WO2009069073A1 - An improved process for the preparation of lamotrigine - Google Patents

An improved process for the preparation of lamotrigine Download PDF

Info

Publication number
WO2009069073A1
WO2009069073A1 PCT/IB2008/054937 IB2008054937W WO2009069073A1 WO 2009069073 A1 WO2009069073 A1 WO 2009069073A1 IB 2008054937 W IB2008054937 W IB 2008054937W WO 2009069073 A1 WO2009069073 A1 WO 2009069073A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
lamotrigine
acetonitrile
alcohol
preparation
Prior art date
Application number
PCT/IB2008/054937
Other languages
French (fr)
Inventor
Keshav Deo
Sanjay Desai
Rajesh Sahu
Pradipkumar Sharma
Original Assignee
Alembic Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alembic Limited filed Critical Alembic Limited
Publication of WO2009069073A1 publication Critical patent/WO2009069073A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D253/075—Two hetero atoms, in positions 3 and 5

Definitions

  • the present invention relates to an improved process for the preparation of Lam- otrigine [3] [4]
  • the structural formula of Lamotrigine is represented by formula (I)
  • Lamotrigine of formula (I) is from the phenyltriazine class and useful as anticonvulsant.
  • the precise mechanism by which Lamotrigine exerts its anticonvulsant action are unknown but In Vitro pharmacological studies suggest that Lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids such as glutamate and aspartate.
  • the cyclization is carried out by refluxing the compound in 1-propanol in neutral condition.
  • total impurities and individual impurity level is high in final step.
  • the process needs recrystallization and charcoalization to purify the crude final product. This makes the process laborious and increases the overall cost.
  • An object of the present invention is to provide an improved process for the preparation of Lamotrigine.
  • Another object of the present invention is to provide an improved process for the preparation of Lamotrigine with high yield and high purity.
  • Yet another object of the present invention is to provide a process which is simple, easy to handle at industrial scale and which is cost effective.
  • the present invention provides an improved process for preparation of Lamotrigine comprising steps of: [29] (i) reacting 2,3-dichlorobenzoyl nitrile (II) with aminoguanidine bicarbonate in the presence of sulfuric acid to give 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile (III);
  • a mino guanidine bicarbonate is slowly added in a solution of sulphuric acid in water at ambient temperature about 28 0 C to about 30° C .
  • Acetonitrile and 2,3-dichloro benzoyl nitrile (II) is added to the reaction mixture.
  • the mixture is stirred 30 to 35 hrs at about 25 0 C to about 35 0 C and heat to about 45 0 C to about 50 0 C.
  • the reaction mixture is cooled, filtered and washed with water.
  • the wet cake is slurred in water and basified with ammonia solution to pH from about 6 to about 7, and filtered.
  • alcohol includes but not limited to C M0 alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol, 2-propanol, hexanol, pentanol.
  • C M0 alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol, 2-propanol, hexanol, pentanol.
  • the preferred alcohol is methanol.
  • the catalytic quantity of acid is added to it.
  • the acid is selected from the group of organic acid and inorganic acid.
  • organic acid includes but not limited to formic acid, oxalic acid, mandalic acid, adipic acid, succinic acid, p- toluene sulfonic acid, methane sulfonic acid, tartaric acid, citric acid and the like or mixture thereof.
  • inorganic acid includes but not limited to HCl, HBr, HI, HF, nitric acid (HNO 3 ), sulfuric acid (H 2 SO 4 ), H 3 PO 3 , polyphosphoric acid, perchloric acid (HClO 4 ), chloric acid (HClO 3 ), chlorous acid (HClO 2 ), hypochlorous acid (HClO) and the like or mixture thereof.
  • the preferred acid used here is sulfuric acid.
  • the reaction mixture is heated to reflux for about 3 to 4 hr.
  • the reaction mixture is filtered and distilled out 75% of original volume of methanol under reduced pressure.
  • Reaction mixture is cooled to about 25 0 C to about 35 0 C and stirred for 30 to 60 minutes.
  • the reaction mixture is filtered and washed with methanol.
  • the wet cake is dissolved in methanol and heated to about 7O 0 C to about 75 ° C.
  • the mixture was filtered to get clear solution.
  • the methanol from filtrate is distilled out 75% of original volume of methanol under reduced pressure.
  • the reaction mixture is cooled to about 25 0 C to about 35 0 C and stirred for 30 to 60 minutes.
  • the reaction mixture was filtered and dried at about 4O 0 C to about 6O 0 C under vacuum to give Lamotrigine.
  • a mino guanidine bicarbonate (102.2g) was slowly added in sulfuric acid (1030g) in water (545ml) at 28° to 30° C .
  • Acetonitrile (2ml) and 2,3-dichloro benzyl chloride (100 ml) was added to the reaction mixture.
  • the reaction mixture was stirred for 30 hr at 25 0 C to 35 0 C and then heated at 45 0 C to 50 0 C.
  • the reaction mixture was cooled, filtered and washed with water (100ml).
  • the wet cake slurry in water (1300ml) was prepared and basified with ammonia solution to pH 6-7. The mixture was filtered.
  • reaction mixture was filtered and distilled out 75% of original volume of methanol under vacuum.
  • the reaction mixture was cooled to 25 0 C to 35 0 C and stirred for 30 to 60 minutes.
  • the reaction mixture was filtered and dried at 4O 0 C to 60 0 C under vacuum to give the title product (20.5g).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to an improved process for the preparation of Lamotrigine (I) comprising a step of cyclizing 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile(III) in the presence of an alcohol and an acid.

