WO2015145333A1 - Process for the preparation of sitagliptin and its intermediate - Google Patents

Process for the preparation of sitagliptin and its intermediate Download PDF

Info

Publication number
WO2015145333A1
WO2015145333A1 PCT/IB2015/052119 IB2015052119W WO2015145333A1 WO 2015145333 A1 WO2015145333 A1 WO 2015145333A1 IB 2015052119 W IB2015052119 W IB 2015052119W WO 2015145333 A1 WO2015145333 A1 WO 2015145333A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
trifluoromethyl
triazolo
trifluorophenyl
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/IB2015/052119
Other languages
French (fr)
Other versions
WO2015145333A8 (en
Inventor
Md Abul Kalam AZAD
Gyanendra Pandey
Kaptan Singh
Mohan Prasad
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.)
Sun Pharmaceutical Industries Ltd
Original Assignee
Sun Pharmaceutical Industries 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 Sun Pharmaceutical Industries Ltd filed Critical Sun Pharmaceutical Industries Ltd
Publication of WO2015145333A1 publication Critical patent/WO2015145333A1/en
Publication of WO2015145333A8 publication Critical patent/WO2015145333A8/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • the present invention provides a process for the preparation of sitagliptin.
  • the present invention also provides a process for the preparation of fert-butyl [(2i?)-4-oxo-4- [3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate, an intermediate of sitagliptin.
  • Sitagliptin phosphate monohydrate of Formula A an orally -active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, chemically designated as 7-[(3i?)-3-amino-l-oxo- 4-(2,4,5 -trifluorophenyl)butyl] -5 ,6,7,8-tetrahydro-3 -(trifluoromethyl)- 1 ,2,4-triazolo [4,3 - ]pyrazine phosphate (1 : 1) monohydrate, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
  • DPP-4 dipeptidyl peptidase-4
  • the present inventors observed that the agents reported above such as 1- hydroxybenzotriazole, N,N'-dicyclohexylcarbodiimide, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide, ⁇ , ⁇ -carbonyldiimidazole, and 2-chloro-4,6- dimethoxy-l,3,5-triazine are costly and hazardous, and agents such as 2- chlorophenylboronic acid, 3-chlorophenylboronic acid, 4-chlorophenylboronic acid, and phenyl boronic acid require lengthy reaction times.
  • the prior art processes further require a purification process to remove the unwanted side products by recrystallization, trituration, and/or preparative thin layer chromatography .
  • EP 2 647 624 for the preparation of sitagliptin from fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3 - ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2- yl]carbamate require treating fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3 - ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2- yl]carbamate with hydrochloric acid in a solvent such as methanol or isopropyl alcohol.
  • a solvent such as methanol or isopropyl alcohol.
  • the present inventors have developed a process for the preparation of fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromemyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l- (2,4,5-trifluorophenyl)butan-2-yl]carbamate and sitagliptin which is less expensive, less time consuming, and more commercially viable, by avoiding the use of hazardous and costly reagents.
  • the present invention provides a process for the preparation of fert-butyl [(2i?)-4- oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate which comprises reacting (3R)-3-[(tert- butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid with 3-(trifluoromethyl)- 5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine or a salt thereof in the presence of catalyst, wherein the catalyst is a trialkyl borate or a mixture of boric acid and a trifluoromethyl phenylboronic acid.
  • the present invention also provides a process for the preparation of sitagliptin wherein the process comprises deprotecting fert-butyl [(2i?)-4- oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate in the presence of an activated zeolite.
  • the present inventors have found that the activated zeolite used for the deprotection of fert-butyl
  • treating includes adding, dissolving, slurrying, stirring, and combinations thereof.
  • solvent includes water, esters, alkanols, aromatic hydrocarbons, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, and mixtures thereof.
  • esters include ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and «-butyl acetate.
  • alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms, such as methanol, ethanol, «-propanol, isopropanol, and butanol.
  • aromatic hydrocarbons include toluene and xylene.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1,2- dichloroethane.
  • ketones include acetone and methyl ethyl ketone.
  • ethers include diethyl ether and tetrahydrofuran.
  • polar aprotic solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
  • base includes organic or inorganic bases.
  • organic bases include ethyl amine, triethylamine, diisopropyl amine, diisopropyl ethyl amine, and mixtures thereof.
