WO2012042534A2 - Processes for the preparation of r-sitagliptin and intermediates thereof - Google Patents
Processes for the preparation of r-sitagliptin and intermediates thereof Download PDFInfo
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- WO2012042534A2 WO2012042534A2 PCT/IN2011/000649 IN2011000649W WO2012042534A2 WO 2012042534 A2 WO2012042534 A2 WO 2012042534A2 IN 2011000649 W IN2011000649 W IN 2011000649W WO 2012042534 A2 WO2012042534 A2 WO 2012042534A2
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- MFFMDFFZMYYVKS-SECBINFHSA-N N[C@@H](CC(N1Cc2nnc(C(F)(F)F)[n]2CC1)=O)Cc(cc(c(F)c1)F)c1F Chemical compound N[C@@H](CC(N1Cc2nnc(C(F)(F)F)[n]2CC1)=O)Cc(cc(c(F)c1)F)c1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- ICYJKFGYEJVNHG-CYBMUJFWSA-N O=C(C[C@H]1Cc(c(F)c2)cc(F)c2F)N1OCc1ccccc1 Chemical compound O=C(C[C@H]1Cc(c(F)c2)cc(F)c2F)N1OCc1ccccc1 ICYJKFGYEJVNHG-CYBMUJFWSA-N 0.000 description 1
Classifications
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/12—Formation of amino and carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/18—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
Definitions
- the present invention relates to an improved process for the synthesis of R- sitagliptin and compounds that are useful as intermediates thereof. More particularly the present invention relates to a compound of formula (IV) or its salt, that are useful as key intermediate in the synthesis of R-sitagliptin or pharmaceutically acceptable salts thereof.
- R-sitagliptin is commonly available as sitagliptin phosphate, 7-[(37?)-3-amino- l-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)- 1 ,2,4- triazolo[4,3-o]pyrazine phosphate (1 : 1) monohydrate, and has the following structural formula:
- Sitagliptin phosphate is a glucagone-like peptide 1 metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase-4 (DPP-4) inhibitor.
- DPP-4 dipeptidyl peptidase-4
- JANUVIA® glucagone-like peptide 1 metabolism modulator
- JANUVIA® dipeptidyl peptidase-4
- JANUVIA® is indicated to improve glycemic control in patients with type-2 diabetes mellitus.
- United States Patent No. 6,699,871 describes various DPP-4 inhibitors including sitagliptin and their pharmaceutically acceptable salts, a pharmaceutical composition and method of treatment and a process for the preparation of sitagliptin hydrochloride.
- United States Patent No. 7,326,708 describes the dihydrogen phosphate salt of sitagliptin and processes for the preparation thereof.
- United States Patent Nos. 7,468,459 and 7,495, 123 and PCT Patent Publication WO2006/81 151 describe processes for sitagliptin and its pharmaceutically acceptable salts using specific chiral disphosphine ligands.
- PCT Patent Publication WO2004/087650 describes a process for the preparation of sitagliptin via benzyloxy protected tetrazolylpyrazine intermediate.
- PCT Patent Publication WO2004/085661 describes a process for the preparation of enantiomerically enriched sitagliptin via (S)-phenylglycine amide protected tetrazolyl pyrazine intermediate.
- PCT Patent Publications WO2009/085990 and WO2010/032264 also describe processes for preparation of sitagliptin or pharmaceutically acceptable salts thereof.
- the process of the present invention provides a process which is simple, ecofriendly, inexpensive, reproducible, robust and well suited on commercial scale.
- the present invention relates generally to an improved process for the preparation of R-sitagliptin of formula I or pharmaceutically acceptable salts thereof. More particularly to compounds and processes for their preparation, whereupon said compounds are intermediates useful in the preparation of R-sitagliptin of formula I or pharmaceutically acceptable salts thereof.
- the present invention provides an isolated com ound of formula (IV),
- the present invention further provides tert-butyl amine (TBA) compound of formula (IV).
- the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having purity more than about 98.0%, as measured by high performance liquid chromatography (HPLC).
- the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having an X-ray Powder Diffraction (XRPD) pattern with reflections at about: 5.06, 9.33, 13.32, 15.08, 17.26, 19.04, 19.19, 19.58, 19.73, 20.12, 20.46, 21.69, 22.66, 24.45, 26.75, 27.40 and 28.29 ⁇ 0.2 degrees 2 theta.
- TSA X-ray Powder Diffraction
- the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having an XRPD pattern which is substantially in accordance with Fig. 1.
- the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having a differential scanning calorimetry (DSC) thermogram with sharp endotherm at about 129.81°C with onset at about 123.53°C and endset at about 133.88°C.
- DSC differential scanning calorimetry
- the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having a DSC thermogram which is substantially in accordance with Fig. 2.
- the present invention provides a process for the preparation of tert- but lamine (TBA) salt of compound of formula (IV),
- the present invention provides a process for the preparation amine salt of compound of formula (IV), comprising:
- the present invention provides a process for the preparation of R-sitagliptin formula I, or pharmaceutically acceptable salt thereof, comprising: a) reacting amine salt of compound of formula IV
- the present invention provides R-sitagliptin phosphate obtained by the process herein described having an X-ray powder diffraction (XRPD) pattern with reflections at about: 4.6, 9.3, 13.9, 15.0, 15.1 , 18.2, 18.6, 19.1 , 19.4, 22.1 , 23.6, and 24.1 + 0.2 degrees 2 theta.
- XRPD X-ray powder diffraction
- the present invention provides R-sitagliptin phosphate obtained by the process of present invention having an XRPD which is substantially in accordance with Fig. 3.
- the present invention provides R-sitagliptin phosphate obtained by the process herein described having a differential scanning calorimetry (DSC) thermogram with sharp endotherm at about 218.30°C with onset at about 216.47°C and endset at about 220.73°C.
- DSC differential scanning calorimetry
- the present invention provides R-sitagliptin phosphate obtained by the process of present invention having a DSC thermogram which is substantially in accordance with Fig. 4.
- the present invention provides R-sitagliptin phosphate having a specific surface area higher than about 4 m 2 /g as measured by Brunauer-Emmett-Teller (B.E.T).
- the present invention further provides R-sitagliptin phosphate having a specific surface area of about 5 m 2 /g to about 20 m 2 /g as measured by Brunauer-Emmett- Teller (B.E.T) particle size analysis.
- B.E.T Brunauer-Emmett- Teller
- the present invention provides R-sitagliptin phosphate having chemical purity more than about 99.8%, as measured by high performance liquid chromatography (HPLC).
- the present invention provides R-sitagliptin phosphate having stereochemical purity of 100%, as measured by chiral HPLC.
- the present invention further provides R-sitagliptin phosphate having S- sitagliptin phosphate below detection limit.
- the present invention provides R-sitagliptin phosphate having a tapped density higher than about 0.200 g/ml.
- the present invention further provides R-sitagliptin phosphate having a tapped density of about 0.300 g/ml to about 0.800 g/ml.
- the present invention provides R-sitagliptin phosphate having a bulk density higher than about 0.100 g/ml.
- the present invention further provides R-sitagliptin phosphate having a bulk density of about 0.200 g/ml to about 0.700 g/ml.
- the present invention provides a pharmaceutical composition comprising sitagliptin or its pharmaceutically acceptable salts obtained by the processes of present invention and at least a pharmaceutically acceptable carrier.
- Fig. 1 X-ray Powder diffraction Pattern (XRPD) of tert-butylamine (TBA) salt of compound of formula (IV) prepared by Example 4.
- XRPD X-ray Powder diffraction Pattern
- TAA tert-butylamine
- Fig. 2 Differential Scanning Calorimetry (DSC) endotherm of tert-butylamine (TBA) salt of compound of formula (IV) prepared by Example 4.
