|Title of Invention||AN IMPROVED PROCESS OF GLIMEPIRIDE|
|Abstract||Disclosed herein is a process for manufacture of glimepiride (Formula I) and its intermediates that comprises a 4-pyrrolidinopyridine or 4-(dimethylamino)pyridine catalyzed reaction of compound of Formula IX, wherein R= lower alkyl group, with trans 4-methyl cyclohexyl amine in an organic solvent to form glimepiride substantially free of said starting compound (IX) and other impurities, in higher yield.|
|Full Text||FORM 2
THE PATENT ACT 1970
(39 of 1970)
The Patents Rules, 2003
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"An improved process of Glimepiride"
(a) NAME: IPCA LABORATORIES LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400 067
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner
in which it is to be performed.
Field of Invention:
The present invention relates to an improved process to manufacture an anti-diabetic pharmaceutical drug commonly known as glimepiride in high purity and yield.
Background of the invention:
The chemical name of Glimepiride is 3-Ethyl-2,5-dihydro-4-methyl-A^-[2-[4-[[[[(trans-4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-lH-pyrole-l-carboxamide and is represented by the structure of Formula I. Glimepiride is a new generation sulphonyl urea anti-diabetic drug and is one of the best sulphonyl urea drugs in the clinical appraisal. It is approved by FDA to cure diabetes type II, which cannot be cured by the dietic adjustment or exercise. Glimepiride lowers blood glucose in non-insulin dependent diabetic mellitus (Type-II diabetic mellitus), by stimulating the release of insulin from functioning pancreatic beta cells. It may also be used along with insulin. Glimepiride has the advantages of higher activity, less side effect and low dosage requirement. So the synthesis of this anti-diabetic drug in high purity is of extreme importance in the current scenario.
Glimepiride and its synthetic route was first disclosed in US 4,379,785(herein after referred as '785 patent). The '785 patent teaches a general preparative method for the heterocyclic substituted sulfonylureas, particularly 3-Ethyl-2,5-dihydro-4-methyl-A^-[2-[4-[[[[(trans-4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl] phenyl]ethyl]-2-oxo-l//-pyrole-l-carboxamide i e. Glimepiride. The preparation started with a 3-ethyl-4-methyl -2,5-dihydro-l//-pyrrol-2-one (II), which was reacted with phenylethyl isocyanate
■(IFI) to form [2-(3-ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene (IV). This intermediate of Formula IV was then reacted with Chlorosulphonic acid to get corresponding sulphonyl chloride (V), which was isolated by filtration. The sulphonyl chloride intermediate was reacted with ammonia to get the corresponding sulphonamide (VI). This sulphonamide i.e 4[2-(3-ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (VI), was finally condensed with 4- methyl cyclohexyl isocyanate (VII) to get glimepiride (I). (Scheme I)
Scheme I The product obtained by following this process yielded glimepiride of lower purity and yield. The possible reasons are as under:
1. The chlorosulphonation of compound of Formula IV results in two isomers, viz. ortho- and para- isomers, wherein an effective purification to remove the unwanted ortho-isomer is not disclosed or known. WO 03057131 states that the purity of sulphonamide intermediate (VI) never exceeds 95% and hence not useful in the synthesis.
2. This process employs isolation of sulphonyl chloride intermediate (V) and it results in the hydrolysis of: sulphonyl chloride moiety to sulphonic acid, which reflects in purity and yield.
3. The isolation of sulphonyl chloride (Formula V) is not industrially practical as the filtration takes considerably longer time increasing the overheads, as well as formation of corresponding sulphonic aoid impurity.
4. The use of 4-methylcyclohexyl isocyanate generates polymeric impurities due to polymerization/heat instability of this reagent under the reaction conditions, resulting in tedious isolation/purification.
Another report, WOO 1053 54 A2, addresses these problems and teaches a different' process wherein the sulfonamide (VI) was reacted with a carbamate of Formula VIII to get Glimepiride. (I) and thereby provides an alternative for the use of 4-methylcyclohexyl isocyanate. Although the problem regarding use of 4- methylcyclohexyl isocyanate is resolved to an extent but the other problems still remains, additionally, a carbamate of Formula VIII must be prepared separately (Scheme II).