  • inorganic bases include hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals, and the like.
  • hydroxides, carbonates, and bicarbonates of an alkali or alkaline earth metals include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • a first aspect of the present invention provides a process for the preparation of sitagliptin of Formula 1
  • a second aspect of the present invention provides a process for the
  • the catalyst is trialkyl borate or a mixture of boric acid and trifluoromethyl phenylboronic acid.
  • a third aspect of the present invention provides a process for the preparation of sitagliptin of Formula 1
  • the starting material, (3i?)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid of Formula 2 can be prepared by methods known in the art, including that described in European Patent No. EP 2 647 624.
  • the starting material, 3- (trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof, can be prepared by the methods known in the art, including those described in PCT Publication Nos. WO 2004/085661 and WO 2010/122578.
  • trialkyl borates include trimethyl borate, triethyl borate, triisopropyl borate, and triisobutyl borate.
  • trifluoromethyl phenylboronic acids include 2- (trifluoromethyl)phenylboronic acid, 3-(trifluoromethyl)phenylboronic acid, and 4- (trifluoromethy l)phenylboronic acid .
  • salts of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine include acid addition salts such as hydrochloride, hydrobromide, and sulfate.
  • 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine hydrochloride in toluene is treated with an aqueous sodium hydroxide solution at reflux temperature.
  • boric acid, 4-trifluoromethyl(phenylboronic) acid, and triethylamine are added to a mixture of toluene, (3i?)-3-[(feri-butoxycarbonyl)amino]-4- (2,4,5 -trifluorophenyl)butanoic acid, and 3-(trifluoromethyl)-5, 6,7,8- tetrahydro[l,2,4]triazolo[4,3- ]pyrazine hydrochloride to obtain a reaction mixture, then refluxed while stirring for about 24 hours to complete the reaction.
  • teri-butyl[(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3- ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2- yl]carbamate can be either isolated or can be carried to the next step of the process without isolation. Suitable isolation techniques include cooling, evaporation under vacuum, washing, precipitation, filtration, filtration under vacuum, decantation, centrifugation, and combinations thereof.
  • the activated zeolite may be obtained by treating zeolite (CBV-712) with 6N hydrochloric acid at a temperature of about 20°C to 30°C for about 30 minutes, and then filtering the mixture under vacuum.
  • a mixture of activated zeolite and isopropyl acetate is added to fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin- 7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-yl]carbamate and heated to about 50°C to about 80°C while stirring for a time period sufficient to complete the reaction.
  • Sitagliptin can be isolated by cooling, precipitation, washing, filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.
  • Example 1 Preparation of ferf-butyl r(2j?)-4-oxo-4-r3-(trifluoromethvn-5.6- dihydro[1.2.4]triazolo[4 - ]pyrazin-7(8H)-yl]-l-(2.4.5-trifluorophenyl)butan-2- yl] carbamate (Formula 4)
  • the reaction mixture was cooled to 70°C to 75°C and then (3i?)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid (Formula 2; 5 g, 1 equivalent), boric acid (0.93 g, 1 equivalent), and 4-(trifluoromethyl)phenylboronic acid (0.28 g; 0.1 equivalents) were added to the reaction mixture at 70°C to 75°C.
  • the temperature of the reaction mixture was raised to reflux (110°C) and refluxed for 20 hours to 24 hours.
  • the reaction mixture was cooled to 50°C to 55°C and toluene was recovered completely under vacuum at 50°C to 55°C to obtain a semi-solid residue.
  • Example 2 Preparation of ferf-butyl [(2j?)-4-oxo-4-[3-(trifluoromethyl)-5.6- dihydro[1.2.4]triazolo[4 - ]pyrazin-7(8H)-yl]-l-(2.4.5-trifluorophenyl)butan-2- yl] carbamate (Formula 4)
  • Zeolite (CBV-712, 5 g) was added to 6N hydrochloric acid (25 mL) at 20°C to 25°C and the mixture was stirred for 30 minutes. The reaction mixture was filtered under vacuum and suck dried for 30 minutes to obtain activated zeolite.
  • the activated zeolite and isopropyl acetate (45 mL) were added to fert-butyl [(2R)- 4-0X0-4- [3 -(trifluoromethyl)-5 ,6-dihydro [ 1 ,2,4]triazolo [4,3- ]pyrazin-7(8H)-yl] - 1 -(2,4,5 - trifluorophenyl)butan-2-yl]carbamate (Formula 4; 5 g) at 20°C to 25°C.
  • the reaction mixture was heated to 70°C, stirred for 49 hours at 70°C to 75°C, and then filtered at 70°C.
  • the filtrate was cooled to 20°C to 25°C, then stirred for 2 hours at 20°C to 25°C.
  • the wet solid was washed with isopropyl alcohol (5 mL), then dried under vacuum for 15 hours at 40°C to 45°C to obtain the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention provides a process for the preparation of sitagliptin. The present invention also provides a process for the preparation of tert-butyl [(2R)-4-oxo-4- [3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluorophenyl)butan-2-yl]carbamate, an intermediate of sitagliptin.

