WO2023175492A1 - Novel intermediates and its use in manufacturing of sitagliptin - Google Patents

Novel intermediates and its use in manufacturing of sitagliptin Download PDF

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WO2023175492A1
WO2023175492A1 PCT/IB2023/052451 IB2023052451W WO2023175492A1 WO 2023175492 A1 WO2023175492 A1 WO 2023175492A1 IB 2023052451 W IB2023052451 W IB 2023052451W WO 2023175492 A1 WO2023175492 A1 WO 2023175492A1
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formula
compound
solvent
preparation
acid
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PCT/IB2023/052451
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French (fr)
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Rahul Arvind Bhalerao
Sandeep Rameshrao TAPKIR
Manikrao Ramrao Warpe
Shivaji Balbhim Gugale
Sharad Sidram Gaikwad
Manoj Nanda JADHAV
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Hikal Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to novel intermediate of formula (V) and formula (VI) and process for preparation thereof.
  • the present invention further relates to an industrially feasible and commercially viable process for preparation of sitagliptin and pharmaceutically acceptable salts using novel intermediates of formula (V) and formula (VI) in high yield with greater chemical and chiral purity.
  • Sitagliptin is chemically known as (7?)-3-amino-l-[3-(trifluoromethyl)-5,6, dihydro [1,2,4] triazo lo [4, 3 -a] pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl) butan-l-one and useful as a potent second-generation inhibitor of dipeptidyl-peptidase (DPP)-IV for the treatment of Type-2 diabetes.
  • DPP dipeptidyl-peptidase
  • the inventors of the present invention developed process for preparation sitagliptin and pharmaceutically acceptable salts thereof which involve use of novel intermediates.
  • the present process overcome the limitations of the prior arts processes in a cost effective, industrially convenient way.
  • the instant five-step process is easy to perform on industrial scale with use of commercially available reagents, solvents which further results into greater purity (>99%) with high yield (>90%) of Sitagliptin.
  • the present invention relates to novel intermediates of formula (V) and formula
  • the present invention provides a process for preparation of novel intermediates of formula (V) and formula (VI) and their use in preparation of Sitagliptin of formula (I) or its pharmaceutically acceptable salts thereof.
  • the present invention provides a process for the preparation of Sitagliptin of formula (I) or its pharmaceutically acceptable salts thereof using novel intermediates of formula (V) and formula (VI) comprising the steps of: a) reacting a compound of formula (II) with Meldrum’s acid in the presence of a base, acyl chloride, solvent with or without catalyst to obtain a compound of formula (III); b) reacting a compound of formula (III) with an aniline in solvent to obtain a compound of formula (IV); c) reacting a compound of formula (IV) with chiral 2-halo-phenyl glycine methyl ester in presence of acid or base, and solvent to obtain a compound of formula (V); wherein X is halogen d) reducing compound of formula (V) in presence
  • the present invention provides a compound of formula (V) and compound of formula (VI).
  • the present invention relates to a process for preparation of compound of formula (I) by using intermediates of formula (V) and formula (VI) comprising steps of: a) reacting a compound of formula (IV) with chiral 2-halo-phenyl glycine methyl ester in presence of acid or base and solvent to obtain compound of formula (V); b) reducing compound of formula (V) in presence of reducing agent, acid and solvent to obtain compound of formula (VI);
  • solvent used herein refers to the single solvent or mixture of solvents.
  • the present invention provides a process for the preparation of sitagliptin of formula (I) and its salt thereof via use of novel intermediate and synthetic approach.
  • the present invention provides the preparation of compound (VI), wherein the compounds of formula (IV) and compound of formula (V) were not isolated, which makes present process more economic.
  • the compound of formula (VI) is further converted into Sitagliptin compound of formula (I) and pharmaceutically acceptable salts.
  • acyl chloride used is selected from pivaloyl chloride, propionyl chloride, butanoyl chloride and the like.
  • the base used for preparation of compound (III) is selected from N, A-Diisopropylethylamine and triethyl amine.
  • the base used for preparation of compound (VII) is selected from organic or inorganic or aromatic bases.
  • the catalyst used in catalytic amount selected from tetra-butyl ammonium chloride, tetra-butyl ammonium iodide and the like.
  • the compound of formula (V) is obtained by reacting compound of formula (IV) with chiral 2-halo phenyl glycine methyl ester compound of formula (XI) selected from (S)-(+)-2-Chlorophenylglycine methyl ester, (S)-(+)- 2-bromophenylglycine methyl ester, and (S)-(+)-2-Iodophenylglycine methyl ester or its salt.
