Indian Patents. 190806:"A PROCESS FOR PREPARING CARBAMAZEPINE FROM IMINOSTILBENE"

Title of Invention	"A PROCESS FOR PREPARING CARBAMAZEPINE FROM IMINOSTILBENE"
Abstract	A process for preparing carbamazepine from iminostilbene is disclosed. The iminostilbene is reacted with urea in a protonating medium. This process results in improvements over prior art processes involving iminostilbene. Carbamazepine is a known muscle relaxant, anticonvulsant and antidepressant drug.

Full Text	The present invention relates to an improved process for the preparation of preparing carbamazepine from iminostilbene. Carbamazepine, or 5-carbamoyl-5H-dibenz(b,f)azepine, is a known muscle relaxant/anticonvulsant, e.g. antiepileptic and psychotropic drug, described in, inter alia, US Patent Specification No. 2 948 718. The compound is also known as N-carbamoyliminostilbene, and various processes for preparing it from iminostilbene (hereinafter referred to as 'ISB') have been described. For example, European Patent Specification No. 29 409 discloses the preparation of carbamazepine by reacting ISB with a halocyanogen to produce the 5-cyano derivative, followed by hydrolysation. However, this is an inconvenient two-stage process that involves the use of toxic reagents. To try to overcome these disadvantages, persons skilled in the art have attempted other methods. For example, European Patent Specifications Nos. 277 095 and 688 768 disclose the reaction of ISB with cyanic acid (HOCN), which may be generated in situ, in an organic solvent in the presence of an acidic agent. An alternative method is disclosed in European Patent Specification No. 423 679, which relates to the chlorocarbonylation and subsequent ammonolysis of ISB; similarly, European Patent Specification No. 485 685 relates to the use of phosgene. These, and other known alternatives, also involve two process steps and/or toxic reagents. All the known methods therefore suffer from disadvantages, in particular, the requirement to use 'environmentally-unfriendly' reactants, but we have surprisingly found that reaction of urea with a protonated from of ISB enables the disadvantages of the prior art to be overcome. Accordingly, the present invention provides a process for the preparation of carbamazepine which comprises reacting at a temperature in the range of from 40°C. to 100°C. iminostibene (ISB) or a salt thereof with urea (of formula H2NCONH2) or a salt thereof in a protonating medium such as herein described to produce the desired carbamazepine and recovering in a manner known per se the carbamazepine so produced from the reaction mixture. In this way, there is provided a single-step process that can be carried out at moderate temperatures at atmospheric pressure and that requires the use of only 'environmentally-friendly' reagents. The protonating medium is one that allows protonation of the ISB and/or the urea in the reaction. Preferably, it allows proton transfer from the ISB to the urea. For example, the protonating medium may comprise a polar organic solvent and at least a catalytic amount of proton-donor that can donate a proton to the ISB. Preferably, the proton-donor is an inorganic acid, such as a mineral acid, eg sulphuric, hydrochloric or phosphoric acid. The preferred proton donor is sulphuric acid. Conveniently, the ISB and proton donor may be present as the corresponding salt of ISB. For example, the process may comprise reaction of a mineral acid salt of ISB, such as ISB.HC1, ISB.H2SO4 or ISB.H3PO4, with the urea in a polar organic solvent. Alternatively, the urea and proton donor may be present as the corresponding salt of urea. For example, the process may comprise reaction of a mineral acid salt of urea, such as urea.HCl or urea.H2SO4, etc, with the ISB in a polar organic medium. Preferred ISB or urea salts are hydrochlorides. Preferably, the polar organic solvent is an organic acid, such as an aliphatic carboxylic acid, preferably a C1-4 carboxylic acid, most preferably acetic acid. Preferably, the molar ratio of ISB: urea used in the reaction is in the range of from 1: about 10-about 14 (moles), more preferably about 1:12-14 (moles). As well as overcoming the disadvantages of the prior art methods, the process of the present invention provides further advantages in that the preparation of carbamazepine proceeds in near-quantitative yields, and is particularly suitable for large-batch production. The reaction may be carried out at moderately elevated temperatures (at atmospheric pressure), such as in the range of from about 40° to about 100°C, preferably in the range of from about 80° to about 90°C, more preferably from about 80-85°C. The reaction may be completed during a period in the range of from about 4 to about 14 hours, preferably in the range of from about 6 to about 8 hours, such as from about 7 to about 8 hours. Once complete, the reaction mixture may be diluted with water to precipitate the carbamazepine, which may then be separated from the mother liquor by filtration, followed by