Description

PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND ITS
INTERMEDIATE
Field of the Invention
The present invention provides a process for the preparation of sitagliptin. The present invention also provides a process for the preparation of fert-butyl [(2i?)-4-oxo-4- [3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate, an intermediate of sitagliptin.
Background of the Invention
Sitagliptin phosphate monohydrate of Formula A, an orally -active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, chemically designated as 7-[(3i?)-3-amino-l-oxo- 4-(2,4,5 -trifluorophenyl)butyl] -5 ,6,7,8-tetrahydro-3 -(trifluoromethyl)- 1 ,2,4-triazolo [4,3 - ]pyrazine phosphate (1 : 1) monohydrate, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Figure imgf000002_0001
Formula A
Several processes are known in the literature for making fert-butyl [(2i?)-4-oxo-4- [3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate and/or sitagliptin, for example, those disclosed in U.S. Patent No. 6,699,871; PCT Publication Nos. WO 2009/064476, WO 2010/097420, WO 2010/122578, WO 2012/035549, WO 2012/099381, WO 2013/114173, WO
2013/013833, and WO 2014/023930; European Patent Nos. EP 2 423 178 and EP 2 647 624; and Indian Application No. 2575/CHE/2009.
The prior art processes reported for the preparation of fert-butyl [(2i?)-4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate utilize agents such as 1-hydroxybenzotriazole, N,N'- dicyclohexylcarbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1,1 '- carbonyldiimidazole, 2-chloro-4,6-dimethoxy-l,3,5-triazine, 2-chlorophenylboronic acid, 3-chlorophenylboronic acid, 4-chlorophenylboronic acid, or phenyl boronic acid; a base, generally diisopropylethylamine or triethylamine; and a solvent such as NN- dimethylformamide (DMF), dichloromethane, or acetonitrile.
The present inventors observed that the agents reported above such as 1- hydroxybenzotriazole, N,N'-dicyclohexylcarbodiimide, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide, Ι, Γ-carbonyldiimidazole, and 2-chloro-4,6- dimethoxy-l,3,5-triazine are costly and hazardous, and agents such as 2- chlorophenylboronic acid, 3-chlorophenylboronic acid, 4-chlorophenylboronic acid, and phenyl boronic acid require lengthy reaction times.
The prior art processes further require a purification process to remove the unwanted side products by recrystallization, trituration, and/or preparative thin layer chromatography .
The prior art processes reported, for example, those disclosed in U.S. Patent No. 6,699,871; PCT Publication Nos. WO 2009/064476, WO 2010/122578, WO 2013/114173; Indian Application No. 2575/CHE/2009; and European Publication No. EP 2 647 624 for the preparation of sitagliptin from fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3 - ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2- yl]carbamate require treating fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3 - ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2- yl]carbamate with hydrochloric acid in a solvent such as methanol or isopropyl alcohol.
The present inventors have developed a process for the preparation of fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromemyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l- (2,4,5-trifluorophenyl)butan-2-yl]carbamate and sitagliptin which is less expensive, less time consuming, and more commercially viable, by avoiding the use of hazardous and costly reagents.
Summary of the Invention
The present invention provides a process for the preparation of fert-butyl [(2i?)-4- oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate which comprises reacting (3R)-3-[(tert- butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid with 3-(trifluoromethyl)- 5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine or a salt thereof in the presence of catalyst, wherein the catalyst is a trialkyl borate or a mixture of boric acid and a trifluoromethyl phenylboronic acid. The present invention also provides a process for the preparation of sitagliptin wherein the process comprises deprotecting fert-butyl [(2i?)-4- oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate in the presence of an activated zeolite. The present inventors have found that the activated zeolite used for the deprotection of fert-butyl
[(2i?)-4-oxo-4-[3-(trifluorome l)-5,6-dmydro[l,2,4]triazolo[4,3-o]pyrazin-7(8H)-yl]-l- (2,4,5-trifluorophenyl)butan-2-yl]carbamate can be recycled.
Detailed Description of the Invention
The term "treating" includes adding, dissolving, slurrying, stirring, and combinations thereof.
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term "solvent" includes water, esters, alkanols, aromatic hydrocarbons, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, and mixtures thereof. Examples of esters include ethyl acetate, ^-propyl acetate, isopropyl acetate, and «-butyl acetate. Examples of alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms, such as methanol, ethanol, «-propanol, isopropanol, and butanol. Examples of aromatic hydrocarbons include toluene and xylene. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2- dichloroethane. Examples of ketones include acetone and methyl ethyl ketone. Examples of ethers include diethyl ether and tetrahydrofuran. Examples of polar aprotic solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
The term "base" includes organic or inorganic bases. Examples of organic bases include ethyl amine, triethylamine, diisopropyl amine, diisopropyl ethyl amine, and mixtures thereof. Examples of inorganic bases include hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals, and the like. Examples of hydroxides, carbonates, and bicarbonates of an alkali or alkaline earth metals include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate. A first aspect of the present invention provides a process for the preparation of sitagliptin of Formula 1