Yet another report, see Chinese Journal of Medicinal chemistry 2000, Vol. 10. No. 2 page No. 134-137, discloses improvements over the preparation of glimepiride, wherein an isolated sulphonyl chloride was used in reaction, which was converted to Sulphonamide of Formula VI. The compound of Formula VI was reacted with ethyl chloroformate to
form the carbamate of Formula IX (R = C2H5) in presence of an inorganic base like sodium hydroxide. This intermediate carbamate was converted to a salt of trans 4-methyl cyclohexyl amine in acetone, and the isolated salt (79.0% yield) was heated in a second solvent like toluene to form glimepiride. Although this synthetic pathway has advantages of using a reactive intermediate like carbamate (IX) in place of a sulphonamide (VI) and also use of a stable reactant like trans 4-methylcyclohexylamine (X) in place of trans 4-methylcyclohexyl isocyanate (VII), it still exhibits lower yields and purity.
The yield of glimepiride is only about 67% from carbamate (IX). This is because of the incomplete reaction of carbamate (IX) with trans 4-methyl cyclohexyl amine and also due to the yield losses in a two stage conversion. In this paper, the carbamate formation is carried out in PEG 400-water solvent medium in presence of NaOH and, as a result, either because of incomplete reaction or carbamate gets hydrolyzed during work-up, the product remains contaminated with a significant amount of sulphonamide (VI) impurity. The removal of this impurity from product is difficult.
Other reports viz. WO 2004073585 A2, WO03057131 A2, and Journal of China Pharmaceutical University - 1999, 30 (3) 163-165 deal with improvements over the synthetic pathway disclosed in the '785 patent.
Therefore, there is a need to develop a synthetic process for glimepiride that consists of faster reaction, effective purification methods or avoiding steps which generates impurities, having better outputs.
The present invention deals with improvements over the synthetic pathway disclosed in the prior art described before, which ameliorates most of the problems, associated with purity and yield.
Objective of the Invention:
It is an objective of the present invention to overcome or ameliorate at least one of the
disadvantages of the prior art or to provide a useful alternative.
The main objective of the present invention in its preferred form is to prepare glimepiride
of high purity in an acceptable yield by providing effective purification of intermediates,
avoiding tedious isolation procedures and providing suitable alternatives, and enhancing
the speed and completion of reaction using catalysts or the like.
Another objective is to provide better reagents & conditions for completion of reaction in
the carbamate (IX) formation thereby reducing level of sulphonamide impurity to
acceptable limit, as well as to drive final condensation reaction of carbamate with trans
4-methylcyclohexylamine to completion.
Summary of the invention:
Accordingly, a process for preparation of high purity glimepiride in high throughput conditions is disclosed.
In one embodiment of the present invention, the carbamate of Formula IX (wherein R = lower alkyl, preferably ethyl) is reacted with trans 4-methyl cyclohexylamine (X) in presence of an activation catalyst selected from 4-pyrrolidinopyridine or 4-(dimethylamino)pyridine (DMAP) or the like in a single solvent without isolation of a trans 4-methylcyclohexyl amine salt of IX. In a preferred-process, the compound IX is reacted with trans 4-methylcyclohexyl amine X in presence of DMAP.. in an aromatic hydrocarbon solvent like toluene, at reflux temperature with optional removal of byproduct (alcohol) from the reaction medium by distillation or other means like Dean Stark arrangement.
I; 1 another embodiment of the present invention the starting carbamate is prepared by reaction of sulphonamide of Formula VI with (alkyl) ethylchloroformate in presence of an organic base and a solvent media selected from-chlorinated hydrocarbon solvents at a temperature ranging from about - 10 to +35 °C till completion of the reaction.
In yet another embodiment of the present invention, the starting sulphonamide is prepared by reacting a compound of Formula IV with chlorosulphonic acid at a temperature of - 10 to + 10°C and directly reacting it with aqueous ammonia solution preventing sulphonyl chloride hydrolysis to sulphonic acid impurity.
