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WO2016083790A1 - Procédé de préparation de canagliflozine - Google Patents

Procédé de préparation de canagliflozine Download PDF

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Publication number
WO2016083790A1
WO2016083790A1 PCT/GB2015/053567 GB2015053567W WO2016083790A1 WO 2016083790 A1 WO2016083790 A1 WO 2016083790A1 GB 2015053567 W GB2015053567 W GB 2015053567W WO 2016083790 A1 WO2016083790 A1 WO 2016083790A1
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WO
WIPO (PCT)
Prior art keywords
formula
process according
compound
canagliflozin
acid
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/GB2015/053567
Other languages
English (en)
Inventor
Dharmaraj Ramachandra Rao
Geena Malhotra
Manjinder Singh Phull
Ashwini Amol Sawant
Kapil Ramesh HIRE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cipla Ltd
Original Assignee
Cipla Ltd
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 Cipla Ltd filed Critical Cipla Ltd
Publication of WO2016083790A1 publication Critical patent/WO2016083790A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a novel process for the preparation of canagliflozin (a compound of formula I), and to novel intermediates which are produced during the course of carrying out the novel process.
  • Diabetes me!!itus is a serious and chronic metabolic disease that is characterized by high blood glucose (hyperglycemia) and affects millions of people world-wide,
  • p ⁇ C ⁇ aryiglucosides that possess known SGLT2 inhibition that are currently in clinical development are canagliflozin, empagliflozin, and ipragliflozin.
  • Formula I or (1 S)-1 ,5-anhydro-1 -[3-[[5-(4-fluorophenyl)-2-thienyl]-methyl]-4-methylphenyl]-D-glucitol is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which exhibits an inhibitor activity, against sodium-dependent glucose transporter being present in the intestine and kidney of mammalian species.
  • SGLT2 sodium-glucose transport protein
  • EP2200606A1 discloses a process for the preparation of compounds having inhibitory activity against sodium-dependent glucose transporter (SGLT2) being present in the intestine or kidney, including canagliflozin and salts thereof.
  • SGLT2 sodium-dependent glucose transporter
  • S. Nomura et al., Journal of Medicinal Chemistry, 2010, Volume 53, Issue 17, Pages 6355-6360 discloses stereoselective C-Glycosylation reactions with aryl zinc reagents applied to the stereoselective synthesis of canagliflozin.
  • the object of the present invention is to provide a novel process for the preparation canagliflozin of formula I.
  • Yet another object of the present invention is to provide a novel process for the preparation of canagliflozin of formula I which proceeds via novel chemical intermediates.
  • Yet another object of the present invention is to provide a novel process for the preparation of novel chemical intermediates.
  • Yet another object of the present invention is to provide a process for the preparation of canagliflozin of formula I which is simple, economical and suitable for industrial scale-up.
  • novel intermediates for the preparation of canagliflozin of formula I there is provided novel intermediates for the preparation of canagliflozin of formula I.
  • the present invention provides a novel process for the preparation of canagliflozin through novel intermediates which are more effective and easy to scale up in commercial batches in a convenient and cost effective manner, in high purity.
  • a novel process through novel intermediates is provided for the preparation of canagliflozin as described hereinafter.
  • Protecting groups and associated deprotection methods are widely used in organic synthesis.
  • Protecting groups are often used to prevent a particular functional group or part of a molecule (e.g., an amine, a carboxylic acid, a hydroxy!, a heterocycle, etc) from reacting under certain reaction conditions.
  • Hydroxyi-protecting groups are among the most commonly used protecting groups and are of great importance in organic synthesis.
  • hydroxyl protecting groups include, but are not limited to, the protecting groups designated as such and disclosed in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, (2007), which is incorporated herein by reference in its entirety.
  • halogen includes chloro, bromo, fluoro and iodo.
  • Yet another aspect of the present invention provides a process for the preparation of a compound of formula I lie,
  • R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicylic, alkoxy, aryloxy, thioalkoxy, thioaryloxy, carboxy, thiocarboxy, carbamate, thiocarbamate, amide, thioamide, carbonyl, thiocarbonyl, urea, and thiourea; M is any metal suitable for forming a Grignard reagent; and X is halide.
  • the compound of formula lllc depicted in Scheme 1 hitherto is a novel intermediate useful in the process for the preparation of canagliflozin as described herein.
  • a compound of formula lllc optionally for use as an intermediate in the preparation of canagliflozin.
  • R is H or lower alkyl, such as Ci -6 alkyl.
  • Suitable Grignard reagents which may be employed in the Grignard reaction step of the present invention are commercially available and/or may be prepared according to conventional methods in the art.
  • Non-limiting examples include tert-butyl magnesium chloride, tert-buty! magnesium bromide, tert-amyl magnesium chloride, tert-amyl magnesium bromide, 1 ,1 -diethylpropy! magnesium chloride, 1-meihylcydopeniyl magnesium chloride and 1-metbyicyclohexyimagnesiisrn chloride, Sec-butyl magnesium chloride, ethyl magnesium bromide, methyl magnesium bromide, vinyl magnesium bromide, ally!
  • Suitable metal ion complexes which may be employed in the Grignard reaction step of the present invention include, but are not limited to, n-butyl lithium, sec butyl lithium, hexyl lithium, and the like.
  • Suitable organic solvents which may be employed in the Grignard reaction step of the present invention include, but are not limited to, one or more of toluene, tetrahydrofuran (THF), diethyl ether, diglyme, methyl t-buiyl ether, and the like.
