Process for preparing optically active amines and optically...

Details Process for preparing optically active amines and optically... Process for preparing optically active amines and optically...

1998-10-28

2002-01-29

Geist, Gary (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C562S490000, C562S494000

Reexamination Certificate

active

06342636

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention concerns a process for optical resolution of racemic 1-aryl- and 2-aryl-alkylamines including various compounds with an optically active naphthylglycolic acid. The invention also concerns a process for optical resolution of racemic 1- and 2-naphthylglycolic acid with 1-aryl- or 2-aryl-alkylamine. The invention encompasses novel diastereomeric salts, which are formed as the intermediate compounds in the process of optical resolution of 1-aryl- or 2-aryl-alkylamines, or 1- or 2-naphthylglycolic acids.
1-Aryl- and 2-aryl-alkylamines have been used as starting materials or intermediates for production of various medicines and chemicals, and further, known as resolving agents for optical resolution. Examples of such use of 1-arylalkylamines are as follows:
1-(m-Methoxyphenyl)ethylamine is used as a material for brain function improving medicine. 1-(p-Methylphenyl)ethylamine is a resolving agent for 2-hydroxyl-4-phenylbutanoic acid, which is the intermediate for angiotensin converting enzyme inhibitors such as Cilazapril, Enalapril and Benazepril and also a resolving agent for cis-permethric acid, which is a material for an insecticide. 1-(p-Chlorophenyl)ethylamine is known to be useful as a material for a bactericide in agricultural use. It is expected that use of these arylalkylamines will develop further in the future.
For the optical resolution of racemates of these amines there has been employed diastereomeric salt process, because of easy application thereof to industrial production and good reproducibility. With respect to the resolution by diastereomeric salt formation, even in the limited scope of combinations of amines and carboxylic acids, statistic data as of around 1981 shows that more than 2500 cases have been reported. [P. Newman, “Optical Resolution Procedures for Chemical Compounds”, vol. 1 and 2 (1981), Optical Resolution Information Center, Manhattan College, Riverdale, N.Y.] Though such a large number of experimental results have been reported, as pointed out by Jacques et al [J. Jacques et al., “Enantiomers, Racemates, and Resolutions”, John Willy & Sons, New York, Chichester, Brisbane, Toronto (1981) p.380] and Sheldon [R. Sheldon, “Chirotechnology-Industrial Synthesis of Optically Active Compounds”, Marcel Dekker, Inc., New York, Basel, Hong Kong (1993) p.20], when a novel compound is; to be resolved, there is no reliable principle or theory for choosing the resolving agent, and it is inevitable to seek the resolving agent by trial and error.
Therefore, in order to resolve a racemate of this kind of amines, it has been necessary to carry out a search for a suitable resolving agent by a trial and error method, which is of course troublesome and requires a lot of time. There has been thus a strong demand, in the field of diastereomeric salt method of optical resolution, for either standards of choosing suitable resolving agents or, more specifically, acidic resolving agents which may be applied to the racemates of a wide range of amines.
The inventors resolved 1-arylalkylamines using various hydroxycarboxylic acids as the resolving agents. The results are summarized in Table 1 below. In the row of the resolving agents, the hydroxycarboxylic acids, in Table 1, “A” stands for mandelic acid, “B” for p-methylmandelic acid, “C” for p-methoxymandelic acid, “D” for 2-hydroxyphenylpropionic acid, “E” for 2-hydroxyphenylbutanoic acid and “F” for 3-hydroxy-2-phenylpropionic acid. Chemical structures of these compounds are shown below.
TABLE 1
Optical Resolution of 1-Arylalkylamines (formula Ia)
with Acidic Resolving Agents
Resol-
Optical
Resolving
Run
ving
Yield
Purity
Efficiency
No.
Agent
R
3
R
1
(%)
D %
E %
1
A
H
H
76
87
66
2
A
o-methyl
H
71
100
71
3
A
o-methoxy
H
69
81
56
4
A
o-Cl
H
76
29
22
5
A
m-methyl
H
94
12
11
6
A
m-Cl
H
59
38
22
7
A
m-methoxy
H
69
89
62
8
A
p-methyl
H
88
4
4
9
A
p-methoxy
H
84
4
3
10
A
p-Cl
H
109
2
2
11
A
H
p′-tolyl
84
97
73
12
B
H
H
74
80
59
13
B
p-methyl
H
85
63
54
14
C
H
H
