US2002137937A1PendingUtilityA1
Process for preparing [S- (R*, S*) ] -beta- [ [ [1- [1-oxo-3- (4-piperidinyl) propyl] -3-piperidinyl] carbonyl]amino] -3-pyridinepropanoic acid and derivatives
Priority: Mar 22, 1999Filed: Feb 22, 2002Published: Sep 26, 2002
Est. expiryMar 22, 2019(expired)· nominal 20-yr term from priority
Inventors:Judith CohenMichael JustusCynthia MaryanoffArmin RosslerFridtjof SchröderKirk L. SorgiFrank J. VillaniChristian Weh
C07D 401/14A61P 9/10A61K 31/444C07D 213/55C07D 211/60
41
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Claims
Abstract
A process for preparing a compound of formula I wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, lower alkyl and halogen
Claims
exact text as granted — not AI-modified1 . A process for preparing a compound of formula I
wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, lower alkyl and halogen, comprising reacting the salt of formula II
with the salt of formula III
at a pH in the range of about 6 to 10 to form the compound of formula IV
reacting the compound of formula IV to form the compound of formula V
reacting the compound of formula V with a compound of formula VI
at a pH in the range of about 7 to 11 to form the compound of formula VII
reacting the compound of formula VII to form the compound of formula VIII
and reacting the compound of formula VIII with hydrogen in the presence of a hydrogenation catalyst to form the compound of formula I.
2 . The process of claim 1 , wherein in the compound of formula I R 1 and R 2 are hydrogen.
3 . A process for preparing a compound of formula VI
wherein R 1 and R 2 are independently selected from hydrogen, lower alkyl and halogen, and R 4 is lower alkyl or aralkyl, or salt thereof comprising reacting a compound of formula XI
with (+)tartaric acid to form the salt of formula XII
and reacting the salt of formula XII to form the compound of formula VI or salt thereof.
4 . The process of claim 3 , wherein in the compound of formula XI R 4 is methyl and the (+)tartaric acid is present in an amount of 0.25 equivalents.
5 . The process of claim 4 , wherein in the compound of formula VI, R 1 and R 2 are hydrogen and R 4 is methyl.
6 . The process of claim 4 , wherein the salt of formula XII is reacted with gaseous HCl in methanol to form the dihydrochloride salt of formula VI.
7 . A process of preparing a salt of formula III
wherein R 3 is lower alkyl comprising reacting a compound of formula XIII
with (+)tartaric acid in a mixture of isopropyl alcohol and water.
8 . The process of claim 7 , wherein in the salt of formula III, R 3 is ethyl.
9 . The process of claim 8 , wherein in the mixture of isopropyl alcohol and water the isopropyl alcohol is present in a ratio of from 90 percent isopropyl alcohol to 10 percent water to 100 percent isopropyl alcohol.
10 . A process of purifying a compound of formula I
wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, lower alkyl and halogen, comprising reacting the free base of formula I at a pH in the range of from about 4 to 12 in the presence of an organic amine base.
11 . The process of claim 10 , wherein in the compound of formula I R 1 and R 2 are hydrogen.
12 . The process of claim 11 , wherein the organic amine base is triethylamine, cyclohexylamine, or t-butylamine and the reaction is carried out at a pH in the range of from about 7 to 11.
13 . The process of claim 12 , wherein the reaction is carried out at a pH of 7.5.
14 . The process of claim 13 , wherein the organic amine base is t-butylamine.
15 . A process for preparing a compound of formula VIII
wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, lower alkyl and halogen, comprising reacting a compound of formula V
wherein Ph is phenyl,
with a carboxylic acid salt of a compound of formula VI
wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, lower alkyl and halogen, and R 4 is lower alkyl or aralkyl,
in the presence of a calcium salt, in an amount equal to at least 1 equivalents, at a pH in the range of about 6-10.
16 . The process of claim 15 , wherein the carboxylic acid salt of the compound of formula VI is tartrate salt.
17 . The process of claim 15 , wherein the calcium salt is calcium hydroxide.
18 . The process of claim 15 , wherein the pH is in the range of about 6-7.
19 . A crystalline form of the compound of formula Ia
characterized essentially by the following X-ray diffraction pattern:
d Spacing
Relative
Angle ° 2θ
(Å)
Intensity (%)
8.77
10.09
17.50
10.52
8.41
16.20
15.57
5.69
100.00
15.90
5.65
22.70
16.52
5.37
48.30
17.48
5.08
25.80
17.72
5.01
24.70
18.32
4.85
58.10
19.62
4.53
21.50
19.98
4.45
47.30
20.28
4.38
41.50
21.08
4.22
67.80
21.36
4.16
18.10
22.82
3.90
23.50
23.26
3.83
50.40
24.01
3.71
57.60
24.73
3.60
24.10
25.62
3.48
9.90
25.99
3.43
8.00
26.37
3.38
4.60
27.37
3.26
13.50
27.98
3.19
23.20
28.62
3.12
15.70
30.20
2.96
19.00
30.71
3.41
17.30
31.29
2.86
32.40
31.40
2.85
33.30
31.73
2.82
25.10
32.71
2.74
12.40
33.84
2.65
9.70
34.55
2.60
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