WO2010079405A2 - An improved process for preparing 1-(pentanoylamino)cyclopentanecarboxylic acid - Google Patents

An improved process for preparing 1-(pentanoylamino)cyclopentanecarboxylic acid Download PDF

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WO2010079405A2
WO2010079405A2 PCT/IB2009/055960 IB2009055960W WO2010079405A2 WO 2010079405 A2 WO2010079405 A2 WO 2010079405A2 IB 2009055960 W IB2009055960 W IB 2009055960W WO 2010079405 A2 WO2010079405 A2 WO 2010079405A2
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pentanoylamino
acid
cyclopentanecarboxylic acid
reacting
preparation
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PCT/IB2009/055960
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French (fr)
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WO2010079405A3 (en
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Ravi Ponnaiah
Sanjay Desai
Dhiraj Rathod
Chirag Parikh
Ramesh Mokal
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Alembic Limited
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Publication of WO2010079405A3 publication Critical patent/WO2010079405A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to an improved process for preparing l-(pentanoylamino)cyclopentanecarboxylic acid formula (I) which is useful intermediate for the preparation of Irbesartan.
  • Irbesartan is l-Butyl-S-CP'-ClH-tetrazol-S-yOClJ'-biphenyll- ⁇ yllmethyll-l ⁇ -diazaspiroK ⁇ non-l- en-4-one and formula is C 2S H 2S N 6 O and molecular weight is 428.53.
  • the current pharmaceutical product containing this drug is being sold by Sanofi Synthelabo using the tradename AVAPRO, in the form of tablets.
  • Irbesartan is useful in the treatment of diabetic nefropathy, heart failure therapy and hypertension.
  • Irbesartan is angiotension II type I (AIIi )-recep tor antagonist.
  • An- giotension II is the principal pressor agent of the rennin- angiotension system and also stimulates aldosterone synthesis and secretion by adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system and smooth muscle cell growth.
  • Irbesartan blocks the vasoconstrictor and aldosterone- secreting effects of angiotension II by selectively binding to the AT 1 angiotension II receptor.
  • [H] l-(pentanoylamino)cyclopentanecarboxylic acid (I) is useful intermediate in the preparation of Irbesartan. The present invention provides an improved process for the pareparation of this intermediate.
  • US 5270317 disclose process for preparation of 1-Aminocyclopentanenitrile by reacting cyclopentanone with sodium cyanide in the presence of ammonium chloride in water and 20% aqueous ammonia.
  • Canadian Patent No. 2050769 provides a process for the preparation of intermediate l-(pentanoylamino)cyclopentanecarboxylic acid (I) and preparation of Irbesartan from this intermediate.
  • the synthetic scheme is as given below.
  • This process comprises the steps of protecting carboxylic group present on cy- clopentane ring which is deprotected in consecutive step by vigourous hydrogenation condition in autoclave which is operationally difficult at a large scale.
  • WO2005113518 discloses the process of preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I) and subsequently Irbesartan by condensing 1-amino-cyclopentanecarboxylic acid with valeroyl chloride in presence of inorganic or organic base to give l-(pentanoylamino)cyclopentanecarboxylic acid (I).