- DSC Differential Scanning Calorimetry
- Fig. 3 X-ray Powder diffraction Pattern (XRPD) of sitagliptin phosphate prepared by Example 7.
- Fig. 4 Differential Scanning Calorimetry (DSC) endotherm of sitagliptin phosphate prepared by Example 7.
- the present invention is directed to an improved process for the preparation of R-sitagliptin of formula (I) or pharmaceutically acceptable salt thereof.
- the present invention provides the development of an isolated compound of formula (IV) or its salt, and particularly tert-butylamine (TBA) salt of compound of formula (IV), which advantageously in turn provides sitagliptin of formula (I) with a good yield and high purity, subsequently providing the final sitagliptin phosphate with high purity for pharmaceutical use.
- TAA tert-butylamine
- R- Sitagliptin phosphate obtained by process herein described, having a high surface area, which exhibit improved physiochemical properties such as solubility, stability to stress, and rate of dissolution, confers fitness for the manufacture of various pharmaceutical dosage forms.
- R-Sitagliptin phosphate obtained by process herein described having higher density, which when used in the formulation of a pharmaceutical composition in the manner of a drug product, provides beneficial uniformity of content of the drug product.
- the present invention provides a cost effective industrial process for the preparation of R- sitagliptin phosphate.
- the present invention provides an isolated compound of formula (IV),
- the amine salt may be aliphatic amine or aromatic amine and may be selected from the group consisting of methylamine, ethylamine, isopropylamine, tert-butylamine (TBA), tris(hydroxymethyl) methylamine, cyclohexylamine, benzylamine, 4- methoxybenzylamine ethanolamine, diethanolamine, piperazine, tromethamine and the like, preferably tert-butylamine (TBA).
- TSA tert-butylamine
- the present invention provides tert-butylamine (TBA) salt of compound of formula (IV .
- the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having purity more than about 98.0%, as measured by high performance liquid chromatography (HPLC).
- the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), in solid state with X-ray powder diffraction pattern, which is substantially characterized in Fig. 1, X-ray powder were performed on ARL (scanting) X-ray diffractometer model XPERT-PRO (PANalytical) scanning parameters start position [ ° 2Th.] 2.01 and end position [°2Th.] 49.98.
- TAA tert-butylamine
- the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having an X-ray Powder Diffraction (XRPD) pattern with reflections at about: 5.06, 9.33, 13.32, 15.08, 17.26, 19.04, 19.19, 19.58, 19.73, 20.12, 20.46, 21.69, 22.66, 24.45, 26.75, 27.40 and 28.29 + 0.2 degrees 2 theta, which is substantially in accordance with Fig 1.
- TSA X-ray Powder Diffraction
- the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), in solid state with a differential scanning calorimetry thermogram, which is substantially characterized in Fig 2, is measured by a Differential Scanning Calorimeter (DSC 822, Mettler Toledo) at a scan rate of 10 ° C per minute with an Indium standard.
- TSA tert-butylamine
- the endotherm measured by a particular differential scanning calorimeter is dependent upon a number of factors, including the rate of heating (i.e., scan rate), the calibration standard utilized, instrument calibration, relative humidity, and upon the chemical purity of the sample being tested.
- rate of heating i.e., scan rate
- instrument calibration i.e., relative humidity
- chemical purity of the sample being tested i.e., relative humidity
- an endotherm as measured by DSC on the instrument identified above may vary as much as ⁇ 1 ° C or even ⁇ 2 ° C.
- the present invention provides a process for the preparation of tert-butylamine (TBA salt of compound of formula (IV),
- Suitable azodicarboxylate is selected from the group consisting of di-(C
- DEAD diethyl azodicarboxylate
- DIAD diisopropyl azodicarboxylate
- DIAD di-tert.-butyl azodicarboxylate
- dibenzyl azodicarboxylate bis(2,2,2-trichloroethyl)azodicarboxylate and 1,1-azodicarbonyldipiperidine.
- DIAD diisopropyl azodicarboxylate
- Suitable phosphine is a triarylphosphine selected from the group consisting of triphenylphosphine, p-trichiorotriphenylphosphine and p-trimethoxytriphenylphosphine.
- triphenylphosphine is a triarylphosphine selected from the group consisting of triphenylphosphine, p-trichiorotriphenylphosphine and p-trimethoxytriphenylphosphine.
- triphenylphosphine is a triarylphosphine selected from the group consisting of triphenylphosphine, p-trichiorotriphenylphosphine and p-trimethoxytriphenylphosphine.
- triphenylphosphine is a triarylphosphine selected from the group consisting of triphenylphosphine, p-trichiorotriphenylphosphine and
- the reaction of compound of formula (VI) with an azodicarboxylate and a phosphine is carried out in the presence of an organic solvent.
- the organic solvent that can be used is selected from the group of ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), 2-methyl tetrahydrofuran, dioxane and the like; halogenated solvents such as methylene chloride (MDC), ethylene dichloride, chloroform and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, xylene; ethyl acetate, isopropyl acetate, dimethoxymethane, diethoxyethane, acetonitrile, propionitrile, dimethyl formamide and the like; water or mixtures thereof
- Suitable base includes an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide; an alkaline earth metal hydroxide such as barium hydroxide, calcium hydroxide, magnesium hydroxide; or an alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate or aqueous mixture thereof.
- an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide
- an alkaline earth metal hydroxide such as barium hydroxide, calcium hydroxide, magnesium hydroxide
- an alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate or aqueous mixture thereof.
- sodium hydroxide sodium hydroxide.
- Suitable acid includes, but are not limited to hydrochloric acid, sulphuric acid, hydrobromic acid, acetic acid and the like or aqueous mixtures thereof.
- hydrochloric acid Preferably, hydrochloric acid.
- the amount of azodicarboxylate used is from about 1.2 moles to about 5 moles per mole compound of formula VI, preferably the amount of azodicarboxylate is about 1.5 moles per mole compound of formula VI.
- the amount of phosphine used is from about 1.2 moles to about 3 moles per mole compound of formula VI, preferably the amount of phosphine is about 1.5 moles per mole compound of formula VI.
- the amount of tert-butylamine is from about 1.5 moles to about 5 moles per mole compound of formula VI, preferably the amount of tert-butylamine is about 2 moles per mole compound of formula VI.
- the compound of formula (V) may be isolated or may be present in the reaction mixture.
- tert-butyl amine (TBA) salt is added to the reaction mass of (b), at a temperature in the range of about 10 ° C to about 50 ° C, preferably at room temperature.
- the present invention provides the isolation process of the tert-butylamine salt of formula (IV) in the process described above, from the reaction mixture of c), the process comprising:
- the present invention provides a process for the preparation of tert-butylamine (TBA) salt of compound of formula (IV), comprising: a) reacting compound of formula (VI), with diisopropyl azodicarbox late, a triphenylphosphine and organic solvent to form (4R)-l -(benzyloxy)-4-(2,4,5- trifluoro benzyl)azitidine-2-one of formula (V),
- the present invention provides a process for the preparation of tert-butylamine (TBA) salt of compound of formula (IV),
- the present invention provides a process for the preparation of amine salt of com ound of formula (IV),
- the present invention provides an isolated compound of formula (IV) as an acid.
- the present invention provides a process for the preparation of free acid of compound (IV) by treating an amine salt of compound of formula (IV) with an acid.
- the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
- the working- up of reaction mixtures especially in order to isolate desired compounds, follows procedures and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like, customarily known to the organic chemists skilled in the norms of the art.