  • the Grignard reaction step of the present invention is typically carried out at a temperature in the range of from about -60°C to about 60°C.
  • Non-limiting examples of suitable reducing reagents which may be employed in the processes of the present invention include, but are not limited to, silane reagents such as triethyl silane and triisopropylsilane; borohydrides, such as sodium borohydride (NaBH 4 ), potassium borohydride (KBH 4 ), zinc borohydride (Zn(BH 4 ) 2 ), sodium cyanoborohydride (NaBH 3 CN) and sodium triacetoxyborohydride; and aluminum hydrides such as lithium aluminum hydride.
  • silane reagents such as triethyl silane and triisopropylsilane
  • borohydrides such as sodium borohydride (NaBH 4 ), potassium borohydride (KBH 4 ), zinc borohydride (Zn(BH 4 ) 2 ), sodium cyanoborohydride (NaBH 3 CN) and sodium triacetoxyborohydride
  • aluminum hydrides such as lithium aluminum hydride.
  • Suitable Lewis acids which may be employed in the processes of the present invention include boron trifiuoride etherate, trimethylsiiyi trif!ate, titanium tetrachloride, tin tetrachloride, hydrochloric acid, toluenesuifonic acid, trifiuoroacetic acid, acetic acid, and the like.
  • Suitable organic solvents which may be employed in the reduction step of the present invention to obtain the compound of formula II include, but are not limited to, one or more of ethers, nitriles, halogenated solvents, dimethylformamide, dimethyl sulfoxide, or any mixture thereof.
  • the reduction reaction to obtain the compound of formula II is typically carried out at a temperature in the range of from about -40°C to about 60°C.
  • the deprotection step to obtain canagliflozin of formula I may be undertaken using conventional methods.
  • the compound of formula II may be treated with a suitable deprotection reagent such as a base or an acid in a suitable solvent.
  • the base may be an anhydrous base such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide or the like.
  • Suitable solvents include alcoholic solvents, preferably methanol, and the like.
  • Non-limiting examples of reagents which may be employed for the (keto) reduction of the compound of formula Vld to obtain the compound of formula IVd-l in accordance with the present invention include borohydrides, such as sodium borohydride (NaBH 4 ); potassium borohydride (KBH 4 ); zinc borohydride (Zn(BH 4 ) 2 ); sodium cyanoborohydride (NaBH 3 CN); sodium triacetoxyborohydride; and aluminum hydrides, such as lithium aluminum hydride and the like.
  • Suitable solvents which may be employed in the (keto) reduction step to obtain the compound of formula IVd-l include, but are not limited to, one or more of alcohols, esters, ethers, nitriles, tetrahydrofuran (THF), water, halogenated solvents, dimethylformamide, dimethyl sulfoxide, sulfolane, or any mixture thereof.
  • the (keto) reduction step is typically carried out at a temperature in the range of from about 0°C to about 100°C.
  • Suitable acids which may be employed for the esterification step to obtain the compound of formula IVd-2 include, but are not limied to, sulfuric acid, p-toluene sulfonic acid, methane sulfonic acid, methane disulfonic acid, benzenesulfonic acid, methanesulfonic acid, and the like.
  • Suitable solvents which may be employed in the esterification step to obtain the compound of formula IVd-2 include, but are not limited to, one or more of alcohols, esters, ethers, nitriles, tetrahydrofuran (THF), water, halogenated solvents, dimethylformamide, dimethyl sulfoxide, sulfolane, or any mixture thereof.
  • the esterification step is typically carried out at a temperature in the range of from about 0°C to about 100°C.
  • a compound of formula Vila is coupled with a compound of formula Via to obtain a compound of formula Va, which is then subjected to reduction to obtain a compound of formula IVa.
  • the compound of formula IVa is condensed with a compound of formula Villa to obtain a compound of formula Ilia.
  • the compound of formula Ilia is subsequently reduced and deprotected to obtain canagliflozin of formula I.
  • Compound of formula Via is obtained by esterification of compound of formula IXa.
  • R 2 , R 3 andR 4 are hydroxyl protecting groups and is halogen.
  • the compounds of formulae IVa and Va are hitherto novel intermediates useful in the process for the preparation of canagliflozin as described herein.
  • a compound of formula IVa or of formula Va optionally for use as an intermediate in the preparation of canagliflozin.
  • a compound of formula Vila is coupled with a compound of formula Vb to obtain a compound of formula IVb, which is then subjected to reduction to obtain a compound of formula 1Mb.
  • the compound of formula 1Mb is subsequently condensed with compound of formula VIb to obtain a compound of formula lib, which is finally deprotected to obtain canagliflozin of formula I.
  • R 2 , R 3 and R4 are hydroxyl protecting groups, and and X 2 are halogen.
  • Example 1 Preparation of Compound of Formula-lllc Part-A: To a reaction mixture of 100 gm (0.2540 moles) compound of Formula-IV-c in 60 ml toluene, 399 ml (0.3553 moles) of sec-butyl magnesium chloride in lithium chloride complex (15% solution in THF) was charged at 0°C to -5°C and stirred for 2 hours.
  • Part-B The reaction mixture of 1 10.24 gm (0.3186 moles) of formula Vc (obtained by the protection of D-Gluconolactone using acetic anhydride/trifluoroacetic acid) in 300 ml toluene and 60.0 ml tetrahydrofuran was cooled to -35°C to -45°C and charged part-A solution slowly into the prepared reaction mixture and stirred for 30-45 minutes at -35°C to -45°C. Charged 20.0 ml Acetic acid and 80ml water until neutral pH of the reaction mixture. The temperature of the reaction mixture was raised to 30°C. Organic layer was separated. Extracted aqueous layer twice with 200 ml toluene.
  • Part-B The reaction mixture of 110.24 gm (0.3186 moles) of formula Vd (obtained by the protection of D-Gluconolactone using acetic anhydride/trifluoroacetic acid) in 300 ml toluene and

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

La présente invention concerne un nouveau procédé pour préparer de la canagliflozine de formule I, (I), ainsi que de nouveaux intermédiaires qui sont produits au cours de la mise en oeuvre du nouveau procédé.
PCT/GB2015/053567 2014-11-25 2015-11-24 Procédé de préparation de canagliflozine Ceased WO2016083790A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3731/MUM/2014 2014-11-25
IN3731MU2014 2014-11-25

Publications (1)

Publication Number Publication Date
WO2016083790A1 true WO2016083790A1 (fr) 2016-06-02

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WO (1) WO2016083790A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110698468A (zh) * 2019-09-24 2020-01-17 杭州华东医药集团新药研究院有限公司 一种坎格列净的制备方法
CN111205265A (zh) * 2020-03-02 2020-05-29 沧州那瑞化学科技有限公司 2-(4-氟苯基)-5-[(5-溴-2-甲基苯基)甲基]噻吩的制备方法
CN113429379A (zh) * 2021-06-28 2021-09-24 江苏法安德医药科技有限公司 一种lh-1801中间体及其制备方法和应用
CN113683593A (zh) * 2021-09-07 2021-11-23 湖北石河医药科技有限公司 一种卡格列净中间体的制备方法及其在制备卡格列净中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010043682A2 (fr) * 2008-10-17 2010-04-22 Janssen Pharmaceutica Nv Procédé pour la préparation de composés utiles en tant qu'inhibiteurs de sglt
EP2200606A1 (fr) 2007-09-10 2010-06-30 Janssen Pharmaceutica, N.V. Procédé pour la préparation de composés utiles en tant qu'inhibiteurs de sglt
CN104557895A (zh) * 2015-01-27 2015-04-29 江苏嘉逸医药有限公司 1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的合成工艺

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2200606A1 (fr) 2007-09-10 2010-06-30 Janssen Pharmaceutica, N.V. Procédé pour la préparation de composés utiles en tant qu'inhibiteurs de sglt
WO2010043682A2 (fr) * 2008-10-17 2010-04-22 Janssen Pharmaceutica Nv Procédé pour la préparation de composés utiles en tant qu'inhibiteurs de sglt
CN104557895A (zh) * 2015-01-27 2015-04-29 江苏嘉逸医药有限公司 1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的合成工艺

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
S. NOMURA ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 17, 2010, pages 6355 - 6360
WUTS; GREENE: "Protective Groups in Organic Synthesis", 2007, JOHN WILEY & SONS

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110698468A (zh) * 2019-09-24 2020-01-17 杭州华东医药集团新药研究院有限公司 一种坎格列净的制备方法
CN111205265A (zh) * 2020-03-02 2020-05-29 沧州那瑞化学科技有限公司 2-(4-氟苯基)-5-[(5-溴-2-甲基苯基)甲基]噻吩的制备方法
CN111205265B (zh) * 2020-03-02 2022-12-02 沧州那瑞化学科技有限公司 2-(4-氟苯基)-5-[(5-溴-2-甲基苯基)甲基]噻吩的制备方法
CN113429379A (zh) * 2021-06-28 2021-09-24 江苏法安德医药科技有限公司 一种lh-1801中间体及其制备方法和应用
CN113683593A (zh) * 2021-09-07 2021-11-23 湖北石河医药科技有限公司 一种卡格列净中间体的制备方法及其在制备卡格列净中的应用
CN113683593B (zh) * 2021-09-07 2023-11-17 湖北石河医药科技有限公司 一种卡格列净中间体的制备方法及其在制备卡格列净中的应用

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