg) in dichloromethane (5.356 kg) over 6.5
hours, stirred for 45 minutes, treated with hexanes (12.23 kg),
stirred for 55 minutes, and filtered with ethyl acetate (16.013
kg). The filtrate was concentrated to provide a 35% (w/w) solution
of the desired product (93.5%, 98% ee) in ethyl acetate. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 6.55 (br s, 1H), 4.62 (dd, J=9, 9
Hz, 1H), 4.53 (dd, J=4, 9 Hz, 1H), 4.45 (dd, J=4, 9 Hz, 1H), 3.83
(s, 3H).
EXAMPLE 1B
(4R)-4-(hydroxymethyl)-1,3-oxazolidin-2-one
[0305] The solution of Example 1A was concentrated to remove the
bulk of the ethyl acetate, treated with ethanol (6.79 kg),
concentrated to approximately one half of its original volume,
treated again with ethanol (53.36 kg), cooled to 0.degree. C.,
treated with sodium borohydride (855 g) over 3 hours and 42
minutes, stirred for 60 minutes, treated with phosphoric acid (2.20
kg) over 51 minutes, and warmed to room temperature over 18 hours
to provide a reaction mixture with a pH of 5.55. The reaction
mixture was filtered with ethanol (27.4 kg). The filtrate was
concentrated to approximately 25 L and treated with toluene (30 L)
to provide a white precipitate which was collected by filtration,
rinsed with toluene (3 L), air dried, and vacuum dried (100 mmHg)
at 45.degree. C. with a nitrogen bleed to provide 3.592 kg (94.7%,
>98% ee) of the desired product. .sup.1H NMR (300 MHz, D.sub.2O)
.delta. 4.36 (dd, J=9, 9 Hz, 1H), 4.20 (dd, J=6, 9 Hz, 1H),
3.90-3.80 (m, 1H), 3.48 (dd, J=3, 12 Hz, 1H), 3.40 (dd, J=4, 12 Hz,
1H).
EXAMPLE 1 C
((4S)-2-oxo-1,3-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate
[0306] A solution of Example 1B (3.430 kg) in pyridine (12.82 kg)
at 5.degree. C. was treated with para-toluenesulfonyl chloride
(6.702 kg), stirred for 16 hours at room temperature, cooled to
5.degree. C., treated with water (55.0 kg) over 1 hour and 48
minutes, warmed to room temperature, stirred for 17 hours, and
filtered with water (28.2 kg). The filtrate was suction dried then
vacuum dried (100 mmHg) at 50.degree. C. with a nitrogen bleed to
provide 6.895 kg (84.6%, >99% ee) of the desired product.
.sup.1H NMR (300 MHz, D.sub.2O) .delta. 7.9 (br s, 1H), 7.81 (d,
J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 4.31 (t, J=9 Hz, 1H), 4.05-3.90
(m, 4H), 2.42 (s, 3H).
EXAMPLE 1D
(4R)-4-((4-bromophenoxy)methyl)-1,3-oxazolidin-2-one
[0307] A solution of Example 1C (4.154 kg), potassium carbonate
(2.522 kg), and 4-bromophenol (3.183 kg) in acetonitrile (30.3 kg)
was stirred at 70.degree. C. for 23.5 hours, cooled to 55.degree.
C., treated with 2% (w/w) K.sub.2CO.sub.3 (41.52 kg) over 20
minutes, cooled to room temperature, and separated into an aqueous
fraction and an organic fraction. The organic fraction was
concentrated to approximately one third of its original volume,
treated with the aqueous fraction to provide a precipitate,
concentrated to remove the remainder of the acetonitrile, treated
with the 2% (w/w) K.sub.2CO.sub.3 solution (41.52 kg), stirred at
room temperature for 18 hours, and filtered. The filter cake was
rinsed with 2% K.sub.2CO.sub.3 (16.62 L) air-dried, slurried in
ethyl acetate (9.44 kg), and heated at 55.degree. C. This solution
was treated with hexanes (23.615 kg) and cooled to room temperature
to provide a solid. The solid was filtered, rinsed with a solution
of ethyl acetate (2.24 kg) and hexanes (7.3 kg), air dried, and
vacuum dried (100 mm/Hg) at 50.degree. C. with a nitrogen bleed to
provide 3.307 kg (79.6%, >99.5% ee) of the desired compound.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.91 (br s, 1H), 7.47
(dd, J=17 Hz, 2H), 6.93 (dd, J=17 Hz, 2H), 4.44 (m, 1H), 4.15 (m,
2H), 3.95 (m, 2H).