- the present invention provides a process for the preparation of sitagliptin formula I, or pharmaceutically acceptable salt thereof, as shown in Scheme 2.
- the present invention provides a process for the preparation of sitagliptin formula I, comprising:
- the present invention provides a process for the preparation of sitagliptin formula I, or a pharmaceutically acceptable salt thereof, comprising:
- the amine salt may be an aliphatic amine or an aromatic amine and may be selected from the group consisting of methylamine, ethylamine, isopropylamine, tert- butylamine (TBA), tris(hydroxymethyl) methylamine, cyclohexylamine, benzylamine, 4- methoxybenzylamine ethanolamine, diethanolamine, piperazine, tromethamine and the like, preferably tert-butylamine (TBA).
- TSA tert-butylamine
- Suitable salt of compound of formula III may be selected from HC1, HBr, HF and HI.
- HC1 salt of compound of formula (III) may be selected from HC1, HBr, HF and HI.
- reaction of compound of amine salt of compound of formula (IV) with compound of formula (III) or salt may be carried out in presence of coupling agent.
- the coupling agent may be selected from the group consisting of ⁇ , ⁇ 1 - diethylcarbodiimide, ⁇ , ⁇ '-dipropyl carbodiimide ⁇ , ⁇ '-diisopropylcarbodiimide, ⁇ , ⁇ '- dicyclohexylcarbodiimide, N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide, ⁇ , ⁇ '- carbonyldiimidazole and ⁇ , ⁇ '-carbonyldithiazole, l -(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC-HC1), l -cyclohexyl-3-(2- mo holinoethyl)carbodiimide, l,3-di-tert-butylcarbodiimide, l-(dimethylaminopropyl)-
- the present invention provides a process for the preparation of sitagliptin formula I, comprising:
- the present invention provides a process for the preparation of sitagliptin formula I, comprising:
- the present invention provides a process for the preparation of sitagliptin formula I, comprising:
- the present invention provides a process for the preparation of sitagliptin formula I, comprising:
- the reaction of amine salt of compound of formula (IV) with compound of formula (III) may be carried out in the presence of base.
- the base may be selected from organic base or inorganic base.
- the organic base selected from triethylamine, N,N- diisopropylethylamine, diisopropylamine, 2,4,6-collidine, imidazole, pyridine, lutidine, N,N- dimethylaniline, dimethylaminopyridine and the like.
- triethylamine triethylamine.
- the inorganic base selected from an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide; an alkaline earth metal hydroxide such as barium hydroxide, calcium hydroxide, magnesium hydroxide; or an alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate or mixture thereof.
- an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide
- an alkaline earth metal hydroxide such as barium hydroxide, calcium hydroxide, magnesium hydroxide
- an alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate or mixture thereof.
- the reaction of amine salt of compound of formula (IV) with compound of formula (III) may be carried out in the presence of organic solvent.
- the organic solvent may be selected from Ci-C 5 alcohol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dichloromethane (MDC), ethyl acetate, 1 ,2-dichloroethane, isopropyl acetate, chloroform, propionitrile, water and the like and mixtures thereof.
- MDC dichloromethane
- TBA salt of compound of formula (IV) is reacted with the HC1 salt of compound of formula (III) in the presence of coupling agent selected from l -ethyl-(3-dimethylaminopropyl) carbodiimide (EDAC), 1-hydroxybenzotriazole (HOBT) and triethyl amine (TEA) as base to obtain compound of formula (II).
- coupling agent selected from l -ethyl-(3-dimethylaminopropyl) carbodiimide (EDAC), 1-hydroxybenzotriazole (HOBT) and triethyl amine (TEA) as base to obtain compound of formula (II).
- the compound of formula (II) obtained may be isolated or may be present in the reaction mixture.
- debenzylation of compound of formula (II) may be carried out by hydrogenating in the presence of metal catalyst and suitable organic solvent.
- Metal catalysts include Pd/C, Pd/Al 2 0 3 , Pd/CaC0 3 , and Pd(OH) 2 /C.
- Others catalyst can also be used such as Pt, Rh, and Ni based catalysts, or oxides thereof, alone or on supports such as carbon, silica, and alumina.
- Suitable solvent may be selected from Ci-C 5 alcohol such as methanol, ethanol, n-propanol, isopropanol; tetrahydrofuran, dichloromethane, 1,2-dimethoxyetane, diethoxyethane, ethyl acetate, isopropyl acetate and the like and aqueous mixture thereof.
- Ci-C 5 alcohol such as methanol, ethanol, n-propanol, isopropanol
- tetrahydrofuran dichloromethane, 1,2-dimethoxyetane, diethoxyethane, ethyl acetate, isopropyl acetate and the like and aqueous mixture thereof.
- Acetates can also be used with an additive, such as HCl, HBr, acetic acid, and formic acid and the like.
- Hydrogenation is carried out in the presence of hydrogen gas or hydrogen transfer reagent selected from ammonium formate, phosphonic acid hydrazine hydrate, monosodium dihydrogen orthophosphate, cyclohexene, sodium formate.
- hydrogen gas or hydrogen transfer reagent selected from ammonium formate, phosphonic acid hydrazine hydrate, monosodium dihydrogen orthophosphate, cyclohexene, sodium formate.
- debenzylation of compound of formula (II) is carried out by hydrogenating using hydrogen gas at about 2.0 kg/Cm 2 to about 6.0 kg/Cm 2 of hydrogen pressure and at a temperature range of about 45 °C to about 65 °C. Preferably at about 3.0 kg/Cm 2 to about 4.0 kg/Cm 2 of hydrogen pressure and about 50 °C to about 55 °C.
- debenzylation of compound of formula (II) is carried out with 10% Pd/C as a catalyst in MDC as the solvent at about 3 kg/Cm 2 to about 4 kg/Cm 2 of hydrogen pressure.
- R-sitagliptin prepared by the above methods can also be converted into its pharmaceutically acceptable salts.
- suitable pharmaceutically acceptable acids which can be used include, but are not limited to: inorganic acids such as phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid; and organic acids such as acetic acid, tartaric acid, oxalic acid, and the like.
- phosphoric acid Preferably, phosphoric acid.
- the acid is dissolved in a solvent before adding it to the solution of R-sitagliptin free base.
- the solvent used for the dissolution of R-sitagliptin and the acid may be the same, or different solvents may be used.
- the acid addition salt obtained can be purified further by recrystallization or slurrying in suitable solvents.
- Suitable solvents in which the acid addition salt of R-sitagliptin can be dissolved for purification include but are not limited to: C1-C5 alcohols such as methanol, ethanol, and isopropanol and the like* C1-C5 ketones such as acetone, ethyl methyl ketone, butanone and the like; ethers such as tetrahydrofuran, 1 ,4-dioxane, ethyl acetate and the like; water; and mixtures thereof.
- ⁇ refers to "micrometer” which is l xl0 ⁇ 6 meter.
- PSD particle size distribution
- di 0 as used herein is defined as the particle size at which the cumulative percentage undersize is 10 (i.e. the bottom 10% of particles are less than or equal to the stated size).
- d 5 o means the median particle size and dgo is defined as the particle size at which the cumulative percentage undersize is 90 (i.e. the bottom 90% of particles are less than or equal to the stated size).
- Specific surface area is defined in units of square meters per gram (m2/g). It is usually measured by nitrogen absorption analysis.
- nitrogen is absorbed on the surface of the substance.
- the amount of the absorbed nitrogen (as measured during the absorption or the subsequent desorption process) is related to the surface area via a formula known as the Brunauer Emmet Teller (B.E.T.) formula.
- B.E.T. Brunauer Emmet Teller
- density is a measurement defined as the mass of a substance per unit volume.
