US2003176471A1PendingUtilityA1
Process of preparing 3S-3-amino-3aryl propionic acid and derivatives thereof
Priority: Mar 22, 1999Filed: Mar 27, 2003Published: Sep 18, 2003
Est. expiryMar 22, 2019(expired)· nominal 20-yr term from priority
C07D 213/55C07D 213/40
48
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Claims
Abstract
The present invention is directed to a process for preparing 3S-3-amino-3-aryl propionic acid and derivatives thereof.
Claims
exact text as granted — not AI-modified1 . Form 2 of the compound of formula Va
characterized by the following x-ray powder diffraction pattern:
Powder X-Ray Diffraction Results
Angle
d value
Intensity
2θ
Angstrom
Cps
Intensity %
5.186
17.028
1.67
0.1
5.405
16.338
4.17
0.2
6.069
14.550
163
6.2
6.526
13.532
1350
51.1
7.659
11.534
28.3
1.1
9.111
9.698
22.5
0.9
10.786
8.196
1417
53.6
13.073
6.767
83.3
3.2
15.660
5.654
659
25.0
17.063
5.192
1105
41.8
18.405
4.817
102
3.8
18.843
4.706
212
8.0
19.108
4.641
343
13.0
19.679
4.507
417
15.8
20.755
4.276
36.7
1.4
21.514
4.127
2641
100.0
22.796
3.898
652
24.7
23.944
3.713
101
3.8
24.363
3.650
340
12.9
25.502
3.490
89.2
3.4
25.640
3.471
89.2
3.4
26.265
3.390
172
6.5
26.786
3.326
98.3
3.7
27.770
3.210
1152
43.6
28.722
3.106
164
6.2
29.151
3.061
764
28.9
29.656
3.010
70.8
2.7
30.468
2.9315
58.3
2.2
31.214
2.8631
61.7
2.3
31.868
2.8058
61.7
2.3
32.301
2.7692
95.8
3.6
32.874
2.7222
147
5.6
33.480
2.6743
53.3
2.0
34.081
2.6285
122
4.6
34.626
2.5884
68.3
2.6
2 . A process of preparing the compound of formula I
wherein
R 1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R 2 is hydrogen, alkyl or aralkyl, or acid addition salts thereof,
comprising reacting a compound of formula II, at a pH range of between about 7 and about 11,
to form a compound of formula III
wherein R 5 is N-t-butoxycarbonyl,
reacting a compound of formula III with at least 0.5 equivalents of (1R,2S)-(−)ephedrine, in an alkyl acetate solvent, to form a salt of formula IV
wherein Ph is phenyl,
reacting the salt of formula IV with an inorganic base in water to form a carboxylate salt of the compound of formula V, acidifying the carboxylate salt of the compound of formula V with an acid of pKa less than or equal to three, to a pH of between about 3.5 and about 6.5, to form the compound of formula V
reacting the compound of formula V, at a temperature less than about 25° C., to form the compound of formula I.
3 . A process of preparing a compound of formula I
wherein R 1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R 2 is hydrogen, alkyl or aralkyl, or acid addition salts thereof,
comprising reacting a compound of formula III
wherein R 5 is N-t-butoxycarbonyl,
with at least 0.5 equivalents of (1R,2S)-(−)ephedrine, in alkyl acetate solvent, to form a salt of formula IV
wherein Ph is phenyl,
reacting the salt of formula IV with an inorganic base, in water, to form a carboxylate salt of the compound of formula V, acidifying the carboxylate salt of the compound of formula V with an acid of pKa less than or equal to three, to a pH of between about 3.5 and about 6.5, to form the compound of formula V
reacting the compound of formula V, at a temperature less than about 25° C., to form the compound of formula I.
4 . A process of claim 2 , further comprising isolating the compound of formula III by acidifying the compound of formula III with an acid of pKa less than or equal to three, to a pH of between about 3.5 and about 6.5.
5 . A process of claim 2 , wherein the alkyl acetate solvent is ethyl acetate.
6 . A process of claim 2 , wherein the reaction of formula III with (1R,2S)-(−)ephedrine occurs at a temperature in the range of from about 25° to about 78° C.
7 . A process of claim 2 , further comprising acidifying the carboxylate salt of the compound of formula V with an acid of pKa less than or equal to three, to a pH of about 3.8, to form the compound of formula V.
8 . A process of claim 2 , wherein the acid of pKa less than or equal to three is selected from the group consisting of monochloroacetic, dichloroacetic, trichloroacetic, hydrochloric, hydrobromic, hydroiodic, perchloric, picric, nitric, sulfuric, phosphoric, methanesulfonic, tosic, trifluoromethanesulfonic, trifluoracetic, potassium bisulfate, sodium bisulfate and citric.
9 . A process of claim 2 , further comprising reacting the compound of formula V with an acid of pKa less than or equal to three, other than potassium bisulfate, sodium bisulfate and citric acid.
10 . A process of claim 3 , further comprising acidifying the compound of formula III with an acid of pKa less than or equal to three, to a pH of between about 3.5 and about 6.5.
11 . A process of claim 3 , wherein the alkyl acetate solvent is ethyl acetate.
12 . A process of claim 3 , wherein the reaction of formula III with (1R,2S)-(−)ephedrine occurs at a temperature from about 25° to about 78° C.
13 . A process of claim 3 , further comprising acidifying the carboxylate salt of the compound of formula V with an acid of pKa less than or equal to three, to a pH of about 3.8, to form the compound of formula V.
14 . A process of claim 3 , wherein the acid of pKa less than or equal to three is selected from the group consisting of monochloroacetic, dichloroacetic, trichloroacetic, hydrochloric, hydrobromic, hydroiodic, perchloric, picric, nitric, sulfuric, phosphoric, methanesulfonic, tosic, trifluoromethanesulfonic, trifluoracetic, potassium bisulfate, sodium bisulfate and citric.
15 . A process of claim 3 , further comprising reacting the compound of formula V with an acid of pKa less than or equal to three, other than potassium bisulfate, sodium bisulfate and citric acid.
16 . A process of claim 2 , wherein R 1 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methylpyridyl, 5-bromopyridyl, 6-chloropyridyl or 5,6-dichloropyridyl.
17 . A process of claim 3 , wherein R 1 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methylpyridyl, 5-bromopyridyl, 6-chloropyridyl or 5,6-dichloropyridyl.
18 . A process of claim 2 , wherein R 2 is alkyl.
19 . A process of claim 3 , wherein R 2 is alkyl.
20 . A process of claim 2 , wherein R 1 is 3-pyridyl.
21 . A process of claim 3 , wherein R 1 is 3-pyridyl.
22 . A process of claim 2 , wherein R 1 is 3-pyridyl and R 2 is methyl.
23 . A process of claim 3 , wherein R 1 is 3-pyridyl and R 2 is methyl.
24 . A process of claim 2 , wherein the acid addition salt of formula I is hydrochloric.
25 . A process of claim 3 , wherein the acid addition salt of formula I is hydrochloric.
26 . A process for preparing a compound of formula V
wherein R 1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R 5 is N-t-butoxycarbonyl
comprising reacting a compound of formula III
with at least 0.5 equivalents of (1R,2S)-(−)ephedrine, in alkyl acetate solvent, to form a salt of formula IV
wherein Ph is phenyl,
reacting the salt of formula IV with an inorganic base, in water, to form a carboxylate salt of the compound of formula V, acidifying the carboxylate salt of the compound of formula V with an acid of pKa less than or equal to three, to a pH of between about 3.5 and about 6.5.Join the waitlist — get patent alerts
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