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WO2018142422A1 - Procédé de préparation de dapagliflozine - Google Patents

Procédé de préparation de dapagliflozine Download PDF

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Publication number
WO2018142422A1
WO2018142422A1 PCT/IN2018/050048 IN2018050048W WO2018142422A1 WO 2018142422 A1 WO2018142422 A1 WO 2018142422A1 IN 2018050048 W IN2018050048 W IN 2018050048W WO 2018142422 A1 WO2018142422 A1 WO 2018142422A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
reaction
benzyloxy
group
Prior art date
Application number
PCT/IN2018/050048
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English (en)
Inventor
Srinivasan Subramanian Kuduva
Sandip Kacharu Deshmukh
Palangat Vayalileveetil RAMESAN
Aditi Milind Panandikar
Original Assignee
Indoco Remedies 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 Indoco Remedies Limited filed Critical Indoco Remedies Limited
Publication of WO2018142422A1 publication Critical patent/WO2018142422A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
    • C07D309/10—Oxygen atoms

Definitions

  • the present invention relates to a novel process for the preparation Dapagliflozin or its (S)-propylene glycol hydrate.
  • SGLTs such as SGLT1 and SGLT2 inhibitors provide new therapeutic targets to reduce hyperglycemia in patients with diabetes.
  • SGLT2 is responsible for reab sorption of most of the glucose filtered by the kidney.
  • Inhibitors with varying specificities for these transporters can slow the rate of intestinal glucose absorption and increase the renal elimination of glucose into the urine.
  • SGLT2 inhibitor drugs have been approved or in clinical phase for treatment of type 2 diabetes.
  • a significant numbers of SGLT2 are ⁇ -C- arylglucosides derived drug candidates, most of which comprises a central 1- deoxyglucose ring moiety that is arylated at CI .
  • Dapagliflozin is one of the approved SGLT2 inhibitor which is marketed under the trade name Farxiga in U.S. and Forxiga in Europe. Dapagliflozin and its pharmaceutically acceptable salts and process for their preparation are described in US 6,515,117 ("US' 117 Patent).
  • Scheme 1 Process discloses, the reaction where after C-C bond formation resultant hemiketal formed is methylated using methanesulfonic acid. During the process trimethylsilyl groups get hydrolyzed. After demethoxylation compound, crude Dapagliflozin is protected again doing acetylation and the resultant compound is purified. After deacetylation the compound pure dapagliflozin of Formula I is isolated. The repeated protection and deprotection to isolate the required compound increases the number of process steps, thereby results in increasing the cost of production and thus affects economy of the process.
  • One of the processes discloses the protection of hydroxyl group of the gluconolactone moiety with acetyl group using controlled substance acetic anhydride.
  • the protected gluconolactone is not available commercially and has to be prepared before the reaction.
  • process requires couple of protection and deprotection of the glucose moiety, or formation of complex for obtaining pure compound, which increases the number of steps and loss in yield of the final compound making the process uneconomical and cumbersome;
  • glucose compound when protected with pivaloyl group requires the pivaloyl-D-glucopyranose compound to react with bromine reagent which increases the process cost and the number of steps and also involves the problem of handling of bromine reagent.
  • the objective of present invention is to develop cost effective process employing industrially safe and readily available starting materials for the preparation of dapagliflozin c mpound of Formula I,
  • Formula I Yet another objective of the present invention is to prepare dapagliflozin with stereoselective orientation to obtain more of ⁇ -anomer.
  • Yet another objective of the present invention is to carry out debenzylation using easily available cost effective reagent.
  • Yet another objective of the present invention is to prepare the compound Dapaglifl -propylene glycol hydrate of Formula II
  • the present invention provides a process for preparing dapagliflozin, the compound of Formula I using readily available, cost effective, and industrially safe starting materials.
  • the present invention provides a process for the preparation of dapag glliflozin the compound of Formula I or its (S)-propylene glycol hydrate,
  • the present invention relates to a process for the preparation of dapagliflozin, the compound of Formula I or its (S)-propylene glycol hydrate of formula II, which process comprises the steps of:
  • step (a) the compound (2-chloro-5- iodophenyl)(4-ethoxyphenyl)methanone of Formula III is reacted with the compound (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-2-one of Formula IV in presence of a reagent selected from the group consisting of phenylsilane, tri-n-propylsilane, dimethylphenylsilane, polymethylhydroxysilane, triethylsilane, tris(trimethylsilyl)silane, triisobutylsilane, triphenylsilane, tert- butyldimethylsilane, triisopropylsilane, diisobutylaluminium hydride, lithium aluminum hydride, sodium borohydride, boron trifluoride-diethyl