EXAMPLE 1E
4-(trifluoromethoxy)phenylboronic Acid
[0308] A solution of 1-bromo-4-(trifluoromethoxy)benzene (1.69 kg)
and triisopropyl borate (1.46 kg) in THF (6.75 L) at -70.degree. C.
was treated with 2.25 M butyllithium in hexanes (3.27 L) over 2.3
hours, stirred for 10 minutes, treated with 6M HCl (1.52 L) over 50
minutes, stirred for 18 hours at room temperature, and poured into
a mixture of heptane (8.43 L) and 20% (w/w) sodium chloride (8.44
kg). This mixture was stirred for 10 minutes and separated into an
aqueous fraction and an organic fraction. The organic fraction was
concentrated to provide a white paste. The paste was dried under
vacuum (100 mmHg) at ambient temperature with a nitrogen bleed for
2 days then at 40-50.degree. C. for 18 hours to provide 1.306 kg
(90.4%) of the desired product as a solid. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 7.24-7.19 (m, 2H), 8.14-8.10 (m, 2H) with
additional absorptions at 7.19-7.15 (m, 2H) and 8.04-8.00 (m, 2H)
corresponding to the cyclic boronic acid trimer.
EXAMPLE 1F
(4R)-4-(((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)oxy)methyl)-1,3-oxazol-
idin-2-one
[0309] A room temperature solution of potassium phosphate (9.22 kg,
43.4 mol) in water (25 L) was treated sequentially with Example 1D
(3.94 kg), a solution of Example 1E (3.15 kg) in THF (19.6 L), and
THF (5.1 L), sparged with nitrogen for 20 minutes, treated with
Pd(dppf)Cl.sub.2 (59.4 g), purged with nitrogen, heated to
60-65.degree. C. for 1 hour, cooled to ambient temperature,
concentrated, and treated with water (25 L). The resulting mixture
was repeatedly filtered until the filtrate was clear, and the solid
was washed with water (4.times.25 L) until the pH of the wash was
neutral. The solid was dried, treated with THF (51.1 L),
concentrated, treated with THF (37.1 L), concentrated again, and
treated with THF (68.1 L). Commercial Deloxan resin (3.2 kg) was
dehydrated by rinsing with methanol (4.times.4 L) and THF (16.1 L),
added to the solution of product in THF, and stirred at ambient
temperature for 18 hours. The mixture was filtered through a pad of
silica gel 60 (10.3 kg slurried with THF) and the pad was
thoroughly rinsed with THF. The combined filtrates were
concentrated to a volume of approximately 11 L, treated with
heptanes (59.7 L), stirred for 1 hour and filtered. The solid was
washed with heptanes (2.times.14.6 L) and dried at 45.degree. C.
under vacuum for 18 hours to provide 4.93 kg (97%, >99% ee) of
the desired product. MS (DCI/NH.sub.3) m/z 371 (M+NH.sub.4).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.96 (br s, 1H), 7.73
(d, J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H),
7.05 (d, J=8.8 Hz, 2H), 4.46 (t, J=10.0 Hz, 1H), 4.18 (m, 2H), 4.06
(dd, J=10.0 Hz, 4.1 Hz, 1H), 3.99 (dd, J=10.0 Hz, 5.0 Hz, 1H);
.sup.13C NMR (DMSO-d.sub.6) d 158.9 (q), 158.3 (q), 147.4 (q),
139.1 (q), 131.6 (q), 128.0 (CH), 121.5 (CH), 115.2 (CH), 69.4
(CH.sub.2), 66.2 (CH.sub.2), 51.0 (CH).
EXAMPLE 1G
(2S)-2-amino-3-((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)oxy)-1-propanol
[0310] A solution of KOH (2.502 kg) in water (2.492 kg) at
0.degree. C. was treated sequentially with ethanol (11.548 kg) and
Example 1F, stirred at 80.degree. C. for 7 hours, treated with
water (37.059 kg) over 25 minutes, and cooled to room temperature
over 18 hours to provide a solid. The solid was filtered, washed
with water (7.035 kg), and dried under vacuum (100 mm Hg) at
50.degree. C. with a nitrogen bleed to provide 3.316 kg (96.6%,
>99.5% ee) of the desired product. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 7.83 (dt, J=3, 9 Hz, 2H), 7.71 (dt, J=3, 9
Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.14 (dt, J=3, 9 Hz, 2H), 4.77 (br
s, 1H), 4.01 (m, 2H), 3.51 (m, 2H), 3.15 (t, J=5 Hz 1H).
