WO2014057495A1 - Procédé de préparation industrielle de la [(s)-n-tert butoxycarbonyl-3-hydroxy]adamantylglycine - Google Patents

Procédé de préparation industrielle de la [(s)-n-tert butoxycarbonyl-3-hydroxy]adamantylglycine Download PDF

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Publication number
WO2014057495A1
WO2014057495A1 PCT/IN2012/000865 IN2012000865W WO2014057495A1 WO 2014057495 A1 WO2014057495 A1 WO 2014057495A1 IN 2012000865 W IN2012000865 W IN 2012000865W WO 2014057495 A1 WO2014057495 A1 WO 2014057495A1
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WIPO (PCT)
Prior art keywords
compound
temperature
stirring
adamantane
hydroxy
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PCT/IN2012/000865
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English (en)
Inventor
Venkat Reddy Alla
Raghu Mitra ALLA
Ajay Kumar DUBEY
P. Ramakrishna REDDY
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Lee Pharma Limited
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Publication of WO2014057495A1 publication Critical patent/WO2014057495A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the invention relates to a process for industrial preparation of [(S)-n-tert butoxy carbonyl-3- hydroxy]adamantylglycine. More particularly, the invention relates to a commercially viable process for industrial preparation of [(S)-n-tert butoxycarbonyl-3-hydroxy]adamantylglycine which is a key intermediate for saxagliptin synthesis and is represented by compound of Formula- VI.
  • the compound-VI obtained by the process of present invention has more than 99.5% HPLC purity.
  • Saxagliptin is dipeptidyl peptidase-4 (DPP-4) chemically known as (IS, 3S, 5S)-2-((2S)-2-Am o-2- (3 -hydroxyadamantan-l-yl)-acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile and represented by the compound of Formula-A.
  • DPP-4 dipeptidyl peptidase-4
  • Saxagliptin is an oral hypoglycemic drug used for the treatment of Type-2 diabetes and is disclosed in US 6,395,767 alongwith its hydrochloride and trifluoroacetic acid salts. Additionally, US 7,420,079 discloses saxagliptin and its hydrochloride, trifluoroacetic acid and benzoate salts, as well as saxagliptin monohydrate.
  • WO 2005/012249 discloses a process for preparation of the [(S)-n-tert. butoxy carbonyl-3-hydroxy]adamantylglycine represented by a process of Scheme-I comprising an eight step process starting with adamantine- 1 -carboxylic acid.
  • the process disclosed in this prior art comprises esterification of adamantine 1 -carboxylic acid by an asymmetric Strecker reaction using either methanol with hydrochloric acid at reflux temperature or using trimethylsilyldiazomethane in solvent ether /methanol to give the corresponding methyl ester.
  • the ester is reduced with LAH to alcohol and subsequently oxidized to aldehyde.
  • the aldehyde is transformed into corresponding nitrile compound under asymmetric Strecker conditions with KCN, NaHS0 3 and R-(-)-2-phenylglycinol.
  • the nitrile group of the obtained compound is hydrolyzed under strong acidic conditions, using, for example, 12M HC1 in AcOH to give the corresponding carboxylic acids.
  • the chiral auxiliary is removed by catalytic reduction using Pearlman's catalyst to give, after protection of the resulting amino group, protected adamantyl glycine amino acids.
  • process disclosed in this prior art may be useful for lab scale synthesis but it is not commercially viable for industrial scale preparation of the intermediate Compound-VI.
  • the process disclosed in this prior art primarily comprises an eight step process wherein the intermediates obtained in each step are purified by column / flash chromatography which due to its high cost and complexities is not commercially viable for industrial scale preparation of this compound. If used in anyways, the cost of the end product would be very high. Further various steps in the prior art discloses use of either as solvent which due to its highly volatile and hazardous nature is found to be highly difficult and complicated in an industrial scale preparations.
  • Primary object of the invention is to provide a process for industrial preparation of [(S)-n-tert butoxy carbonyl-3-hydroxy] adamantylglycine, a key intermediate for saxagliptin synthesis.
  • Another object of the invention is to provide a simplified, cost effective and commercially viable process for industrial scale preparation of [(S)-n-tert butoxy carbonyl -3- hydroxy]adamantylglycine with more than 99.5% HPLC purity.
  • the process uses adamantine- 1 -carboxilic acid as starting material and comprises following steps: a) , treating adamantine- 1-carboxylic acid with thionyl chloride to obtain adamantane- 1 -carboxylic methyl ester (compound-I);
  • the invention relates to a process for preparation of (a-S)-a-[[l ,l -dimethylethoxy carbonyl]amino]-3-hydroxytricyclo [3.3.1.1 ' ]decane-l -acetic acid, commonly known as [(S)-n- tert butoxy carbony 1-3 -hydroxy] adamantylglycine, represented by Compound- VI.
  • the process broadly comprises six stages which are summarized below. Each stage is described in details hereinafter in later paragraphs.
  • This comprises treating adamantine-l -carboxylic acid with thionyl chloride to obtain adamantine- l-carboxylic methyl ester (compound-I);
  • This comprises reducing adamantine-l-carboxylic methyl ester to obtain adamantine- 1 -methanol (compound-II); .
  • This stage comprises treating adamantine-l-carboxylic acid with thionyl chloride in methanol with stirring at room temperature for 2-6 hours. Removing excess of solvent and thionyl chloride under reduced pressure at temperature between 10-40° C to obtain adamantane- 1-carboxylic methyl ester (compound-I)having more than 95% of GC urity.
  • the process of this stage comprises dissolving compound-II in MDC and adding sodium bi carbonate and KBr at room temperature and cooling the solution to 0 - 5°C and stirring for 15 min; adding TEMPO solution and sodium hypo chloride (1 1% chlorine content) at 0 - 5°C and stirring; adding 10% sodium thio sulphate solution at 0-5°C; slowly raising the temperature to room temperature; separating the organic layer and washing with saturated sodium chloride solution and drying over sodium sulphate; distilling the organic layer under vacuum at below 35°C to get a semi-solid Step-A product with more than 99 % of GC purity; suspending the step-A product in water and cooling the mixture to 0-5°C; treating the mixture with NaHS0 3 and NaCN and a solution of (R)(-)phenyl glycinol in methanol; stirring the resulting mixture at 0-5°C for 10- 15min and then heating to 25-30°C and maintaining at this temperature for 1-2 hrs.
  • Step-B nitrile compound having more than 95% HPLC purity; adding the Step-B nitrile compound in cone.
  • This comprises dissolving compound-Ill in methanol arid acetic acid and hydrogenating with 3 ⁇ 4 and Pearlman's catalyst (10% palladium hydroxide) or Palladium carbon and, maintaining the reaction mass for 10 -12hrs at room temperature; filtering and washing the filter with methanol; completely distilling the methanol and acetic acid under reduced pressure .at below 50° C and co- distilling with n-hexane and stirring at this temperature for 15 minutes and cooling to room temperature and obtaining the amino compound-IV with more than 90% of HPLC purity.
  • This comprises dissolving compound- IV in sodium hydroxide at room temperature and cooling the. temperature to 0 - 5°C and stirring for 15 minutes; adding THF at 0-5°C and maintaining the reaction mass at this temperature for 4-5 hrs.; raising the temperature to room temperature; separating the aqueous layer and washing with n- hexane; cooling the aqueous layer to 0-5°C and adding ethyl acetate; adjusting the pH of reaction mass to 2- 4 with HCl and extracting the aqueous layer with ethyl acetate and washing with saturated sodium chloride solution and drying over sodium sulphate and obtaining compound-V with more than 99% HPLC purity and less than 0.1% impurity.
  • This comprises treating compound-V with potassium permanganate, KOH and TBAB at 20-25° C and stirring at this temperature for 1 hour at 40-45 RPM; maintain the reaction mass at this temperature for 20-25 hrs with intermittent stirring for 15 to 20 seconds after every one hour; adding sodium bi sulphate solution to reduce the oxidizing agent and adjusting the pH to 2-3 with HCl and extracting the reaction mass with MDC; distilling the MDC layer and dissolving the residue in ethyl acetate and isolating the [(S)-n-tert butoxy carbonyl-3-hydroxy] adamantylglycine (compound-VI) with more than 99% HPLC purity and less than 0.1% impurity.
  • Example-3 Oxidation of the adamantane-l-methanol (compound-II) to corresponding aldehyde and hydrolysis of the nitrile to corresponding 2-adamantane-2(R)-2-hydroxy-2- phenylethyl amino acetic acid (compoun -Ill);
  • reaction mass was cooled to 40-45°C, and 1000 mL of ethyl acetate was charged and mixed. After mixing for 15minutes, the layers were separated. The aqueous fraction was extracted with 500mL of ethyl acetate. The combined ethyl acetate layer was washed with l OOOmL saturated sodium chloride solution and dried over anhydrous Na 2 S0 4. Combined organic layer was concentrated under vacuum at below 50°C and 287 g of the desired Step-B nitrile compound having HPLC purity above 95 % was obtained.
  • the 100 g of compound-Ill was dissolved in 1000 mL of methanol and 200 mL of acetic acid and was hydrogenated with 3 ⁇ 4 and Pearlman's catalyst (10% palladium hydroxide 10 g,0.07M) or Palladium carbon and the reaction mass was maintained for 10 -12hrs at room temperature. Upon completion of the reaction, the mass was filtered and the carbon cake was washed with lOOmL of methanol. Methanol and acetic acid combined filtrate was completely distilled under reduced pressure at below 50° C and 100 mL of n-hexane was added to the crude and distilled again.
  • Aqueous and organic layers were separated and aqueous layer was washed with 150mL of n-hexane. Separated aqueous layer was cooled to 0-5°C and 413mL of ethyl acetate was added. The pH was adjusted to 3.0 with 700mL of IN HC1 at 0-5°C. The reaction mixture was stirred for 10- 15 minutes and both layers were separated. Aqueous layer was extracted with 600mL of ethyl acetate and total organic layer was combined and washed with saturated sodium chloride solution and dried over sodium sulphate.
  • Example-6 Oxidation of compound-V to give corresponding hydroxyl derivative[(S)-n-tert butoxy carbonyl-3-hydroxy] adamantyl glycine (compound-VI) in presence of phase transfer catalyst.
  • DM water refers to demineralized water.
  • MDC refers to methylene dichloride
  • TBAB Tetra Butyl Ammonium Bromide
  • OH refers to potassium hydroxide
  • THF Tetra hydro furan
  • TLC refers to Thin Layer chromatography
  • Di hydroxy impurity refers to ((alphaS)-alpha-[ [(1 ,1 -Dimethylethoxy)carbonyl] amino] -3,5- Dihydroxytricyclo[3.3.1.1 3 ' 7 ] decane-1 -acetic acid
  • R - Isomer refers to (R)-N-boc-3-hydroxyadamant- l -yl glycine

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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 porte sur un procédé viable de préparation industrielle de la [(s)-n-tert butoxycarbonyl-3-hydroxy]adamantylglycine qui est un produit intermédiaire clé pour la synthèse de la saxagliptine et constitue un composé représenté par la formule-VI. Le composé-VI obtenu par le biais du procédé faisant l'objet de la présente invention est caractérisé par une pureté CLHP de 99,5 %, une impureté dihydroxy de 0,15 % ou moins, une impureté isomère de 0,05 % ou moins et des impuretés inconnues de 0,1 % ou moins. Formule (VI).
PCT/IN2012/000865 2012-10-11 2012-12-31 Procédé de préparation industrielle de la [(s)-n-tert butoxycarbonyl-3-hydroxy]adamantylglycine WO2014057495A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN4256/CHE/2012 2012-10-11
IN4256CH2012 2012-10-11

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WO2014057495A1 true WO2014057495A1 (fr) 2014-04-17

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104098487A (zh) * 2014-07-31 2014-10-15 天津民祥生物医药科技有限公司 一种n-叔丁氧羰基-3-羟基-1-金刚烷基甘氨酸的制备方法
CN104817476A (zh) * 2015-03-25 2015-08-05 重庆医科大学 一种制备非天然氨基酸的方法
CN106568849A (zh) * 2015-10-10 2017-04-19 深圳翰宇药业股份有限公司 一种沙格列汀中有关物质的检测方法
CN113666846A (zh) * 2021-08-31 2021-11-19 济南立德医药技术有限公司 沙格列汀中间体的合成方法
GB2595768A (en) * 2020-09-08 2021-12-08 Hangzhou Junling Pharmaceutical Tech Co Ltd A synthesis method of saxagliptin intermediate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
WO2005012249A2 (fr) 2003-08-01 2005-02-10 Bristol-Myers Squibb Company Inhibiteurs a base d'adamantyglycine de la dipeptidyl peptidase iv et procedes associes
US7420079B2 (en) 2002-12-09 2008-09-02 Bristol-Myers Squibb Company Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US7420079B2 (en) 2002-12-09 2008-09-02 Bristol-Myers Squibb Company Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof
WO2005012249A2 (fr) 2003-08-01 2005-02-10 Bristol-Myers Squibb Company Inhibiteurs a base d'adamantyglycine de la dipeptidyl peptidase iv et procedes associes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BRIAN S. BODNAR ET AL: "An Improved Bouveault-Blanc Ester Reduction with Stabilized Alkali Metals", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 74, no. 6, 20 March 2009 (2009-03-20), pages 2598 - 2600, XP055068706, ISSN: 0022-3263, DOI: 10.1021/jo802778z *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104098487A (zh) * 2014-07-31 2014-10-15 天津民祥生物医药科技有限公司 一种n-叔丁氧羰基-3-羟基-1-金刚烷基甘氨酸的制备方法
CN104817476A (zh) * 2015-03-25 2015-08-05 重庆医科大学 一种制备非天然氨基酸的方法
CN104817476B (zh) * 2015-03-25 2020-09-11 重庆医科大学 一种制备非天然氨基酸的方法
CN106568849A (zh) * 2015-10-10 2017-04-19 深圳翰宇药业股份有限公司 一种沙格列汀中有关物质的检测方法
GB2595768A (en) * 2020-09-08 2021-12-08 Hangzhou Junling Pharmaceutical Tech Co Ltd A synthesis method of saxagliptin intermediate
CN113666846A (zh) * 2021-08-31 2021-11-19 济南立德医药技术有限公司 沙格列汀中间体的合成方法

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