Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-06
2003-06-03
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C112S113000
Reexamination Certificate
active
06573381
ABSTRACT:
The present invention concerns, in a general fashion, new derivatives of hydroxyacetic esters, and their use as synthesis intermediates.
More specially, the object of the invention is the sulfonyloxyacetic esters with the general formula:
in which R
1
represents a benzyl group, a C
1
-C
4
alkyl, which may be substituted by one or several halogen atoms, such as chlorine or bromine, or a phenyl group, which may be substituted by one or several halogen atoms or by one or several linear or branched C
1
-C
4
alkyl groups or by a nitro group.
In particular, the invention concerns formula-I compounds in which R
1
represents a methyl, ethyl, propyl, trifluoromethyl, benzyl, phenyl, chlorophenyl, tolyl, trimethylphenyl, triisopropylphenyl, dichlorophenyl in particular 2,5-dichlorophenyl or nitrophenyl, in particular p-nitrophenyl, group.
Formula-I compounds have demonstrated themselves to be particularly useful as intermediates, notably for the synthesis of methyl (S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetate or clopidrogel.
This enantiomer, which has the following structural formula:
is known for its therapeutic value, notably for its inhibition of platelet aggregation and antithrombotic properties.
In patent EP 0465358, a process is described for the preparation of the (R) and (S) enantiomers of 2-(halogenophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetate of a C
1
-C
4
alkyl, using 2-arylacetic esters with a labile group in the 2 position.
According to this process:
a) racemic a C
1
-C
4
alkyl 2-(halogenophenyl)-2-halogeno or a C
1
-C
4
alkylsulfonyloxy, or C
6
-C
10
alkyl arylsulfonyloxy)acetate is coupled with 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in the form of a base or salt to obtain a racemic compound.
b) the racemate thus formed is resolved by recrystallising optically active acid salts to obtain the desired (R) or (S) enantiomers.
However, the only example given of this process started from racemic methyl 2(2-chlorophenyl)-2-chloroacetate for the final preparation of clopidogrel and no precise indication or example was given to illustrate the preparation of a C
1
-C
4
alkyl 2-(halophenyl)-2-(bromo or alkylsulfonyloxy or arylsulfonyloxy)-acetate.
According to this example, clopidogrel is obtained by carrying out the following 5 steps, starting from a 2-hydroxyacetic ester:
a) and b) reaction of racemic 2(2-chlorophenyl)-2-hydroxyacetic acid with phosphorus pentachloride and esterification with methanol to form racemic methyl 2-(2-chlorophenyl)-2-chloroacetate with a 45% yield,
c) coupling of the methyl 2-(2-chlorophenyl)-2-chloroacetate formed in this way, with 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in the presence of potassium carbonate, which yields racemic methyl 2-(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)-2(2-chlorophenyl)-acetate, with a mean yield of 80%,
d) resolution of the racemate obtained by salification with camphosulphonic acid (yield: 88% in terms of the salt desired)
e) regeneration of clopidogrel in basic form by treating the camphosulphonic salt in question with sodium bicarbonate
Using this process, clopidogrel is obtained with a chemical yield of up to 30% from 2(2-chlorophenyl)-2-hydroxyacetic acid.
During the preliminary trials carried out in the context of the present invention, an attempt was made to prepare clopidogrel or its (R) enantiomer by means of an analogous reaction to that described in the patent already referred to, but starting from the (R) or (S) enantiomer of methyl 2(2-chlorophenyl)-2-chloroacetate.
However, all the tests performed in methanol, acetonitrile or ethyl acetate as solvent at a temperature between room temperature and 65° C., with 1 or 2 equivalents of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine either in the form of the base or in the form of the hydrochloride, with or without sodium bicarbonate, led to the production of 72 to 88% of racemic methyl 2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetate.
Other tests carried out with heating to 80° C. and using methyl (S)-2(2-chlorophenyl)-2-chloroacetate and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in the presence of sodium carbonate and in a solvent mixture of methylisobutyl ketone/water yielded methyl (R)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)-2(chlorophenyl)acetate with an entantiomeric excess of only 20%.
Consequently, the development of a process for the preparation of clopidogrel from 4,5,6,7-tetrahydrothieno[3,2-c]pyridine using a stereoselective method, which involves as few steps as possible and providing an appreciable yield of the desired compound remains of incontestable importance.
It has been discovered rather surprisingly, according to the invention, that clopidogrel can be obtained in just 3 steps from (R)-2(2-chlorophenyl)-2-hydroxyacetic acid with a global yield of the order of 80% by replacing the methyl-(R)-2(2-chlorophenyl)-2-halogenoacetate, by methyl-(R)-2(2-chlorophenyl)-acetate, which has a sulfonyloxy group in the 2 position, i.e. a compound with the above formula I.
This process is all the more surprising because:
A) the 2-methanesulfonyloxy groups and 2-toluenesulfonyloxy groups of carboxyl esters are known to undergo racemisation when they are involved in a nucleophilic substitution by an amine function (Angew. Chem. Int. Ed. Eng. 22 (1983), no. 1 pp 65-66).
These claims have been confirmed in
Tetrahedron,
Vol. 47, no. 7, pp 1109-1135 (1991), where it is reported that the 2-methanesulfonyloxy and 2-p-toluenesulfonyloxy esters of carboxylic acids are inappropriate substrates for a stereoselective nucleophilic substitution reaction in the 2 position.
Similar observations have been published in Leibigs. Ann. Chem. 1986, p. 314-433, where yields of <30% are reported as being obtained during the substitution of methyl-2-p-toluenesulfonyloxy- or methyl-2-methanesulfonyloxy-propionate with benzylamine.
B) The (R) and (S) enantiomers of 2-sulphonyloxyacetic esters, which include an additional 2-phenyl group, are known to produce compounds with considerably reduced stereoselectivity after nucleophilic substitution in the 2-position.
For example,
Tetrahedron,
Vol. 44, no. 17, pp 5583-5595 (1988) reports the substitution of derivatives of (S) or (R) methyl-2-triflyloxy-2-X-acetate by O-benzylhydroxylamine in dichloromethane as a solvent and at a temperature between 0° C. and room temperature in order to form the (R) and (S) acetic esters of 2-O-benzylhydroxylamino-2-X respectively. As is known, the triflyl group designates the trifluoromethylsulfonyl radical.
This reaction is found to be highly selective in the case of esters in which X represents an alkyl group, which may be substituted, such as methyl or benzyl (enantiomeric excess, ee≧95%), but has much lower selectivity when X represents the phenyl group since the enantiomeric excess of the corresponding (R)-2-O-benzylhydroxylamino-2-phenyl ester is no more than 50%. Very similar results have been reported after other experiments carried out using 2-sulphonyloxy derivatives of 2-phenylacetic esters.
Thus:
a)
Tetrahedron
Letters, Vol. 31, no. 21, pp 2953-2956 (1990) describes the substitution reaction of the methyl (S)-2-triflyloxy-2-X-acetate esters with t-butyloxycarbonylhydrazine or BOC-hydrazine, in dichloromethane and at 0° C., to form (R)-2-BOC-hydrazinyl-2-X-acetic esters.
The selectivity of this reaction has also been shown to be very considerable when X represents an alkyl group, which may be substituted, such as methyl, isobutyl or benzyl (ee>95%), but in contrast, very limited when X represents phenyl (ee: 28%).
b)
Tetrahedron,
Vol. 48, no. 15, pp 3007-3020 (1992) reports the substitution of methyl (S)-2-nosyloxy-2-X-acetate derivatives with an azido group, the reaction taking place in dichloromethane and at room temperature, in order to form (R)-2-azido-2-X acetic esters.
Once more, the substitution of the 2-sulfonyloxy group, in this case the nosyloxy group, takes place in a highly selective manner when X rep
Bousquet Andre
Musolino Andrée
Alexander Michael D.
Dupont Paul E.
Sanofi-Synthelabo
Vollano Jean F.
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