- bulk density refers to a density measurement of a loose, uncompacted substance, wherein the volume of the substance includes the air trapped between particles.
- tapped density refers to a density measurement of a substance that has been tapped or vibrated, thus minimizing the volume of the substance by eliminating or minimizing the air trapped between particles.
- the bulk density, tapped density and of the batches of R-sitagliptin phosphate crystals were determined using the following methods:
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having the following characteristics:
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having chemical purity more than about 99.8% as measured by HPLC and having stereo chemical purity of 100% ee, as measured by chiral HPLC.
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having a specific surface area higher than about 4 m 2 /g, more preferably higher than about 7, most preferably higher than about 9 such as about 10.5 as measured by Brunauer-Emmett-Teller (B.E.T) method.
- B.E.T Brunauer-Emmett-Teller
- the surface area is about 5 m /g to about 20 m /g.
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having S-sitagliptin phosphate below detection limit.
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having a tapped density higher than about 0.200 g/ml.
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having a tapped density of about 0.300 g/ml to about 0.800 g/ml.
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having a bulk density higher than about 0.100 g/ml.
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having a bulk density of about 0.200 g/ml to about 0.700 g/ml.
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having tapped density of about 0.300 g/ml to about 0.900 g/ml, after micronization. [00120] In yet another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having bulk density of about 0.2 00 g/ml to about 0.800 g/ml, after micronization.
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, characterized by X-ray Powder Diffraction (XRPD) pattern with reflections at about: 4.68, 9.33, 14.00, 15.04,18.29,18.68, 19.13, 19.49, 22.1 1, 24.13, 32.97 and 33.52 + 0.2 degrees 2 theta, which is substantially in accordance with Fig. 3.
- XRPD X-ray Powder Diffraction
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, characterized by differential scanning calorimetry (DSC) thermogram with sharp endotherm at about 218.38°C with onset at about 216.65°C and endset at about 220.68°C, which is substantially in accordance with Fig. 4.
- DSC differential scanning calorimetry
- the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having residual organic solvent less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. Pharmacopoeia; the recommended amount is less than 5000 ppm for acetone, ethanol, ethyl acetate and methyl tert-butyl ether; less than 3880 ppm for cyclohexane; less than 3000 ppm for methanol; less than 890 ppm for toluene; less than 720 ppm for tetrahydrofuran; less than 600 ppm for methylene chloride; less than 410 ppm for acetonitrile; less than 250 ppm for diisopropyl ether.
- the particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state sitagliptin phosphate into any of the foregoing desired particle size range.
- One common technique to decrease particle size is by micronization.
- Micronization is a mechanical process that involves the application of force to a particle, thereby resulting in the break-up of the particle. Such force may applied by collision of particles at high speeds. Micronization may be carried out, for example, by grinding or by air-jet micronizer.
- the present invention provides pharmaceutical compositions comprising sitagliptin or pharmaceutically acceptable salt thereof obtained by the processes herein described, having a D 50 and ⁇ 90 particle size of less than about 200 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns.
- the present invention provides pharmaceutical compositions comprising sitagliptin or pharmaceutically acceptable salt thereof obtained by the processes herein described, having a D 50 and D90 particle size after micronization less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns.
- THF was distilled out under vacuum at about 40-45 °C, followed by the acidification of the reaction mass by charging 60 ml of con. HC1 (35- 36%).
- 255 gm of (3S)-N-(benzyloxy)-3-hydroxy-4-(2,4,5-trifluorophenyl) butanamide of formula (VI) was isolated and dried the isolated product under vacuum.
- the isolated compound was characterized by Mass, 1HNMR, melting points and HPLC purity.
- THF solution of diisopropyl azodicarboxylate (DIAD) (made by dissolving 223.44 gm of DIAD in 500 ml of THF) to the reaction mass, followed by addition of THF solution of (35 -N-(benzyloxy)-3-hydroxy-4-(2,4,5-trifluorophenyl) butanamide of formula (VI) (made by dissolving 250 gm of formula VI in 1000 ml of THF) followed by stirring for about 5°C for about 3 hours.
- the progress of reaction of was monitored by HPLC.
- Triphenylphosphine oxide was filter out as solid (side product), washed the solid with water and add 1250 ml of MTBE to the filtrate under stirring for about 30°C for about 20 to 30 minutes and separate out the MTBE, followed by acidification of aqueous layer to pH of 1.5 to 2.5 using 36% HC1, extracted the aqueous layer twice with 1250 ml of methyl dichloride and to the MDC layer of 5% sodium chloride solution was added. Separate out MDC layer and distilled out the MDC under vacuum at about 30-35°C for about 2-3 hours. Degas the reaction mass (oily product) under vacuum at about 30-35°C and add MTBE.
- the isolated compound of formula (IV) was characterized by HNMR, Mass, Melting point and tert-butylamine (TBA) assay, SOR.
- Example 5 Preparation of (/?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[ 1,2,4] triazolo[4,3- ⁇ 3]pyrazin-7(8H)-yI]-l -(2,4,5-trifluorophenyI)butan-2-amine (Formula I)
- Example 6 Preparation of (7?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[ 1 ,2,4] triazolo[4,3-o]pyrazin-7(8H)-yl]- 1 -(2,4,5-trifluorophenyl)butan-2-amine (Formula I)
- Example 7 Preparation of (i?)-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-amine phosphate (1 : 1)
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Abstract
Provided is preparation method of R-sitagliptin. Compound of formula (IV), amine salt thereof and method for preparation thereof are also provided. Said compound of formula (IV) or amine salt thereof is useful as key intermediate in the synthesis of R-sitagliptin or pharmaceutically acceptable salts thereof.
Description
PROCESSES FOR THE PREPARATION OF R-SITAGLIPTIN AND
INTERMEDIATES THEREOF PRIORITY
[0001] This application claims the benefit to Indian Provisional Application
2698/MUM/2010, filed on September 28, 2010, the contents of which is herein incorporated by reference.
BACKGROUND OF THE INVENTION
1. Technical Field
[0002] The present invention relates to an improved process for the synthesis of R- sitagliptin and compounds that are useful as intermediates thereof. More particularly the present invention relates to a compound of formula (IV) or its salt, that are useful as key intermediate in the synthesis of R-sitagliptin or pharmaceutically acceptable salts thereof.
2. Description of the Related Art
[0003] R-sitagliptin is commonly available as sitagliptin phosphate, 7-[(37?)-3-amino- l-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)- 1 ,2,4- triazolo[4,3-o]pyrazine phosphate (1 : 1) monohydrate, and has the following structural formula:
[0004] Sitagliptin phosphate is a glucagone-like peptide 1 metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase-4 (DPP-4) inhibitor. R-Sitagliptin is currently marketed in its phosphate salt in the United States under the trade name JANUVIA® in its monohydrate form as tablets in the dosage strengths of 25, 50, or 100 mg equivalent base.
[0005] JANUVIA® is indicated to improve glycemic control in patients with type-2 diabetes mellitus.
[0006] United States Patent No. 6,699,871 describes various DPP-4 inhibitors including sitagliptin and their pharmaceutically acceptable salts, a pharmaceutical composition and method of treatment and a process for the preparation of sitagliptin hydrochloride.
[0007] United States Patent No. 7,326,708 describes the dihydrogen phosphate salt of sitagliptin and processes for the preparation thereof.
[0008] United States Patent Nos. 7,468,459 and 7,495, 123 and PCT Patent Publication WO2006/81 151 describe processes for sitagliptin and its pharmaceutically acceptable salts using specific chiral disphosphine ligands.