EXAMPLE 1H
(2S)-2-(((E)-(4-methoxyphenyl)methylidene)amino)-3-((4'-(trifluoromethoxy)-
(1,1'-biphenyl)-4-yl)oxy)-1-propanol
[0311] A solution of Example 1G (3.236 kg) and para-anisaldehyde
(1.484 kg) in toluene (6.631 kg) was heated at 80.degree. C. for 2
hours, treated with heptane (33.147 kg) over 50 minutes, cooled to
room temperature over 20 hours, and filtered. The filter cake was
rinsed with heptane (6.994 kg), air dried, then vacuum dried (100
mmHg) at 50.degree. C. to provide 4.297 kg (97.6%) of the desired
product. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.35 (s, 1H),
7.73 (dt, 2H, J=8.9, 2.9 Hz), 7.61 (dt, 2H, J=8.8, 2.9 Hz), 7.41
(dd, 2H, J=8.9, 1.1 Hz), 7.05 (dt, 2H, J=8.8, 2.9 Hz), 7.01 (dt,
2H, J=8.8, 2.9 Hz), 4.87 (br s, 1H), 4.31 (dd, 1H, J=9.9, 4.1 Hz),
4.13 (dd, 1H, J=9.9, 7.4 Hz), 3.81 (s, 3H), 3.64-3.80 (m, 2H), 3.56
(dd, 1H, J=10.0, 6.3 Hz).
EXAMPLE 1I
3-((2S)-2-(((E)-(4-methoxyphenyl)methylidene)amino)-3-((4'-(trifluorometho-
xy)(1,1'-biphenyl)-4-yl)oxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione
[0312] A solution of Example 1H (2.80 kg), triphenylphosphine
(2.475 kg), and 5,5-dimethylhydantoin (1.37 kg) in THF (24.89 kg)
at 1-2.degree. C. was treated with diisopropyl azodicarboxylate
(2.01 kg) over 75 minutes to provide a solution of the desired
product.
EXAMPLE 1J
3-((2S)-2-(3-(4-methoxyphenyl)-1,2-oxaziridin-2-yl)-3-((4'-(trifluorometho-
xy)(1,1'-biphenyl)-4-yl)oxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione
[0313] The solution of Step 11 was cooled to -67.degree. C.,
treated with a solution of 3-chloroperoxybenzoic acid (3.15 kg) in
THF (6.30 kg) over 30 minutes, and warmed to 0-2.degree. C. over
100 minutes to provide a solution of the desired product.
EXAMPLE 1K
3-((2S)-2-(hydroxyamino)-3-((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)oxy-
)propyl)-5,5-dimethyl-2,4-imidazolidinedione, Para Toluene
Sulfononic Acid Salt
[0314] The solution of Example 1J was diluted with toluene (27.34
kg) and washed sequentially with 10% (w/w) sodium thiosulfate (31
kg), 5% (w/w) sodium bicarbonate (31 kg), and 10% (w/w) sodium
chloride (30 kg). The mixture was treated with para-toluenesulfonic
acid hydrate (1.79 kg), stirred at ambient temperature several
hours, treated with a solution of N-hydroxylamine hydrochloride
(0.88 kg) in water (2.8 kg), and stirred at ambient temperature
several hours. The reaction mixture was washed with 10% (w/w)
sodium carbonate (31 kg) and 5% (w/w) sodium bicarbonate (30 kg),
diluted with ethyl acetate (9.47 kg), washed with 10% (w/w) sodium
chloride (30 kg), concentrated, and diluted to a concentration of
30 mg/mL in toluene. The solution was treated with
para-toluenesulfonic acid hydrate (19.5 g), stirred for 2 hours,
filtered through a pad of diatomaceous earth (Celite.RTM. 521),
treated with para-toluenesulfonic acid hydrate (1.05 kg), and
warmed to 50.degree. C. to provide a white suspension which
thickened after 30 minutes. After six hours the heating was
discontinued, the suspension was cooled to ambient temperature,
stirred for 18 hours, and filtered. The filter cake was rinsed with
toluene (29 kg), suction dried, then vacuum dried (100 mm Hg) at
40-45.degree. C. with a nitrogen bleed to provide 3.422 kg (83%
potency adjusted yield) of the desired product. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.4 (br s, 1H), 10.8 (br s, 1H), 8.48
(s, 1H), 7.66 (dt, 2H, J=8.8, 2.9 Hz), 7.68 (dt, 2H, J=8.8, 2.9
Hz), 7.50 (dt, 2H, J=8.0, 1.4 Hz), 7.45 (d, 2H, J=8.0 Hz), 7.13 (d,
2H, J=8.0 Hz), 7.08 (dt, 2H, J=8.0, 1.4 Hz), 4.30 (dd, 1H, J=3.6,
11.0 Hz), 4.21 (dd, 1H, J=4.4, 11.0 Hz), 4.0-3.9 (m, 1H), 3.90-3.75
(m, 2H), 2.30 (s, 3H), 1.31 (br s, 6H). The NMR spectrum also
showed approximately 5 wt % toluene.