standard washing and drying procedures. By analogy, therefore, the present invention further provides a process for the preparation of analogues or derivatives of carbamazepine, which process comprises reaction of a corresponding 5- or N-decarbamoyl derivative thereof with urea. The present invention therefore still further provides a process for the preparation of an N-carboxamido-cyclic secondary amine, which process comprises reaction of the corresponding cyclic secondary amine with urea. The present invention further surprisingly provides the use of urea or a salt thereof in the preparation of a cyclic secondary amide, particularly carbamazepine, in particular, in the presence of a protonating medium, such as urea (base) in the presence of a proton donor, eg a catalytic amount of a mineral acid. The carbamazepine, or analogue or derivative thereof, thereby prepared, may then be formulated, for example, by bringing it into association with a suitable carrier therefor, into a pharmaceutical formulation, as is known in the art. The present invention will now be illustrated by the following non-limiting examples. EXAMPLE 1: Preparation of Carbamazepine - Sulphuric Acid Catalyst To a suspension of urea (400g, 6.66 mols) in acetic acid (500ml), sulphuric acid (15ml) was added, followed by iminostilbene (100g, 0.518 mols), under stirring at 25-30°C. The resulting reaction mixture was heated to 80-85°C and maintained for a period of 7-8 hours, and the reaction was monitored by thin layer chromatography (TLC). The reaction mass was diluted with water, and the resulting carbamazepine product (m.p. 188-189°C) separated by filtration, washed with water until neutral and dried at 90-100°C until constant weight. The identity of the product was further verified by tlc (toluene/methanol 18/03, uv=254nm) to be identical to the reference compound and by infra-red spectroscopy (KBr) Vmax = 3466, 1677, 1605, 1595 cm-1. EXAMPLE 2: Preparation of Carbamazepine - Phosphoric Acid Catalyst To a suspension of urea (80g, 1.333 mols) in acetic acid (100ml), phosphoric acid (8ml) was added, followed by iminostilbene (20g, 0.103 mols), under stirring at 25-30°C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1. EXAMPLE 3: Preparation of Carbamazepine using ISB.HC1 To a suspension of urea (80g, 1.333 mols) in acetic acid (100ml), iminostilbene hydrochloride (20.5g, 0.089 mols) was added under stirring at 25-30°C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1. EXAMPLE 4: Preparation of Carbamazepine using Urea.HCl To a suspension of urea hydrochloride (100g, 1.036 mols) in acetic acid (125ml), iminostilbene (25g, 0.129 mols) was added under stirring at 25-30°C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1. WE CLAIM : 1. A process for the preparation of carbamazepine which comprises reacting at a temperature in the range of from 40°C. to 100°C. iminostibene (ISB) or a salt thereof with urea (of formula H2NCONH2) or a salt thereof in a protonating medium such as herein described to produce the desired carbamazepine and recovering in a manner known per se the carbamazepine so produced from the reaction mixture. 2. A process as claimed in claim 1, wherein the protonating medium is one that allows protonation of the ISB and/or the urea in the reaction. 3. A process as claimed in claim 1 or claim 2, wherein the protonating medium is one that allows proton transfer from the ISB to the urea. 4. A process as claimed in any of claims 1 to 3, wherein the protonating medium comprises a polar organic solvent and at least a catalytic amount of proton-donor. 5. A process as claimed in claim 4, wherein the proton-donor is an inorganic acid, such as a mineral acid, eg sulphuric, hydrochloric or phosphoric acid. 6. A process as claimed in claim 5, wherein the proton-donor is sulphuric acid. 7. A process as claimed any one of claims 4 to 6, wherein the ISB and proton donor are present as the corresponding salt of ISB. 8. A process as claimed any one of claims 1 to 4 or 7, wherein the process comprises reaction of a mineral acid salt of ISB, such as ISB.HC1, ISB.H2SO4 or ISB.H3PO4, with the urea in a polar organic solvent. 9. A process as claimed any one of claims 4 to 8, wherein the urea and proton donor are present as the corresponding salt of urea. 10. A process as claimed any one of claims 1 to 4 or 9, wherein the process comprises reaction of a mineral acid salt of urea, such as urea.HCl or urea.H2SO4 with the ISB in a polar organic medium. 11. A process as claimed any of claims 4 to 10, wherein the polar organic solvent is an organic acid. 12. A process as claimed in claim 11, wherein the polar organic solvent is acetic acid. 13. A process as claimed in any of claims 1 to 12, wherein the reaction is carried out (at atmospheric pressure) at a temperature in the range of from about 80°C to about 90°C, more preferably from about 85°C to about 90°C. 14. A process for the preparation of carbamazepine substantially as herein described with particular reference to the foregoing Examples.