  • chiral 2-halo phenyl glycine methyl ester compound of formula (XI) selected from (S)-(+)-2-Chlorophenylglycine methyl ester, (S)-(+)- 2-bromophenylglycine methyl ester, and (S)-(+)-2-Iodophenylglycine methyl ester or its salt.
  • the said acid used for the preparation of compound of formula (V) and (VI) is selected from sulfuric acid, acetic acid, trifluoro acetic acid, and the like.
  • the said base used for the preparation of compound of formula (V) is selected from organic base such as triethyl amine, pyridine and the like; and inorganic bases such as sodium hydroxide, potassium hydroxide sodium carbonate, potassium carbonate, and the like.
  • the said reducing agent is selected from group consisting of suitable metal catalyst, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, sodium cyanoborohydride, sodium triacetoxyborohydride, platinum oxide, palladium on carbon.
  • suitable metal catalyst such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, sodium cyanoborohydride, sodium triacetoxyborohydride, platinum oxide, palladium on carbon.
  • the metal catalyst used for preparation of compound of formula (VII) is selected from palladium on carbon, palladium hydroxide on carbon, nickel on carbon and the like.
  • base used for the preparation of compound of formula (IX) is selected from morpholine, triethyl amine, pyridine and the like.
  • the acid used in preparation of compound of formula (I) is selected from organic or inorganic acids.
  • the said organic acid is selected from acetic acid and propionic acid
  • the inorganic acid such as cone, hydrochloric acid, cone, sulfuric acid, nitric acid, phosphoric acid, and the like or mixture of acids.
  • the base used in preparation of compound of formula (I) is selected from organic or inorganic base; where organic base selected from triethyl amine, tert. -butyl amine, pyridine, imidazole, and the like and inorganic base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like.
  • a compound of formula (I) may be further converted into its pharmaceutically acceptable salts by treating with a suitable acid, more preferably phosphoric acid.
  • the said solvent used in preparation compound of formula (III), (IV), (V), (VI), (VII), (IX) and (I) is selected from alcoholic solvents, ketonic solvents, esters, halogenating solvents, ethereal solvents, hydrocarbon solvent and the like or mixture of solvent.
  • the said solvent used for preparation of compound of formula (III) and (IV) is a hydrocarbon solvent which is selected from cyclohexane, n-hexane, n- heptane, toluene, xylene and the like or mixture of solvents.
  • the said solvent used for preparation of compound of formula (V) is a halogenating solvent such as dichloroethane, chloroform, dichloromethane and the like, or mixture of solvents and aprotic solvent such as dimethoxyethane, tetrahydro furan, 1-4 dioxane and the like.
  • the said solvent used for preparation of compound of formula (VI) is a halogenating solvent such as dichloroethane, chloroform, dichloro methane and the like, or mixture of solvents.
  • the said solvent(s) used for preparation of compound of formula (VII) is selected from halogenating solvent such as dichloroethane, chloroform, dichloro methane; ethereal solvents such as methyl tert-butyl ether, 1,4-dioxane, tetrahydro furan, 1,2-dimethoxy ethane and the like or mixture of solvents, more preferably 1,2-dimethoxy ethane; and alcoholic solvent such as methanol, ethanol, isopropanol, and hydrocarbon solvent such as heptane, hexane and the like or mixture thereof.
  • halogenating solvent such as dichloroethane, chloroform, dichloro methane
  • ethereal solvents such as methyl tert-butyl ether, 1,4-dioxane, tetrahydro furan, 1,2-dimethoxy ethane and the like or mixture of solvents, more preferably 1,2-dime
  • (IX) is selected from halogenating solvent such as dichloroethane, chloroform, dichloro methane; ester solvent such as ethyl acetate, ethyl aceto acetate, ethyl butyrate, and the like.
  • halogenating solvent such as dichloroethane, chloroform, dichloro methane
  • ester solvent such as ethyl acetate, ethyl aceto acetate, ethyl butyrate, and the like.
  • alcoholic solvent such as methanol, ethanol, isopropanol, and the like or mixture thereof.
  • reaction temperature for the preparation of compound of formula (III), (IV) and (V) is 0°C to 50°C.
  • reaction temperature for the preparation of compound of formula (VI) is -60°C to -40°C.
  • reaction temperature for the preparation of compound of formula (VII) is 30°C to 70°C.
  • reaction temperature for the preparation of compound of formula (IX) is -20°C to 0°C.
  • reaction temperature for the preparation of compound of formula (I) is 10°C to 50°C.
  • step (a) to step (f) wherein all the crude involved in step (a) to step (f) is used as such or purified by distillation or crystallization or by different purification techniques well understood by those skilled in the art.
  • step (f) wherein one or all the steps may be performed in in- situ manner.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like, particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine.