Description

Description AN IMPROVED PROCESS FOR THE PREPARATION OF LAM-
OTRIGINE
Field of invention
[1]
[2] The present invention relates to an improved process for the preparation of Lam- otrigine [3] [4] The structural formula of Lamotrigine is represented by formula (I)
Figure imgf000002_0001
(I)
[5]
Background of the invention
[6]
[7] The chemical name of Lamotrigine is
6-(2,3-Dichlorophenyl)-l,2,4-triazine-3,5-diamine, molecular formula is C9H7Cl2N5 and molecular weight is 256.09. The current pharmaceutical product containing this drug is being sold by Glaxo Wellcome using tradename Lamictal, in the form of tablets.
[8]
[9] Lamotrigine of formula (I) is from the phenyltriazine class and useful as anticonvulsant. The precise mechanism by which Lamotrigine exerts its anticonvulsant action are unknown but In Vitro pharmacological studies suggest that Lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids such as glutamate and aspartate.
[10]
[11] US4602017A first time discloses process for preparation of Lamotrigine according to the scheme shown below.
[12] *"
Figure imgf000003_0001
2,3-dι chloro benzoyl cyanide
Figure imgf000003_0002
Figure imgf000003_0003
Lamotrigine 2-(2,3-dιchloro phenyl) -2- (guanidinoimino) acetonitrile
[13] The cyclization step is conducted in basic medium in alcohol. [14] [15] US6333198 discloses a process for the preparation of Lamotrigine as shown below in the scheme.
Figure imgf000003_0004
(II) (III) Lamotrigine (I)
[16] In this process, the cyclization is carried out by refluxing the compound in 1-propanol in neutral condition. In this process total impurities and individual impurity level is high in final step. The process needs recrystallization and charcoalization to purify the crude final product. This makes the process laborious and increases the overall cost.
[17] [18] Therefore, there is a need to develop a process for the preparation of Lamotrigine which minimize the generation of impurities and overcomes the drawbacks of the state of art.
[19] [20] Surprisingly, the present inventors have observed that the cyclization of 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile in acidic medium reduces the level of impurities generated during the process and also increases the overall yield of the Lamotrigine. The cyclization reaction is performed in acidic media using a mineral acid such as sulfuric acid in alcoholic solvent such as methanol.The total impurities and individual impurity level is very low than existing procedures in final step. The individual impurity i.e. (z)-2-(2,3-Dichlorophenyl)-(guanidine imino) acetonitrile is well controlled below the limit about 0.05% by using the process of the present invention. This isomeric impurity tends to cyclize in next step and is isolated with Lamotrigine which is effectively controlled.
[21]
Object of the invention [22] An object of the present invention is to provide an improved process for the preparation of Lamotrigine.
[23] [24] Another object of the present invention is to provide an improved process for the preparation of Lamotrigine with high yield and high purity.
[25] [26] Yet another object of the present invention is to provide a process which is simple, easy to handle at industrial scale and which is cost effective.
[27]
Summary of the invention [28] Accordingly the present invention provides an improved process for preparation of Lamotrigine comprising steps of: [29] (i) reacting 2,3-dichlorobenzoyl nitrile (II) with aminoguanidine bicarbonate in the presence of sulfuric acid to give 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile (III);
[30] (ii) cyclizing 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile in the presence of alcohol and acid to give Lamotrigine (I). [31]
Detailed description of the invention [32] The process of the present invention is as shown below in the scheme.
Figure imgf000004_0001
(II) (III) Lamotrigine (I)