70
89
62
15
C
m-methyl
H
76
75
57
16
C
p-methyl
H
72
85
61
17
C
p-methoxy
H
62
46
29
18
D
H
H
49
85
41
19
D
p-methyl
H
no crystal obtainable
20
D
H
methyl
no crystal obtainable
21
E
H
H
110
80
88
22
E
p-methyl
H
77
85
65
23
E
p-methoxy
H
98
54
53
24
E
H
methyl
oily substance occurred
25
F
H
H
81
3
2
*Resolution Efficiency E = Yield × Optical Purity (%)
From the results shown in Table 1 the following was concluded:
(1) Resolving agent “A” resolves non-substituted and some of o- or m-substituted 1-arylalkylamines, but does not resolve p-substituted amines at all.
(2) Resolving agents “B” and “C” which have substituent at p-position resolve non-substituted, and m- and p-substituted 1-arylalkylamines with relatively high resolving efficiency. Optical purities of the products are generally low.
(3) Resolving agents “D” and “E” which have one or two methylene groups in the molecules resolve non-substituted and p-substituted 1-arylalkylamines. Optical purities of the products are also low.
(4) Resolving agent “F” which has a hydroxy group at the &bgr;-position does not resolve non-substituted 1-arylalkylamines, which are resolved by other a-hydroxycarboxylic acids.
The above conclusion can be summarized as follows: The non-substituted 1-arylalkylamines can be resolved with any of &agr;-hydroxycarboxylic acids, the o-substituted 1-arylalkylamines can be resolved with non-substituted &agr;-hydroxycarboxylic acid (resolving agent “A”); the m-substituted 1-arylalkylamines can be resolved with non-substituted or p-substituted &agr;-hydroxy-carboxylic acids; and p-substituted 1-arylalkylamines can be resolved with p-substituted &agr;-hydroxycarboxylic acids. On the other hand, there is no effective resolving agent for the 1-(o-, m-, p-halogen-substituted aryl)alkylamines.
Based on the above experimental results we reached the final conclusion that optical resolution can be carried out by choosing the hydroxycarboxylic acids used as the resolving agents having such molecular structures that are similar to those of 1-arylalkylamines to be resolved, in other words, by choosing a resolving agent of substantially equal molecular length to that of the substrates [K. Kinbara et al., Tetrahedron Asymmetry, 7(6),1539 (1996)] Correctness of this rule based on experience was proved by X-ray crystal structure analysis of the obtained diastereomeric salts [K. Kinbara et al., J. Chem. Soc., Perkin Trans. 2, 1996, 2615].
However, in the optical resolutions using the known substituted hydroxycarboxylic acids as the resolving agents shown in Table 1 optical purities of the products are low except for some minor cases, and therefore, it is necessary to improve the optical purities of the products by, for example, repeating recrystallization of the diastereomeric salts. This is of course a disadvantageous factor of the processes.
The inventors continued to make efforts, on the basis of the above knowledge, in finding resolving agents which may be commonly effective for optical resolution of 1-aryl- and 2-aryl-alkylamines inclusive of m- and p-substituted 1-arylalkylamines which could not have been resolved by the known technologies. As a result, the inventors discovered the facts that non-substituted and substituted 1- or 2-naphthyl-glycolic acids are useful as the novel resolving agents and that these resolving agents very efficiently resolve amines which could not have been resolved with known resolving agents or optical purities of which were low, particularly, the amine derivatives having a substituent of an alkyl group, alkyloxy group or halogen atom at m-position or p-position. It has been believed that, in optical resolution of halogen-substituted derivatives, efficient resolution could be done only when a homologous or corresponding halogen-substituted hydroxy-carboxylic acid is used as the resolving agent. The above fact that even a non-homologous resolving agent can resolve the halogen-substituted 1-aryl- or 2-aryl-alkylamines is a surprising discovery.
SUMMARY OF THE INVENTIO

Affiliated with

Also associated with

Rating

Process for preparing optically active amines and optically... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for preparing optically active amines and optically..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing optically active amines and optically... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2875590