  • This compound is further condensed with 2-(4-aminomethyl phenyl) benzonitrile using dicyclocarbodiimide (DCC) and 1 -hydroxy benzotriazole as catalyst to give an open chain intermediate which is then cyclized in the presence of an acid to give cyano derivative which in turn is converted to Irbesartan by treating it with tributyl tin chloride and sodium azide.
  • DCC dicyclocarbodiimide
  • 1 -hydroxy benzotriazole as catalyst to give an open chain intermediate which is then cyclized in the presence of an acid to give cyano derivative which in turn is converted to Irbesartan by treating it with tributyl tin chloride and sodium azide.
  • Farmaco-Ed. Sc.-vol XXI. FASC.9 discloses a process for preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I) according the below given scheme.
  • US Patent No. 7038060 also discloses the process of preparation of Irbesartan from
  • an object of the present invention is to provide an improved process for the preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I).
  • Another object of the present invention is to provide an improved process for the preparation of Irbesartan using l-(pentanoylamino)cyclopentanecarboxylic acid (I).
  • Another object of the present invention is to provide a process for preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I) which is simple and easy to handle at an industrial scale.
  • Another object of the present invention is to provide a process for preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I) in which amide impurity (a) is less than 0.5%.
  • amide impurity (a) is less than 0.5%.
  • the present invention provides an improved process of preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I)
  • the present invention provides an improved process of preparation of Irbesartan
  • step (iii) reacting N-(l-cyanocyclopentyl)pentanamide (V) obtanined in step (ii) with hydrochloric acid and acetic acid to give l-(pentanoylamino)cyclopentanecarboxylic acid
  • the present invention provides an improved process of preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I)
  • l-(pentanoylamino) cyclopentanecarboxylic acid (I) is converted to Irbesartan by the methods known in the art.
  • l-(pentanoylamino) cyclopentanecarboxylic acid (I) is reacted with 2-(4-aminomethyl phenyl) benzonitrile in the presence of DCC to give condensed intermediate.
  • the corresponding intermediate is cyclized in presence of acid and then the formed cyano irbesartan is converted to Irbesartan by reacting it with sodium azide to form tetrazole moiety.
  • N ⁇ l-cyanocyclopentyOpentanamide (V) [148] 1-aminocyclopenatne carbonitrile (30.0 g) in dichloromethane (180 ml) was cooled to 1O 0 C. Triehtyl amine (24 ml) was added to the reaction mixture and stirred. Valeroyl chloride (32.8 ml) was added at 5 0 C to 1O 0 C and stirred at the same temperature for 2 hrs. The reaction mixture was further stirred at room temperature for 1 hour. DM Water was charged to the reaction mixture and organic layer was separated. The organic layer was evaporated to dryness to get N-(l-cyanocyclopentyl) pentanamide (V) as an oil (30.0g).
  • N-(l-cyanocyclopentyl) pentanamide (V) (30.0 g) obtained in example-2 is mixed with reacts with cone, hydrochloric acid (30.0 ml), water (60.0 ml), acetic acid (10.0 ml) and heated at 6O 0 C for about 24 hrs.
  • the reaction mixture is cooled to room temperature and maintain for 1 hour.
  • the solid product is filtered and washed with water.
  • the product is suck dried and dried in oven under reduced pressure to give 1- (pentanoylamino) cyclopentanecarboxylic acid (I) (24.0 g).