  • basic ion exchange resins such as arginine
  • Part-A To a stirred solution of compound IV (40.0g, 0.123 moles) in dichloromethane (10 V), (S)-(+) (2-Chlorophenyl) glycine methyl ester (1.4 eq.) and cone, sulphuric acid (O.leq) was added at room temperature. The reaction mixture was heated to 40°C to 50°C for 2-3 h. The solvent was removed by atmospheric distillation till minimum stirrable reaction volume. The reaction mixture was allowed to cool to room temperature and dichloromethane (4 V) and water (5V) was added. The organic layer washed with 10% citric acid, saturated sodium carbonate and brine solution. The solvent was removed by atmospheric distillation till obtain minimum stirrable reaction volume.
  • Part-B In another vessel a cold solution of dichloromethane (3.5 V), 1,2-dimethoxy ethane (3.5 V) and sodium borohydride (1.05 eq.) at -60 ⁇ 40 °C under nitrogen atmosphere was prepared. To this cold solution, acetic acid (3.0eq) was added slowly for 30min. To this reaction mixture Part -A reaction volume was added at -60 ⁇ 40 °C for 1-2 h and maintained under stirring for 1 h. The completion of rection was monitored by HPLC. After completion of to 60reaction, the reaction mixture was quenched by adding into water (7 V) at 0°C to 10°C. The aq. layer extracted with dichloromethane, and combined organic layer washed with brine solution. The solvent was removed by distillation till minimum stirrable reaction volume. To this reaction solution methanol (7 V) was charged and entire organic layer was distilled at 50°C to 60°C till minimum stirrable volume.
  • Part-C To a hydrogenation unit (autoclave) a reaction volume (Part B), methanol (5V), 10% Pd/C (10%w/w) was added. The hydrogen gas was purged with a pressure of 12 ⁇ 2 Kg/cm 2 at 60°C to 75°C for 6-8 h. The completion of rection was monitored by HPLC. After completion, the reaction mixture was cooled to room temperature and filtered to remove catalyst. The solvent was removed by distillation and cone, hydrochloric acid was added and heated to 90°C to 100°C for 6 h. The reaction mixture was cooled to room temperature and 50% aq. Sodium hydroxide solution and dichloromethane was added. The organic layer separated, and to the aq.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to novel intermediate of formula (V) and formula (VI) and preparation thereof. The present invention further relates to an industrially feasible and commercially viable process for preparation of sitagliptin or its pharmaceutically acceptable salts using novel intermediates of formula (V) and formula (VI) in high yield with greater chemical and chiral purity.

Description

“NOVEL INTERMEDIATES AND ITS USE IN MANUFACTRING OF SITAGLIPTIN”
RELATED APPLICATION
This application claims the benefit of Indian Provisional Application No. IN202221013755 filed on March 14, 2023, the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to novel intermediate of formula (V) and formula (VI) and process for preparation thereof. The present invention further relates to an industrially feasible and commercially viable process for preparation of sitagliptin and pharmaceutically acceptable salts using novel intermediates of formula (V) and formula (VI) in high yield with greater chemical and chiral purity.
Figure imgf000002_0001
BACKGROUND OF THE INVENTION
Sitagliptin is chemically known as (7?)-3-amino-l-[3-(trifluoromethyl)-5,6, dihydro [1,2,4] triazo lo [4, 3 -a] pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl) butan-l-one and useful as a potent second-generation inhibitor of dipeptidyl-peptidase (DPP)-IV for the treatment of Type-2 diabetes. The structure of sitagliptin is represented below.
Figure imgf000002_0002
The PCT publication W02004/085378 (henceforth '378), W02005/097733 (henceforth '733), W02006/081151 (henceforth T51), J. Am. Chem. Soc., 2004, 126 (32), 9918-9919 and J. Am. Chem. Soc., 2009, 131(25), 8798-8804 discloses the preparation of sitagliptin and pharmaceutically acceptable salts thereof in pure form. The said process is described in scheme (I)-
Scheme-I:
Figure imgf000003_0001
The PCT Publication W02004/085661 disclose the process which involves the preparation of sitagliptin using (S)-phenyl glycine amide as a chiral auxiliary. The said process is described in scheme (II).
Scheme-II:
Figure imgf000003_0002
The PCT Publication W02004/087650 discloses the preparation of sitagliptin using the chiral benzyloxylazetidinone as an intermediate. The said process is described in scheme (III).
Scheme (III):
Figure imgf000004_0001
The research publication IP.com Journal, Vol.9, Iss.5B, Page 36, 2009 discloses the novel process for the preparation of sitagliptin by reacting l-(3-(trifluoromethyl)-5,6-dihydro- [1, 2, 4]triazolo[4, 3-a]pyrazin-7(8H)-yl)-4-(2, 4, 5-trifluorophenyl)butane- 1,3-dione with optically pure (S)-phenylethylamine (which may be substituted with an alkyl or alkoxy group on phenyl ring) in the presence of a drying agent to obtain (Z)-3-(l-phenylethylamino)-l-(3- (trifluoromethyl)-5,6-dihydro-[l,2,4] triazo lo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)but-2-en-l-one which on stereoselective reduction in presence of catecho Iborane or a derivative of catecholborane and further hydrogenolysis in the presence of Pd/C and hydrogen source provides sitagliptin. The process involves expensive reagents and involve combi-Flash chromatography technique for purification of compound. The said process is substantially described in scheme (IV).
Scheme-IV :
Figure imgf000004_0002
The above processes, however, have one or more disadvantages, for example: (i) the use of expensive catalyst like Ruthenium, Platinum; (ii) use of hazardous and difficult to handle reagent like triphenylphosphine; (iii) use of expensive chiral auxiliary like (S)-phenyl glycine amide; (iv) use of expensive organoboron compound such as catecho Iborane; (v) more no of steps; (vi) longer reaction time; (vii) use of column purification or multiple purification and recrystallization technique; and (viii) excess effluent generation. Thus, to overcome the above disadvantages, there is a need for a synthetic approach which is industrially feasible and scalable for preparation of sitagliptin and pharmaceutically acceptable salts thereof.
To address mainly the drawbacks associated with the prior arts, the inventors of the present invention developed process for preparation sitagliptin and pharmaceutically acceptable salts thereof which involve use of novel intermediates. The present process overcome the limitations of the prior arts processes in a cost effective, industrially convenient way. The instant five-step process is easy to perform on industrial scale with use of commercially available reagents, solvents which further results into greater purity (>99%) with high yield (>90%) of Sitagliptin.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to novel intermediates of formula (V) and formula
(VI).
Figure imgf000005_0001
In another aspect, the present invention provides a process for preparation of novel intermediates of formula (V) and formula (VI) and their use in preparation of Sitagliptin of formula (I) or its pharmaceutically acceptable salts thereof.
Figure imgf000005_0002
In another aspect, the present invention provides a process for the preparation of Sitagliptin of formula (I) or its pharmaceutically acceptable salts thereof using novel intermediates of formula (V) and formula (VI) comprising the steps of: a) reacting a compound of formula (II) with Meldrum’s acid in the presence of a base, acyl chloride, solvent with or without catalyst to obtain a compound of formula (III);
Figure imgf000006_0001
b) reacting a compound of formula (III) with an aniline in solvent to obtain a compound of formula (IV);
Figure imgf000006_0002
c) reacting a compound of formula (IV) with chiral 2-halo-phenyl glycine methyl ester in presence of acid or base, and solvent to obtain a compound of formula (V);
Figure imgf000006_0003
wherein X is halogen d) reducing compound of formula (V) in presence of reducing agent, acid and solvent(s) to obtain a compound of formula (VI);
Figure imgf000006_0004
e) reacting compound of formula (VI) with di-tert-butyl dicarbonate in presence of metal catalyst, solvent(s) to obtain a compound of formula (VII);
Figure imgf000007_0001
f) coupling a compound of formula (VII) with a compound of formula (VIII) or its salt in presence of base, acyl chloride, and solvent to obtain a compound of formula (IX);
Figure imgf000007_0002
g) reacting compound of formula (IX) with an acid, in presence of solvent to obtain a compound of formula (I) or pharmaceutically acceptable salt.
Figure imgf000007_0003
In another aspect, the present invention provides a compound of formula (V) and compound of formula (VI).
Figure imgf000007_0004
In yet another aspect, the present invention relates to a process for preparation of compound of formula (I) by using intermediates of formula (V) and formula (VI) comprising steps of: a) reacting a compound of formula (IV) with chiral 2-halo-phenyl glycine methyl ester in presence of acid or base and solvent to obtain compound of formula (V);
Figure imgf000008_0001
b) reducing compound of formula (V) in presence of reducing agent, acid and solvent to obtain compound of formula (VI);
Figure imgf000008_0002
DETAILED DESCRIPTION OF THE INVENTION
The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.
The term solvent used herein, refers to the single solvent or mixture of solvents.
In an embodiment, the present invention provides a process for the preparation of sitagliptin of formula (I) and its salt thereof via use of novel intermediate and synthetic approach.
In another embodiment, the present invention provides the preparation of compound (VI), wherein the compounds of formula (IV) and compound of formula (V) were not isolated, which makes present process more economic.
In another embodiment, the present invention the compound of formula (VI) is further converted into Sitagliptin compound of formula (I) and pharmaceutically acceptable salts.
In another embodiment of the present invention, wherein the acyl chloride used is selected from pivaloyl chloride, propionyl chloride, butanoyl chloride and the like.
In another embodiment of the present invention, wherein the base used for preparation of compound (III) is selected from N, A-Diisopropylethylamine and triethyl amine.
In another embodiment of the present invention, wherein the base used for preparation of compound (VII) is selected from organic or inorganic or aromatic bases.
In another embodiment of the present invention, wherein the catalyst used in catalytic amount and selected from tetra-butyl ammonium chloride, tetra-butyl ammonium iodide and the like.
In another embodiment of the present invention, wherein the compound of formula (V) is obtained by reacting compound of formula (IV) with chiral 2-halo phenyl glycine methyl ester compound of formula (XI) selected from (S)-(+)-2-Chlorophenylglycine methyl ester, (S)-(+)- 2-bromophenylglycine methyl ester, and (S)-(+)-2-Iodophenylglycine methyl ester or its salt. MeOOC^/^>
NH2
(XI)
X is halogen
In another embodiment of the present invention, wherein the said acid used for the preparation of compound of formula (V) and (VI) is selected from sulfuric acid, acetic acid, trifluoro acetic acid, and the like.
In another embodiment of the present invention, wherein the said base used for the preparation of compound of formula (V) is selected from organic base such as triethyl amine, pyridine and the like; and inorganic bases such as sodium hydroxide, potassium hydroxide sodium carbonate, potassium carbonate, and the like.
In another embodiment of the present invention, wherein the said reducing agent is selected from group consisting of suitable metal catalyst, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, sodium cyanoborohydride, sodium triacetoxyborohydride, platinum oxide, palladium on carbon.
In another embodiment of the present invention, wherein the metal catalyst used for preparation of compound of formula (VII) is selected from palladium on carbon, palladium hydroxide on carbon, nickel on carbon and the like.
In another embodiment of the present invention, wherein base used for the preparation of compound of formula (IX) is selected from morpholine, triethyl amine, pyridine and the like.
In another embodiment of the present invention, wherein the acid used in preparation of compound of formula (I) is selected from organic or inorganic acids.
In another embodiment of the present invention wherein the said organic acid is selected from acetic acid and propionic acid, and the inorganic acid such as cone, hydrochloric acid, cone, sulfuric acid, nitric acid, phosphoric acid, and the like or mixture of acids.
In another embodiment of the present invention, wherein the base used in preparation of compound of formula (I) is selected from organic or inorganic base; where organic base selected from triethyl amine, tert. -butyl amine, pyridine, imidazole, and the like and inorganic base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like.
A compound of formula (I) may be further converted into its pharmaceutically acceptable salts by treating with a suitable acid, more preferably phosphoric acid.
In another embodiment of the present invention, wherein the said solvent used in preparation compound of formula (III), (IV), (V), (VI), (VII), (IX) and (I) is selected from alcoholic solvents, ketonic solvents, esters, halogenating solvents, ethereal solvents, hydrocarbon solvent and the like or mixture of solvent.
In another embodiment of the present invention, wherein the said solvent used for preparation of compound of formula (III) and (IV) is a hydrocarbon solvent which is selected from cyclohexane, n-hexane, n- heptane, toluene, xylene and the like or mixture of solvents.
In another embodiment of the present invention, wherein the said solvent used for preparation of compound of formula (V) is a halogenating solvent such as dichloroethane, chloroform, dichloromethane and the like, or mixture of solvents and aprotic solvent such as dimethoxyethane, tetrahydro furan, 1-4 dioxane and the like.
In another embodiment of the present invention, wherein the said solvent used for preparation of compound of formula (VI) is a halogenating solvent such as dichloroethane, chloroform, dichloro methane and the like, or mixture of solvents.
In another embodiment of the present invention, wherein the said solvent(s) used for preparation of compound of formula (VII) is selected from halogenating solvent such as dichloroethane, chloroform, dichloro methane; ethereal solvents such as methyl tert-butyl ether, 1,4-dioxane, tetrahydro furan, 1,2-dimethoxy ethane and the like or mixture of solvents, more preferably 1,2-dimethoxy ethane; and alcoholic solvent such as methanol, ethanol, isopropanol, and hydrocarbon solvent such as heptane, hexane and the like or mixture thereof.
In another embodiment of the present invention, wherein the said solvent(s) used for preparation of compound of formula (VI), (IX) is selected from halogenating solvent such as dichloroethane, chloroform, dichloro methane; ester solvent such as ethyl acetate, ethyl aceto acetate, ethyl butyrate, and the like. In another embodiment of the present invention, wherein the said solvent(s) used for preparation of compound of formula (I) is selected from alcoholic solvent such as methanol, ethanol, isopropanol, and the like or mixture thereof.
In another embodiment of the present invention, wherein the reaction temperature for the preparation of compound of formula (III), (IV) and (V) is 0°C to 50°C.
In another embodiment of the present invention, wherein the reaction temperature for the preparation of compound of formula (VI) is -60°C to -40°C.
In another embodiment of the present invention, wherein the reaction temperature for the preparation of compound of formula (VII) is 30°C to 70°C.
In another embodiment of the present invention, wherein the reaction temperature for the preparation of compound of formula (IX) is -20°C to 0°C.
In another embodiment of the present invention, wherein the reaction temperature for the preparation of compound of formula (I) is 10°C to 50°C.
In another embodiment of the present invention, wherein the characterization data of compound of formula (VI), where X is chlorine is as given below:
Figure imgf000012_0001
JH NMR (DMSO, 400 MHz): 2.32 (1H, t); 2.63 (1H, t); 2.71 (1H, dd); 2.88 (1H, t); 3.05 (1H, t); 3.53 (3H, s); 3.57 (1H, s); 4.92 (1H, d); 7.19 (2H, t); 7.29 (5H, m); 7.47 (2H, m); 7.58 (2H, d); 10.05 (1H, s); and LCMS: 491 [M+H]+.
In another embodiment of the present invention, wherein all the crude involved in step (a) to step (f) is used as such or purified by distillation or crystallization or by different purification techniques well understood by those skilled in the art. In another embodiment of the present invention, wherein one or all the steps may be performed in in- situ manner.
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like, particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine.
The following non-limiting examples are given by way of illustration of the present invention and therefore should not be construed as limitation of the invention scope.
EXPERIMENTAL
Example 1: Preparation of compound of formula (III).
To a stirred solution of compound II (200.0g, l.Oeq.) in toluene (3.0V), Meldrum’s acid (1.2 eq.), tetrabutylammonium bromide (0.03 eq.) and dimethyl aminopyridine (0.08 eq.) was added at room temperature. The reaction mixture was cooled to 0°C to 10°C. To the reaction mixture V,V-Diisopropylethylamine (2.2 eq) and pivaloyl chloride (1.2 eq) was added slowly and maintained to 0°C to 10°C for 30 min. The reaction mixture was heated at 40°C to 50°C for 2- 4h. The completion of reaction is monitored by HPLC. After completion, the reaction mixture was allowed to cool to 0°C to 10°C and quenched by adding 10% hydrochloric acid for 1-2 h. The solid compound was filtered and washed with water to yield compound III as a pale yellow solid (150g, 90%), MS: 315 [M-H]+. Example 2: Preparation of compound of formula (IV).
A stirred solution of compound III (200.0g, l.Oeq.) in toluene (4.0V) was heated at 50°C to 60°C. To this reaction mixture benzylamine (l.Oeq) was added slowly and further heated for 4-6 h. The completion of reaction is monitored by HPLC. After completion, the solvent was removed till minimum stirrable volume and further cooled to 0°C to 10°C. The solid compound was filtered and washed with toluene to yield compound IV as off white solid (80g, 82%) MS: 308 [M+H]+.
Example 3: Preparation of compound of formula (VII).
Part-A : To a stirred solution of compound IV (40.0g, 0.123 moles) in dichloromethane (10 V), (S)-(+) (2-Chlorophenyl) glycine methyl ester (1.4 eq.) and cone, sulphuric acid (O.leq) was added at room temperature. The reaction mixture was heated to 40°C to 50°C for 2-3 h. The solvent was removed by atmospheric distillation till minimum stirrable reaction volume. The reaction mixture was allowed to cool to room temperature and dichloromethane (4 V) and water (5V) was added. The organic layer washed with 10% citric acid, saturated sodium carbonate and brine solution. The solvent was removed by atmospheric distillation till obtain minimum stirrable reaction volume.
Part-B: In another vessel a cold solution of dichloromethane (3.5 V), 1,2-dimethoxy ethane (3.5 V) and sodium borohydride (1.05 eq.) at -60 ±40 °C under nitrogen atmosphere was prepared. To this cold solution, acetic acid (3.0eq) was added slowly for 30min. To this reaction mixture Part -A reaction volume was added at -60 ±40 °C for 1-2 h and maintained under stirring for 1 h. The completion of rection was monitored by HPLC. After completion of to 60reaction, the reaction mixture was quenched by adding into water (7 V) at 0°C to 10°C. The aq. layer extracted with dichloromethane, and combined organic layer washed with brine solution. The solvent was removed by distillation till minimum stirrable reaction volume. To this reaction solution methanol (7 V) was charged and entire organic layer was distilled at 50°C to 60°C till minimum stirrable volume.
Part-C: To a hydrogenation unit (autoclave) a reaction volume (Part B), methanol (5V), 10% Pd/C (10%w/w) was added. The hydrogen gas was purged with a pressure of 12±2 Kg/cm2 at 60°C to 75°C for 6-8 h. The completion of rection was monitored by HPLC. After completion, the reaction mixture was cooled to room temperature and filtered to remove catalyst. The solvent was removed by distillation and cone, hydrochloric acid was added and heated to 90°C to 100°C for 6 h. The reaction mixture was cooled to room temperature and 50% aq. Sodium hydroxide solution and dichloromethane was added. The organic layer separated, and to the aq. layer tetrahydro furan (5 V), di-tert-butyl decarbonate (1.0 eq) was added and stirred for 3-4 h. The solvent was removed, and dichloro methane was added. The pH of reaction solution was maintained 1-2 using cone, hydrochloric acid. The reaction mixture extracted with dichloromethane, washed with water and brine. The solvent was removed by distillation to obtain pale yellow oil. To this oil heptane was added and stirred for 30 min. The solid obtained was filtered and washed with cold heptane to obtain off-white solid compound (VII) with (28.2g, 65%) with HPLC purity 99.93%, Chiral HPLC Purity 99.88% and MS: 332 [M-H]+.
Example 4: Preparation of compound of formula (IX).
To a stirred solution of compound VII (20g, l.Oeq) in ethyl acetate (24 V), triethyl amine (3.0eq) was added at room temperature. The reaction mixture was cooled to -10°C to -15°C and pivaloyl chloride (1.20 eq.) was added slowly. The reaction mixture was a stirred at -10°C to - 15°C for 1 h. To this reaction mixture compound of formula (VIII) was added and maintain at stirring at -10°C to -15°C for 1 h. The reaction mixture was warm to room temperature and further stirred for 12 h. The completion of reaction was monitored b HPLC. After completion, the reaction mixture was quenched by adding aq. sodium bicarbonate. The organic layer separated and washed with aq. potassium bisulfate, brine solution. The solvent was removed by distillation to obtain white solid. To this solid reaction mass, methyl ter. butyl ether (9V) was added and stirred for 30 min. The solid was filtered and washed with methyl ter. butyl ether to obtain off white solid compound (IX) (25.8 g, 85%) with HPLC purity 97.70%, and MS: 508 [M+H]+.
Example 5: Preparation of compound of formula (I).
The isopropyl alcohol (3.0 V) was added into compound of formula (IX, 20 g l.Oeq) at room temperature. The reaction solution was cooled to 10°C to 15 °C. The cone. Hydrochloric acid (1.2 V) was added at heated to 40°C to 50 °C for 16-18 h. The completion of reaction was monitored b HPLC. After completion, the solvent was removed by distillation and reaction was quenched by adding water. The pH of reaction was maintained in 9-10 by using 2N sodium hydroxide solution. To the reaction mixture dichloromethane was added and stirred for 30 min. The organic layer washed with water, brine solution and solvent was removed by distillation to obtain off white solid compound (I) (14.4g, 90%) with HPLC purity 99.87%, Chiral purity 99.83% and MS: 408 [M+H]+.

Claims

CLAIM:
1) A process for preparation of compound of formula (VI) comprising steps of: a) reacting a compound of formula (IV) with chiral 2-halo-phenyl glycine methyl ester in presence of acid or base and solvent to obtain compound of formula (V);
Figure imgf000016_0001
b) reducing compound of formula (V) in presence of reducing agent, acid and solvent to obtain compound of formula (VI);
Figure imgf000016_0002
2) A process for preparation of Sitagliptin of formula (I) or its pharmaceutically acceptable salts
Figure imgf000016_0003
comprising the steps of: a) reacting a compound of formula (II) with Meldrum’s acid in the presence of a base, acyl chloride, solvent with or without catalyst to obtain a compound of formula (ill);
Figure imgf000017_0001
b) reacting a compound of formula (III) with an aniline in solvent to obtain a compound of formula (IV);
Figure imgf000017_0002
c) reacting a compound of formula (IV) with chiral 2-halo-phenyl glycine methyl ester in presence of acid or base and solvent to obtain a compound of formula (V);
Figure imgf000017_0003
wherein X is halogen d) reducing compound of formula (V) in presence of reducing agent, acid and solvent(s) to obtain a compound of formula (VI);
Figure imgf000017_0004
e) reacting compound of formula (VI) with di-tert-butyl dicarbonate in presence of metal catalyst, solvent(s) to obtain a compound of formula (VII);
Figure imgf000018_0001
f) coupling a compound of formula (VII) with a compound of formula (VIII) or its salt in presence of base, acyl chloride, and solvent to obtain a compound of formula
(IX);
Figure imgf000018_0002
g) reacting compound of formula (IX) with an acid, in presence of solvent to obtain a compound of formula (I) or pharmaceutically acceptable salt.