EXAMPLE 1L
2,2,2-trifluoroethyl Formate
[0315] A solution of 2,2,2-trifluoroethanol (18.212 kg) and formic
acid (36.324 kg) was stirred at 80.degree. C. for 6 hours, cooled
to room temperature, and sirred for 18 hours to provide a mixture
of product and unreacted starting materials. The mixture was
distilled (head temperature 60-80.degree. C.) over 23 hours to
provide a distillate (14.79 kg) comprising 10.64 kg (71.9% (w/w)
solution, 45.5%) of the desired product in addition to unreacted
starting materials. .sup.1H NMR (300 MHz, CDCl.sub.3)
(71.9:13.6:4.4/2,2,2-trifluoroethyl formate:2,2,2-trifluoroet-
hanol:formic acid): formic acid: .delta. 8.06 (s, 1H);
2,2,2-trifluoroethanol: 8 3.96 (q, 2H, J=8.8 Hz); and
2,2,2-trifluoroethyl formate: 8 8.13 (q, 1H, J=0.7 Hz), 4.57 (dq,
2H, J=0.7, 8.4 Hz).
EXAMPLE 1M
3-((2S)-2-(hydroxyamino)-3-((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)oxy-
)propyl)-5,5-dimethyl-2,4-imidazolidinedione
[0316] A solution of the product from Example 1K (1.95 kg) in 15%
(w/w) potassium carbonate (4.29 kg), THF (5.07 kg), and methyl
tert-butyl ether (4.12 kg) was stirred until all solids dissolved
and separated into an aqueous fraction and an organic fraction. The
organic fraction was washed with 25% (w/w) sodium chloride (3.83
kg), treated with THF (0.58 kg), and concentrated to provide a
20-30% (w/w) solution of the desired product.
EXAMPLE 1N
(1S)-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-1-(((4'-(trifluoromethoxy-
)(1,1'-biphenyl)-4-yl)oxy)methyl)ethyl(hydroxy)formamide
[0317] The solution of Example 1M was treated with the distillate
containing Example 1L (5.27 kg of the 71.9% (w/w) solution (3.79
kg, 10 equivalents), stirred at reflux for 4 hours, cooled to less
than 30.degree. C., treated with water (5.33 kg) and MTBE (7.62
kg), washed with 15% (w/w) potassium bicarbonate (5.3 kg portions)
until the pH of the wash was .gtoreq.8, and concentrated. The
residue was dissolved in ethyl acetate (7.133 kg), treated with
heptane (10.71 kg) during which a solid began to precipitate,
stirred for 18 hours, and filtered. The filter cake was rinsed with
1:2 (v/v) ethyl acatate/heptane (5.63 kg), suction dried, then
vacuum dried (100 mmHg) at 100.degree. C. with a nitrogen bleed to
provide 2.685 kg (91.8%, >99% ee) of the desired product.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.95 (br s, 0.5H), 9.80
(br s, 0.5H), 8.41 (br s, 0.5H), 8.37 (br s, 0.5H), 8.35 (s, 0.5H),
7.95 (s, 0.5H), 7.76 (d, 2H, J=8.9 Hz), 7.65 (d, 2H, J=8.5 Hz),
7.43 (d, 2H, J=8.5 Hz), 7.04 (d, 2H, J=8.9 Hz), 4.92-4.80 (m,
0.5H), 4.50-4.38 (m, 0.5H), 4.28-4.06 (m, 2H), 3.82-3.68 (m, 1H),
3.66-3.54 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H).
ALTERNATE SYNTHESIS OF EXAMPLE 1M
EXAMPLE 2A
(2S)-2-amino-3-(4-bromophenoxy)-1-propanol
[0318] The desired product (160 g) was prepared by substituting
Example 1D (177 g) for Example 1F in Example 1G. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 7.38 (d, 2H, J=7.2 Hz), 6.85 (d, 2H,
J=7.2 Hz), 3.79 (m, 2H), 3.35 (m, 2H), 2.95 (m, 1H).
EXAMPLE 2B
(2S)-3-(4-bromophenoxy)-2-(((E)-(4-methoxyphenyl)methylidene)amino)-1-prop-
anol
[0319] The desired product (225 g) was prepared by substituting
Example 2A (155 g) for Example 1G in Example 1H. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 8.3 (s, 1H), 7.69 (d, 2H, J=9 Hz), 7.41
(d, 2H, J=9 Hz), 6.99 (d, 2H, J=9 Hz), 6.90 (d, 2H, J=9 Hz), 4.81
(m, 1H), 4.15(m, 2H), 3.80 (s, 3H), 3.61 (m, 3H).