The present invention also provides a novel purification method for effective removal of ortho-isomer to give a pure sulphonamide (VI) of acceptable quality to proceed for the next step by treating the crude compound containing ortho- & para- isomer in solvent acetone.
The invention describes a process for 3-Ethyl-2,5-dihydro-4-methyl-A'-[2-[4-[[[[(trans-4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1 //-pyrole-1 -carboxamide (glimepiride) in a purity of at least 99.50% without additional purification in higher yields. The process according to the invention is detailed as follows:
The compound of Formula IV is prepared according to process disclosed in the '785 patent to get a purity of 99% (HPLC) and is used in the present invention. According to the present invention, the compound of Formula IV is chlorosulphonated with chlorosulphonic acid under neat conditions at a temperature of about - 10 to + 10°C for a period of 2 to 12 hrs. Chlorosulphonic acid in this case acts as both, a solvent as well as reactant, in the said reaction and is preferably used in 10 times molar excess relative to the starting compound of Formula IV.
In a preferred embodiment of the present invention the chiorosulphonated product (V) is not isolated separately, it is directly converted to its sulphonamide on completion of the reaction. This is performed by directly quenching the reaction mass of chlorosulphonation into ammonia solution. This process improvement prevents the hydrolysis of the sulphonyl chloride moiety and thus avoids contamination of the resulting sulphonic acid in the product. Alternately the ammonia may be incorporated
into the reaction mass with appropriate cooling of the reaction mass. It is preferable to use ammonia solution as it is operation-wise easy on large scale. In the process, in its preferred form, the chlorosulphonated product is quenched into an aqueous solution of ammonia, preferably about 20% to 25 % solution, at a temperature of about -10 to +30°C. The precipitated sulphonamide is isolated by simple filtration.
The isolated sulphonamide of Formula VI may be contaminated with its ortho-isomeric impurity. This invention provides a novel, practical and efficient removal of the ortho-isomeric impurity in a single purification step.
Accordingly, the crude sulphonamide of Formula VI containing ortho- & para- isomers is refluxed with a ketone solvent, especially acetone and allowing to cool to about 0°C and then filtered to get the product.
In a second step the sulphonamide of Formula VI is converted to the compound of
Formula IX (herein called carbamate) by reaction with alkyl (ethyl) chloroformate of
formula XI. In the process, according to the present invention, the sulphonamide is
reacted with ethylchloroformate in presence of an organic base in a solvent selected from
hydrocarbon and chlorinated hydrocarbon solvent. Chlorinated hydrocarbons are
methylene chloride, ethylene chloride, chloroform etc. and the preferred solvent is
The organic base used is selected from trialkyl amine such as triethylamine, ethyldiisopropyl amine or 4-(dimethylamino)pyridine (herein after referred as DMAP) etc. and a combination of trialkylamine, preferably triethyl amine, & DMAP is used in the reaction. The reaction is carried out at a temperature ranging from about -10 to 35°C and preferably in methylene chloride. Preferably the organic base may be used in a molar equivalent ratio relative to the sulphonamide of Formula VI. On completion of reaction, the solvent is distilled and carbamate is isolated using a second solvent like acetone or toluene. The mass is then filtered & dried which gives a purity of at -least 99.7% and the sulphonamide impurity content less than 0.20% (based on HPLC analysis).
In the final stage, the carbamate of Formula IX is converted to glimepiride by reaction with trans 4-methyl cyclohexylamine in a single step and in a single solvent in presence of an activation catalyst, and isolated to give a product having purity of about 99.50 % which-contains carbamate (IX, R= C2H5) impurity around 0.06% only and sulphonamide (VI) impurity around 0.3% straightway without purification.
Accordingly, in the present invention, the carbamate is reacted with trans 4-methylcyclohexyamine (X), preferably in presence of a catalyst selected from 4-pyrrolidino pyridine or 4-(dimethylamino)pyridine (DMAP), preferably DMAP, in a single solvent selected from hydrocarbon solvents such as, but not limited to, toluene or xylene. In the reaction the trans 4-methyicyclohexyl amine is preferably used in molar amounts or in excess ranging from about 1.0 to 1.5 relative to the carbamate used. The DMAP catalyst is preferably used in molar amounts ranging from 0.1 to 1.0 moles relative to the starting carbamate. The most preferred amount of DMAP is in the range of about 0.3 to 0.5 moles. The reaction temperature is reflux temperature.