Figure imgf000005_0001
Formula 1
comprising the steps of:
treating (3R)-3 - [(fert-butoxycarbonyl)amino]
trifluorophenyl)butanoic acid of Formula 2
Figure imgf000005_0002
Formula 2
with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof
Figure imgf000005_0003
Formula 3
in the presence of a catalyst wherein the catalyst is a trialkyl borate or a mixture of boric acid and a trifluoromethyl phenylboronic acid to obtain tert- butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl] - 1 -(2,4,5-trifluorophenyl)butan-2-yl]carbamate of Formula 4: and
Figure imgf000006_0001
Formula 4
b) deprotecting the fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3 -a]pyrazin-7(8H)-yl] - 1 -(2,4,5 - trifluorophenyl)butan-2-yl]carbamate of Formula 4 in the presence of an activated zeolite to obtain sitagliptin.
A second aspect of the present invention provides a process for the
preparation of fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4] triazolo [4,3 - ]pyrazin-7(8H)-yl]-l -(2,4,5 -trifluorophenyl)butan-2-yl] carbamate of Formula 4
Figure imgf000006_0002
Formula 4
which comprises treating (3i?)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid of Formula 2
Figure imgf000006_0003
Formula 2
with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof
Figure imgf000007_0001
Formula 3
in the presence of a catalyst, wherein the catalyst is trialkyl borate or a mixture of boric acid and trifluoromethyl phenylboronic acid.
A third aspect of the present invention provides a process for the preparation of sitagliptin of Formula 1
Figure imgf000007_0002
Formula 1
which comprises deprotecting fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3 - ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2 - yl] carbamate of Formula 4
Figure imgf000007_0003
Formula 4
in the presence of an activated zeolite.
The starting material, (3i?)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid of Formula 2, can be prepared by methods known in the art, including that described in European Patent No. EP 2 647 624. The starting material, 3- (trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof, can be prepared by the methods known in the art, including those described in PCT Publication Nos. WO 2004/085661 and WO 2010/122578.
(3i?)-3-[(teri-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid of Formula 2 is treated with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof in the presence of catalyst, wherein the catalyst is a trialkyl borate or a mixture of boric acid and a trifluoromethyl phenylboronic acid, in a solvent at a temperature of about 25 °C to reflux for a time period of about 24 hours to about 36 hours to complete the reaction.
Examples of trialkyl borates include trimethyl borate, triethyl borate, triisopropyl borate, and triisobutyl borate. Examples of trifluoromethyl phenylboronic acids include 2- (trifluoromethyl)phenylboronic acid, 3-(trifluoromethyl)phenylboronic acid, and 4- (trifluoromethy l)phenylboronic acid .
Examples of salts of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine include acid addition salts such as hydrochloride, hydrobromide, and sulfate.
In one embodiment, 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine hydrochloride in toluene is treated with an aqueous sodium hydroxide solution at reflux temperature. (3i?)-3-[(fert-Butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid of Formula 2, boric acid, and 4- (trifluoromethyl)phenylboronic acid are added to 3-(trifluoromethyl)-5,6,7,8- tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 in toluene at a temperature of about 60°C to about 80°C to obtain a reaction mixture, then refluxed while stirring for about 24 hours to complete the reaction.
In another embodiment, boric acid, 4-trifluoromethyl(phenylboronic) acid, and triethylamine are added to a mixture of toluene, (3i?)-3-[(feri-butoxycarbonyl)amino]-4- (2,4,5 -trifluorophenyl)butanoic acid, and 3-(trifluoromethyl)-5, 6,7,8- tetrahydro[l,2,4]triazolo[4,3- ]pyrazine hydrochloride to obtain a reaction mixture, then refluxed while stirring for about 24 hours to complete the reaction.
In yet another embodiment, a mixture of (3i?)-3-[(fert-butoxycarbonyl)amino]-4- (2,4,5 -trifluorophenyl)butanoic acid, triisopropyl borate, and concentrated sulfuric acid in toluene is refluxed for about 2 hours and then cooled to 80°C to 85°C. 3-
(Trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine hydrochloride and triethylamine are added to the mixture at about 80°C to 85°C and refluxed while stirring for about 36 hours to complete the reaction.
After completion of the reaction, teri-butyl[(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3- ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2- yl]carbamate can be either isolated or can be carried to the next step of the process without isolation. Suitable isolation techniques include cooling, evaporation under vacuum, washing, precipitation, filtration, filtration under vacuum, decantation, centrifugation, and combinations thereof.
Deprotection of fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2- yl]carbamate in the presence of an activated zeolite can be performed in one or more solvents at a temperature of about 50°C to about 80°C for a time period sufficient to complete the reaction.