  • the preferred reagent used are selected from triethylsilane, phenylsilane, tris(trimethylsilyl)silane, boron trifluoride-diethyl etherate and titanium tetrachloride.
  • the reaction is carried out in presence of a solvent selected from the group consisting of dichloromethane, dichloroethane, acetonitrile, toluene, tetrahydrofuran, diethyl ether or a mixture thereof.
  • the reaction is carried out at the temperature in the range of -80°C to 30°C.
  • the preferred temperature of the reaction is in the range of 10°C to 30°C.
  • a base selected from the group consisting of n- butyllithium, Mg-diisobutylaluminium hydride (Mg-DIBAL-H), isopropyl magnesium chloride-LiCl and 2,2,6,6-tetramethylpiperidide-MgCl-LiCl (TMPMgCl-LiCl).
  • the preferred temperature range for the reaction is -80°C to - 30°C, wherein the most preferred temperature range for the reaction is -80°C to - 60°C.
  • dilute solution of mild base selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate and potassium bicarbonate.
  • the compound of Formula V is further purified using solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol and butanol to isolate the pure compound (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6- ((benzyloxy)methyl)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl) tetrahydro-2H- pyran-2-ol of Formula V.
  • solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol and butanol to isolate the pure compound (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6- ((benzyloxy)methyl)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl) tetrahydro-2H- pyran-2-ol of Formula V.
  • the compound (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone of Formula III used in the present invention can be procured commercially or can be prepared as per the process disclosed in the prior art.
  • ((benzyloxy)methyl)tetrahydro-2H-pyran-2-one of Formula IV used in the reaction of the present invention is prepared form commercially available compound 2,3,4,6-tetra-O-benzyl-D-glucopyranose, the compound 5.
  • the compound 5 is subjected to oxidation using sodium hypochlorite solution in presence of buffer, catalyst and solvent medium to prepare solution of 2,3,4,6- tetra-O-benzyl-D-gluconolactone by maintaining the temperature of the reaction at -5°C to 30°C and pH of the reaction at 7.0 to 8.0.
  • the solvent used in the reaction is selected from group consisting of dichloromethane, dichloroethane, chloroform, toluene, xylene, tetrahydrofuran, ether, water either alone or in combinations thereof.
  • the preferred buffer used for the reaction is sodium bicarbonate and acetic acid.
  • the catalyst used for the reaction is 2,2,6,6- teteamethylpiperidine-l-oxyl either alone or in combination with potassium bromide.
  • the reaction completion is monitored on HPLC.
  • the reaction mass is quenched by adding aqueous sodium thiosulphate solution.
  • the reaction is worked up by separating the organic layer and concentrated to obtain residual mass of the compound 2,3,4,6-tetra-O-benzyl-D-gluconolactone of Formula IV.
  • step (b) the reaction of step (b), the compound of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(4- chloro-3-(4-ethoxybenzyl)- phenyl)tetrahydro-2H-pyran-2-ol of Formula V, as obtained in the above step (a) is subjected to reduction of hemiketal using a reducing reagent and boron trifluoride-diethyl etherate in presence of a solvent to obtain the intermediate compound (2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6- ((benzyloxy)methyl)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl) tetrahydro-2H-pyran of Formula VI.
  • the reducing reagent used for reduction of hemiketal is selected from group of reagents, such as phenylsilane, tri-n-propylsilane, dimethylphenyl silane, triethylsilane, tris(trimethylsilyl)silane, triisobutylsilane, triphenylsilane, tert-butyldimethylsilane, triisopropylsilane and diisobutylaluminium hydride.
  • group of reagents such as phenylsilane, tri-n-propylsilane, dimethylphenyl silane, triethylsilane, tris(trimethylsilyl)silane, triisobutylsilane, triphenylsilane, tert-butyldimethylsilane, triisopropylsilane and diisobutylaluminium hydride.
  • the preferred reagent that can be used for the reduction are triethylsilane, phenylsilane, and tris(trimethylsilyl)silane, whereas the most preferred reagents for the reduction used is triethylsilane.
  • the solvent used for the reduction reaction is selected from the group of solvents consisting of dichloromethane, dichloroethane, toluene, xylene tetrahydrofuran, ether, ethyl acetate and acetonitrile either alone or mixture thereof.
  • the reaction is carried out at temperature in the range of 20°C to 30°C.
  • the completion of reaction is monitored on TLC/HPLC. After completion the reaction is quenched with water and neutralised the quenched mass with ammonia solution. Separated the organic layer, washed and concentrated the solvent under vacuum at 40°C to 45°C to get the residual mass.