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

Abstract

The present invention relates to an improved process for preparing 1-(pentanoylamino)cyclopentanecarboxylic acid formula (I) which is useful intermediate for the preparation of Irbesartan.

Description

Description
Title of Invention: AN IMPROVED PROCESS FOR PREPARING 1-(PENTANOYLAMINO)CYCLOPENTANECARBOXYLIC
ACID
Field of the invention:
[1]
[2] The present invention relates to an improved process for preparing l-(pentanoylamino)cyclopentanecarboxylic acid formula (I) which is useful intermediate for the preparation of Irbesartan.
Figure imgf000002_0001
[5]
Background of the invention:
[6]
[7] The chemical name of Irbesartan is l-Butyl-S-CP'-ClH-tetrazol-S-yOClJ'-biphenyll-^yllmethyll-l^-diazaspiroK^non-l- en-4-one and formula is C2SH2SN6O and molecular weight is 428.53. The current pharmaceutical product containing this drug is being sold by Sanofi Synthelabo using the tradename AVAPRO, in the form of tablets.
[8]
[9] Irbesartan is useful in the treatment of diabetic nefropathy, heart failure therapy and hypertension. Irbesartan is angiotension II type I (AIIi )-recep tor antagonist. An- giotension II is the principal pressor agent of the rennin- angiotension system and also stimulates aldosterone synthesis and secretion by adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system and smooth muscle cell growth. Irbesartan blocks the vasoconstrictor and aldosterone- secreting effects of angiotension II by selectively binding to the AT1 angiotension II receptor. [10] [H] l-(pentanoylamino)cyclopentanecarboxylic acid (I) is useful intermediate in the preparation of Irbesartan. The present invention provides an improved process for the pareparation of this intermediate.
[12] [13] US 5270317 disclose process for preparation of 1-Aminocyclopentanenitrile by reacting cyclopentanone with sodium cyanide in the presence of ammonium chloride in water and 20% aqueous ammonia.
[14] [15] Canadian Patent No. 2050769 provides a process for the preparation of intermediate l-(pentanoylamino)cyclopentanecarboxylic acid (I) and preparation of Irbesartan from this intermediate. The synthetic scheme is as given below.
[16]
Figure imgf000003_0001
Yellowish oil Irbesartan
[18] [19] This process comprises the steps of protecting carboxylic group present on cy- clopentane ring which is deprotected in consecutive step by vigourous hydrogenation condition in autoclave which is operationally difficult at a large scale.
[20] [21] WO2005113518 discloses the process of preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I) and subsequently Irbesartan by condensing 1-amino-cyclopentanecarboxylic acid with valeroyl chloride in presence of inorganic or organic base to give l-(pentanoylamino)cyclopentanecarboxylic acid (I). This compound is further condensed with 2-(4-aminomethyl phenyl) benzonitrile using dicyclocarbodiimide (DCC) and 1 -hydroxy benzotriazole as catalyst to give an open chain intermediate which is then cyclized in the presence of an acid to give cyano derivative which in turn is converted to Irbesartan by treating it with tributyl tin chloride and sodium azide.
Figure imgf000004_0001
[23] [24] Farmaco-Ed. Sc.-vol XXI. FASC.9 discloses a process for preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I) according the below given scheme.
[25]
Figure imgf000004_0002
[27] [28] In this process 1 -amino cyclopentanecarboxylic acid is reacted with valeroyl chloride in the presence of pyridine to give l-(pentanoylamino)cyclopentanecarboxylic acid (I).
[29] [30] However, pyridine is hazardous reagent and it is not advisable to use at industrial scale because of environment concern. The reaction requires low temperature such as 0 to 50C. Further, in this process dimer impurity forms which is difficult to remove after repeated crystallization.
[31] [32] Synthetic Communication, 37: 2897-2905, 2007 discloses a process for preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I) according the below given scheme.
[33]
Figure imgf000005_0001
1 -amιnocyclopentane N-(i -cyanocyclopentyl) i-(pentanoylamino) carbonitrile pentanamide cyclopentane carboxylic acid
(IV) (V) (!)
[35]
[36] In second step of this process, cyano group is first converted to amide to give amide intermediate (a)
Figure imgf000005_0002
[38]
[39]
[40] which is then further converted acid of formula (I). In the conversion of amide intermediate (a) to l-(pentanoylamino)cyclopentanecarboxylic acid (I), there always remains 4 to 5% amide intermediate (a) unreacted. It leads to presence of unwanted 3-4% amide impurity in the final compound (I) which is difficult to remove after repeated crystallization. The prolonged duration of the reaction time and the excess amount of hydrochloric acid does not reduce the amount of amide intermediate (a) in the final compound (I).