[0009] PCT Patent Publication WO2004/087650 describes a process for the preparation of sitagliptin via benzyloxy protected tetrazolylpyrazine intermediate.
[0010] PCT Patent Publication WO2004/085661 describes a process for the preparation of enantiomerically enriched sitagliptin via (S)-phenylglycine amide protected tetrazolyl pyrazine intermediate.
[0011] PCT Patent Publications WO2009/085990 and WO2010/032264 also describe processes for preparation of sitagliptin or pharmaceutically acceptable salts thereof.
[0012] In light of the evolving and more rigorous requirements demanded of drug manufacturers and the prevailing disadvantages present with the prior art, there is a need for an improved process for the preparation of sitagliptin and its intermediates, which circumvents the likely formation of isomeric and other process-related impurities; while ensuring a target sitagliptin product with optimum yield and purity
[0013] Hence, there is a need for an improved process for the preparation of R- sitagliptin or its pharmaceutically acceptable salts, which alleviate the problems associated with aforementioned processes.
[0014] The process of the present invention provides a process which is simple, ecofriendly, inexpensive, reproducible, robust and well suited on commercial scale.
SUMMARY OF THE INVENTION
[0015] The present invention relates generally to an improved process for the preparation of R-sitagliptin of formula I or pharmaceutically acceptable salts thereof. More particularly to compounds and processes for their preparation, whereupon said
compounds are intermediates useful in the preparation of R-sitagliptin of formula I or pharmaceutically acceptable salts thereof.
[0016] The present invention provides an isolated com ound of formula (IV),
(IV)
or its amine salt thereof.
[0017] The present invention further provides tert-butyl amine (TBA) compound of formula (IV).
(IV)
[0018] The present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having purity more than about 98.0%, as measured by high performance liquid chromatography (HPLC).
[0019] The present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having an X-ray Powder Diffraction (XRPD) pattern with reflections at about: 5.06, 9.33, 13.32, 15.08, 17.26, 19.04, 19.19, 19.58, 19.73, 20.12, 20.46, 21.69, 22.66, 24.45, 26.75, 27.40 and 28.29 ± 0.2 degrees 2 theta.
[0020] The present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having an XRPD pattern which is substantially in accordance with Fig. 1.
[0021] The present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having a differential scanning calorimetry (DSC) thermogram with sharp endotherm at about 129.81°C with onset at about 123.53°C and endset at about 133.88°C.
[0022] The present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having a DSC thermogram which is substantially in accordance with Fig. 2.
[0023] The present invention provides a process for the preparation of tert- but lamine (TBA) salt of compound of formula (IV),
(VI)
with azodicarboxylate, a phosphine to form (4R)-l-(benzyloxy)-4-(2,4,5-trifluoro benzyl)azitidine-2-one of formula (V),
(V)
b) reacting compound of formula (V) with an acid or a base to form a reaction mass,
c) adding the tert-butyl amine (TBA) to the reaction mass of b), and
d) isolating the compound of formula (IV) as TBA salt.
[0024] The present invention provides a process for the preparation amine salt of compound of formula (IV), comprising:
a) reacting a compound of formula (VI), with azodicarboxylate, a phosphine and organic solvent to form (4R)-l-(benzyloxy)-4-(2,4,5-trifluoro benzyl)azitidine-2- one of formula (V),
b) reacting compound of formula (V) with an acid or a base to form a reaction mass,
c) adding the tert-butyl amine (TBA) to the reaction mass of b), and
d) isolating the compound of formula (IV) as a salt.
[0025] The present invention provides a process which is defined in Scheme 2, for the preparation of R-sitagliptin formula I, or pharmaceutically acceptable salt thereof,
comprising:
a) reacting compound of formula (VI) with azodicarboxylate, a phosphine to form a compound of formula (V),
c) reacting compound of formula (V) with an acid or a base to form a compound of formula (IV),
d) isolating the compound of formula (IV) or its salt from a reaction mass thereof, e) converting the compound of formula (IV) into sitagliptin (I) or pharmaceutically acceptable salt thereof.
[0026] The present invention provides a process for the preparation of R-sitagliptin formula I, or pharmaceutically acceptable salt thereof, comprising:
a) reacting amine salt of compound of formula IV
(IV)
with compound of formula III, or its salt,
(III)
to form a compound of formula II; and
(Π)
b) debenzylating the compound of formula II.
[0027] The present invention provides R-sitagliptin phosphate obtained by the process herein described having an X-ray powder diffraction (XRPD) pattern with reflections at about: 4.6, 9.3, 13.9, 15.0, 15.1 , 18.2, 18.6, 19.1 , 19.4, 22.1 , 23.6, and 24.1 + 0.2 degrees 2 theta.
[0028] The present invention provides R-sitagliptin phosphate obtained by the process of present invention having an XRPD which is substantially in accordance with Fig. 3.
[0029] The present invention provides R-sitagliptin phosphate obtained by the process herein described having a differential scanning calorimetry (DSC) thermogram with
sharp endotherm at about 218.30°C with onset at about 216.47°C and endset at about 220.73°C.
[0030] The present invention provides R-sitagliptin phosphate obtained by the process of present invention having a DSC thermogram which is substantially in accordance with Fig. 4.
[0031] The present invention provides R-sitagliptin phosphate having a specific surface area higher than about 4 m2/g as measured by Brunauer-Emmett-Teller (B.E.T).
[0032] The present invention further provides R-sitagliptin phosphate having a specific surface area of about 5 m2/g to about 20 m2/g as measured by Brunauer-Emmett- Teller (B.E.T) particle size analysis.
[0033] The present invention provides R-sitagliptin phosphate having chemical purity more than about 99.8%, as measured by high performance liquid chromatography (HPLC).
[0034] The present invention provides R-sitagliptin phosphate having stereochemical purity of 100%, as measured by chiral HPLC.
[0035] The present invention further provides R-sitagliptin phosphate having S- sitagliptin phosphate below detection limit.
[0036] The present invention provides R-sitagliptin phosphate having a tapped density higher than about 0.200 g/ml.
[0037] The present invention further provides R-sitagliptin phosphate having a tapped density of about 0.300 g/ml to about 0.800 g/ml.
[0038] The present invention provides R-sitagliptin phosphate having a bulk density higher than about 0.100 g/ml.
[0039] The present invention further provides R-sitagliptin phosphate having a bulk density of about 0.200 g/ml to about 0.700 g/ml.
[0040] The present invention provides a pharmaceutical composition comprising sitagliptin or its pharmaceutically acceptable salts obtained by the processes of present invention and at least a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
[0041] Fig. 1 : X-ray Powder diffraction Pattern (XRPD) of tert-butylamine (TBA) salt of compound of formula (IV) prepared by Example 4.
[0042] Fig. 2: Differential Scanning Calorimetry (DSC) endotherm of tert-butylamine (TBA) salt of compound of formula (IV) prepared by Example 4.
[0043] Fig. 3: X-ray Powder diffraction Pattern (XRPD) of sitagliptin phosphate prepared by Example 7.
[0044] Fig. 4: Differential Scanning Calorimetry (DSC) endotherm of sitagliptin phosphate prepared by Example 7.
DETAILED DESCRIPTION OF THE INVENTION
[0045] The present invention is directed to an improved process for the preparation of R-sitagliptin of formula (I) or pharmaceutically acceptable salt thereof.
[0046] Surprisingly, the present invention provides the development of an isolated compound of formula (IV) or its salt, and particularly tert-butylamine (TBA) salt of compound of formula (IV), which advantageously in turn provides sitagliptin of formula (I) with a good yield and high purity, subsequently providing the final sitagliptin phosphate with high purity for pharmaceutical use.