Figure imgf000018_0003
) The process as claimed in claim 1 and 2, wherein chiral 2-halo phenyl glycine methyl ester is selected from (S)-(+)-2-Chlorophenylglycine methyl ester, (S)-(+)-2- bromophenylglycine methyl ester, and (S)-(+)-2-Iodophenylglycine methyl ester. ) The process as claimed in claim 1 and 2, wherein the reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, aluminium hydrides, sodium cyanoborohydride, sodium triaceto xyborohydride, platinum oxide, and palladium on carbon. ) The process as claimed in claim 2, wherein acyl chloride is selected from pivaloyl chloride, propionyl chloride, and butanoyl chloride; catalyst is selected from tetra-butyl ammonium chloride, tetra-butyl ammonium iodide; and metal catalyst is selected from palladium on carbon, palladium hydroxide on carbon, nickel on carbon. ) The process as claimed in claim 1 and claim 2 , wherein acid used for i) preparation of compound of formula (V) and (VI) is selected from sulfuric acid, acetic acid, and trifluoro acetic acid; ii) preparation of compound of formula (I) is organic acid selected from acetic acid , propionic acid; and inorganic acid selected from cone, hydrochloric acid, cone, sulfuric acid, nitric acid, and phosphoric acid. ) The process as claimed in claim 1 and claim 2, wherein base used for i) preparation of compound (III) is selected from N,N-Diisopropylethylamine, triethyl amine; ii) preparation of compound of formula (V) is selected from organic base such as triethyl amine, pyridine and the like; and inorganic bases such as sodium hydroxide, potassium hydroxide sodium carbonate, potassium carbonate; and iii) preparation of compound of formula (IX) is selected from morpholine, triethyl amine, and pyridine. ) The process as claimed in claim 1 and claim 2, wherein solvent used for i) preparation of compound of formula (III) and (IV) is hydrocarbon solvent selected from cyclohexane, n-hexane, n-heptane, toluene, xylene; ii) preparation of compound of formula (V) is halogenating solvent selected from dichloroethane, chloroform, dichloromethane, and aprotic solvent selected from dimethoxyethane, tetrahydro furan, 1-4 dioxane; iii) preparation of compound of formula (VI) is selected from dichloroethane, chloroform, and dichloromethane; iv) preparation of compound of formula (VII) is halogenating solvent selected from dichloroethane, chloroform, dichloro methane; ethereal solvent selected from methyl tert-butyl ether, 1,4-dioxane, tetrahydro furan, 1,2-dimethoxy ethane; and alcoholic solvent selected from methanol, ethanol, isopropanol; and hydrocarbon solvent selected from heptane, hexane; v) preparation of compound of formula (VI) and (IX) is halogenating solvent selected from dichloroethane, chloroform, dichloro methane; ester solvent selected from ethyl acetate, ethylaceto acetate, and ethyl butyrate; and vi) preparation of compound of formula (I) is alcoholic solvent selected from methanol, ethanol, and isopropanol. ) A compound of formula (V).
Figure imgf000020_0001
wherein X is halogen0)
Figure imgf000020_0002
Figure imgf000020_0003
wherein X is halogen
PCT/IB2023/052451 2022-03-14 2023-03-14 Novel intermediates and its use in manufacturing of sitagliptin WO2023175492A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004085661A2 (en) * 2003-03-24 2004-10-07 Merck & Co., Inc Process to chiral beta-amino acid derivatives
CN105017260A (en) * 2015-07-30 2015-11-04 新发药业有限公司 Preparation method of sitagliptin intermediate triazolopyrazine derivative
WO2020089828A1 (en) * 2018-11-01 2020-05-07 Stereokem Pvt. Ltd. An improved process for the preparation of sitagliptin and its intermediates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004085661A2 (en) * 2003-03-24 2004-10-07 Merck & Co., Inc Process to chiral beta-amino acid derivatives
CN105017260A (en) * 2015-07-30 2015-11-04 新发药业有限公司 Preparation method of sitagliptin intermediate triazolopyrazine derivative
WO2020089828A1 (en) * 2018-11-01 2020-05-07 Stereokem Pvt. Ltd. An improved process for the preparation of sitagliptin and its intermediates

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