Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1999-12-20
2000-09-19
Barts, Samuel
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
564394, 560 38, 562449, C07C22900
Patent
active
061214914
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process for the preparation of cericlamine (INN), the intermediate synthesis compounds of the said process and their preparation.
Field of the Invention and Prior Art.
Cericlamine is (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropan-1-ol of formula (I) ##STR1## whose hydrochloride turns out to be an inhibitor of recapture of serotonin from the pharmacological point of view, and to show, in man, an anti-depressant activity.
The preparation of cericlamine is essentially described n the patent EP 237 366 published on Sep. 16, 1987 as well as the publication which appeared in J. CHEM. SOC. PERKIN TRANS.I, 1996 pp. 1495-1498. In these two documents, the pivotal precursor compound of cericlamine is 2-amino-3-(3,4-dichlorophenyl)-2-methylpropionic acid, which, similarly, is reduced in a first step by boron hydride to 2-amino-3-(3,4-dichlorophenyl)-2-methylpropan-1-ol, the compound, which, in a second step, is N,N-dimethylated by reaction with formaldehyde and formic acid as shown in scheme 1 which follows. ##STR2##
In its first step, this synthesis necessitates strong reducing agents and energetic conditions to efficiently reduce the carboxylic function. These conditions favour side reactions which result in sub-products, especially from dehalogenations, such as indicated in J. CHEM. SOC. PERKIN TRANS.I referred to above, products whose removal can only be to the detriment of the yield, and which, present in the state of traces in the final product, are considered as possibly toxic impurities from the pharmaceutical point of view.
As far as the preparation of 2-amino-3-(3,4-dichlorophenyl)-2-methylpropionic acid is concerned, a pivotal compound of these procedures: described in the patent FR 77 02360, which consists in alkylating an isocyano ester of formula CH.sub.3 --CH--(NC)--COOR with a 3,4-dichlorobenzyl halide, then in subjecting the intermediate obtained to simultaneous hydrolysis of the isocyano and ester groups to respectively generate the amine and acid functions of the amino acid.
This synthesis appears to be adaptable with difficulty to industrial production because of the reagents concerned, whose commercial access is improbable, or which necessitates delicate preparations, especially as far as the preparation of the isocyano ester is concerned, describes a synthesis starting from the amide of N-benzylidenealanine, which is alkylated by 3,4-dichlorobenzyl chloride to obtain an intermediate which is subjected to two successive hydrolyses, at first that of the Schiff base and then that of the amide function, to finally obtain the amino acid.
In the same way as the process of FR 77 02360, this synthesis has major disadvantages such as the necessity to prepare the amide of N-benzylidenealanine.
Alternative procedures can be envisaged to prepare this pivotal compound. Thus, starting from 1-(3,4-dichlorophenyl)propan-2-one, it is possible, either by Strecker reaction to obtain an aminonitrile which, hydrolysed, leads to the acid, or, and more particularly, by Bucherer-Bergs reaction to prepare 5-(3,4-dichlorobenzyl)-5-methylhydantoin which, hydrolysed in alkaline medium, likewise leads to the acid. This last method can easily be carried out by a minor adaptation of the procedure described in the patent EP 569 276. However, these syntheses are dependent on the obtainment of 1-(3,4-dichlorophenyl)-propan-2-one which, whatever the preparation envisaged, necessitates an economically penalizing multi-step synthesis such as that starting from 3,4-dichlorobenzaldehyde, such as described in Chimie Ther., 3, 1968, pp. 313-320.
For the purposes of development and of commercialization of cericlamine as a pharmaceutical active principle intended for the treatment of depression in man, there appears, in view of this prior art, to be a need to have an industrial preparation process which is reliable and of indisputable economic significance.
SUMMARY OF THE INVENTION
Breaking with the prior art which, whatever the process, calls on elaborate starting compounds themselves necessitati
REFERENCES:
patent: 4536342 (1985-08-01), Oyama
patent: 4994617 (1991-02-01), Aubard
patent: 5472970 (1995-12-01), Calvet
Theodoridis, G., et al., J. of Heterocyclic Chemistry, "A New Approach to the Synthesis of Substituted 2(1H)-Quinolinones", 1991 vol. 28:849-852.
Patent Abstract of Japan, 1987 vol. 11:38, PCT International Search Report, PCT/EP98/02213.
Kaptain, B., et al., J. of the Chem. Soc., Perkins Trans. 1, "Chemo-Enzymatic Synthesis of (S)-(+)-Cericlamine . . . ", 1994, pp. 1495-1498.
Binovic, K., et al., Chimie Therapeutique, "Etude D'Une Nouvelle Serie De Derives Anorexigenes", 1968, vol. 3, pp. 313-320.
Depernet Dominique
Laboue Blandine
Nicolas Marc
Ashbrook Charles W.
Barts Samuel
Warner-Lambert & Company
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