In a preferred embodiment of the invention, the reaction is driven to completion by effectively removing the by-product, i.e., alcohol, from the reaction vessel continuously by means of distillation during the reaction. This means for effective removal it is preferably by distillation using a Dean-Stark arrangement or by normal distillation.
Glimepiride from the reaction mixture is isolated directly by simple cooling of the reaction mass after completion of reaction to a temperature of-10 to 30°C and filtration. The glimepiride so obtained shows a purity of about 99.50 % or more. The process of the present invention also avoids the isolation of trans 4-methylcyclohexyl amine salt of IX. The yield of glimepiride in the final step is nearly 95%, wherein the reported yield in Chinese Journal of Medicinal Chemistry 'Vol. 10, No. 2, page No. 134-137 is only 67% in similar reaction. Finally the crude glimepiride is digested in acetone solvent, cooled and filtered to increase the purity of glimepiride to more than 99.7 % having carbamate (IX, R= C2H5) impurity around 0.05% and sulphonamide (VI) impurity around 0.20%.
This drastic yield improvement caused by the above-described inventive variation from prior art can lead to an efficient and commercially acceptable synthetic process for the production of pharmaceutically valuable glimepiride.
Preparation of 4[2-(3-ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene
In a reaction vessel, 100 gm of [2-(3-ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene (Formula IV) was added slowly over a period of 3 hrs. into 428 gm of chilled chlorosulphonic acid with stirring & maintaining the temperature around 0°C. It was then stirred at same temperature till completion of reaction. The reaction mass was quenched into 1800 ml. chilled ammonia solution (25% aqueous solution) while maintaining temperature around 0°C. Then the temperature was raised to 25-30°C and maintained under stirring for about 30 minutes and filtered and washed with water and dried to get 118 gm (91.5% yield) of crude sulphonamide of Formula VI.
Purification of crude sulphonamide of Formula VI.
In a reaction vessel, the crude material obtained as above was refluxed in 2.36 litre of acetone and charcoalized with activated charcoal. Charcoal was filtered off by filtering hot over filter aid. The solvent was distilled to about 75 to 90 % by volume, cooled and filtered and washed with chilled acetone. The wet cake was dried to get 80 gm. of pure sulphonamide of Formula VI (purity 96 %, ortho isomer less than 1%). Melting point: 177 to l81°C.
In a reaction vessel, the crude material obtained as above v/as heated with 1.18 liter
toluene to 70°C for 30 minutes and then was cooled to about 30°C, filtered and the wet
cake was washed with toluene.
The wet cake was again heated with 590 ml.of isopropyl alcohol at about 70°C for»30
minutes, cooled to 0°C maintained for 3 hours and filtered. The wet cake is washed with
isopropyl alcohol and dried to get 91 gm pure sulphonamide of Formula VI (purity 96%
by HPLC analysis) Melting point: 177 to 181 °C.
Preparation of carbamate of Formula IX (R= ethyl)
In a reaction vessel 100 gm of 4[2-(3-ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide, 72 gm triethyl amine and 1.6 lit dichloromethane were taken and the mixture cooled to 0 °C. 46.15 gm of ethyl chloroformate was diluted separately with 200 ml dichloromethane and added into the reaction vessel drop wise while maintaining the temperature at around 5°C and maintained for 2 hours at 5°C and then at 25 to 30°C till completion of reaction. 2 L water and 0.7 L dichloromethane was added and the pH of the reaction mass were adjusted to 4 by addition of acetic acid. The organic layer was separated and washed with water and concentrated to dryness. The residue was refluxed with 300 ml acetone and cooled to 25 to 30 °C, maintained for 1 hour, filtered and washed with 100 ml chilled acetone to get 100 gm carbamate of Formula IX (yield 83%, purity 99.7%). Melting Point: 177 to 182°C
Example 3: ■ Preparation of Glimepiride (Formula I) In a reaction vessel, 80 gm of carbamate of Formula IX, 27.2 gm trans 4-methylcyclohexyl amine, 11.5 gm 4-dimethylamino pyridine and 1.6 lit. toluene was taken and the mixture was heated to reflux and toluene was distilled out maintaining total volume of the reaction constant. After completion of reaction the mass was cooled to 25 to 30 °C, to precipitate the glimepiride. filtered and washed with 800 ml of toluene. The filtered material was dried to get 88 gm (95% yield) of Glimepiride (purity 99.5%)
80 gm of Glimepiride, obtained as per the above example, was stirred with 800 ml of acetone at reflux temperature for 30 minutes and cooled to 25 to 30 UC, filtered, washed with 400 ml acetone. The filtered material was dried to weigh 75 gm Glimepiride of 99.7% purity (by HPLC) and impurity of sulphonamide (VI) and carbamate (IX) 0.2 and 0.05 % respectively. Melting point: 207 to 211 °C.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
1. A process for manufacture of glimepiride of Formula I
comprising reacting a compound of Formula IX, wherein R= lower alkyl group, with trans 4-methyl cyclohexyl amine of Formula X in an organic-solvent in presence of a catalyst selected from 4-pyrrolidinopyridine or 4-(dimethylamino)pyridine at reflux temperature to form glimepiride substantially free of said starting compound (IX).
2. The process as claimed in claim 1, wherein the catalyst is 4-(dimethylamino)pyridine.
3. The process as claimed in any one of the preceding claims, wherein the organic solvent is selected from hydrocarbon solvent like toluene.
4. The process as claimed in any one of the preceding claims, wherein the by-product alcohol generated in the reaction is continuously removed by means of distillation or the like.
5. The process as claimed in claim 1, wherein the compound of Formula IX is prepared by reacting 4[2-(3-ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide of Formula VI with a compound of Formula XI, wherein R has the same definition as in claim 1, in an organic solvent in presence of an organic base.
6. The process as claimed in claim 5, wherein the organic base is selected from trialkyl amine or 4-(dimethylamino)pyridine.
7. The process as claimed in claim 6, wherein the organic base is triethyl amine.
8. The process as claimed in claim 5, wherein the organic solvent is chlorinated or non-chlorinated hydrocarbons like dichloromethane or toluene.
9. The process as claimed in claim 5 to 8, wherein the reaction is performed at -10 to 35°C.
10. The process as claimed in claim 5, wherein the 4[2-(3-ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide of Formula VI is prepared by reacting a carboxamide of Formula IV with chlorosulphonic acid characterized by quenching the resulting reaction mass in ammonia to obtain a sulphonamide of Formula VI and purifying said sulphonamide from an organic solvent like acetone, toluene or
isopropyl alcohol or their combination thereof.
11. The process as claimed in claim 10, wherein the reaction of chlorosulphonic acid and
compound of Formula IV is carried out at about -10 to 10 °C
12. The process as claimed in claim 11, wherein the reaction is carried out in the absence of solvent.
13. The process as claimed in claim 10, wherein the ammonia is aqueous ammonia solution.
14. Glimepiride prepared substantially according to any one of the preceding claims.
15. A process for preparation of glimepiride as substantially described herein with reference to the foregoing examples 1 to 3.
Dated this the 11th day of March 2005
DR. GOPAKUMAR G. NAIR Agent for the Applicant
Disclosed herein is a process for manufacture of glimepiride (Formula I) and its intermediates that comprises a 4-pyrrolidinopyridine or 4-(dimethylamino)pyridine catalyzed reaction of compound of Formula IX, wherein R= lower alkyl group, with trans 4-methyl cyclohexyl amine in an organic solvent to form glimepiride substantially free of said starting compound (IX) and other impurities, in higher yield.
|Indian Patent Application Number||271/MUM/2005|
|PG Journal Number||28/2009|
|Date of Filing||11-Mar-2005|
|Name of Patentee||IPCA LABORATORIES LTD.|
|Applicant Address||48, KANDIVLI INDUSTRIAL ESTATE, MUMBAI|
|PCT International Classification Number||A61K31/420 C07D277/41|
|PCT International Application Number||N/A|
|PCT International Filing date|