Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-01-28
2001-01-30
Raymond, Richard L. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C560S017000
Reexamination Certificate
active
06180785
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for preparing diltiazem, and novel intermediates for use in that process, and to their preparation.
BACKGROUND OF THE INVENTION
Diltiazem, is a compound of the type of formula (VI)
More specifically, Diltiazem is (2S-cis)-3-(acyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1.,5-benzothiazepin-4(5H)-one of the formula
Diltiazem is a calcium channel blocker with coronary vasodilating, antihypertensive, and psychotropic activity. Vasodilating action is specific for the &agr;-cis-isomer. Diltiazem is the highest selling chiral cardiac prescription drug which is synthesized by resolution methods. A number of methods for its resolution are known in the literature.
A few chiral syntheses of diltiazem are known and some of these are described below. One process for the preparation of Diltiazem involves resolution of the key intermediate (&agr;S,&bgr;S)-&bgr;[(2-aminophenyl)thio]-&agr;-hydroxy-&bgr;-(4-methoxyphenyl) propanoic acid alkyl ester of formula (V).
The process is described by Senuma, M.; Shibazaki, M.; Nishimoto, S.; Shibata, K.; Okamura, K.; Date, T.; in Chem. Pharm. Bull. 1989, Vol. 37, P. 3204; U.S. Pat. No. 4,416,819 of Tanabe Seiyaka Co., Ltd.; and in Chem. Abstr. 100, P 85733a; or by a stereoselective synthesis of cis-phenylglycidic acid esters as described by Jgarash, K.: Honma, T.: in German Patent No. 3,415,035 of Shionogi & Co. Ltd. and Chem. Abstr. 102, p185114f, followed by a stereo- and regioselective opening of the epoxide with either 2-aminothiophenol as described by Hulshof, L. A.; Roskam, J. Chem; Schwartz A., in U.S. patent application Ser. No. 197,934 of 1988; Eur. Pat. No. 343,714 of 1989; Chem. Abstr., 1989, 113,77912, or 2-nitrothiophenol as described by Miyazaki, M.; Iwakuma, T.; Tanaka, T., Tanabe Seiyaku Co. Ltd., in Chem. Pharm. Bull., 1978, Vol. 26, P. 2889.
More recently, optically active trans-phenylglycidic acid esters were prepared using a stoichiometric amount of a chiral auxiliary followed by a stereoselective opening of the epoxide by various substituted aminothiophenol to give the desired intermediate ester of formula (V) as described by Schwartz. A.; Madan, P. B.; Monacsi, E: O'Brien, J. P.; Todaro, L. J.; Coffen, D. L., in J. Org. Chem 1992, Vol. 57, P. 851.
Alternatively, a stereoselective Michael addition to an (&agr;,&bgr;-unsaturated carbonyl compound leading to the derivative of formula (V) has been reported by Miyata, O.; Shinada, T.; Ninomiya, 1; Nsito, T., in Tetrahedron Lett. 1991, Vol. 32, P. 3519. The compound of formula (V) was converted into Diltiazem of formula (VI) in four steps:
(i) Hydrolysis of the ester to free carboxylic acid.
(ii) Cyclizing the free carboxylic acid to (2S-cis)-(3-hydroxy)2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one.
(iii) Acetylating the benzothiazepinone with acetic anhydride and pyridine to (2S-cis)-3-(acetyloxy)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one.
(iv) Converting the benzothiazepinone from step (iii) to Diltiazem of formula (VI) by treating it with a N, N-dialkyl alkyl halide in presence of a suitable base and a suitable solvent.
All the above procedures have one or more drawbacks:
(i) They involve resolution of either the key intermediate of formula (V) or of the final product Diltiazem of formula (VI).
(ii) In most of the known stereochemical syntheses, a chiral auxiliary is used in stoichiometric amount.
(iii) cis-p-methoxycinnamyl esters are prepared in several steps and it is uneconomical to get them in their stereomerically pure form.
(iv) Asymmetric epoxidation of cis-p-methoxycinnamyl esters involves expensive chiral auxiliaries and even catalytic method of synthesizing these epoxides requires at least 20% of the catalyst.
(v) When trans-p-methoxycinnamyl esters are used, they are converted into epoxides with a stoichiometric amount of a chiral auxiliary, and upon nucleophilic opening with 2-aminothiophenol or 2-nitrothiophenol the epoxides produce both desired and undesired intermediates of formula (V).
(vi) In the synthesis using trans-p-methoxycinnamyl esters, the esters, are first dihydroxylated to furnish a diol of formula (III)
wherein R
1
is a methoxy, and R an ethyl residue. The diol of formula (III) is then transformed to a cis-epoxide in two steps. The cis-epoxide then undergoes nucleophilic ring opening to produces the desired intermediate of formula (V).
DESCRIPTION OF THE INVENTION
An object of the present invention is to provide a novel 5S-(p-alkoxyphenyl)-4R-carbalkoxy-1,2,3-dioxathiolene-2-oxide of formula (IV)
wherein
R
1
is hydrogen, or a hydroxy, alkoxy, alkyl, alkylthio, alkylamino, aryl, or aryloxy residue, suitably a methyl, ethyl, propyl, napthyl, phenyl, 1,2-naphthyl, methoxy, ethoxy, halogen, or a phenoxy residue.
R is an alkyl or an aryl residue, suitably a methyl, ethyl, or benzoyl residue; and
X is S or C.
For the synthesized Diltiazem R
1
is most suitably a methoxy residue and R is most suitably ethyl.
Another object of the present invention is to provide a process for the preparation of the compound of formula (IV) by a stereoselective and easy method. The compound of formula (IV) is a key intermediate in the stereoselective synthesis of the amino ester of formula (V) which is key intermediate for the preparation of Diltiazem of formula (VI).
Yet another object of the present invention is to provide a process for the preparation of (&agr;S, &bgr;-S)-&bgr;-[(2-aminophenyl) thiol]-&agr;-hydroxy-&bgr;-(4-methoxyphenyl) propanoic acid alky ester of formula (V) from the cyclic sulfite or cyclic carbonate of formula (IV). The compound of formula (V) is a key intermediate in the production of Diltiazem of formula (VI).
REFERENCES:
patent: 4590188 (1986-05-01), Takeda et al.
Bhushan Lohray Braj
Bhushan Lohray Vidya
Jayachandran Balakrishnan Ezhuthachan
Thottappillil Ravindranathan
Coleman Brenda
Raymond Richard L.
Schweitzer Cornman Gross & Bondell LLP
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