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WO2007135533A1 - Procédé de préparation de cristaux de natéglinide de type b - Google Patents

Procédé de préparation de cristaux de natéglinide de type b Download PDF

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Publication number
WO2007135533A1
WO2007135533A1 PCT/IB2007/001301 IB2007001301W WO2007135533A1 WO 2007135533 A1 WO2007135533 A1 WO 2007135533A1 IB 2007001301 W IB2007001301 W IB 2007001301W WO 2007135533 A1 WO2007135533 A1 WO 2007135533A1
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WIPO (PCT)
Prior art keywords
process according
nateglinide
formula
trans
solvent
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2007/001301
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English (en)
Inventor
Brajesh Kumar Sinha
Pandu Ranga Rao Vaddi
Sankar Reddy Budidet
Ramesh Dandala
Sivakumaran Meenakshisunderam
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Aurobindo Pharma Ltd
Original Assignee
Aurobindo Pharma Ltd
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Filing date
Publication date
Application filed by Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Publication of WO2007135533A1 publication Critical patent/WO2007135533A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to an improved process for preparing essentially B-type crystals of (-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D- phenylalanine of Formula I.
  • Nateglinide is an antidiabetic drug. Nateglinide is being marketed under the name STARLIX as an oral tablet.
  • RE 34,878 discloses a method of preparing Nateglinide in example 31.
  • the process comprises hydrogenating cumic acid to produce a cis/trans mixture of 4-isopropylcyclohexane carboxylic acid, wherein the cis isomer is in 3 parts and trans isomer in 1 part.
  • This mixture is esterified and treated with sodium hydride to increase the trans isomer ratio to 6 parts to 1 part of cis isomer.
  • This product is hydrolysed and coupled with D-phenylalanine methyl ester.
  • the resulting product is desterif ⁇ ed to give Nateglinide.
  • the process is as shown below:
  • the above process is a multistep process, with low yields and poor quality of the Nateglinide. Further, technology involved in some of the steps of above process are tedious to work-up.
  • US 5,463,116 discloses a process to prepare Nateglinide B-type crystals in comparative example A2, which comprises dissolving Nateglinide in a mixture of ethanol and water at 30 0 C and further cooling the reaction mass to 5 0 C. The resulting precipitated crystals were filtered and dried at 9O 0 C under reduced pressure overnight to yield Nateglinide B-type crystals.
  • EP 1 535 900 Al discloses a process to prepare Nateglinide, by reacting D-phenylalanine methyl ester or a salt thereof with trans-4-isopro ⁇ yl cyclohexane carboxylic acid in presence of an acyl chloride in a water-miscible organic solvent or water non-miscible organic solvent to give Nateglinide methylester.
  • Nateglinide methylester thus obtained was hydrolysed to Nateglinide and further converted to sodium salt of Nateglinide.
  • the sodium salt was further converted to Nateglinide hydrochloride salt by treating with an hydrochloric acid at room temperature, preferably in the temperature range from 5 0 C to 20 0 C, such that Nateglinide in the pure B-type precipitates therefrom.
  • This process uses a toxic reagent thionyl chloride, which is corrosive, moisture sensitive and not eco-friendly.
  • WO 2004/018408 Al discloses a process to prepare Nateglinide, by reacting trans-4- isopropyl cyclohexyl carboxylic acid in acetone with alkyl chloroformate in the presence of triethylamine to give a solution of trans-4-isopropyl cyclohexyl carboxylic acid alkylformate and was reacted with alkali solution of D-phenylalanine to give Nateglinide and is further purified and then converted to H-type crystals.
  • the yields of pure Nateglinide B-type crystals are in the range of 50-60 %. This B-type crystals are further converted in to H-type crystals with an average yield of 45 %.
  • Nateglinide B-type crystals which comprises drying solvated materials containing Nateglinide hydrates obtained by crystallizing out from a Nateglinide containing solution under cooling at a temperature of 50 0 C or lower until no solvent remains and heating the resultant at a temperature of 60 to 11O 0 C to yield Nateglinide B-type crystals.
