FORM 2
THE PATENTS ACT,
1970 (39 OF 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)
"A NOVEL METHOD FOR THE SYNTHESIS OF DESACETYL DILTIAZEM HYDROCHLORIDE"
Dr. V.S. Velingkar, Vice-Principal, Professor and Head of the Department, Department of
Pharmaceutical Chemistry, Principal K.M. Kundnani College of Pharmacy, Plot No. 47, Dr. R.G.
Thadani Marg, Worli Sea face, Worli, Mumbai - 400 018, Maharashtra, India is an Indian
and
Ms. Tumuluri Haripriya, a research fellow, pursuing Master of Pharmaceutical Sciences in Pharmaceutical Chemistry in Principal K.M. Kundnani College of Pharmacy, Plot No. 47, Dr. R.G. Thadani Marg, Worli Sea face, Worli, Mumbai - 400 018 Maharashtra, India is an Indian
The following specification describes the nature of this invention -


This invention relates to a novel process for the synthesis benzothiazepine derivative.
In the said patent, diltiazem hydrochloride can be converted to penultimate impurity (compound) by refluxing it by acid buffer.
In Yuki Gosei Kagaku Kyokaishi 57 (5), 394-400 (1999), an article entitled "An efficient method for the preparation of diltiazem" was published.
The method of synthesis involved reaction between 2-nitro thiophenol with trans-3 -phenyl glycidic esters carrying various substituents on the benzene ring.
In 1997, Plaum, Marcus Joseph Maria prepared desacetyl diltiazem hydrochloride by intramolecular cyclization of amino phenyl thio propanoic acid derivative. (2R,3S)-2,3-epoxy-3-(4-methoxy phenyl) propanoic acid methyl ester in non-halogenated solvent in the presence of chloro alkanoic acid to give 71-84% yield. (2R,3S)-2,3-epoxy-3-(4-methoxy phenyl) propanoic acid methyl ester and 2-amino thio phenol in the presence of trichloro acetic acid reacted for- 2 hours, after cyclization, produced 71% yield of (+)-(2S, 3S)-3-hydroxy-2-(4-methoxy phenyl)-2,3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)one.
"Assymetric reduction of 1, 5 Benzothiazepine derivative with sodium borohydride-(S)-a-amino acids. An effective efficient synthesis of a key intermediate of diltiazem". A key intermediate of diltiazem synthesis, (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxy phenyl)-1,5-benzothiazepin-4(5H)one", published in J.Org. Chem., 1996, 61 (24), 8586-8590 stated the following method for the preparation of desacetyl diltiazem hydrochloride. (2S,3S) has been efficiently synthesized by an assymetrical reduction of the prochiral ketone 2-(4-methoxy phenyl)l,5-benzothiazepin-3,4 (2H,5H) dione, with sodium borohydride and chiral a-amino acids.
In the US patent 5,559,229, the process for the manufacture of desacetyl diltiazem hydrochloride comprises N-alkylation of the corresponding lactam with a suitable 2-(N,N-dimethyl amino)ethyl derivative using methyl isobutyl ketone as a solvent and sodium hydroxide as base.
In Japan Kokai Tokkyokaho journal dated 10th August 1993, an article entitled "Preparation of 1,5-benzothiazepine"; stated the method as follows: desacetyl diltiazem hydrochloride was

prepared by the reaction of phenyl thio propionates with 2-(N,N-dimethyl amino)ethyl chloride [Cl-CH2-CH2-N-(CH3)2]or its acid salts in ether solvents in the presence of solid alkali metal hydroxides. A solution of phenyl thio propionates in dioxane was treated with 2-(N,N-dimethyl amino)ethyl chloride.HCl [C1-CH2-CH2-N-(CH3)2.HC1] and potassium hydroxide at 100-105°C for 2 hours to obtain desacetyl diltiazem hydrochloride after the treatment with HCl/ethanol.
An article "A new synthetic route to 1,5-benzothiazepine synthesis of derivatives of diltiazem" by Harada Tsunehiro at al prepared several derivatives of diltiazem from the oxamates.
Another method for the preparation of benzothiazepinone comprises N-alkylation of benzothiazepinone with a (dimethyl amino)-ethyl halide where in the N-alkylation reaction is carried out in a mixture comprising 2-butanone and water.
Desacetyl diltiazem hydrochloride was prepared by cyclization of amino phenyl thio propionates in the presence of alkyl/aryl sulphonic acids.
In Chem. Pharm. Bull 1978 26 (9), 2889-93, Diltiazem hydrochloride and its metabolites were synthesixzed from methyl-p-benzyloxy phenyl glycidate and o-nitro thio benzene.
In an article entitled "Resolution of 3-(amino phenyl thio)-3-(methoxy phenyl)-2-hydroxy propionates in preparation of chiral 1,5-benzothiazepines", the authors synthesized title compounds via resolution of phenyl thio propionates using optically active tartaric acid analogs in organic solvent. Thus methyl threo-2-hydroxy-3(2-amino phenyl thio)-3-(4-methoxy phenyl) propionates (I) was added to solution of 2R,3R- tartaric acid in ethanol/water recrystallized from isopropanol to give 2S,3S of (I), the latter was refluxed with p-methyl benzene sulfonic acid in xylene to give 90% 2S, 3S-2,3-dihydro-3-hydroxy-2-(4-methoxy phenyl)-1,5-benzothiazepine-4(5H) one.

The objective of the present invention is as follows -
1. To synthesize the working standards of impurity substances/degradation products in the drugs of clinical significance
2. To design a novel process for the synthesis of degradation products
3. To develop a precise method of synthesis
4. To design an economical, simple and efficient method.
5. To develop a process which involves easily available raw materials
In accordance with the present invention, a new process has been provided using acidic buffer to achieve desacetyl diltiazem hydrochloride from diltiazem hydrochloride with high purity and yield.
is obtained after acid hydrolysis of diltiazem hydrochloride of the formula.
According to the present invention, Desacetyl diltiazem hydrochloride of the formula:



Desacetyl diltiazem hydrochloride was synthesized by carrying out acid hydrolysis of diltiazem hydrochloride using the method given below:
To the weighed quantity of diltiazem hydrochloride HCl: KCl buffer (pH 2) was added. The mixture was stirred and refluxed on a water bath for 48 hours. The reaction mixture was evaporated to dryness. The crude product was then heated with chloroform to separate potassium chloride salt, which was obtained as a by-product. The chloroform mixture was vacuum dried to obtain the crude product. This crude product was washed repeatedly using different organic solvents and purified by column chromatography.
We claim:
1. A new process for preparing Desacetyl diltiazem hydrochloride of the below given formula and structure from diltiazem hydrochloride.
Formula: C20H24N2O3S • HCl

2. The process according to claim 1 wherein Desacetyl diltiazem hydrochloride was prepared by acid hydrolysis of diltiazem hydrochloride using buffer.
3. The process according to claim 2 wherein the said buffer is in the range of pH 1 to pH 4.
4. The process according to claim 3 wherein reaction is carried out by refluxing the compound with buffer at temperature between 50-80°C.
5. The process according to claim 4 where in reaction is carried out by refluxing diltiazem hydrochloride for a period of 40-50 hours.

Signature:
Name: Tumuluri Haripriya
Signature:

Name : Dr. V.S. Velingkar
Abstract of Invention -
A process for preparing desacetyl diltiazem hydrochloride from diltiazem hydrochloride using buffer at a temperature of 50-80°C for a period of 40-50 hours.