[0047] It is well known that certain factors such as chemical activity, adsorption, dissolution, and bioavailability of drugs may depend on the surface area of solids. R- Sitagliptin phosphate obtained by process herein described, having a high surface area, which exhibit improved physiochemical properties such as solubility, stability to stress, and rate of dissolution, confers fitness for the manufacture of various pharmaceutical dosage forms.
[0048] Surprisingly, it has also been found that R-Sitagliptin phosphate obtained by process herein described, having higher density, which when used in the formulation of a pharmaceutical composition in the manner of a drug product, provides beneficial uniformity of content of the drug product.
[0049] The present invention provides a cost effective industrial process for the preparation of R- sitagliptin phosphate.
[0050] In one embodiment, the present invention provides an isolated compound of formula (IV),
(IV)
or an amine salt thereof.
[0051] The amine salt may be aliphatic amine or aromatic amine and may be selected from the group consisting of methylamine, ethylamine, isopropylamine, tert-butylamine (TBA), tris(hydroxymethyl) methylamine, cyclohexylamine, benzylamine, 4- methoxybenzylamine ethanolamine, diethanolamine, piperazine, tromethamine and the like, preferably tert-butylamine (TBA).
[0052] In another embodiment, the present invention provides tert-butylamine (TBA) salt of compound of formula (IV .
(IV)
[0053] In another embodiment, the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having purity more than about 98.0%, as measured by high performance liquid chromatography (HPLC).
[0054] In another embodiment, the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), in solid state with X-ray powder diffraction pattern, which is substantially characterized in Fig. 1, X-ray powder were performed on ARL (scanting) X-ray diffractometer model XPERT-PRO (PANalytical) scanning parameters start position [ °2Th.] 2.01 and end position [°2Th.] 49.98.
[0055] In another embodiment, the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), having an X-ray Powder Diffraction (XRPD) pattern with reflections at about: 5.06, 9.33, 13.32, 15.08, 17.26, 19.04, 19.19, 19.58, 19.73, 20.12, 20.46, 21.69, 22.66, 24.45, 26.75, 27.40 and 28.29 + 0.2 degrees 2 theta, which is substantially in accordance with Fig 1.
[0056] In another embodiment, the present invention provides tert-butylamine (TBA) salt of compound of formula (IV), in solid state with a differential scanning calorimetry thermogram, which is substantially characterized in Fig 2, is measured by a Differential Scanning Calorimeter (DSC 822, Mettler Toledo) at a scan rate of 10°C per minute with an Indium standard. Tert-butylamine (TBA) salt of compound of formula (IV) exhibits an endotherm peak at about 129.81 C. Whereupon, the endotherm measured by a particular differential scanning calorimeter is dependent upon a number of factors, including the rate of heating (i.e., scan rate), the calibration standard utilized, instrument calibration, relative humidity, and upon the chemical purity of the sample being tested. Thus, an endotherm as measured by DSC on the instrument identified above may vary as much as ±1°C or even ± 2°C.
[0057] In another embodiment, the present invention provides a process for the preparation of tert-butylamine (TBA salt of compound of formula (IV),
(IV)
comprising:
(VI)
with azodicarboxylate, a phosphine to form (4R)-l-(benzyloxy)-4-(2,4,5-trifluoro benzyl)azitidine-2-one of formula V),
(V)
b) reacting compound of formula (V) with a base or an acid to form a reaction mass,
c) adding the tert-butyl amine (TBA) to the reaction mass of b),
d) isolating the compound of formula (IV) as TBA salt.
[0058] Suitable azodicarboxylate is selected from the group consisting of di-(C|.4 alky l)azodicarboxy late such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert.-butyl azodicarboxylate, dibenzyl azodicarboxylate, bis(2,2,2-trichloroethyl)azodicarboxylate and 1,1-azodicarbonyldipiperidine. Prefearbly, diisopropyl azodicarboxylate (DIAD).
[0059] Suitable phosphine is a triarylphosphine selected from the group consisting of triphenylphosphine, p-trichiorotriphenylphosphine and p-trimethoxytriphenylphosphine. Preferably, triphenylphosphine.
[0060] The reaction of compound of formula (VI) with an azodicarboxylate and a phosphine is carried out in the presence of an organic solvent.
[0061] The organic solvent that can be used is selected from the group of ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), 2-methyl tetrahydrofuran, dioxane and the like; halogenated solvents such as methylene chloride (MDC), ethylene dichloride, chloroform and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, xylene; ethyl acetate, isopropyl acetate, dimethoxymethane, diethoxyethane, acetonitrile, propionitrile, dimethyl formamide and the like; water or mixtures thereof. Preferably, tetrahydrofuran, methylene chloride and methyl tert-butyl ether.
[0062] Suitable base includes an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide; an alkaline earth metal hydroxide such as barium hydroxide, calcium hydroxide, magnesium hydroxide; or an alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate or aqueous mixture thereof. Preferably, sodium hydroxide.
[0063] Suitable acid includes, but are not limited to hydrochloric acid, sulphuric acid, hydrobromic acid, acetic acid and the like or aqueous mixtures thereof. Preferably, hydrochloric acid.
[0064] The amount of azodicarboxylate used is from about 1.2 moles to about 5 moles per mole compound of formula VI, preferably the amount of azodicarboxylate is about 1.5 moles per mole compound of formula VI. The amount of phosphine used is from about 1.2 moles to about 3 moles per mole compound of formula VI, preferably the amount of phosphine is about 1.5 moles per mole compound of formula VI. The amount of tert-butylamine is from about 1.5 moles to about 5 moles per mole compound of formula VI, preferably the amount of tert-butylamine is about 2 moles per mole compound of formula VI.
[0065] In b) of the process described above, the compound of formula (V) may be isolated or may be present in the reaction mixture.
[0066] In c) of the process described above, tert-butyl amine (TBA) salt is added to the reaction mass of (b), at a temperature in the range of about 10°C to about 50°C, preferably at room temperature.
[0067] In one embodiment, the present invention provides the isolation process of the tert-butylamine salt of formula (IV) in the process described above, from the reaction mixture of c), the process comprising:
d) subjecting the reaction mixture of (c) to filtration to obtain a solid; and e) drying the solid at a temperature of about 50°C to about 55°C.
[0068] In another embodiment, the present invention provides a process for the preparation of tert-butylamine (TBA) salt of compound of formula (IV), comprising: a) reacting compound of formula (VI), with diisopropyl azodicarbox late, a triphenylphosphine and organic solvent to form (4R)-l -(benzyloxy)-4-(2,4,5- trifluoro benzyl)azitidine-2-one of formula (V),
b) reacting compound of formula (V) with a base to form the reaction mass, c) adding the tert-butyl amine (TBA) to the reaction mass of b),
d) isolating the compound of formula (IV) as TBA salt.
[0069] In another embodiment, the present invention provides a process for the preparation of tert-butylamine (TBA) salt of compound of formula (IV),
comprising:
a) reacting compound of formula (VI), with diisopropyl azodicarboxylate, a triphenylphosphine and organic solvent to form (4R)-l-(benzyloxy)-4-(2,4,5- trifluoro benzyl)azitidine-2-one of formula (V),
b) reacting compound of formula (V) with sodium hydroxide to form the reaction mass,
c) adding the tert-butyl amine (TBA) to the reaction mass of b),
d) isolating the compound of formula (IV) as TBA salt.