EXAMPLE 2C
3-((2S)-3-(4-bromophenoxy)-2-(((E)-(4-methoxyphenyl)methylidene)amino)prop-
yl)-5,5-dimethyl-2,4-imidazolidinedione
[0320] The desired product was prepared without isolation by
substituting Example 2B (208 g) for Example 1H in Example 1I.
EXAMPLE 2D
3-((2S)-3-(4-bromophenoxy)-2-(3-(4-methoxyphenyl)-1,2-oxaziridin-2-yl)prop-
yl)-5,5-dimethyl-2,4-imidazolidinedione
[0321] The desired product was prepared without isolation by
substituting the in situ derived Example 2C for Example 1I in
Example 1J.
EXAMPLE 2E
3-((2S)-3-(4-bromophenoxy)-2-(hydroxyamino)propyl)-5,5-dimethyl-2,4-imidaz-
olidinedione
[0322] The desired product (113 g) was prepared by substituting in
situ prepared Example 2D for Example 1J in Example 1K. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 8.22 (br s, 1H), 7.35 (m, 2H), 7.22
(br s, 1H), 6.80 (m, 2H), 5.74 (br s, 1H), 3.85 (m, 2H), 3.47 (m,
2H), 3.25 (m, 1H), 1.19 (s, 3H), 1.17 (s, 3H).
EXAMPLE 1M
3-((2S)-2-(hydroxyamino)-3-((4'-(trifluoromethoxy)(1,1'-biphenyl)-4-yl)oxy-
)propyl)-5,5-dimethyl-2,4-imidazolidinedione
[0323] The desired product (94 g) was prepared by substituting
Example 2E (108 g) for Example 1D in Example 1F. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 8.21 (br s, 1H), 7.55 (m, 2H), 7.44 (m,
2H), 7.21 (m, 2H), 7.12 (br s, 1H), 6.80 (m, 2H), 5.64 (br s, 1H),
3.89 (m, 1H), 3.75 (m, 1H), 3.39 (m, 2H), 3.13 (m, 1H), 1.08 (s,
3H), 1.06 (s, 3H).
Synthesis of
(1R)-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-1-(((4'-(tri-
fluoromethoxy)(1,1'-biphenyl)
4-yl)oxy)methyl)ethyl(hydroxy)formamide
EXAMPLE 3A
ethyl 4-(4-bromophenoxy)-3-oxobutanoate
[0324] A solution of 50% (w/w) NaOH in water (188 mL) in DMSO (800
mL) was stirred at room temperature until a precipitate formed,
treated dropwise with a solution of 4-bromophenol (101.2 g) in DMSO
(200 mL) over 25 minutes, stirred for 25 minutes, treated with
ethyl 4-chloro-3-oxobutanoate (102.2 g) over 40 minutes, adjusted
to pH 3 with 6M HCl, treated with water (200 mL) over 12 minutes,
stirred for 5 hours, treated with water (150 mL) over 20 minutes,
and filtered. The solid was washed with sequentially with water and
40% ethanol/water and dried under vacuum (100 mm Hg) at 50.degree.
C. with a nitrogen bleed to provide 119.8 g of the desired product.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.40 (m, 2H), 6.79 (m,
2H), 4.65 (s, 2H), 4.20 (q, 2H, J=7 Hz), 3.62 (s, 2H), 1.26 (t, 3H,
J=7 Hz).
EXAMPLE 3B
ethyl 4-(4-bromophenoxy)-3-hydroxybutanoate
[0325] A solution of Example 3A (99.5 g) in ethanol (480 mL) was
deoxygenated with nitrogen, treated with
(Ru.sub.2Cl.sub.5(R)-BINAP.sub.2- ).sup.-Et.sub.2NH.sub.2.sup.+
(825 mg) and 2M HCl (0.5 mL), flushed with nitrogen, heated to
100.degree. C. with shaking under 50 psi of hydrogen for 8 hours,
cooled, treated with hexanes (30 mL), and filtered to provide a
solution of the desired product. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.37 (m, 2H), 6.80 (m, 2H), 4.41 (m, 1H), 4.20 (q, 2H, J=7
Hz), 3.96 (d, 2H, J=6 Hz), 3.19 (d, 1H, J=6 Hz), 2.67 (m, 2H), 1.30
(t, 3H, J=7 Hz).
EXAMPLE 3C
(3S)-4-(4-bromophenoxy)-3-hydroxybutanoic Acid
[0326] The solution of Example 3B (154.2 g) was cooled to 5.degree.