  • the residual mass is treated with a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, butanol, acetone and ethyl acetate either alone or in combinations thereof to isolate the compound (2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2- (4-chloro-3-(4-ethoxybenzyl)phenyl)tetra- hydro-2H-pyran of Formula VI.
  • a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, butanol, acetone and ethyl acetate either alone or in combinations thereof to isolate the compound (2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2- (4-chloro-3-(4-ethoxybenzyl)phenyl)tetra- hydro-2H-
  • step (c) the reaction of step (c), the compound (2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(4- chloro-3-(4-ethoxy-benzyl)phenyl)tetrahydro-2H-pyran of Formula VI, as obtained in the above step (b) is subjected to deprotection / debenzylation using deprotection reagents selected from sodium iodide/boron trifluoride-diethyl etherate or Palladium/carbon or iodotrimethylsilane or palladium hydroxide/carbon reagent in presence of a solvent selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, diethyl ether, toluene, dichloromethane, dichloroethane and water or in combinations thereof to yield
  • the preferred deprotection reagent is sodium iodide/boron trifluoride-diethyl etherate.
  • the temperature of the reaction is maintained in the range of 0°C to 40°C for 3 to 5 hours.
  • the reaction is monitored on UPLC for the completion.
  • the reaction mixture is quenched with triethyl amine at 25°C to 30°C and stirred for four hours, the precipitated solid mass is filtered. Charged the wet solid mass in water and made the pH acidic by using concentrated hydrochloric acid.
  • the product is extracted using the solvent selected from the group consisting of methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate and isopropyl acetate, wherein the preferred solvent used is methyl isobutyl ketone.
  • the organic layer is washed with water. The solvent is concentrated under reduced pressure till half of the volume.
  • (S)- propylene glycol is charged and stirred.
  • An anti-solvent selected from the group consisting of n-hexane, n-heptane and cyclohexane is added to isolate the crude compound dapagliflozin (S)-propylene glycol hydrate of formula II.
  • the crude compound dapagliflozin (S)- propylene glycol hydrate of formula II is purified using the solvents selected from the group consisting of ethyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, isopropyl acetate and water either alone or in combinations thereof.
  • solvents selected from the group consisting of ethyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, isopropyl acetate and water either alone or in combinations thereof.
  • To the clear solution of dapagliflozin (S)-propylene glycol hydrate of formula II charged (S)-propylene glycol solvent, water and an anti-solvent selected from the group of solvents such as n- hexane, n-heptane and cyclohexane to precipitate the pure product.
  • the precipitated product is filtered to isolate the pure compound
  • phenatole (86.49gm, 0.7080 moles) to the reaction mixture and maintained under stirring for 2 hours at -10°C to -5°C.
  • the progress of the reaction was monitored by HPLC.
  • the reaction mixture was quenched by adding water and dilute hydrochloric acid. Raised the temperature of the reaction mixture to 25°C to 30°C and maintained for 30 minutes. Separated the organic layer, extracted the aqueous layer again with dichloromethane (400 ml). The combined organic layer was washed with 10% of sodium bicarbonate solution (600 ml) followed with 5% brine solution (600 ml). Concentrated the organic layer under reduced pressure maintaining temperature below 45°C to get the residual mass.
  • reaction mass was quenched with water (600 ml) and distilled out solvent under reduced pressure maintaining temperature below 55°C. Charged water (400 ml) and toluene (600 ml) and stirred reaction mass for 30 minutes. Separated the organic layer and extracted the aqueous layer again with toluene (400 ml).
  • reaction completion was monitored on TLC. After reaction completion, the reaction mixture was quenched by adding triethylamine (250 ml) maintaining temperature at 25°C to 30°C and stirred for 4 hours. Filtered the solid mass, charged the wet cake in water (500 ml) and adjusted the pH ⁇ 2-3 using cone, hydrochloric acid. The solution was extracted with methyl isobutyl ketone (500 ml) and separated the organic layer. The aqueous layer was further extracted with methyl isobutyl ketone (500 ml). Combined the organic layer, washed with water (3 x 300 ml) and concentrated the solvent under reduced pressure up to half the volume.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation d'hydrate de Dapagliflozine (S)-propylèneglycol de formule II. (Formule II)
PCT/IN2018/050048 2017-02-02 2018-02-01 Procédé de préparation de dapagliflozine WO2018142422A1 (fr)

Applications Claiming Priority (2)

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IN201721003897 2017-02-02
IN201721003897 2017-02-02

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WO2018142422A1 true WO2018142422A1 (fr) 2018-08-09

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10973836B2 (en) 2019-08-30 2021-04-13 Astrazeneca Ab Methods of treating heart failure with reduced ejection fraction
WO2021176096A1 (fr) 2020-03-05 2021-09-10 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant un inhibiteur du sglt2
WO2021245253A1 (fr) 2020-06-05 2021-12-09 Krka, D.D., Novo Mesto Préparation de dapagliflozine amorphe très pure
CN114539334A (zh) * 2021-03-31 2022-05-27 浙江美诺华药物化学有限公司 一种达格列净中间体化合物晶型及其制备方法
US11826376B2 (en) 2018-07-19 2023-11-28 Astrazeneca Ab Methods of treating heart failure with preserved ejection fraction employing dapagliflozin and compositions comprising the same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6515117B2 (en) * 1999-10-12 2003-02-04 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
WO2004063209A2 (fr) * 2003-01-03 2004-07-29 Bristol-Myers Squibb Company Procedes de production d'inhibiteurs de c-aryle glucoside sglt2
WO2015132803A2 (fr) * 2014-03-06 2015-09-11 Msn Laboratories Private Limited Procédé pour la préparation de (1s)-1,5-anhydro-1-c-[4-chloro-3-[(4-éthoxyphényl)méthyl]phényl]-d-glucitol et de son solvate
US9193751B2 (en) * 2012-04-10 2015-11-24 Theracos, Inc. Process for the preparation of benzylbenzene SGLT2 inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6515117B2 (en) * 1999-10-12 2003-02-04 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
WO2004063209A2 (fr) * 2003-01-03 2004-07-29 Bristol-Myers Squibb Company Procedes de production d'inhibiteurs de c-aryle glucoside sglt2
US9193751B2 (en) * 2012-04-10 2015-11-24 Theracos, Inc. Process for the preparation of benzylbenzene SGLT2 inhibitors
WO2015132803A2 (fr) * 2014-03-06 2015-09-11 Msn Laboratories Private Limited Procédé pour la préparation de (1s)-1,5-anhydro-1-c-[4-chloro-3-[(4-éthoxyphényl)méthyl]phényl]-d-glucitol et de son solvate

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11826376B2 (en) 2018-07-19 2023-11-28 Astrazeneca Ab Methods of treating heart failure with preserved ejection fraction employing dapagliflozin and compositions comprising the same
US10973836B2 (en) 2019-08-30 2021-04-13 Astrazeneca Ab Methods of treating heart failure with reduced ejection fraction
US11903955B2 (en) 2019-08-30 2024-02-20 Astrazeneca Ab Methods of treating heart failure with reduced ejection fraction
WO2021176096A1 (fr) 2020-03-05 2021-09-10 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant un inhibiteur du sglt2
WO2021245253A1 (fr) 2020-06-05 2021-12-09 Krka, D.D., Novo Mesto Préparation de dapagliflozine amorphe très pure
CN114539334A (zh) * 2021-03-31 2022-05-27 浙江美诺华药物化学有限公司 一种达格列净中间体化合物晶型及其制备方法

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