WO2016162877A1 - "a process for preparing 7-[(3r)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyi]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydrate and its crystalline form" - Google Patents
"a process for preparing 7-[(3r)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyi]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydrate and its crystalline form" Download PDFInfo
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- WO2016162877A1 WO2016162877A1 PCT/IN2015/000328 IN2015000328W WO2016162877A1 WO 2016162877 A1 WO2016162877 A1 WO 2016162877A1 IN 2015000328 W IN2015000328 W IN 2015000328W WO 2016162877 A1 WO2016162877 A1 WO 2016162877A1
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- QPUSXOAOLFAWSF-LLVKDONJSA-N C[F]c1cc(F)cc(C[C@H](CC(N2Cc3nnc(C(F)(F)F)[n]3CC2)=O)N)c1F Chemical compound C[F]c1cc(F)cc(C[C@H](CC(N2Cc3nnc(C(F)(F)F)[n]3CC2)=O)N)c1F QPUSXOAOLFAWSF-LLVKDONJSA-N 0.000 description 1
- KRTKJOMGTJIRJK-SNVBAGLBSA-N N[C@@H](CC(N1Cc2nnc(C(F)(F)F)[n]2CC1)=O)Cc(cc(cc1F)F)c1F Chemical compound N[C@@H](CC(N1Cc2nnc(C(F)(F)F)[n]2CC1)=O)Cc(cc(cc1F)F)c1F KRTKJOMGTJIRJK-SNVBAGLBSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- the present invention relates to an industrially feasible process for preparation of 7-[(3R)- 3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)- l,2,4-triazolo[4,3-a]pyrazine Hydrochloride monohydrate and its crystalline form.
- Forma-I is an oral antihyperglvcemic agent of the dipeptidyl peptidase-4 (DPP-4) inhibitor class and is used for the treatment of diabetes mellitus type-2.
- US 6,699,871 discloses class of beta-amino tetra hydrotriazolo [4,3- a] pyrazines, DPP-IV inhibitors and its preparation process. Other pharmaceutically acceptable salts also described in US' 871.
- PCT application WO 2005072530 discloses crystalline hydrochloric acid salt monohydrate of 7-[(3R)-3-amino- 1 -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro- 3-(trifluoromethyl)-l ,2,4-triazolo[4,3-a]pyrazine .
- WO'530 describes process for preparing crystalline hydrochloric acid salt monohydrate of 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l ,2,4-triazolo[4,3- ajpyrazine which comprises dissolving 7-[(3R)-3-amino-l-oxo-4-
- Indian patent application 590/MUM/2011 discloses crystalline hydrochloride salt, gentisate salt, adipate salt, besylate salt, trifluoroacetic acid salt of 7-[(3R)-3-amino-l- oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4- triazolo[4,3-a]pyrazine .
- PCT application WO 2010000469 describes crystalline forms of 7-[(3R)-3-amino-l-oxo-
- the prior art processes involve heating to dissolve 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- ajpyrazine base in solvent while the present invention process carry out at ambient temperature.
- the prior art process describes crystallization with diethyl ether which is highly volatile, highly flammable and difficult to handle at industrial level.
- the present invention involves water for crystallisation which makes the process cheap, eco- friendly, industrially applicable.
- the present invention provides the process for preparation of 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- ajpyrazine free base (Formula-I), 7-[(3R)-3 -amino- 1 -oxo-4-(2,4,5trifluorophenyl)butyl]- 5,6,7, 8-tetrahydro-3-(trifluoromethyl)- 1 ,2,4-triazolo[4,3-a]pyrazine Hydrochloride monohydrate (Formula-II) and crystalline form of 7-[(3R)-3-amino-l-oxo-4- (2,4,5triiluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,
- the present invention provides an insitu process for preparing 7-[(3R)-3- amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)- 1,2,4- triazolo[4,3-a]pyrazine free base (Formula-I) which comprises;
- the present invention provides industrially feasible process for preparing crystalline form of 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)- 1 ,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydratefrom 7-[(3R)-3-amino- 1 -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base which comprises;
- the instant invention provides an efficient, advantageous and economical process for preparing 7-[(3R)-3-amino- 1 -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base (Formula-I), 7-[(3R)-3-amino- l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4- triazolo[4,3-a]pyrazine Hydrochloride monohydrate (Formula-II)and crystalline form of 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-
- the present invention describes theinsitu process for preparing 7- [(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base (Formula-I) which comprises; (a) Reacting (3R)-3-[(l,l-dimethyl ethoxy carbonyl)amino]-4-(2,4,5-trifluorophenyl butanoic acid with 3-trifluromentyl 5,6,7,8-tetrahydro ( 1 ,2,4) triazolo[4,3-a] pyrazine HCl in presence of coupling reagent, base, condensing agent and solvent;
- the coupling reagent is N,N'-dicyclohexylcarbodiimide.
- the condensing agent is 1-hydroxybenzotriazole.
- the base is selected from organic base such as triethyl amine, diisopropyl ethyl amine, N-methyl morpholine, N-methyl pyrrolidine.
- the solvent for above said process is selected from halogenated hydrocarbon such as Dichloromethane.
- the alcoholic HCl is selected from the group consisting of methanolic HCl, ethanolic HCl, IPA.HCl.
- the reaction temperature for said process is maintained between 25-30°C.
- the present invention describes the industrially feasible process for preparing crystalline form of 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydrate from 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base which comprises;
- the solvent is selected from the group consisting of chlorinated solvents, esters, ketones, alcohols or mixture of two or more solvents.
- the chlorinated solvent is selected from methylene dichloride, 1 ,2-dichloroethane and the like; esters are selected from ethyl acetate, isopropyl acetate and the like; the ketone solvent is selected from methyl ethyl ketone, acetone; and the like the alcohol is selected from ethanol, methanol, isopropanol and the like.
- the alcoholic hydrochloride is selected from methanolic hydrochloride, isopropanolic hydrochloride.
- the ambient temperature for above said process is 25-30°C.
- Example-1 Preparation of 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]- 5,6,7,8-tetrahydro-3-(trifluoromethyI)-l,2,4-triazolo[4,3-a]pyrazine free base (Insitu)
- the aqueous layer washed with 300ml MDC and pH adjusted to 10-11 with 10%sodium hydroxide solution.1000ml MDC was further added and the reaction mixture was stirred for another lOmin.
- the organic layer was separated and the aqueous layer extracted twice with 300 ml MDC.
- the separated organic layer was further washed with 300 ml of water followed by addition of 300ml 5% NaCl. Dried with anhydrous sodium sulfate.
- the organic layer was distilled out under vacuum.
- lOOmllPA was added to the residue and again distilled under vacuum followed by addition of 800ml heptane. Filtered the crystallized material and dried under vacuum at 50°C for 12-15 hours to get 96.5% titled compound.
- Example-2 Preparation of crystalline form of7-[(3R)-3-amino-l-oxo-4-
- Example-3 Preparation of crystalline form of7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyI]-5,6,7,8-tetrahydro-3-(trifluoroniethyl)-l,2,4-triazolo[4,3- ajpyrazine Hydrochloride Monohydrate
- Example-4 Preparation of crystalline form of7-[(3R)-3-amino-l-oxo-4-
- Example-5 Preparation of crystalline form of7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifIuoromethyl)-l,2,4-triazolo[4 ⁇ - a]pyrazine Hydrochloride Monohydrate
- Example-6 Preparation of crystalline form of7-[(3R)-3-amino-l-oxo-4-
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Abstract
The present invention discloses industrially feasible process for preparation of 7-[(3R)-3- amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluorornethyl)-l,2,4- triazolo[4,3-a]pyrazine Hydrochloride monohydrate.
Description
"A process for preparing 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyI]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine Hydrochloride monohydrate and its crystalline form"
FIELD OF INVENTION:
The present invention relates to an industrially feasible process for preparation of 7-[(3R)- 3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)- l,2,4-triazolo[4,3-a]pyrazine Hydrochloride monohydrate and its crystalline form.
BACKGROUND OF INVENTION:
7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine (Formula-I) is an oral antihyperglvcemic agent of the dipeptidyl peptidase-4 (DPP-4) inhibitor class and is used for the treatment of diabetes mellitus type-2. 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine is widely used as a therapeutic agent for diabetes mellitus because it has lesser side effects.
Formula-I
US 6,699,871 (herein after US'871) discloses class of beta-amino tetra hydrotriazolo [4,3- a] pyrazines, DPP-IV inhibitors and its preparation process. Other pharmaceutically acceptable salts also described in US' 871.
PCT application WO 2005072530 discloses crystalline hydrochloric acid salt monohydrate of 7-[(3R)-3-amino- 1 -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro- 3-(trifluoromethyl)-l ,2,4-triazolo[4,3-a]pyrazine . WO'530 describes process for preparing crystalline hydrochloric acid salt monohydrate of 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l ,2,4-triazolo[4,3- ajpyrazine which comprises dissolving 7-[(3R)-3-amino-l-oxo-4-
(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)- 1 ,2,4-triazolo[4,3- a]pyrazine free base in isopropanol/methanol followed by adding solution of HC1 in
diethylether to obtain thick slurry of crystals which further heated to 55°C and slowly cooled to room temperature to obtain crystalline hydrochloric acid salt monohydrate of 7- [(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)- 1 ,2,4-triazolo[4,3 -a] pyrazine.
Indian patent application 590/MUM/2011 discloses crystalline hydrochloride salt, gentisate salt, adipate salt, besylate salt, trifluoroacetic acid salt of 7-[(3R)-3-amino-l- oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4- triazolo[4,3-a]pyrazine . Said Indian Patent application describes process for preparing crystalline hydrochloric acid salt monohydrate of 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- a]pyrazine which comprises dissolving 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- a]pyrazine free base in isopropanol/methanol follow by addlPA.HCl and heat at 40-45°C and crystallize with diethyl ether to get crystalline hydrochloride salt monohydrate of 7- [(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)- 1 ,2,4-triazolo[4,3-a]pyrazine .
PCT application WO 2010000469 describes crystalline forms of 7-[(3R)-3-amino-l-oxo-
4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4 ajpyrazine monobasic, dibasic and tribasic acid addition salts like hydrochloric acid (Form I and Form II), sulfuric acid (Form I and Form II), methane sulfonic acid (Form I and Form II), fumaric acid (Form I and Form II), malonic acid, malic acid, succinic acid (Form I, Form II and Form III), lactic acid, glycolic acid, maleic acid (Form I and Form II), citric acid (crystalline and amorphous Form), aspartic acid and mandelic acid and process for the preparation thereof.
The prior art processes involve heating to dissolve 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- ajpyrazine base in solvent while the present invention process carry out at ambient temperature. Moreoverthe prior art process describes crystallization with diethyl ether which is highly volatile, highly flammable and difficult to handle at industrial level. The
present invention involves water for crystallisation which makes the process cheap, eco- friendly, industrially applicable.
SUMMARY OF THE INVENTION:
The present invention provides the process for preparation of 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- ajpyrazine free base (Formula-I), 7-[(3R)-3 -amino- 1 -oxo-4-(2,4,5trifluorophenyl)butyl]- 5,6,7, 8-tetrahydro-3-(trifluoromethyl)- 1 ,2,4-triazolo[4,3-a]pyrazine Hydrochloride monohydrate (Formula-II) and crystalline form of 7-[(3R)-3-amino-l-oxo-4- (2,4,5triiluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-- ajpyrazine Hydrochloride monohydrate.
In an aspect, the present invention provides an insitu process for preparing 7-[(3R)-3- amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)- 1,2,4- triazolo[4,3-a]pyrazine free base (Formula-I) which comprises;
(a) Reacting (3 R)-3-[( 1,1 -dimethyl ethoxy carbonyl)amino]-4-(2,4,5-trifluorophenyl butanoic acid with 3-trifluromentyl 5,6,7,8-tetrahydro ( 1 ,2,4) triazolo[4,3-a] pyrazine HC1 in presence of coupling reagent, base, condensing agent and solvent;
(b) Basifying the reaction mixture with sodium bicarbonate;
(c) Adding alcoholic HC1 and separating the layers;
(d) Adjusting pH to 10-11 of the aqueous layer to obtain 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4- triazolo[4,3-a]pyrazine free base; and
(e) Crystallizing the free base from a mixture of IPA and heptane and isolating the crystallized free base thereof.
In a preferred aspect, the present invention provides industrially feasible process for preparing crystalline form of 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-
5,6,7,8-tetrahydro-3-(trifluoromethyl)- 1 ,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydratefrom 7-[(3R)-3-amino- 1 -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base which comprises;
(a) Dissolving 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine base in a solvent or mixture of two or more solvents and water at ambient temperature;
(b) Adding alcoholic hydrochloric acid to the above mixture at ambient temperature to obtain7-[(3R)-3-amino- 1 -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro- 3-(tri- fluoro methyl)-l,2,4-triazolo[4,3-a]pyrazine hydrochloride;
(c) Crystallizing the salt by adding water and isolating the crystallized 7-[(3R)-3- amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydrate thereof.
DETAILED DESCRIPTION OF THE INVENTION:
The instant invention provides an efficient, advantageous and economical process for preparing 7-[(3R)-3-amino- 1 -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base (Formula-I), 7-[(3R)-3-amino- l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4- triazolo[4,3-a]pyrazine Hydrochloride monohydrate (Formula-II)and crystalline form of 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-
Formula-I Formula-II
In one embodiment, the present invention describes theinsitu process for preparing 7- [(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base (Formula-I) which comprises;
(a) Reacting (3R)-3-[(l,l-dimethyl ethoxy carbonyl)amino]-4-(2,4,5-trifluorophenyl butanoic acid with 3-trifluromentyl 5,6,7,8-tetrahydro ( 1 ,2,4) triazolo[4,3-a] pyrazine HCl in presence of coupling reagent, base, condensing agent and solvent;
(b) Basifying the above mixture with sodium bicarbonate;
(c) Adding alcoholic HCl and separating the layers;
(d) Adjusting pH to 10-1 lof the aqueous layer to obtain 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4- triazolo[4,3-a]pyrazine free base; and
(e) Crystallizing the free base from a mixture of IPA and heptane and isolating the crystallized free base thereof.
The process for preparing 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine base according to the present invention is described b following reaction Scheme-I.
According to the above process, the coupling reagent is N,N'-dicyclohexylcarbodiimide. The condensing agent is 1-hydroxybenzotriazole. The base is selected from organic base such as triethyl amine, diisopropyl ethyl amine, N-methyl morpholine, N-methyl pyrrolidine. The solvent for above said process is selected from halogenated hydrocarbon such as Dichloromethane.The alcoholic HCl is selected from the group consisting of methanolic HCl, ethanolic HCl, IPA.HCl.
The reaction temperature for said process is maintained between 25-30°C.
In the process, to the solution of (3 R)-3-[( 1,1 -dimethyl ethoxy carbonyl)amino]-4-(2,4,5- trifluorophenyl butanoic acid in methylene dichloride is added triethylamine and the mixture is stirred for about 10 minutes. Ν,Ν'-Dicyclohexylcarbodiimide, anhydrous 1- hydroxyl benzotriazole are added to the mixture which is maintained at 0-5°C for about 10-20 minutes. Then, is added 3-trifiuoromethyl 5,6,7,8-tetrahydro ( 1 ,2,4) triazolo[4,3- a] pyrazine.HCl and the mixture is heated to 25-30°C and maintained for 4 hours. After
completion of the reaction the reaction mass is filtered and the filtrate is repeatedly washed with 2.5%sodium bicarbonate. Cooled the separated organic layer, without purification, to a temperature in the range 0 tolO°C. 16%Methanolic HCl is further added and raised the temperature to 25-30°C with stirring for couple of hours. Water is added to the mixture and the layers are separated and the pH of the aqueous layer is adjusted to 10- 11 by adding a base. This is followed by sequential washings of the organic layer with water followed by addition of brine. The organic layer is dried, and the solvent is distilled under vacuum. The residue obtained is crystallized from solvent mixture of IPA and heptane to obtain crystallized free base.
In another embodiment the present invention describes the industrially feasible process for preparing crystalline form of 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydrate from 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base which comprises;
(a) Dissolving 7-[(3R)-3-amino- 1 -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine base in solvent or mixture of two or more solvents and water at ambient temperature;
(b) Adding alcoholic hydrochloride to the above mixture at ambient temperature to obtain7-[(3R)-3-amino-l -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoro- methyl)-l ,2,4-triazolo[4,3-a]pyrazine hydrochloride;
(c) Crystallizing the salt by adding water and isolating thecrystalline form of 7-[(3R)- 3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydrate thereof.
The process for preparing 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)- 1 ,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydrate is given in Scheme-II
Scheme-II
The solvent is selected from the group consisting of chlorinated solvents, esters, ketones, alcohols or mixture of two or more solvents. The chlorinated solvent is selected from methylene dichloride, 1 ,2-dichloroethane and the like; esters are selected from ethyl acetate, isopropyl acetate and the like; the ketone solvent is selected from methyl ethyl ketone, acetone; and the like the alcohol is selected from ethanol, methanol, isopropanol and the like.
The alcoholic hydrochloride is selected from methanolic hydrochloride, isopropanolic hydrochloride.
The ambient temperature for above said process is 25-30°C.
Accordingly, to 7-[(3R)-3-amino-l -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro- 3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base is added a solvent or mixture of solvents and stirred to get clear solution. This is followed by addition of alcoholic HC1 and water at ambient temperature and stirred to obtain the crystals of 7-[(3R)-3-amino-l- oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)- 1 ,2,4- triazolo[4,3-a]pyrazine hydrochloride monohydrate which is further washed and dried to obtain crystalline form.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples:
Example-1: Preparation of 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]- 5,6,7,8-tetrahydro-3-(trifluoromethyI)-l,2,4-triazolo[4,3-a]pyrazine free base (Insitu)
To the lOOgm of (3 R)- 3 -[(1,1 -dimethyl ethoxy carbonyl)amino]-4-(2,4,5-trifluorophenyl butanoic acid was charged 700ml methylene dichloride and 67gm trimethylamine and stirred for 10 minutes. Added 68gm Ν,Ν'-Dicyclohexyl carbodiimide, 44.6 gm of anhydrous 1 -hydroxyl benzotriazole and maintained at 0-5°C for about 10-20 minutes. Added 75.5gm 3-trifluoromethyl 5,6,7,8-tetrahydro ( 1 ,2,4) triazolo[4,3-a] pyrazine.HCl and heated to 25-30°C and maintained for 4 hours. After completion of reaction, filtered the reaction mass and filtrate was washed with 2x350ml of 2.5%sodium bicarbonate solution followed by further washing with 2x500ml of water. Cooled the separated MDC layer, without purification, to 0-10°C. Added 400ml of 16%Methanolic HC1 and raised the temperature to 25-30°Cwith stirring for 4 hours. After completion of the reaction was added 1000ml water and separated the layers. Extracted MDC layer with 2x300ml of DM water. The aqueous layer washed with 300ml MDC and pH adjusted to 10-11 with 10%sodium hydroxide solution.1000ml MDC was further added and the reaction mixture was stirred for another lOmin. The organic layer was separated and the aqueous layer extracted twice with 300 ml MDC. The separated organic layer was further washed with 300 ml of water followed by addition of 300ml 5% NaCl. Dried with anhydrous sodium sulfate. The organic layer was distilled out under vacuum. lOOmllPA was added to the residue and again distilled under vacuum followed by addition of 800ml heptane. Filtered the crystallized material and dried under vacuum at 50°C for 12-15 hours to get 96.5% titled compound.
HPLC purity:99-99,9%
Chiral purity : 99.9%
Example-2: Preparation of crystalline form of7-[(3R)-3-amino-l-oxo-4-
(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- a]pyrazine Hydrochloride Monohydrate
To 100 g 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine base was charged 400 ml of Methylene dichloride.10ml water was added to the reaction mass and stirred to get a clear solution.
This was followed by addition of 29gms Hydrochloric acid. The reaction mixture was stirred for 30 minutes and cooled gradually to 20-25 °C and stirred for 2hours.The reaction mass was filtered and washed with Methylene dichloride. Dried in oven under vacuum at 25°C to get crystalline form of 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- a]pyrazine hydrochloride monohydrate.
HPLC purity: 99-99.9%
Chiral purity: 99.9%
Example-3: Preparation of crystalline form of7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyI]-5,6,7,8-tetrahydro-3-(trifluoroniethyl)-l,2,4-triazolo[4,3- ajpyrazine Hydrochloride Monohydrate
To the lOgm 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine freebase was added 50ml Ethyl acetate and stirred to get clear solution. Added 14% IPA-HCI at ambient temperature and stirred for 2 hours. Added 5ml Water and stirred for 2hours at room temperature. Filtered the material and washed with (lOEthyl acetate : 1 Water) and dried under vacuum at 40-45 °C to get crystalline form of 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)- 1 ,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydrate. HPLC purity: 99-99.9%
Chiral purity: 99.9%
Example-4: Preparation of crystalline form of7-[(3R)-3-amino-l-oxo-4-
(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- ajpyrazine Hydrochloride Monohydrate
To the lOgm 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base was added50ml Methyl Ethyl Ketone and 5ml Water and stirred to get clear solution. Added IPA-HCI at ambient temperature and stirred for 2 hours. Added water and stirred for 2hours at room temperature. Filtered the material and washed with 5ml Methyl Ethyl Ketone and 1ml Water and dried under vacuum at 40-45°C to get crystalline form of 7-[(3R)-3-amino-l- oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4- triazolo[4,3-a]pyrazine hydrochloride monohydrate.
HPLC purity: 99-99.9%
Chiral purity: 99.9%
Example-5: Preparation of crystalline form of7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifIuoromethyl)-l,2,4-triazolo[4^- a]pyrazine Hydrochloride Monohydrate
To the 10 gm 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base was charged ethyl acetate. Added 14% IPA-HCl and 5ml water. The mixture was stirred at ambient temperature for about 20 hours. Filtered under vacuum and washed with l%Ethyl acetate solution. Dried under vacuum at 50°C to get crystalline form of 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- a]pyrazine hydrochloride monohydrate.
HPLC purity: 99-99.9%
Chiral purity: 99.9%
Example-6: Preparation of crystalline form of7-[(3R)-3-amino-l-oxo-4-
(2,4,5trifIuorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- a]pyrazine Hydrochloride Monohydrate
To the lOgm 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine free base was charged ethyl acetate and ethanol. Added 14%IPA-HC1 and 5ml water and stirred at ambient temperature for about 20 hours. Filtered under vacuum and washed with l%Ethyl acetate solution. Dried under vacuum at 50°C to get crystalline form of 7-[(3R)-3-amino-l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3- ajpyrazine hydrochloride monohydrate.
HPLC purity: 99-99.9%
Chiral purity: 99.9%
Claims
1. A process for preparing crystalline form of 7-[(3 R)-3 -amino- l-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4- triazolo[4,3-a]pyrazine hydrochloride monohydrate (FormuIa-II) comprising
Formula-II
(a) Dissolving 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine base in a solvent or mixture of two or more solvents and water at ambient temperature;
(b) Adding alcoholic hydrochloride at ambient temperature to obtain 7-[(3R)-3- amino- 1 -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l ,2,4-triazolo[4,3-a]pyrazine hydrochloride; and
(c) Crystallizing by adding water and isolating thecrystalline form of 7-[(3R)-3- amino-1 -oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)- 1 ,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydrate.
2. The process according to claim 1, wherein the solvent is selected from the group consisting of chlorinated solvents, ester solvents, ketone solvents or alcohol solvents.
3. The process according to claim 2, wherein the chlorinated solvent is methylene dichloride.
4. The process according to claim 2, wherein the ester solvent is ethyl acetate.
• 5. The process according to claim 2, wherein the ketone solvent is methyl ethyl ketone.
The process according to claim 2, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol and the like.
The process according to claim 1, wherein the ambient temperature is 25-30°C.
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| IN1496/MUM/2015 | 2015-04-09 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110857302A (en) * | 2018-08-24 | 2020-03-03 | 江苏瑞科医药科技有限公司 | Preparation method of sitagliptin hydrochloride monohydrate crystal form |
| CN113149991A (en) * | 2020-12-31 | 2021-07-23 | 浙江美诺华药物化学有限公司 | Synthesis method of sitagliptin free base and sitagliptin phosphate monohydrate |
| WO2023139276A1 (en) | 2022-01-24 | 2023-07-27 | Zaklady Farmaceutyczne Polpharma S.A. | Process for preparing crystalline sitagliptin hydrochloride monohydrate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005072530A1 (en) * | 2004-01-16 | 2005-08-11 | Merck & Co., Inc. | Novel crystalline salts of a dipeptidyl peptidase-iv inhibitor |
| US20070021430A1 (en) * | 2003-09-23 | 2007-01-25 | Chen Alex M | Novel crystalline form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
| US7326708B2 (en) * | 2003-06-24 | 2008-02-05 | Merck & Co., Inc. | Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor |
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- 2015-08-24 WO PCT/IN2015/000328 patent/WO2016162877A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7326708B2 (en) * | 2003-06-24 | 2008-02-05 | Merck & Co., Inc. | Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor |
| US20070021430A1 (en) * | 2003-09-23 | 2007-01-25 | Chen Alex M | Novel crystalline form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
| WO2005072530A1 (en) * | 2004-01-16 | 2005-08-11 | Merck & Co., Inc. | Novel crystalline salts of a dipeptidyl peptidase-iv inhibitor |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110857302A (en) * | 2018-08-24 | 2020-03-03 | 江苏瑞科医药科技有限公司 | Preparation method of sitagliptin hydrochloride monohydrate crystal form |
| CN113149991A (en) * | 2020-12-31 | 2021-07-23 | 浙江美诺华药物化学有限公司 | Synthesis method of sitagliptin free base and sitagliptin phosphate monohydrate |
| WO2023139276A1 (en) | 2022-01-24 | 2023-07-27 | Zaklady Farmaceutyczne Polpharma S.A. | Process for preparing crystalline sitagliptin hydrochloride monohydrate |
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