[0070] In yet another embodiment, the present invention provides a process for the preparation of amine salt of com ound of formula (IV),
comprising:
a) reacting compound of formula (VI), with azodicarboxylate, a phosphine and organic solvent to form (4R)-l-(benzyloxy)-4-(2,4,5-trifluoro benzyl)azitidine-2- one of formula (V),
b) reacting compound of formula (V) with a base or an acid to form the reaction mass,
c) adding the amine to the reaction mass of b),
d) isolating the compound of formula (IV) as an amine salt.
[0071] In yet another embodiment, the present invention provides an isolated compound of formula (IV) as an acid.
[0072] In yet another embodiment, the present invention provides a process for the preparation of free acid of compound (IV) by treating an amine salt of compound of formula (IV) with an acid.
[0073] After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art. For example, the working- up of reaction mixtures, especially in order to isolate desired compounds, follows procedures and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like, customarily known to the organic chemists skilled in the norms of the art.
[0074] Procedures for making compound of formula (VI), (35 -N-(benzyloxy)-3- hydroxy-4-(2, 4, 5-trifluorophenyl) butanamide), which serve as a useful intermediate in the synthesis of (3 f)-3-[(benzyloxy) amino]-4-(2, 4, 5-trifluorophenyl) butanoic acid tert- butylamine of Formula (IV) are found in the literature. Illustratively, it is described in PCT publication WO 2004/087650 and Organic Process Research & Development (OPRD) 2005, 9, 634-639, which are incorporated herein by reference, in their entirety, as shown in Scheme 1.
Scheme 1
[0075] In yet another embodiment, the present invention provides a process for the preparation of sitagliptin formula I, or pharmaceutically acceptable salt thereof, as shown in Scheme 2.
a) reacting compound of formula (VI) with azodicarboxylate, a phosphine to form a compound of formula (V),
b) reacting compound of formula (V) with an acid or base to form a compound of formula (IV),
c) isolating the compound of formula (IV) or its salt from the reaction mass thereof,
d) converting the compound of formula (IV) into sitagliptin (I) or pharmaceutically acceptable salt thereof, as prepared by processes exemplified in the present invention.
[0076] In yet another embodiment, the present invention provides a process for the preparation of sitagliptin formula I, comprising:
a) reacting compound of formula (VI), with diisopropyl azodicarboxylate, a triphenylphosphine and organic solvent to form (4R)-l-(benzyloxy)-4-(2,4,5- trifluoro benzyl)azitidine-2-one of formula (V),
b) reacting compound of formula (V) with a base to form the reaction mass, c) adding the tert-butyl amine (TBA) to the reaction mass of b),
d) isolating the compound of formula (IV) as TBA salt, and
e) converting TBA salt of formula (IV) into sitagliptin (I).
[0077] The organic solvent and base are the same as described previously. The process for isolating TBA salt of formula (IV) is same as described above.
[0078] In yet another embodiment, the present invention provides a process for the preparation of sitagliptin formula I, or a pharmaceutically acceptable salt thereof, comprising:
a) reacting amine salt of com ound of formula IV,
(IV)
with compound of formula III, or its salt,
(III)
to form a compound of formula II; and
(Π)
b) debenzylating the compound of formula II.
[0079] The amine salt may be an aliphatic amine or an aromatic amine and may be selected from the group consisting of methylamine, ethylamine, isopropylamine, tert- butylamine (TBA), tris(hydroxymethyl) methylamine, cyclohexylamine, benzylamine, 4- methoxybenzylamine ethanolamine, diethanolamine, piperazine, tromethamine and the like, preferably tert-butylamine (TBA).
[0080] Suitable salt of compound of formula III may be selected from HC1, HBr, HF and HI. Preferably, HC1 salt of compound of formula (III).
[0081] The reaction of compound of amine salt of compound of formula (IV) with compound of formula (III) or salt may be carried out in presence of coupling agent.
[0082] The coupling agent may be selected from the group consisting of Ν,Ν1- diethylcarbodiimide, Ν,Ν'-dipropyl carbodiimide Ν,Ν'-diisopropylcarbodiimide, Ν,Ν'- dicyclohexylcarbodiimide, N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide, Ν,Ν'- carbonyldiimidazole and Ν,Ν'-carbonyldithiazole, l -(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC-HC1), l -cyclohexyl-3-(2- mo holinoethyl)carbodiimide, l,3-di-tert-butylcarbodiimide, l-(dimethylaminopropyl)- 3-ethylcarbodiimide methiodide, l-tert-butyl-3-(triphenylethyl)-carbodiimide, bis- (diphenylmethyl)-carbodiimide, l-tert-butyl-3-ethylcarbodiimide, 1 -methyl-2- chloropyridinium iodide, 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline(EEDQ), BOP-chloride, isobutyl chloroformate, hydroxybenzotriazole (HOBT) and the like or their mixtures, in amount ranging from about 1 to about 5 equivalents.
[0083] In yet another embodiment, the present invention provides a process for the preparation of sitagliptin formula I, comprising:
a) reacting TBA salt of compound of formula IV, with compound of formula III, or its salt, in the presence of coupling agent to form a compound of formula II; and
b) debenzylating the compound of formula II.
[0084] In yet another embodiment, the present invention provides a process for the preparation of sitagliptin formula I, comprising:
a) reacting tert-butylamine salt of formula IV with compound of formula III in the presence of EDC-HC1 to form compound of formula II; and
b) debenzylating the compound of formula II.
[0085] In yet another embodiment, the present invention provides a process for the preparation of sitagliptin formula I, comprising:
a) reacting tert-butylamine salt of formula IV with compound of formula III in the presence of Ν,Ν'-dicyclohexylcarbodiimide to form compound of formula II; and b) debenzylating the compound of formula II.
[0086] In yet another embodiment, the present invention provides a process for the preparation of sitagliptin formula I, comprising:
a) reacting tert-butylamine salt of formula IV with compound of formula III in the presence of Ν,Ν'-carbonyldi imidazole to form compound of formula II; and b) debenzylating the compound of formula II.
[0087] The reaction of amine salt of compound of formula (IV) with compound of formula (III) may be carried out in the presence of base. The base may be selected from organic base or inorganic base. The organic base selected from triethylamine, N,N- diisopropylethylamine, diisopropylamine, 2,4,6-collidine, imidazole, pyridine, lutidine, N,N- dimethylaniline, dimethylaminopyridine and the like. Preferably, triethylamine. The inorganic base selected from an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide; an alkaline earth metal hydroxide such as barium hydroxide, calcium hydroxide, magnesium hydroxide; or an alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate or mixture thereof.
[0088] The reaction of amine salt of compound of formula (IV) with compound of formula (III) may be carried out in the presence of organic solvent. The organic solvent may be selected from Ci-C5 alcohol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dichloromethane (MDC), ethyl acetate, 1 ,2-dichloroethane, isopropyl acetate, chloroform, propionitrile, water and the like and mixtures thereof. Preferably, dichloromethane (MDC).
[0089] In another embodiment of the process of present invention TBA salt of compound of formula (IV) is reacted with the HC1 salt of compound of formula (III) in the presence of coupling agent selected from l -ethyl-(3-dimethylaminopropyl)
carbodiimide (EDAC), 1-hydroxybenzotriazole (HOBT) and triethyl amine (TEA) as base to obtain compound of formula (II).
[0090] The compound of formula (II) obtained may be isolated or may be present in the reaction mixture.
[0091] The compound of formula (II) obtained by the process of the present invention is debenzylated to give compound of formula (I).
[0092] The debenzylation of compound of formula (II) may be carried out by hydrogenating in the presence of metal catalyst and suitable organic solvent.
[0093] Metal catalysts include Pd/C, Pd/Al203, Pd/CaC03, and Pd(OH)2/C. Others catalyst can also be used such as Pt, Rh, and Ni based catalysts, or oxides thereof, alone or on supports such as carbon, silica, and alumina.