C. treated with 44% (w/w) KOH over 10 minutes, warmed to room
temperature, treated with water (150 mL), concentrated, treated
with isopropyl acetate (500 mL) and water (200 mL), cooled to
5.degree. C., adjusted to pH 2 with 6M HCl, and treated with
additional isopropyl acetate (500 mL). The aqueous phase was
extracted with isopropyl acetate (100 mL). The extract was washed
with brine, dried (Na.sub.2SO.sub.4), filtered, concentrated to a
volume of 310 mL, and treated with isopropyl acetate (70 mL) and
heptane (1.2 L) dropwise over 4 hours to provide a precipitate. The
precipitate was collected by filtration, washed with 20% isopropyl
acetate in heptane (700 mL), and dried under vacuum (100 mm Hg) at
50.degree. C. with a nitrogen bleed to provide 121.3 g of the
desired product. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8 7.50 (m,
2H), 6.96 (m, 2H), 5.3 (br s, 1H), 4.23, (m, 1H), 3.95 (d, 2H, J=6
Hz), 2.60 (dd, 1H, J=6, 15 Hz), 2.43 (dd, 1H, J=8, 15 Hz).
EXAMPLE 3D
(3S)-N-(benzyloxy)-4-(4-bromophenoxy)-3-hydroxybutanamide
[0327] A solution of Example 3C (121.2 g) in DMF (1 L) at 5.degree.
C. was treated sequentially with
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (92.9
g), 1-hydroxybenzotriazole (68.5 g), and 4-methylmorpholine (193
mL), stirred for 5 minutes, treated with O-benzylhydroxylamine
hydrochloride (73.5 g), warmed to room temperature, treated with 5%
HCl (2.1 L) over 35 minutes, and filtered. The solid was washed
with water and dried under vacuum (100 mm Hg) at 50.degree. C. with
a nitrogen bleed to provide 156.9 g of the desired product. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.05 (s, 1H), 7.45 (m, 2H),
7.35 (m, 5H), 6.90 (m, 2H), 5.21 (d, 1H, J=5 Hz), 4.80 (s, 2H),
4.20 (m, 1H), 3.88 (m, 2H), 2.25 (dd, 1H, 6, 14 Hz), 2.15 (dd, 1H,
J=8,14 Hz).
EXAMPLE 3E
(3R)-3-((benzyloxy)amino)-4-(4-bromophenoxy)butanoic Acid Lithium
Salt
[0328] A solution of triphenylphosphine (121 g) in THF (1.9 L) was
treated with DEAD (80.1 g) over 30 minutes, treated with a solution
of Example 3D in DMF (600 mL) at 40.degree. C. by cannula over 90
minutes and a solution of triphenylphosphine (6.2 g) and DEAD (3.8
mL) in THF (20 mL), concentrated, treated with toluene (350 mL),
and concentrated. The concentrate was treated with toluene (1.9 L),
washed with water, and concentrated to half of its original volume,
to provide a solution of
(4R)-1-(benzyloxy)-4-((4-bromophenoxy)-methyl)-2-azetidinone.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.4 (m, 7H), 6.70 (m,
2H), 5.00 (d, 1H, J=10), 4.92 (d, 1H, J=12 Hz), 3.86 (m, 1H), 3.82
(dd, 1H, J=1, 4 Hz), 2.81 (dd, 1H, J=6, 15 Hz), 2.66 (dd, 1H, J=2,
15 Hz).
[0329] This solution was treated with a solution of LiOH (27.3 g)
in water (240 mL), heated to 60.degree. C. for 3 hours, cooled to
room temperature, stirred for 16 hours, treated with a solution of
lithium hydroxide (12.3 g) in water (120 mL), heated to 65.degree.
C. for 16 hours, cooled to room temperature, stirred for 2 hours,
and filtered. The precipitate was washed with toluene (200 mL), and
the filtrate was concentrated to half the original volume, treated
with a small amount of the collected solid, and stirred at room
temperature for 16 hours. The resulting precipitate was collected
by filtration, and the combined solids were treated with toluene
(920 mL), heated to 95.degree. C., cooled to room temperature, and
stirred for 16 hours. The resulting precipitate was collected by
filtration, then dried under vacuum (100 mm Hg) at 50.degree. C.
with a nitrogen bleed to provide 87.1 g of the desired product.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.43 (m, 2H), 7.30 (m,
5H), 6.91 (m, 2H), 4.60 (dd, 2H, J=2, 12 Hz) 3.96 (dd, 1H, J=4, 10
Hz), 3.85 (dd, 1H, J=6, 10 Hz), 2.13 (dd, 1H, J=5, 16 Hz), 1.99
(dd, 1H, J=8, 16 Hz).