The activated zeolite may be obtained by treating zeolite (CBV-712) with 6N hydrochloric acid at a temperature of about 20°C to 30°C for about 30 minutes, and then filtering the mixture under vacuum.
In one embodiment, a mixture of activated zeolite and isopropyl acetate is added to fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin- 7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-yl]carbamate and heated to about 50°C to about 80°C while stirring for a time period sufficient to complete the reaction.
Sitagliptin can be isolated by cooling, precipitation, washing, filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.
While the present invention has been described in terms of its specific aspects, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be within the scope of the present invention.
EXAMPLES
Example 1 : Preparation of ferf-butyl r(2j?)-4-oxo-4-r3-(trifluoromethvn-5.6- dihydro[1.2.4]triazolo[4 - ]pyrazin-7(8H)-yl]-l-(2.4.5-trifluorophenyl)butan-2- yl] carbamate (Formula 4)
Water (5 mL) and sodium hydroxide (0.72 g, 1.2 equivalents) were added in a round bottom flask and dissolved at 20°C to 25°C. 3-(Trifluoromethyl)-5, 6,7,8- tetrahydro[l,2,4]triazolo[4,3-a]pyrazine hydrochloride (Formula 3; 5 g, 1.5 equivalents) and toluene (50 mL) were added at 20°C to 25 °C to the sodium hydroxide solution and stirred for 30 minutes. The temperature of the reaction mixture was raised to reflux (110°C) and refluxed for 1 hour to remove water. The reaction mixture was cooled to 70°C to 75°C and then (3i?)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid (Formula 2; 5 g, 1 equivalent), boric acid (0.93 g, 1 equivalent), and 4-(trifluoromethyl)phenylboronic acid (0.28 g; 0.1 equivalents) were added to the reaction mixture at 70°C to 75°C. The temperature of the reaction mixture was raised to reflux (110°C) and refluxed for 20 hours to 24 hours. The reaction mixture was cooled to 50°C to 55°C and toluene was recovered completely under vacuum at 50°C to 55°C to obtain a semi-solid residue. 10% Sodium hydroxide solution (50 mL) was added to the semi-solid residue at 20°C to 25°C, and the mixture was stirred for 30 minutes at 20°C to 25 °C. The solid was filtered under vacuum, washed with water (50 mL) at 20°C to 25°C, and then dried in an air drier at 50°C to 55°C for 15 hours to obtain the title compound.
Yield: 5.0 g
Example 2: Preparation of ferf-butyl [(2j?)-4-oxo-4-[3-(trifluoromethyl)-5.6- dihydro[1.2.4]triazolo[4 - ]pyrazin-7(8H)-yl]-l-(2.4.5-trifluorophenyl)butan-2- yl] carbamate (Formula 4)
Toluene (375 mL), (3i?)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid (Formula 2; 25 g, 1 equivalent), and 3-(trifluoromethyl)- 5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine hydrochloride (Formula 3; 20.5 g, 1.2 equivalents) were added in a round bottom flask. Boric acid (2.3 g, 0.5 equivalents), 4- (trifluoromethyl)phenylboronic acid (1.5 g, 0.1 equivalents), and triethylamine (9.0 g, 1.2 equivalents) were added. The temperature of the reaction mixture was raised to reflux (110°C) and refluxed for 22 hours to 24 hours. The reaction mixture was cooled to 50°C to 55°C and toluene was recovered completely under vacuum at 50°C to 55°C to obtain a semi-solid residue. 10% Sodium carbonate solution (250 mL) was added to the semi-solid residue at 20°C to 25°C, and the mixture was stirred for 1 hour at 20°C to 25°C. The solid was filtered under vacuum, washed with water (125 mL) at 20°C to 25 °C, and then dried under vacuum at 40°C to 45°C for 15 hours to obtain the title compound.
Yield: 26.5 g Example 3 : Preparation of ferf-butyl r(2j?)-4-oxo-4-r3-(trifluoromethvn-5.6- dihvdrori.2.41triazolor4 - lpyrazin-7(8H)-yll-l-(2.4.5-trifluorophenyl)butan-2- yll carbamate (Formula 4)
Toluene (300 mL) and (3i?)-3-[(teri-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid (Formula 2; 20 g, 1.0 equivalent) were charged to a round bottom flask. Triisopropyl borate (12.42 g, 1.1 equivalents) and concentrated sulfuric acid (2 drops) were charged at 20°C to 25°C. The temperature was raised to reflux and refluxed for 2 hours. The reaction mixture was cooled to 80°C to 85°C. 3- (Trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- ]pyrazine hydrochloride (Formula 3; 15 g, 1.1 equivalents) and triethylamine (7.27 g, 1.2 equivalents) were charged at 80°C to 85°C to the reaction mixture and the temperature was raised to reflux and refluxed for 36 hours to 38 hours using a Dean-Stark apparatus. On completion of the reaction, toluene was recovered completely under vacuum at 50°C to 55°C. Water (100 mL) was charged to the solid residue, and the mixture was stirred for 2 hours at 20°C to 25°C. The solid was filtered under vacuum, washed with water (100 mL), and then dried in an air drier at 50°C to 55°C for 14 hours to 16 hours to obtain the title compound.
Yield: 28 g (92.10%)
Example 4: Preparation of sitagliptin (Formula 1)
Zeolite (CBV-712, 5 g) was added to 6N hydrochloric acid (25 mL) at 20°C to 25°C and the mixture was stirred for 30 minutes. The reaction mixture was filtered under vacuum and suck dried for 30 minutes to obtain activated zeolite.
The activated zeolite and isopropyl acetate (45 mL) were added to fert-butyl [(2R)- 4-0X0-4- [3 -(trifluoromethyl)-5 ,6-dihydro [ 1 ,2,4]triazolo [4,3- ]pyrazin-7(8H)-yl] - 1 -(2,4,5 - trifluorophenyl)butan-2-yl]carbamate (Formula 4; 5 g) at 20°C to 25°C. The reaction mixture was heated to 70°C, stirred for 49 hours at 70°C to 75°C, and then filtered at 70°C. The filtrate was cooled to 20°C to 25°C, then stirred for 2 hours at 20°C to 25°C. The wet solid was washed with isopropyl alcohol (5 mL), then dried under vacuum for 15 hours at 40°C to 45°C to obtain the title compound.
Yield: 3.0 g