Full Text

The present invention relates to an improved process for the preparation of preparing carbamazepine from iminostilbene.
Carbamazepine, or 5-carbamoyl-5H-dibenz(b,f)azepine, is a known muscle relaxant/anticonvulsant, e.g. antiepileptic and psychotropic drug, described in, inter alia, US Patent Specification No. 2 948 718. The compound is also known as N-carbamoyliminostilbene, and various processes for preparing it from iminostilbene (hereinafter referred to as 'ISB') have been described.
For example, European Patent Specification No. 29 409 discloses the preparation of carbamazepine by reacting ISB with a halocyanogen to produce the 5-cyano derivative, followed by hydrolysation. However, this is an inconvenient two-stage process that involves the use of toxic reagents. To try to overcome these disadvantages, persons skilled in the art have attempted other methods.
For example, European Patent Specifications Nos. 277 095 and 688 768 disclose the reaction of ISB with cyanic acid (HOCN), which may be generated in situ, in an organic solvent in the presence of an acidic agent. An alternative method is disclosed in European Patent Specification No. 423 679, which relates to the chlorocarbonylation and subsequent ammonolysis of ISB; similarly, European Patent Specification No. 485 685 relates to the use of phosgene. These, and other known alternatives, also involve two process steps and/or toxic reagents.
All the known methods therefore suffer from disadvantages, in particular, the requirement to use 'environmentally-unfriendly' reactants, but we have surprisingly found that reaction of urea with a protonated from of ISB enables the disadvantages of the prior art to be overcome.
Accordingly, the present invention provides a process for the preparation of carbamazepine which comprises reacting at a temperature in the range of from 40°C. to 100°C. iminostibene (ISB) or a salt thereof with urea (of formula H2NCONH2) or a salt thereof in a protonating medium such as herein described to produce the desired carbamazepine and recovering in a manner known per se the carbamazepine so produced from the reaction mixture. In this way, there is