EXAMPLE 3F
(5R)-1-(benzyloxy)-5-((4-bromophenoxy)methyl)-2-imidazolidinone
[0330] A suspension of Example 3E in THF (2.1 L) was treated with
DPPA (90.5 g) and diisopropylethyl amine (56 mL), heated to reflux,
stirred for 3 hours, cooled to 30.degree. C., poured into ice cold
10% HCl, and stirred vigorously. The organic phase was treated with
10% HCl (500 mL) and NaCl (75 g). The aqueous phase was separated
and washed with ethyl acetate. The extract was washed sequentially
with water, saturated NaHCO.sub.3, and brine and concentrated. The
concentrate was treated with toluene (550 mL), warmed to reflux,
cooled to 35.degree. C., treated with heptane (800 mL) over 2
hours, and filtered. The solid was dissolved in 1:1 THF/toluene
(700 mL), and the resulting solution was washed with saturated
NaHCO.sub.3 and brine, and concentrated. The solid was dried under
vacuum (100 mm Hg) at 50.degree. C. with a nitrogen bleed to
provide 54.6 g of the desired product. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.45 (m, 2H) 7.35 (m, 5H), 6.58 (m, 2H), 5.35
(br s, 1H), 5.05 (d, 1H, J=11 Hz), 4.94 (d, 1H, J=11 Hz), 3.85 (m,
1H), 3.73 (dd, 1H, J=7, 9 Hz), 3.55 (dd, 1H, J=7, 9 Hz), 3.51 (t,
1H, J=8 Hz), 3.25 (t, 1H, J=9 Hz).
EXAMPLE 3G
(2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)-1-propanamine
[0331] A mixture of Example 3F in ethanol (300 mL) was treated with
a solution of 30% (w/w) KOH in water (100 mL), heated to reflux,
stirred for 8 hours, treated with additional 30% KOH in water (5
mL), stirred for 40 minutes, cooled to room temperature,
concentrated to a slurry, and extracted with toluene. The extract
was washed with 1 M NaOH and brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated to provide 48.6 g of the desired
product. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.45 (m, 2H),
7.33 (m, 5H), 6.90 (m, 2H), 6.67 (d, 1H, J=5 Hz), 4.63 (s, 2H),
3.95 (m, 2H), 3.08 (m, 1H), 2.73 (m, 1H), 2.62 (m, 1H), 1.40 (br s,
2H).
EXAMPLE 3H
3-((2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)propyl)-5,5-dimethyl-2,4-im-
idazolidinedione
[0332] A solution of 2-aminoisobutyric acid (51.7 g) in methanol
(500 mL) at 0.degree. C. was treated with thionyl chloride (80.4 g)
over 35 minutes, stirred for 30 minutes, warmed to room
temperature, heated to 50.degree. C. for 3 hours, cooled to room
temperature, and concentrated. The concentrate was dissolved in
methanol (200 mL), concentrated, dissolved in warm methanol (50
mL), treated with diethyl ether (300 mL), and filtered. The
resulting solid was dried under vacuum (100 mm Hg) at 50.degree. C.
with a nitrogen bleed to provide 59.6 g of methyl
2-amino-2-methylpropanoate hydrochloride.
[0333] A solution of the methyl 2-amino-2-methylpropanoate
hydrochloride (65.5 g) in THF (650 mL) was treated with
triethylamine (60 mL), heated to reflux, stirred for 30 minutes,
cooled to room temperature, treated dropwise with a solution of
triphosgene (43.2 g) in THF (250 mL) over 5 minutes, heated to
reflux, stirred for 4 hours, cooled to 15.degree. C., treated with
triethylamine (120 mL) over 7 minutes, heated to reflux, stirred
for 40 minutes, cooled to room temperature, and filtered. The solid
was washed with THF and the filtrate was collected to provide a
solution of methyl 2-isocyanato-2-methylpropanoate in THF.
[0334] A solution of Example 3G (19.7 g) in THF (100 mL) at room
temperature was treated with the solution of the methyl
2-isocyanato-2-methylpropanoate in THF, stirred for 25 minutes, and
concentrated to a volume of 170 mL. The concentrate was treated
with THF (80 mL) and 6M HCl (95 mL), heated to reflux, stirred for
6 hours, cooled to room temperature, concentrated, and extracted
with isopropyl acetate. The extract was washed sequentially with
water, saturated NaHCO.sub.3, and brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated to provide 24.2 g of the desired
product. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.33 (s, 1H),
7.47 (m, 2H), 7.35 (m, 5H), 6.90 (m, 2H), 6.78 (d, 1H, J=5 Hz),
4.65 (m, 2H), 4.00 (m, 2H), 3.68 (m, 1H), 3.55 (m, 2H), 1.30 (s,
3H), 1.28 (s, 3H).