[33] A mino guanidine bicarbonate is slowly added in a solution of sulphuric acid in water at ambient temperature about 280C to about 30° C . Acetonitrile and 2,3-dichloro benzoyl nitrile (II) is added to the reaction mixture. The mixture is stirred 30 to 35 hrs at about 250C to about 35 0C and heat to about 450C to about 500C. The reaction mixture is cooled, filtered and washed with water. The wet cake is slurred in water and basified with ammonia solution to pH from about 6 to about 7, and filtered. Again the wet cake is slurried in water and basified with sodium hydroxide solution to pH from about 9.5 to about 10 at 15° to 25 0C and filtered, washed with water. The solid is d ried at about 6O0C to about 70 ° C to give 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile (III)
[34]
[35] 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile is dissolved in alcohol. The examples of alcohol includes but not limited to CM0 alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol, 2-propanol, hexanol, pentanol. The preferred alcohol is methanol. The catalytic quantity of acid is added to it. The acid is selected from the group of organic acid and inorganic acid. The examples of organic acid includes but not limited to formic acid, oxalic acid, mandalic acid, adipic acid, succinic acid, p- toluene sulfonic acid, methane sulfonic acid, tartaric acid, citric acid and the like or mixture thereof. The examples of inorganic acid includes but not limited to HCl, HBr, HI, HF, nitric acid (HNO3), sulfuric acid (H2SO4), H3PO3, polyphosphoric acid, perchloric acid (HClO4), chloric acid (HClO3), chlorous acid (HClO2), hypochlorous acid (HClO) and the like or mixture thereof. The preferred acid used here is sulfuric acid. The reaction mixture is heated to reflux for about 3 to 4 hr. The reaction mixture is filtered and distilled out 75% of original volume of methanol under reduced pressure. Reaction mixture is cooled to about 250C to about 35 0 C and stirred for 30 to 60 minutes. The reaction mixture is filtered and washed with methanol. The wet cake is dissolved in methanol and heated to about 7O0C to about 75 ° C. The mixture was filtered to get clear solution. The methanol from filtrate is distilled out 75% of original volume of methanol under reduced pressure. The reaction mixture is cooled to about 250C to about 35 0 C and stirred for 30 to 60 minutes. The reaction mixture was filtered and dried at about 4O0C to about 6O 0 C under vacuum to give Lamotrigine.
[36]
[37] The advantage of the above process is that a separate purification step is not required.
The purification of the crude takes place in situ which is very convenient at industrial scale. The yield and purity is increased in comparison with the prior art processes.
[38]
[39] The following example illustrates the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.
[40] [41] Example-1
[42] Preparation of 2-(2,3-dichlorophenyl)-2-(guanidinoimino)acetonitrile
[43] A mino guanidine bicarbonate (102.2g) was slowly added in sulfuric acid (1030g) in water (545ml) at 28° to 30° C . Acetonitrile (2ml) and 2,3-dichloro benzyl chloride (100 ml) was added to the reaction mixture. The reaction mixture was stirred for 30 hr at 250C to 35 0C and then heated at 450C to 500C. The reaction mixture was cooled, filtered and washed with water (100ml). The wet cake slurry in water (1300ml) was prepared and basified with ammonia solution to pH 6-7. The mixture was filtered. Again the wet cake slurry in water (900ml) was prepared and basified with sodium hydroxide solution to pH 9.5-10 at 150C to 25 0C. The mixture was filtered and washed with water (300ml). The solid was d ried at 60-70 ° C to give the title product (9Og)
[44] Yield: 70.30%
[45]
[46] Example-2
[47] Preparation of Lamotrigine
[48] 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile (25g) was dissolved in methanol (750ml). Catalytic quantity of cone, sulfuric acid was added to it. The reaction mixture was heated to reflux for 3-4 hr. The reaction mixture was filtered and the filtrate was distilled out 75% of original volume of methanol under vacuum. Reaction mixture was cooled to 250C to 35 0C and stirred for 30 to 60 minutes. The reaction mixture was washed with methanol (50ml). Above wet cake was dissolved in methanol (750ml) and heated at 7O0C to 75 0C to make clear solution. The reaction mixture was filtered and distilled out 75% of original volume of methanol under vacuum. The reaction mixture was cooled to 250C to 35 0C and stirred for 30 to 60 minutes. The reaction mixture was filtered and dried at 4O0C to 60 0C under vacuum to give the title product (20.5g).
[49] Yield: 82%

Claims

Claims
[1] 1. A process for preparation of Lamotrigine (I)
Figure imgf000007_0001
(I) comprising a step of cyclizing
2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile(III) in the presence of an alcohol and an acid.
[2] [3] 2. A process for preparation of Lamotrigine (I)
Figure imgf000007_0002
(I) comprising steps of:
(i) reacting 2,3-dichlorobenzoyl nitrile (II)
Figure imgf000007_0003
(II) with aminoguanidine bicarbonate in the presence of sulfuric acid to give 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile (III) ;
Figure imgf000007_0004
(III)
(ii) cyclizing 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile(III) in the presence of an alcohol and an acid to give Lamotrigine (I). [4] [5] 3. The process as claimed in claim 1 or 2, wherein said acid is selected from the group consisting of organic and inorganic acids or mixture thereof. [6] [7] 4. The process as claimed in claim 3, wherein the organic acid is selected from the group comprising formic acid, oxalic acid, mandalic acid, adipic acid, succinic acid, p-toluene sulfonic acid, methane sulfonic acid, tartaric acid, citric acid. [8] [9] 5. The process as claimed in claim 3, wherein the inorganic acid is selected from the group comprising HCl, HBr, HI, HF, nitric acid (HNO3), sulfuric acid (H2SO4
), H3PO3, polyphosphoric acid, perchloric acid (HClO4), chloric acid (HClO3), chlorous acid (HClO2), hypochlorous acid (HClO) [10] [11] 6. The process as claimed in claim 1 or 2, wherein said alcohol is selected from the group consisting of Cn0 alcohol such as methanol, ethanol, n-propanol, iso- propanol, butanol, 2-propanol, hexanol, pentanol or mixture thereof.
PCT/IB2008/054937 2007-11-28 2008-11-25 An improved process for the preparation of lamotrigine WO2009069073A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2339MU2007 2007-11-28
IN2339/MUM/2007 2007-11-28

Publications (1)

Publication Number Publication Date
WO2009069073A1 true WO2009069073A1 (en) 2009-06-04

Family

ID=40469878

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2008/054937 WO2009069073A1 (en) 2007-11-28 2008-11-25 An improved process for the preparation of lamotrigine

Country Status (1)

Country Link
WO (1) WO2009069073A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103570637A (en) * 2013-09-13 2014-02-12 盐城凯利药业有限公司 Preparation method of lamotrigine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001049669A1 (en) * 2000-01-03 2001-07-12 Rpg Life Sciences Limited A process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine
WO2003078407A1 (en) * 2001-12-24 2003-09-25 Apotex Pharmachem Inc. A new and efficient process for the preparation of lamotrigine and related 3,5-diamino-6-substituted-1,2,4-triazines
WO2004039767A1 (en) * 2002-10-31 2004-05-13 Vita Cientifica, S.L. Process for preparing a pharmaceutically active compound and for preparing its intermediate
WO2007069265A1 (en) * 2005-12-12 2007-06-21 Unichem Laboratories Limited A novel process for the synthesis of lamotrigine and its intermediate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001049669A1 (en) * 2000-01-03 2001-07-12 Rpg Life Sciences Limited A process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine
WO2003078407A1 (en) * 2001-12-24 2003-09-25 Apotex Pharmachem Inc. A new and efficient process for the preparation of lamotrigine and related 3,5-diamino-6-substituted-1,2,4-triazines
WO2004039767A1 (en) * 2002-10-31 2004-05-13 Vita Cientifica, S.L. Process for preparing a pharmaceutically active compound and for preparing its intermediate
WO2007069265A1 (en) * 2005-12-12 2007-06-21 Unichem Laboratories Limited A novel process for the synthesis of lamotrigine and its intermediate

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103570637A (en) * 2013-09-13 2014-02-12 盐城凯利药业有限公司 Preparation method of lamotrigine

Similar Documents

Publication Publication Date Title
KR101357664B1 (en) METHOD FOR PREPARING 4β-AMINO-4'-DEMETHYL-4-DESOXYPODOPHYLLOTOXIN
JP4268871B2 (en) Method for producing pyrimidinone compounds and pharmaceutically acceptable salts thereof
US20160108053A1 (en) Processes for making ponatinib and intermediates thereof
WO2009069073A1 (en) An improved process for the preparation of lamotrigine
US20160214987A1 (en) Method for preparing an intermediate for producing high-purity pemetrexed and method for producing high-purity pemetrexed using the intermediate
EP1140872B1 (en) An improved process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine
Gardiner et al. Synthesis of 1-alkoxy-2-alkyl-benzimidazoles from 2-nitroanilines via tandem N-alkylation-cyclization-O-alkylation
CA2615746C (en) Preparation of 1,7'-dimethyl-2'-propyl-2,5'-bi-1h-benzimidazole
JP2010513410A (en) Preparation of Abacavir
WO2008035378A2 (en) An improved process for the preparation of thalidomide
WO2013059572A1 (en) Process for the preparation of etravirine and intermediates in the synthesis thereof
JP5640283B2 (en) Process for the preparation of pyrimidine derivatives
WO2007069265A1 (en) A novel process for the synthesis of lamotrigine and its intermediate
US10280133B2 (en) Process for the manufacture of 4-aminobenzoamidine dihydrochloride
RU2425038C2 (en) Method of producing 1-[di (4-cyanophenyl)methyl]-1,2,4-triazole
US6680409B2 (en) Process for the preparation of robenidine and salts thereof
CN105111156B (en) 2 amino, 5,5 ' dinitro, 3,3 ' double (1,2,4 triazole) compounds
GB2395483A (en) Crystalline lamotrigine and its monohydrate
Saralaya et al. A collective review of the synthetic approaches disclosed in prior patents to synthesize the renowned drug, Lamotrigine
Srivastava et al. A facile and regioselective 2H-indazol synthesis of t-butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl) piperidine-1-carboxylate and its synthesized derivatives as an antiprotozoal activity.
EP3810600A1 (en) Triazine compounds and uses thereof
US7179913B2 (en) Process for preparing a pharmaceutically active compound and for preparing its intermediate
US3857842A (en) Process for preparing purine compounds by reaction of a carbonitrile with formic acid
JP5004643B2 (en) Process for producing N- (2-amino-1,2-dicyanovinyl) formamidine
KR100392692B1 (en) A Method for the Preparation of Epinastine and a Pharmaceutically Acceptable Salt thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08855642

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08855642

Country of ref document: EP

Kind code of ref document: A1