provided a single-step process that can be carried out at moderate temperatures at atmospheric pressure and that requires the use of only 'environmentally-friendly' reagents.
The protonating medium is one that allows protonation of the ISB and/or the urea in the reaction. Preferably, it allows proton transfer from the ISB to the urea. For example, the protonating medium may comprise a polar organic solvent and at least a catalytic amount of proton-donor that can donate a proton to the ISB. Preferably, the proton-donor is an inorganic acid, such as a mineral acid, eg sulphuric, hydrochloric or phosphoric acid. The preferred proton donor is sulphuric acid.
Conveniently, the ISB and proton donor may be present as the corresponding salt of ISB. For example, the process may comprise reaction of a mineral acid salt of ISB, such as ISB.HC1, ISB.H2SO4 or ISB.H3PO4, with the urea in a polar organic solvent. Alternatively, the urea and proton donor may be present as the corresponding salt of urea. For example, the process may comprise reaction of a mineral acid salt of urea, such as urea.HCl or urea.H2SO4, etc, with the ISB in a polar organic medium. Preferred ISB or urea salts are hydrochlorides.
Preferably, the polar organic solvent is an organic acid, such as an aliphatic carboxylic acid, preferably a C1-4 carboxylic acid, most preferably acetic acid.
Preferably, the molar ratio of ISB: urea used in the reaction is in the range of from 1: about 10-about 14 (moles), more preferably about 1:12-14 (moles).
As well as overcoming the disadvantages of the prior art methods, the process of the present invention provides further advantages in that the preparation of carbamazepine proceeds in near-quantitative yields, and is particularly suitable for large-batch production.
The reaction may be carried out at moderately elevated temperatures (at atmospheric pressure), such as in the range of from about 40° to about 100°C, preferably in the range of from about 80° to about 90°C, more preferably from about 80-85°C. The reaction may be completed during a period in the range of from about 4 to about 14 hours, preferably in the range of from about 6 to about 8 hours, such as from about 7 to about 8 hours.

Once complete, the reaction mixture may be diluted with water to precipitate the carbamazepine, which may then be separated from the mother liquor by filtration, followed by standard washing and drying procedures.
By analogy, therefore, the present invention further provides a process for the preparation of analogues or derivatives of carbamazepine, which process comprises reaction of a corresponding 5- or N-decarbamoyl derivative thereof with urea. The present invention therefore still further provides a process for the preparation of an N-carboxamido-cyclic secondary amine, which process comprises reaction of the corresponding cyclic secondary amine with urea.
The present invention further surprisingly provides the use of urea or a salt thereof in the preparation of a cyclic secondary amide, particularly carbamazepine, in particular, in the presence of a protonating medium, such as urea (base) in the presence of a proton donor, eg a catalytic amount of a mineral acid.
The carbamazepine, or analogue or derivative thereof, thereby prepared, may then be formulated, for example, by bringing it into association with a suitable carrier therefor, into a pharmaceutical formulation, as is known in the art.
The present invention will now be illustrated by the following non-limiting examples.
EXAMPLE 1: Preparation of Carbamazepine - Sulphuric Acid Catalyst
To a suspension of urea (400g, 6.66 mols) in acetic acid (500ml), sulphuric acid (15ml) was added, followed by iminostilbene (100g, 0.518 mols), under stirring at 25-30°C. The resulting reaction mixture was heated to 80-85°C and maintained for a period of 7-8 hours, and the reaction was monitored by thin layer chromatography (TLC). The reaction mass was diluted with water, and the resulting carbamazepine product (m.p. 188-189°C) separated by filtration, washed with water until neutral and dried at 90-100°C until constant weight. The identity of the product was further verified by tlc (toluene/methanol 18/03, uv=254nm) to be identical to the reference compound and by infra-red spectroscopy (KBr) Vmax = 3466, 1677, 1605, 1595 cm-1.
EXAMPLE 2: Preparation of Carbamazepine - Phosphoric Acid Catalyst
To a suspension of urea (80g, 1.333 mols) in acetic acid (100ml), phosphoric acid (8ml) was added, followed by iminostilbene (20g, 0.103 mols), under stirring at 25-30°C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1.
EXAMPLE 3: Preparation of Carbamazepine using ISB.HC1
To a suspension of urea (80g, 1.333 mols) in acetic acid (100ml), iminostilbene hydrochloride (20.5g, 0.089 mols) was added under stirring at 25-30°C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1.
EXAMPLE 4: Preparation of Carbamazepine using Urea.HCl
To a suspension of urea hydrochloride (100g, 1.036 mols) in acetic acid (125ml), iminostilbene (25g, 0.129 mols) was added under stirring at 25-30°C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1.

