Method for preparing 2-thienylethylamine derivatives

Details Method for preparing 2-thienylethylamine derivatives Method for preparing 2-thienylethylamine derivatives

1999-09-02

2000-06-27

Lambkin, Deborah C.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D33322

Patent

active

060808756

DESCRIPTION:

BRIEF SUMMARY
The present invention relates, in a general way, to a new process for the preparation of 2-thienylethylamine derivatives.
In particular, the invention relates to a new process for the preparation of N-phenylacetic derivatives of 2-thienylethylamine of general formula: ##STR4## as well as of their acid addition salts, in which R represents a halogen atom such as chlorine or bromine and R.sub.1 represents a C.sub.1 -C.sub.4 alkyl group, preferably methyl.
These compounds of formula I possess an asymmetric carbon represented by the asterisk and, consequently, may exist in the form of a racemic mixture or of individual optical isomers (-)-R and (+)-(S).
Thus, the invention relates to the preparation of 2-thienylethylamine derivatives of formula I, whether they are in the form of a racemic mixture or of individual dextrorotatory or laevorotatory enantiomers.
In formula I above, the R group may be present at the ortho, meta or para position with respect to the acetate group, preferably at the ortho position.
Moreover, chlorine represents a preferred R group.
Consequently and according to a preferred aspect, the invention relates to a process for the preparation of the (+)-(S) enantiomer of the compounds of formula I, in particular the (+)-(S) enantiomer of methyl .alpha.-(2-thienyl-2-ethylamino)-.alpha.-(2-chlorophenyl)acetate.
These compounds of formula I are known products and may be used for the preparation of pharmacologically active compounds.
For example, methyl (+)-(S)-.alpha.-(2-thienyl-2-ethylamino)-.alpha.-(2-chlorophenyl)acetate has been described in patent EP 466569 as well as its use for the preparation of methyl (+)-(S)-.alpha.-(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)-.alpha.-(2-chl orophenyl)acetate or clopidogrel.
This enantiomer having the structural Formula: ##STR5## is known for its value in therapy in particular for its anti-platelet aggregation and antithrombotic activities.
A process for the preparation of clopidogrel via a racemic compound, namely methyl (R,S)-.alpha.-(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)-.alpha.-(2-chlor ophenyl)acetate which is subjected to a resolution process, has been described in this patent EP 466569.
According to this process, a diastereoisomeric salt of this racemic compound is selectively crystallized with (-)-(R)-10-camphorsulphonic acid, which leads to the chiral camphorsulphonate of clopidogrel and the base is then released therefrom by displacing the (-)-(R)-10-camphorsulphonic acid.
This route of access, although conventionally used to prepare a chiral compound, may be considered not to be very convenient from the economic point of view since it requires both the recycling of the unwanted isomer and that of the salt of the chiral (-)-(R)-10-camphorsulphonic acid used in the resolution.
A more convergent method for the preparation in particular of clopidogrel was proposed in patent EP 466569, a method according to which methyl (+)-2-chlorophenylglycinate is treated, in a first step, with a 2-thienylethyl halide or sulphonate, in a solvent, for several hours, at a temperature of between 50.degree. C. and 100.degree. C. and in the presence of a base, in order to give, after salification, methyl (+)-(S)-.alpha.-(2-thienyl-2-ethylamino)-.alpha.-(2-chlorophenyl)acetate hydrochloride with a yield of about 50%.
However, it has been observed that the choice of the solvent, in this method, is not unimportant if it is desired to obtain only one of the enantiomers of methyl .alpha.-(2-thienyl-2-ethylamino)-.alpha.-(2-chlorophenyl)acetate by reaction of one of the enantiomers of methyl 2-chlorophenylglycinate, partial racemization occurring in some solvents.
Moreover, this process has the disadvantage of requiring a fairly extended contact time at a temperature above ambient, for example for 40 hours at 80.degree. C., for the production of methyl (+)-(S)-.alpha.-(2-thienyl-2-ethylamino)-.alpha.-(2-chlorophenyl)acetate, these operating conditions only being able to negatively influence the cost price of the final product.
Finally, the yields of 2-thienylethylamin

REFERENCES:
patent: 4873343 (1989-10-01), Radisson
patent: 5132435 (1992-07-01), Bousquet et al.
patent: 5204469 (1993-04-01), Descamps et al.
Dullaghan et al., Journal Organic Chemistry, vol. 17, 1183-1186 (1952).
Browne et al., Journal Organic Chemistry, vol. 17, 1187-1193 (1952).

Affiliated with

Also associated with

Rating

Method for preparing 2-thienylethylamine derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Method for preparing 2-thienylethylamine derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for preparing 2-thienylethylamine derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1785631