  • WO 2005/113485 Al claims a process to prepare Nateglinide B-type crystals, which comprises dissolving Nateglinide in an alcohol or ketone solvent and adding the Nateglinide solution to hydrocarbon liquid at temperatures 40 to 45°C and thereafter adding water and cooling the reaction mass to yield Nateglinide B-type crystals.
  • the objective of the present invention is to provide an improved process for preparing Nateglinide.
  • In yet another objective of the present invention is to provide a process for the manufacture of pure Nateglinide B-type crystals free from other crystals.
  • the present invention provides a process for preparing essentially B- type crystals of Nateglinide of Formula I,
  • An embodiment of the present invention relates to an improved process for preparing Nateglinide of Formula I,
  • Figure 1 is a DSC thermogram of wet Nateglinide
  • Figure 2 is a DSC thermogram of wet Nateglinide in cold heptane slurry
  • Figure 3 is a DSC thermogram of wet Nateglinide after drying at less than 4O 0 C wherein the moisture content is above 7 % w/w.
  • Figure 4 is a DSC thermogram of wet Nateglinide after drying at 55-65°C wherein the moisture content is less than 5 % w/w
  • Figure 5 is a DSC thermogram of Nateglinide after drying at 80-90 0 C, which corresponds to B-type crystals.
  • the trans-4-isopropylcyclohexane carboxylic acid of Formula II is treated with a alkali base and a solvent, which is selected from toluene, acetone and mixtures thereof.
  • the obtained product is treated with pivaloyl chloride to obtain trans-4-isopropylcyclohexyl pivalic anhydride of Formula III.
  • the alkali base is selected from sodium hydroxide or potassium hydroxide.
  • the base can be added as such or as an aqueous solution.
  • the reaction is carried out at 0-30 0 C, preferably at 20-30°C.
  • trans-4-isopropylcyclohexyl pivalic anhydride of Formula III may be isolated from the reaction mass or can be directly treated with D- phenylalanine solution of Formula IV in the presence of alkali base at pH 10.0-14.0 and at 10-40 0 C to produce Nateglinide of Formula I.
  • the pH is at 11-13 and temperature at 20-30 0 C.
  • the Nateglinide isolated by the above process is free from H-type crystals and is further purified and dried to yield a single form preferably B-type crystals.
  • Nateglinide produced as per the process of the present invention is free of 2-[2-[(Trans-4-isopropylcyclohexanecarbonyl)amino]-3-phenylpropionylamino]-3- phenylpropionic acid (IPP) of Formula V,
  • the D-phenylalanine solution is prepared by treating D-phenylalanine with sodium hydroxide in the presence of a solvent and water.
  • the solvent used to prepare sodium salt of D-phenylalanine is acetone.
  • Nateglinide is suspended in a mixture of water and aqueous alkali hydroxide at 30-35 0 C.
  • cold dilute hydrochloric acid is added at 5-10 0 C.
  • the precipitated product is filtered and washed with cold water till it is free of chlorides.
  • This wet product is slurried in cold hydrocarbon solvent and stirred at 0-10 0 C for 2 h.
  • the solid product is filtered, washed with cold hydrocarbon solvent and dried at different temperatures so as to yield exclusively B-type crystals.
  • the hydrocarbon solvent is selected from substituted or unsubstituted cyclic or acyclic Cs to Ci 0 alkyl, such as hexane, heptane, cycloheptane, cyclohexane and mixtures thereof.
  • the most preferred hydrocarbon solvent employed is heptane.
  • the wet product is initially dried at below 40 0 C till the moisture content is above 7 %. Subsequently, the drying temperature is raised to 55-65°C until the moisture content of Nateglinide is below 5%. Then the product is finally dried at temperature range of 60-90 0 C, and more preferably at 80-90 0 C to result in pure Nateglinide B-type crystals substantially free from other crystals.
  • the grade of polymorphic purity of the product obtained by the present process has been evaluated by DSC analysis showing only one peak specific for the B-type crystal of Nateglinide.
  • the present invention allows for providing a process for the preparation of Nateglinide in B-type substantially free from other types of crystals starting from solvated wet Nateglinide that initially shows only one broad endothermic peak ( Figure 1).
  • the wet solvated Nateglinide upon stirring in cold heptane, an endotherm peak attributing to B-type crystals slowly appears along with an intermediate peak at 103-104 °C ( Figure 2).