WE CLAIM :
1. A process for the preparation of carbamazepine which comprises reacting at a temperature in the range of from 40°C. to 100°C. iminostibene (ISB) or a salt thereof with urea (of formula H2NCONH2) or a salt thereof in a protonating medium such as herein described to produce the desired carbamazepine and recovering in a manner known per se the carbamazepine so produced from the reaction mixture.
2. A process as claimed in claim 1, wherein the protonating medium is one that allows protonation of the ISB and/or the urea in the reaction.
3. A process as claimed in claim 1 or claim 2, wherein the protonating medium is one that allows proton transfer from the ISB to the urea.
4. A process as claimed in any of claims 1 to 3, wherein the protonating medium comprises a polar organic solvent and at least a catalytic amount of proton-donor.
5. A process as claimed in claim 4, wherein the proton-donor is an inorganic acid, such as a mineral acid, eg sulphuric, hydrochloric or phosphoric acid.
6. A process as claimed in claim 5, wherein the proton-donor is sulphuric acid.
7. A process as claimed any one of claims 4 to 6, wherein the ISB and proton donor are present as the corresponding salt of ISB.
8. A process as claimed any one of claims 1 to 4 or 7, wherein the process comprises reaction of a mineral acid salt of ISB, such as ISB.HC1, ISB.H2SO4 or ISB.H3PO4, with the urea in a polar organic solvent.
9. A process as claimed any one of claims 4 to 8, wherein the urea and proton donor are present as the corresponding salt of urea.
10. A process as claimed any one of claims 1 to 4 or 9, wherein the process comprises reaction of a mineral acid salt of urea, such as urea.HCl or urea.H2SO4 with the ISB in a polar organic medium.
11. A process as claimed any of claims 4 to 10, wherein the polar organic solvent is an organic acid.
12. A process as claimed in claim 11, wherein the polar organic solvent is acetic acid.
13. A process as claimed in any of claims 1 to 12, wherein the reaction is carried out (at atmospheric pressure) at a temperature in the range of from about 80°C to about 90°C, more preferably from about 85°C to about 90°C.
14. A process for the preparation of carbamazepine substantially as herein described with particular reference to the foregoing Examples.

Documents:

3427-del-1998-abstract.pdf

3427-del-1998-assignment.pdf

3427-del-1998-claims.pdf

3427-del-1998-correspondence-others.pdf

3427-del-1998-correspondence-po.pdf

3427-del-1998-description (complete).pdf

3427-del-1998-form-1.pdf

3427-del-1998-form-2.pdf

3427-del-1998-form-3.pdf

3427-del-1998-form-4.pdf

3427-del-1998-form-6.pdf

3427-del-1998-gpa.pdf

3427-del-1998-petition 124.pdf

« Previous Patent

Next Patent »

Patent Number

190806

Indian Patent Application Number

3427/DEL/1998

PG Journal Number

15/2010

Publication Date

09-Apr-2010

Grant Date

30-Mar-2010

Date of Filing

16-Nov-1998

Name of Patentee

JUBILANT ORGANOSYS LTD.

Applicant Address

1A, SECTOR 16 A, INSTITUIONAL AREA, NOIDA-201301, UTTER PRADESH, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	KETAN DHANSUKHLAL YVAS	#858 "PALLAVI" 1ST FLLOR, E & F BLOCK, PANCHAMANTRA ROAD, KUVEMPU NAGAR, MYSORE-570 023, INDIA
2	WAJJID SAJJAD JAFRI	HOUSE NO. 29, N BLOCK, FOURTH CROSS, ARVIND NAGAR, KUVEMPU NAGAR, MYSORE-570 023, INDIA
3	ASHOK KRISHNA KULKARNI	#1199 LALITHADRI ROAD, THIRD CROSS, KUVEMPU NAGAR, MYSORE-570 023, INDIA

PCT International Classification Number

A61K 31/395

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA