Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-07-07
1997-07-15
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548406, 548468, 549 71, C07F 702
Patent
active
056485026
DESCRIPTION:
BRIEF SUMMARY
4-Chloro-2-thiophenecarboxylic acid has the structure ##STR1## It is an important intermediate for the synthesis of pharmaceutical compounds such as, for example, 5-fluoro-6-chloro-3-(4-chloro-2-thenoyl)-2-oxindole-1-carboxamide which is disclosed in Example 72 of U.S. Pat. No. 5,047,554 to Ehrgott et al.
A synthesis of 4-chloro-2-thiophenecarboxylic acid (herein also abbreviated for convenience as "CTCA") is disclosed by J. Iriarte et al., J. Heterocyclic Chem., 13, 393 (1976). It is there reported that CTCA was obtained in quantitative yield in crude form by oxidizing the corresponding 2-aldehyde with silver oxide. The crude acid was reported to have a melting point (m.p.) of 124.degree.-126.degree.. The product was further stated to have a melting point of 131.degree.-132.degree. following "repeated crystallization from methanol or dichloromethane." Iriarte et al. also report, in the same paper, making CTCA, m.p. 125.degree.-126.degree., by saponifying ethyl 4-chlorothiophene-2-carboxylate in methanolic potassium hydroxide, the carboxylate having been made by the direct chlorination of ethyl thiophene-2-carboxylate in the presence of aluminum chloride.
Lemaire et al., J. Electroanal. Chem., 281, 293, (1990) report, inter alia, making 3-chloro-2-trimethylsilylthiophene by a method employing a Grignard reagent, the product being used in an electropolymerization to make poly(3-chlorothiophene). Neither CTCA nor any method for synthesizing it is disclosed.
The present inventors have now determined that CTCA can be produced by a temperature-dependent regioselective process in which potentially reactive sites are blocked and thus prevented from contributing by-products.
SUMMARY OF THE INVENTION
In its broadest aspect, this invention provides a process of making 4-chloro-2-thiophenecarboxylic acid, comprising removing the silyl group SiR.sub.3 from a compound of formula IVa ##STR2## wherein each of the R groups is independently selected from (C.sub.1 -C.sub.6)alkyl, benzyl, and phenyl.
A variation of the above process for making 4-chloro-2-thiophenecarboxylic acid, comprises removing the silyl group SiR.sub.2 from a compound of formula IVb ##STR3## wherein R is as previously defined.
In greater detail, a process of making 4-chloro-2-thiophenecarboxylic acid, comprises the steps of: C., with base, followed by treatment with a silyl compound of the formula R.sub.3 SiX, wherein X is a leaving group and each of the R groups is independently selected from (C.sub.1 -C.sub.6)alkyl, benzyl, and phenyl, thereby forming a compound of the formula ##STR4## 2) treating the product of step (1), at a temperature less than about -50.degree. C., with a base sufficient to deprotonate at the 5-position of the chlorothiophene ring, thereby correspondingly forming an anion of formula IIa ##STR5## 3) treating the product of step (2), at a temperature less than -50.degree. C., with carbon dioxide to form, correspondingly, the monocarboxylate of formula IIIa ##STR6## 4) converting the product of step (3) to the corresponding acid (i.e. of formula IVa); and
A variation of the immediately preceding process for making 4-chloro-2-thiophenecarboxylic acid comprises the steps of: -50.degree. C., with base, followed by treatment with a silyl compound of the formula R.sub.2 SiX.sub.2, wherein X and R are as previously defined, thereby forming a compound of the formula ##STR7## 2) treating the product of step (1), at a temperature less than about -50.degree. C., with a base sufficient to deprotonate at the 5 and 5' positions of the two thiophene rings, thereby correspondingly forming a dianion of formula IIb ##STR8## 3) treating the product of step (2), at a temperature less than -50.degree. C., with carbon dioxide to form the corresponding dicarboxylate of formula IIIb ##STR9## 4) converting the product of formula step (3) to the corresponding diacid (i.e. of formula IVb); and
As leaving groups "X", halogeno groups including chloro, bromo, and iodo, trifluoromethanesulfonate, trifluoroacetate, acetamide, trifluoroacetamide, 1,2,4-triazole
REFERENCES:
patent: 4432974 (1984-02-01), Haber
patent: 5047554 (1991-09-01), Ehrgott et al.
patent: 5118703 (1992-06-01), Reiter et al.
patent: 5498630 (1996-03-01), Phillion et al.
M. Lemaire et al., J. Electroanal. Chem., vol. 281, 292-298 (1990).
J. Iriarte et al., J. Heterocyclic Chem., vol. 13, 393-394 (1976).
T. Greene, "Protective Groups in Organic Synthesis", pp. 39-43, John Wiley & Sons, New York (1981).
Burgess Laurence E.
Schulte Gary R.
Benson Gregg C.
Jones James T.
Pfizer Inc.
Raymond Richard L.
Richardson Peter C.
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