[41]
[42] US Patent No. 7038060 also discloses the process of preparation of Irbesartan from
4-bromomethyl biphenyl 2'-(lH-tetrazol (2-triphenylmethyl) 5-yl) and Ethyl ester of 1-Valeramido cyclopentanecarboxylic acid in toluene in presence of base and PTC, and then hydrolyzing the protecting group. However this requires chromatographic purification.
[43]
[44] All the above patents/applications are incorporated herein as reference.
[45]
[46] It is therefore, a need to develop a process which not only overcomes the disadvantages of the prior art but also economical, operationally simple and industrially applicable.
[47]
[48] Present inventors have directed their research work towards developing a process for the preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I) which is devoid of the above disadvantages. The present inventors found that when N- (l-cyanocyclopenty^pentanamide (V) is hydrolyzed with hydrochloric acid alone, the unreacted amide intermediate (a) in remains 4 to 5% in final compound (I). Whereas when it is hydrolyzed in the presence of combination of hydrochloric acid and acetic acid, the amount of unreacted amide intermediate (a) reduces to less than 0.5% in the final compound l-(pentanoylamino)cyclopentanecarboxylic acid (I). [49]
Summary of the invention: [50] [51] It is therefore an object of the present invention is to provide an improved process for the preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I). [52] [53] Another object of the present invention is to provide an improved process for the preparation of Irbesartan using l-(pentanoylamino)cyclopentanecarboxylic acid (I). [54] [55] Another object of the present invention is to provide a process for preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I) which is simple and easy to handle at an industrial scale. [56] [57] Another object of the present invention is to provide a process for preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I) in which amide impurity (a) is less than 0.5%. [58] [59] Accordingly, present invention provides an improved process of preparation of
1 - (pentanoylamino)cyclopentanecarboxylic acid(I) .
Figure imgf000006_0001
(I)
[61] [62] comprising a step of reacting N-(l-cyanocyclopentyl)pentanamide (V) [63]
Figure imgf000006_0002
(V)
[65]
[66] with hydrochloric acid and acetic acid to give l-(pentanoylamino)cyclopentanecarboxylic acid (I). [68] The present invention provides an improved process of preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I)
Figure imgf000007_0001
(I)
[70] having an amide impurity (a) less than 0.5% [71]
Figure imgf000007_0002
(a)
[73] [74] comprising a step of reacting N-(l-cyanocyclopentyl)pentanamide (V) [75]
Figure imgf000007_0003
[77] [78] with hydrochloric acid and acetic acid to give l-(pentanoylamino)cyclopentanecarboxylic acid (I)
[79] [80] The present invention provides an improved process of preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I)
Figure imgf000007_0004
(I)
[82] [83] comprising steps of: [84] (i) reacting cyclopentanone (III)
Figure imgf000007_0005
(III)
[86] [87] with sodium cyanide in the presence of ammonium chloride and solvent dichloromethane to obtain 1-aminocyclopentane carbonitrile (IV)
Figure imgf000008_0001
[89] [90] (ii) reacting 1-aminocyclopentane carbonitrile (IV) obtained in step (i) with valeroyl chloride in the presence of triethylamine and dichloromethane to obtain N- ( 1 -cyanocyclopenty^pentanamide (V)
Figure imgf000008_0002
[92] [93] (iii) reacting N-(l-cyanocyclopentyl)pentanamide (V) obtanined in step (ii) with hydrochloric acid and acetic acid to give l-(pentanoylamino)cyclopentanecarboxylic acid (I).
[94] [95] The present invention provides an improved process of preparation of Irbesartan
Figure imgf000008_0003
[97] [98] comprising steps of: [99] (i) reacting cyclopentanone (III)
Figure imgf000008_0004
(III)
[101]
[102] with sodium cyanide in the presence of ammonium chloride and solvent dichloromethane to obtain 1-aminocyclopentane carbonitrile (IV) [103]
Figure imgf000009_0001
[104]
[105] (ii) reacting 1-aminocyclopentane carbonitrile (IV) obtained in step (i) with valeroyl chloride in the presence of triethylamine and dichloromethane to obtain N-
( 1 -cyanocyclopenty^pentanamide (V)
Figure imgf000009_0002
[107]
[108] (iii) reacting N-(l-cyanocyclopentyl)pentanamide (V) obtanined in step (ii) with hydrochloric acid and acetic acid to give l-(pentanoylamino)cyclopentanecarboxylic acid
(I)
Figure imgf000009_0003
[HO]
Detailed description of the invention:
[111]
[112] The present invention provides an improved process of preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I)
Figure imgf000009_0004
[113] comprising steps of:
[114] (i) reacting cyclopentanone (III)
Figure imgf000009_0005
(III)
[116]
[117] with sodium cyanide in the presence of ammonium chloride and solvent dichloromethane to obtain 1-aminocyclopentane carbonitrile (IV) [118]
Figure imgf000010_0001
[120] [121] (ii) reacting 1-aminocyclopentane carbonitrile (IV) obtained in step (i) with valeroyl chloride in the presence of triethylamine and dichloromethane to obtain N- ( 1 -cyanocyclopenty^pentanamide (V)
[122]
Figure imgf000010_0002
[124] [125] (iii) reacting N-(l-cyanocyclopentyl)pentanamide (V) obtanined in step (ii) with hydrochloric acid and acetic acid to give l-(pentanoylamino)cyclopentanecarboxylic acid (I).
[126] [127] The schematic representation of the present invention is as given below. [128] [129]
Figure imgf000010_0003
i-(pentanoylamιno) cyclopentane carboxylic acid
(I)
[131] [132] sodium cyanide is dissolved in water. An aq. ammonium chloride solution and 20% aq. ammonia solution is added to the reaction mixture. Cyclopentanone in methanol is added to the reaction mixture and stirred for about one and a half hour. The mixture is heated at about 6O0C for about 45 min. The reaction mixture is cooled to 250C and extracted several times with dichloromethane. The combined dichloromethane is dried over sodium sulfate and concentrated under vacuum to give 1-aminocyclopentane carbonitrile (IV) in the form of oil. [133]
[134] 1-aminocyclopenatne carbonitrile in dichlorome thane is cooled at 1O0C and triehtyl amine is added to it. Valeroyl chloride is added to the reaction mixture at about 50C to about 1O0C. The reaction mixer is stirred at the same temperature for about 2 hrs and then further stirred at room temperature for about 1 hrs. DM Water is charged to the reaction mixture and organic layer is separated. The organic layer is evaporated to get N-(l-cyanocyclopentyl)pentanamide (V) as oil. This oil is used for hydrolysis step.
[135]
[136] The oil obtained above is mixed with water, cone, hydrochloric acid and acetic acid and heated at about 6O0C for about 24 hrs. The reaction mixture is cooled to room temperature and maintain for 1 hour. The solid product is filtered and washed with water. The product is suck dried and dried in oven under reduced pressure to give l-(pentanoylamino) cyclopentanecarboxylic acid (I).
[137]
[138] l-(pentanoylamino) cyclopentanecarboxylic acid (I) is converted to Irbesartan by the methods known in the art. l-(pentanoylamino) cyclopentanecarboxylic acid (I) is reacted with 2-(4-aminomethyl phenyl) benzonitrile in the presence of DCC to give condensed intermediate. The corresponding intermediate is cyclized in presence of acid and then the formed cyano irbesartan is converted to Irbesartan by reacting it with sodium azide to form tetrazole moiety.
[139]
[140] The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.
[141]
[142] Example-1
[143] Preparation of 1-aminocyclopentane carbonitrile (IV)
[144] 1.97 g of sodium cyanide are dissolved in 3.9 ml of water in a round-bottomed flask and a solution containing 2.33 g of ammonium chloride in 5.9 ml of water and 3.5 ml of 20% aqueous ammonia is added; finally, 3 g of cyclopentanone in 3.8 ml of methanol are added to the flask. After stirring for 1 and a half hours, the mixture is heated at 6O0C for 45 minutes, heating is then stopped, stirring is continued for 45 minutes and the mixture is then cooled to 250C It is extracted several times with dichloromethane. The extracts are dried over sodium sulfate, filtered and concentrated under vacuum to give 1-aminocyclopentane carbonitrile (IV) in the form of oil (4 g).
[145]
[146] Example-2
[147] Preparation of N^l-cyanocyclopentyOpentanamide (V) [148] 1-aminocyclopenatne carbonitrile (30.0 g) in dichloromethane (180 ml) was cooled to 1O0C. Triehtyl amine (24 ml) was added to the reaction mixture and stirred. Valeroyl chloride (32.8 ml) was added at 50C to 1O0C and stirred at the same temperature for 2 hrs. The reaction mixture was further stirred at room temperature for 1 hour. DM Water was charged to the reaction mixture and organic layer was separated. The organic layer was evaporated to dryness to get N-(l-cyanocyclopentyl) pentanamide (V) as an oil (30.0g).
[149]
[150] Example-3
[151] Preparation of 1 - (pentanoylamino) cyclopentane carboxylic acid
[152] N-(l-cyanocyclopentyl) pentanamide (V) (30.0 g) obtained in example-2 is mixed with reacts with cone, hydrochloric acid (30.0 ml), water (60.0 ml), acetic acid (10.0 ml) and heated at 6O0C for about 24 hrs. The reaction mixture is cooled to room temperature and maintain for 1 hour. The solid product is filtered and washed with water. The product is suck dried and dried in oven under reduced pressure to give 1- (pentanoylamino) cyclopentanecarboxylic acid (I) (24.0 g).
[153] Purity by HPLC: 99%

Claims

Claims
[Claim 1] 1. A process of preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I)
Figure imgf000013_0001
(I) comprising a step of reacting N-(l-cyanocyclopentyl)pentanamide (V)
Figure imgf000013_0002
(V) with hydrochloric acid and acetic acid to give l-(pentanoylamino)cyclopentanecarboxylic acid (I).
[Claim 2] 2. A process of preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I)
Figure imgf000013_0003
(I) having an amide impurity (a) less than 0.5%
Figure imgf000013_0004
(a) comprising a step of reacting N-(l-cyanocyclopentyl)pentanamide (V)
Figure imgf000013_0005
(V) with hydrochloric acid and acetic acid to give l-(pentanoylamino)cyclopentanecarboxylic acid (I).
[Claim 3] 3. A process of preparation of l-(pentanoylamino)cyclopentanecarboxylic acid (I)
Figure imgf000013_0006
(I) comprising steps of:
(i) reacting cyclopentanone (III)
Figure imgf000014_0001
(III) with sodium cyanide in the presence of ammonium chloride and solvent dichloromethane to obtain 1-aminocyclopentane carbonitrile
(IV)
Figure imgf000014_0002
(ii) reacting 1-aminocyclopentane carbonitrile (IV) obtained in step (i) with valeroyl chloride in the presence of triethylamine and dichloromethane to obtain N-(l-cyanocyclopentyl)pentanamide (V)
Figure imgf000014_0003
(iii) reacting N-(l-cyanocyclopentyl)pentanamide (V) obtanined in step (ii) with hydrochloric acid and acetic acid to give l-(pentanoylamino)cyclopentanecarboxylic acid (I).
[Claim 4] 4. A process of preparation of Irbesartan
Figure imgf000014_0004
comprising steps of:
(i) reacting cyclopentanone (III)
Figure imgf000014_0005
(III) with sodium cyanide in the presence of ammonium chloride and solvent dichloromethane to obtain 1-aminocyclopentane carbonitrile
(IV)
Figure imgf000015_0001
(IV)
(ii) reacting 1-aminocyclopentane carbonitrile (IV) obtained in step (i) with valeroyl chloride in the presence of triethylamine and dichloromethane to obtain N-(l-cyanocyclopentyl)pentanamide (V)
Figure imgf000015_0002
(iii) reacting N-(l-cyanocyclopentyl)pentanamide (V) obtanined in step (ii) with hydrochloric acid and acetic acid to give l-(pentanoylamino)cyclopentanecarboxylic acid (I)
Figure imgf000015_0003
(I)
[Claim 5] 5. A process of preparation of Irbesartan
Figure imgf000015_0004
comprising a step of reacting N-(l-cyanocyclopentyl)pentanamide (V)
Figure imgf000015_0005
with hydrochloric acid and acetic acid to give l-(pentanoylamino)cyclopentanecarboxylic acid (I)
Figure imgf000015_0006
(I)
PCT/IB2009/055960 2009-01-06 2009-12-28 An improved process for preparing 1-(pentanoylamino)cyclopentanecarboxylic acid WO2010079405A2 (en)

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
E.C. HORNING ET AL: 'alpha-Phenylglutaric Anhydride' ORGANIC SYNTHESES, COLL. vol. 4, 1963, page 790 *
RAO, KORRAPATI V. V. PRASADA ET AL.: 'Improved methods for the synthesis of irbesartan, an antihypertensive active pharmaceutical ingredient' SYNTHETIC COMMUNICATIONS vol. 37, no. 17, 2007, pages 2897 - 2905 & DATABASE CASREACT STN Database accession no. 147:486388 *

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