EXAMPLE 3I
benzyloxy((1R)-2-(4-bromophenoxy)-1-((4,4-dimethyl-2,5-dioxo-1-imidazolidi-
nyl)methyl)ethyl)formamide
[0335] A solution of Example 3H (57.7 g) in formic acid (200 mL)
was treated with a mixture of acetic anhydride (35 mL) in formic
acid (35 mL) over 10 minutes, stirred for 10 minutes, and
concentrated. The concentrate was dissolved in ethyl acetate (500
mL), washed sequentially with 1:1 water:brine, saturated
NaHCO.sub.3, and brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The concentrate was dissolved in warm (60.degree. C.)
toluene, cooled, and filtered. The solid was washed with
1:1/toluene:heptane then dried under vacuum (100 mm Hg) at
50.degree. C. with a nitrogen bleed to provide 51.7 g of the
desired product. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.42
(br s, 0.5H), 8.38 (br s, 0.5H), 8.32 (br s, 0.5H), 8.10 (br s,
0.5H), 7.4 (m, 7H), 6.95 (m, 2H), 5.00 (m, 1H), 4.91 (m, 1H) 4.80
(m, 0.5H), 4.55 (m, 0.5H), 4.28(m, 1H), 4.17 (m, 1H), 3.88 (dd, 1H,
J=9, 14 Hz), 3.60 (m, 1H), 1.25 (s, 3H), 1.22 (s, 3H).
EXAMPLE 3J
4-(((2R)-2-((benzyloxy)(formyl)amino)-3-(4,4-dimethyl-2,5-dioxo-1-imidazol-
idinyl)propyl)oxy)-4'-(trifluoromethoxy)-1,1'-biphenyl
[0336] A mixture of magnesium (3.25 g) in THF (25 mL) at room
temperature was treated with several drops of
1-bromo-4-(trifluoromethoxy)benzene, stirred for several minutes,
treated with THF (100 mL), treated with
1-bromo-4-(trifluoromethoxy)benzene (30.8 g), heated to reflux,
stirred for 16 hours, treated with triisopropyl borate (34 mL) over
10 minutes, stirred for 1 hour, cooled to 0.degree. C., treated
with 6M HCl (50 mL), stirred for 45 minutes, and extracted with
isopropyl acetate. The extract was washed with brine, filtered, and
concentrated to provide 21.5 g of 4-(trifluoromethoxy)phenylboronic
acid.
[0337] A solution of 2M Na.sub.2CO.sub.3 (180 mL) in toluene (180
mL) was sparged with nitrogen, treated with Example 31 (49.8 g),
4-(trifluoromethoxy)phenylboronic acid (21.5 g), and
Pd(PPh.sub.3).sub.4 (0.68 g), heated to reflux, stirred for 1 hour,
treated with additional boronic acid (6.4 g), refluxed for 2 hours,
and cooled to room temperature. The organic phase was washed with
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated. The
concentrate was purified on a flash silica gel plug with
4:1/hexanes:ethyl acetate to 1:3/hexanes:ethyl acetate to provide
49.6 g of the desired product. 1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.25 (br s, 1H), 8.07 (br s, 1H), 7.75 (m, 2H), 7.61 (m,
2H), 7.40 (m, 7H), 7.05 (m, 2H), 5.04 (d, 1H, J=10 Hz), 4.98 (d,
1H, J=10 Hz), 4.70 (br s, 1H), 4.33 (dd, 1H, J=8, 10 Hz), 4.26 (dd,
1H, J=5, 10 Hz), 3.90 (dd, 1H, J=8, 14 Hz), 3.67 (dd, 1H, J=5, 14
Hz), 1.26(s, 3H), 1.25 (s, 3H).
EXAMPLE 3K
(1R)-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-1-(((4'-(trifluoromethoxy-
)(1,1'-biphenyl)-4-yl)oxy)methyl)ethyl(hydroxy)formamide
[0338] A solution of Example 3J (65.9 g) in ethyl acetate (450 mL)
was treated with 10% Pd/C (10 g), and shaken under a hydrogen
atmosphere (50 psi) at room temperature for 8 hours, filtered
through a 0.45 .mu.m nylon millipore filter, concentrated, treated
with toluene, concentrated, dissolved in warm (75.degree. C.)
toluene, cooled to 60.degree. C., and filtered. The filtrate was
cooled to room temperature, treated with heptane (100 mL) over 45
minutes, stirred for 72 hours, and filtered. The solid was washed
with heptane and dried under vacuum (100 mm Hg) at 50.degree. C.
with a nitrogen bleed to provide 39.7 g of the desired product.
* * * * *