  • this solvated wet Nateglinide is dried at below 40°C till the moisture content is above 7 % w/w ( Figure 3) and subsequently at 55-65°C until the moisture content is less than 5 % w/w ( Figure 4).
  • this material is further dried at 60-90 0 C wherein all the intermediate endotherm peaks are transformed to give only one single endotherm peak, which is attributed to the B-type crystals ( Figure 5).
  • the major advantage of the process of the present invention is obtaining exclusively B-type crystals in good yields requiring no further chemical purification. Also in the process of the present invention the inventors have observed that wet Nateglinide when stirred with a hydrocarbon solvent B-type crystal seeds were generated thus facilitating the conversion of the remaining polymorphic mixture to exclusively B- type upon drying at various temperature ranges.
  • Trans-4-isopropylcyclohexane carboxylic acid 50 g was dissolved in acetone (300 ml) and treated with 40% w/w aqueous sodium hydroxide solution (30.81 g) at 20-30 0 C. The reaction mass was stirred for 30 min and cooled to 10-15 0 C. Pivaloyl chloride (39 g) was added to the reaction mass at 10-15 0 C and allowed to 20-25 0 C and stirred for 3 h, filtered and washed with acetone (25 ml).
  • the filtrate containing trans-4-isopropylcyclohexyl carboxylic pivalic anhydride was added to the mixture of D- ⁇ henylalanine (53.4 g), DM water (300 ml), acetone (100 ml) and 10% w/w aqueous sodium hydroxide solution (130 g) at 20-25 0 C in 30 min while maintaining the reaction mass pH at 11.5-12.5 with 10% w/w aqueous sodium hydroxide solution (130 g).
  • the reaction mass was stirred for completion of reaction and distilled out acetone under reduced pressure.
  • the residue was diluted with DM water (750 ml) and acidified with 10% w/v aqueous hydrochloric acid till the pH 1.0-2.0.
  • the precipitated product was filtered and washed with DM water (150 ml).
  • the wet product was treated with DM water (2000 ml) followed by n-heptane (1000 ml) and dried to yield Nateglinide as B-type crystals. Yield: 72 g (77.23 %)
  • Trans-4-isopropylcyclohexane carboxylic acid 120 g was dissolved in toluene (600 ml) and treated with 40% w/w aqueous sodium hydroxide solution (74.2 g) at 20-30 0 C.
  • the reaction mass was heated to reflux temperature and water was separated azeotropically.
  • Toluene was distilled out completely from the reaction mass under reduced pressure and cooled to 40-50 0 C.
  • the reaction mass was treated with acetone (480 ml) followed by pivaloyl chloride (90.94 g) at 10-15 0 C.
  • the reaction mass stirred for 5 h for completion of reaction at 25-30°C, filtered and washed with acetone (25 ml).
  • the filtrate containing trans-4-isopropylcyclohexyl carboxylic pivalic anhydride was added to the mixture of D-phenylalanine (128.0 g), DM water (720 ml), acetone (240 ml) and 10% w/w aqueous sodium hydroxide solution (335 g) at 20-30 0 C in 30 min while maintaining the reaction mass pH at 11.5-12.5 with 10% w/w aqueous sodium hydroxide solution (335 g).
  • the reaction mass was stirred for completion of reaction and distilled out acetone under reduced pressure.
  • the residue was diluted with DM water (1800 ml) and acidified with 10% w/v aqueous hydrochloric acid till the pH 1.0-2.0.
  • the precipitated product was filtered and washed with DM water (150 ml).
  • the wet product was treated with DM water (10800 ml) followed by n-heptane (4320 ml) and dried to yield Nateglinide as B-type crystals.
  • the solid product was filtered and washed with cold n-heptane (20 ml).
  • the wet product was dried at 20-40 0 C till 7.2% w/w of moisture content was achieved and then dried at 55-65 0 C till ⁇ 1% w/w of moisture content was achieved.
  • the product was further dried at 80-90 0 C to obtain pure Nateglinide B-type crystals. Yield: 9.5 g
  • the solid product was filtered and washed with cold n-heptane (20 ml).
  • the wet product was dried at 20-40 0 C till 7.2% w/w of moisture content was achieved and then dried at 55-65 0 C till ⁇ 1% w/w of moisture content was achieved.
  • the dry product was mixed with cold n-heptane (70 ml), stirred for 1 h at 0-5°C, filtered, washed with cold n-heptane (20 ml) and dried at 20-40 0 C till constant weight was obtained.
  • the product was further dried at 80-90°C to obtain pure Nateglinide B- type crystals. Yield: 9.0 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

L'invention concerne un procédé amélioré de préparation de (-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phénylalanine de formule I.
PCT/IB2007/001301 2006-05-23 2007-05-10 Procédé de préparation de cristaux de natéglinide de type b Ceased WO2007135533A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN889CH2006 2006-05-23
IN889/CHE/2006 2006-05-23
IN1171/CHE/2006 2006-07-06
IN1171CH2006 2006-07-06

Publications (1)

Publication Number Publication Date
WO2007135533A1 true WO2007135533A1 (fr) 2007-11-29

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7767847B2 (en) 2003-07-10 2010-08-03 Richter Gedeon Vegyeszeti Gyar Rt. Process for the preparation of chirally pure N-(trans-4-is)
CN104402756A (zh) * 2014-11-27 2015-03-11 天方药业有限公司 一种高纯度那格列奈的制备方法
CN109369443A (zh) * 2018-11-05 2019-02-22 扬子江药业集团江苏海慈生物药业有限公司 一种新的那格列奈h晶型的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5463116A (en) * 1991-07-30 1995-10-31 Ajinomoto Co., Inc. Crystals of N- (trans-4-isopropylcyclohexlycarbonyl)-D-phenylalanine and methods for preparing them
US20030229249A1 (en) * 2000-10-24 2003-12-11 Ajinomoto Co. Inc Methods for producing nateglinide B-type crystals
WO2004018408A1 (fr) * 2002-08-26 2004-03-04 Glenmark Pharmaceuticals Limited Synthese et purification de nateglinide
EP1496048A1 (fr) * 2002-04-15 2005-01-12 Ajinomoto Co., Inc. Nouveau cristal de nateglinide
EP1535900A1 (fr) * 2003-11-26 2005-06-01 A.M.S.A. ANONIMA MATERIE SINTETICHE E AFFINI S.p.A. Procédé de production de nateglinide à forme B
WO2005113485A2 (fr) * 2004-05-20 2005-12-01 Dr. Reddy's Laboratories Ltd. Compositions stables de forme b de nateglinide

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5463116A (en) * 1991-07-30 1995-10-31 Ajinomoto Co., Inc. Crystals of N- (trans-4-isopropylcyclohexlycarbonyl)-D-phenylalanine and methods for preparing them
US20030229249A1 (en) * 2000-10-24 2003-12-11 Ajinomoto Co. Inc Methods for producing nateglinide B-type crystals
EP1496048A1 (fr) * 2002-04-15 2005-01-12 Ajinomoto Co., Inc. Nouveau cristal de nateglinide
WO2004018408A1 (fr) * 2002-08-26 2004-03-04 Glenmark Pharmaceuticals Limited Synthese et purification de nateglinide
EP1535900A1 (fr) * 2003-11-26 2005-06-01 A.M.S.A. ANONIMA MATERIE SINTETICHE E AFFINI S.p.A. Procédé de production de nateglinide à forme B
WO2005113485A2 (fr) * 2004-05-20 2005-12-01 Dr. Reddy's Laboratories Ltd. Compositions stables de forme b de nateglinide

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7767847B2 (en) 2003-07-10 2010-08-03 Richter Gedeon Vegyeszeti Gyar Rt. Process for the preparation of chirally pure N-(trans-4-is)
CN104402756A (zh) * 2014-11-27 2015-03-11 天方药业有限公司 一种高纯度那格列奈的制备方法
CN104402756B (zh) * 2014-11-27 2016-08-31 天方药业有限公司 一种高纯度那格列奈的制备方法
CN109369443A (zh) * 2018-11-05 2019-02-22 扬子江药业集团江苏海慈生物药业有限公司 一种新的那格列奈h晶型的制备方法

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