Claims

Claims:
1. A process for the preparation of sitagliptin of Formula 1
Figure imgf000012_0001
Formula 1
comprising the steps of:
a) treating (3i?)-3-[(teri-butoxycarbonyl)amino]
trifluorophenyl)butanoic acid of Formula 2
Figure imgf000012_0002
Formula 2
with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof
Figure imgf000012_0003
Formula 3
in the presence of a catalyst, wherein the catalyst is a trialkylborate or a mixture of boric acid and a trifluoromethyl phenylboronic acid, to obtain butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl] - 1 -(2,4,5-trifluorophenyl)butan-2-yl]carbamate of Formula 4; and
Figure imgf000013_0001
Formula 4
b) deprotecting the fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3 -a]pyrazin-7(8H)-yl] - 1 -(2,4,5 - trifluorophenyl)butan-2-yl]carbamate of Formula 4 in the presence of an activated zeolite to obtain sitagliptin.
2. A process for the preparation of fert-butyl [(2i?)-4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate of Formula 4
Figure imgf000013_0002
Formula 4
which comprises treating (3i?)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid of Formula 2
Figure imgf000013_0003
Formula 2
with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof
Figure imgf000014_0001
Formula 3
in the presence of a catalyst, wherein the catalyst is a trialkylborate or a mixture of boric acid and a trifluoromethyl phenylboronic acid.
3. A process for the preparation of sitagliptin of Formula 1
Figure imgf000014_0002
Formula 1
which comprises deprotecting tert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3 - ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2 - yl] carbamate of Formula 4
Figure imgf000014_0003
Formula 4
in the presence of an activated zeolite.
4. The process according to claim 1 or claim 2, wherein the treatment of (3i?)-3- [(teri-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid of Formula 2 with 3- (trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof is performed in a solvent at a temperature of 25 °C to reflux.
5. The process according to claim 1 or claim 2, wherein the trialkylborate is selected from the group consisting of trimethyl borate, triethyl borate, triisopropyl borate, or triisobutyl borate.
6. The process according to claim 1 or claim 2, wherein the trifluoromethyl phenylboronic acid is selected from the group consisting of 2- (trifluoromethyl)phenylboronic acid, 3-(trifluoromethyl)phenylboronic acid, or 4- (trifluoromethyl)phenylboronic acid.
7. The process according to claim 1 or claim 3, wherein the deprotection is performed in one or more solvents at a temperature of 50°C to 80°C.
8. The process according to claim 1 or claim 3, wherein the activated zeolite is obtained by treating zeolite (CBV-712) with 6N hydrochloric acid at a temperature of 20°C to 30°C.
9. The process according to claim 4 or claim 7, wherein the solvent is selected from the group consisting of water, esters, alkanols, aromatic hydrocarbons, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, and mixtures thereof.
PCT/IB2015/052119 2014-03-26 2015-03-23 Process for the preparation of sitagliptin and its intermediate Ceased WO2015145333A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN876/DEL/2014 2014-03-26
IN876DE2014 2014-03-26

Publications (2)

Publication Number Publication Date
WO2015145333A1 true WO2015145333A1 (en) 2015-10-01
WO2015145333A8 WO2015145333A8 (en) 2015-11-26

Family

ID=54194049

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2015/052119 Ceased WO2015145333A1 (en) 2014-03-26 2015-03-23 Process for the preparation of sitagliptin and its intermediate

Country Status (1)

Country Link
WO (1) WO2015145333A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111039900A (en) * 2019-02-28 2020-04-21 上海弈柯莱生物医药科技有限公司 Preparation method of 1-morpholine-4- (2,4, 5-trifluorophenyl) butane-1, 3-dione

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6699871B2 (en) 2001-07-06 2004-03-02 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004085661A2 (en) 2003-03-24 2004-10-07 Merck & Co., Inc Process to chiral beta-amino acid derivatives
WO2009064476A1 (en) 2007-11-13 2009-05-22 Teva Pharmaceutical Industries Ltd. Preparation of sitagliptin intermediate
WO2010097420A1 (en) 2009-02-25 2010-09-02 Esteve Química, S.A. Process for the preparation of a chiral beta aminoacid derivative and intermediates thereof
WO2010122578A2 (en) 2009-04-20 2010-10-28 Msn Laboratories Limited Process for the preparation of sitagliptin and its intermediates
EP2423178A1 (en) 2010-07-28 2012-02-29 Chemo Ibérica, S.A. Process for the production of sitagliptin
WO2012035549A2 (en) 2010-09-13 2012-03-22 Panacea Biotec Ltd An improved process for the synthesis of beta amino acid derivatives
WO2012099381A2 (en) 2011-01-20 2012-07-26 St Pharm Co., Ltd. Preparation method of intermediate of sitagliptin
WO2013013833A1 (en) 2011-07-27 2013-01-31 Farma Grs, D.O.O. Process for the preparation of sitagliptin and its pharmaceutically acceptable salts
WO2013114173A1 (en) 2012-01-30 2013-08-08 Smilax Laboratories Limited A novel process for the preparation of sitagliptin
EP2647624A1 (en) 2010-12-03 2013-10-09 Zhejiang Hisoar Pharmaceutical Co., Ltd Intermediates of sitagliptin and preparation process thereof
WO2014023930A1 (en) 2012-08-08 2014-02-13 Cipla Limited Process for the preparation of sitagliptin and intermediate compounds

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6699871B2 (en) 2001-07-06 2004-03-02 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004085661A2 (en) 2003-03-24 2004-10-07 Merck & Co., Inc Process to chiral beta-amino acid derivatives
WO2009064476A1 (en) 2007-11-13 2009-05-22 Teva Pharmaceutical Industries Ltd. Preparation of sitagliptin intermediate
WO2010097420A1 (en) 2009-02-25 2010-09-02 Esteve Química, S.A. Process for the preparation of a chiral beta aminoacid derivative and intermediates thereof
WO2010122578A2 (en) 2009-04-20 2010-10-28 Msn Laboratories Limited Process for the preparation of sitagliptin and its intermediates
EP2423178A1 (en) 2010-07-28 2012-02-29 Chemo Ibérica, S.A. Process for the production of sitagliptin
WO2012035549A2 (en) 2010-09-13 2012-03-22 Panacea Biotec Ltd An improved process for the synthesis of beta amino acid derivatives
EP2647624A1 (en) 2010-12-03 2013-10-09 Zhejiang Hisoar Pharmaceutical Co., Ltd Intermediates of sitagliptin and preparation process thereof
WO2012099381A2 (en) 2011-01-20 2012-07-26 St Pharm Co., Ltd. Preparation method of intermediate of sitagliptin
WO2013013833A1 (en) 2011-07-27 2013-01-31 Farma Grs, D.O.O. Process for the preparation of sitagliptin and its pharmaceutically acceptable salts
WO2013114173A1 (en) 2012-01-30 2013-08-08 Smilax Laboratories Limited A novel process for the preparation of sitagliptin
WO2014023930A1 (en) 2012-08-08 2014-02-13 Cipla Limited Process for the preparation of sitagliptin and intermediate compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JONES R ET AL: "A novel zeolite catalysed deprotection of the tert-butoxycarbonyl group suitable for the synthesis of pharmaceutically active peptides", JOURNAL OF PHARMACY AND PHARMACOLOGY, JOHN WILEY & SONS LTD, LONDON; GB, vol. 46, no. Suppl. 2, 1 January 1994 (1994-01-01), pages 1079, XP009184247, ISSN: 0022-3573 *
PAVEL STARKOV ET AL: "Borate esters as convenient reagents for direct amidation of carboxylic acids and transamidation of primary amides", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 9, no. 5, 1 January 2011 (2011-01-01), pages 1320, XP055189026, ISSN: 1477-0520, DOI: 10.1039/c0ob01069c *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111039900A (en) * 2019-02-28 2020-04-21 上海弈柯莱生物医药科技有限公司 Preparation method of 1-morpholine-4- (2,4, 5-trifluorophenyl) butane-1, 3-dione
CN111039900B (en) * 2019-02-28 2023-12-22 弈柯莱生物科技(集团)股份有限公司 Preparation method of 1-morpholine-4-(2,4,5-trifluorophenyl)butane-1,3-dione

Also Published As

Publication number Publication date
WO2015145333A8 (en) 2015-11-26

Similar Documents

Publication Publication Date Title
US11661424B2 (en) Process for preparing BTK inhibitors
US7998951B2 (en) HCV NS5B inhibitors
CN110582500A (en) Bicyclic nucleocapsid inhibitors and their use as medicaments for the treatment of hepatitis b
AU2011276978A1 (en) Process for the synthesis of substituted morphinans
CN114591339B (en) Toll-like receptor inhibitor and preparation and application thereof
CN120379988A (en) Benzobicyclo compound and preparation method and application thereof
JP2012519173A (en) Cyclopropyl condensed indolobenzazepine HCVNS5B inhibitor
EP4497752A1 (en) Pyrimido-pyridazinone compound as toll-like receptor agonist
WO2018038667A1 (en) Respiratory syncytial virus inhibitors
CN103539773B (en) Method for preparing ticagrelor key intermediate
WO2015145333A1 (en) Process for the preparation of sitagliptin and its intermediate
US20130123501A1 (en) Process for the preparation of the compound osi-906
Yu et al. A high-yielding method for the preparation of isoxazolopyridin-3-amine derivatives
EP2788352A1 (en) Amorphous form of sitagliptin salts
WO2015118110A1 (en) Pyrido[2,3-d]pyrimidine-7(8h)-one derivatives for the treatment of hepatitis c
WO2015162506A1 (en) Process for the preparation of sitagliptin and novel intermediates
AU2014302595B2 (en) Method for the preparation of [1,2,4]-triazolo[4,3-a]pyridines
TWI617562B (en) An improved process for the preparation of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine from 4-amino-2,5-dimethoxypyrimidine
US20090018336A1 (en) Racemization process of R-zopiclone
EP2886544B1 (en) Process for the preparation of crystalline sitagliptin fumarate
CN101781314B (en) Preparation process of levofloxacin hemihydrate
CN119285633A (en) A hydrophobic tag compound for targeted degradation of Tau protein and its preparation and application
CN110437132B (en) Bifused heterocyclic nucleocapsid inhibitors and pharmaceutical uses thereof
WO2018038668A1 (en) Respiratory syncytial virus inhibitors
WO2026020054A1 (en) Compounds and methods for treating neurological disorders

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15716873

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15716873

Country of ref document: EP

Kind code of ref document: A1