[0094] Suitable solvent may be selected from Ci-C5 alcohol such as methanol, ethanol, n-propanol, isopropanol; tetrahydrofuran, dichloromethane, 1,2-dimethoxyetane, diethoxyethane, ethyl acetate, isopropyl acetate and the like and aqueous mixture thereof. Acetates can also be used with an additive, such as HCl, HBr, acetic acid, and formic acid and the like.
[0095] Hydrogenation is carried out in the presence of hydrogen gas or hydrogen transfer reagent selected from ammonium formate, phosphonic acid hydrazine hydrate, monosodium dihydrogen orthophosphate, cyclohexene, sodium formate.
[0096] In one embodiment debenzylation of compound of formula (II) is carried out by hydrogenating using hydrogen gas at about 2.0 kg/Cm2 to about 6.0 kg/Cm2 of hydrogen pressure and at a temperature range of about 45 °C to about 65 °C. Preferably at about 3.0 kg/Cm2 to about 4.0 kg/Cm2 of hydrogen pressure and about 50 °C to about 55 °C.
[0097] In one embodiment debenzylation of compound of formula (II) is carried out with 10% Pd/C as a catalyst in MDC as the solvent at about 3 kg/Cm2 to about 4 kg/Cm2 of hydrogen pressure.
[0098] R-sitagliptin prepared by the above methods can also be converted into its pharmaceutically acceptable salts. Suitable pharmaceutically acceptable acids which can be used include, but are not limited to: inorganic acids such as phosphoric acid,
hydrochloric acid, hydrobromic acid, hydroiodic acid; and organic acids such as acetic acid, tartaric acid, oxalic acid, and the like. Preferably, phosphoric acid.
[0099] Optionally, the acid is dissolved in a solvent before adding it to the solution of R-sitagliptin free base.
[00100] The solvent used for the dissolution of R-sitagliptin and the acid may be the same, or different solvents may be used.
[00101] Optionally, the acid addition salt obtained can be purified further by recrystallization or slurrying in suitable solvents.
[00102] Suitable solvents in which the acid addition salt of R-sitagliptin can be dissolved for purification include but are not limited to: C1-C5 alcohols such as methanol, ethanol, and isopropanol and the like* C1-C5 ketones such as acetone, ethyl methyl ketone, butanone and the like; ethers such as tetrahydrofuran, 1 ,4-dioxane, ethyl acetate and the like; water; and mixtures thereof.
[00103] The following are understood to mean, as used herein, (COCl)2 is oxalyl chloride; DMF is Ν,Ν-dimethylformamide; MDC is methylenedichloride; DMAP is 4- dimethylamino pyridine; DIPE is diisopropyl ether; TEA is triethylamine; HBr is hydrobomic acid; NaOH is sodium hydroxide; LiOH is lithium hydroxide; THF is tetrahydrofuran; EDAC-HC1 is l-ethyl-(3-dimethylamino propyl)carbodiimide- hydrochloric acid; HPLC is high performance liquid chromatography; DIAD is diisopropyl azodicarboxylate; PPh3 is triphenylphosphine; MTBE is methyl tert-butyl ether; TBA is tert-butylamine; RT is room temperature; HOBT is hydroxyl benzotriazole; H3P04 is phosphoric acid.
[00104] As used herein, the term "μηι" refers to "micrometer" which is l xl0~6 meter.
[00105] As used herein, the phrase, "particle size distribution (PSD)" means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction at 1 bar dispersive pressure in Sympatec Helos equipment. di0, as used herein is defined as the particle size at which the cumulative percentage undersize is 10 (i.e. the bottom 10% of particles are less than or equal to the stated size). d5o means the median particle size and dgo is defined as the particle size at which the cumulative percentage undersize is 90 (i.e. the bottom 90% of particles are less than or equal to the stated size).
[00106] Specific surface area is defined in units of square meters per gram (m2/g). It is usually measured by nitrogen absorption analysis. In this analysis, nitrogen is absorbed on the surface of the substance. The amount of the absorbed nitrogen (as measured during the absorption or the subsequent desorption process) is related to the surface area via a formula known as the Brunauer Emmet Teller (B.E.T.) formula.
[00107] As used herein, "density" is a measurement defined as the mass of a substance per unit volume.
[00108] As used herein, "bulk density" refers to a density measurement of a loose, uncompacted substance, wherein the volume of the substance includes the air trapped between particles.
[00109] As used herein, "tapped density" refers to a density measurement of a substance that has been tapped or vibrated, thus minimizing the volume of the substance by eliminating or minimizing the air trapped between particles.
[00110] Experimental Details: Materials and Methods
The bulk density, tapped density and of the batches of R-sitagliptin phosphate crystals were determined using the following methods:
Bulk Density (BD):
1. Take a clean and dry 100 ml graduated cylinder, weighing 130 ± 16 gm;
2. Note down the weight of the empty graduated cylinder (Wl);
3. Take a clean and dry glass funnel (500 ml) and fitted to a stand at about 25 to 30 cm above the base;
4. Carefully pour the sample into the graduated cylinder through the sides of the glass funnel until the apparent volume of the sample attains 50 to 100 ml;
5. Carefully level the powder with the help of spatula without disturbing the cylinder and note down the volume (Vo) to the nearest graduated unit;
6. Note down the weight of the graduated cylinder along with the sample (W2);
7. Calculate the bulk density in g/ml according to the following equation:
BD = (W2-Wl)/Vo
Tapped Density (TD):
1. Continue the test from bulk density;
2. Fixed the cylinder containing the sample on tapped density tester equipment (which provides a fixed drop at 14 ± 2 mm at a nominal rate of 300 drops per minute)
3. Enter the weight and untapped volume of the sample. Press the 'START KEY', unless otherwise specified, tap the cylinder 500 times and measured the tapped volume 'Va' to the nearest graduated unit;
4. Repeat the tapping an additional 750 times and measure the tapped volume '\V to the nearest graduated unit;
5. If the difference between the two volumes is less than 2% then 'Vb' is the final tapped volume;
6. If the difference between the two volumes is more than 2% then continue the tapping in increments of 1250 times till the difference between succeeding measurement is less than 2%
7. After completion of taps, note down the final volume as ' Vf';
8. Calculate the tapped density in g/ml according to the following equation:
TD = (W2-Wl)/Vf
[00111] In another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having the following characteristics:
• Particle size distribution :
d)0: 23.450 μπι
d50: 78.254 μηι
d90: 193.089 μπι
• Particle size distribution after micronization:
di0: 6.999 μηι
d50: 35.620 μπι
d90: 89.703 μηι
• Specific surface area of about 10.76 m2/g, as measured by Brunauer- Emmett-Teller (B.E.T.)
• Bulk density of about 0.39 g/ml
• Tapped density of about 0.62 g/ml
• Bulk density of about 0.42 g/ml, after micronization
• Tapped density of about 0.69 g/ml, after micronization
[00112] In an embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having chemical purity more than about 99.8% as measured by HPLC and having stereo chemical purity of 100% ee, as measured by chiral HPLC.
[00113] In another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having a specific surface area higher than about 4 m2/g, more preferably higher than about 7, most preferably higher than about 9 such as about 10.5 as measured by Brunauer-Emmett-Teller (B.E.T) method. Preferably the surface area is about 5 m /g to about 20 m /g.
[00114] In another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having S-sitagliptin phosphate below detection limit.
[00115] In yet another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having a tapped density higher than about 0.200 g/ml.
[00116] In yet another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having a tapped density of about 0.300 g/ml to about 0.800 g/ml.
[00117] In yet another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having a bulk density higher than about 0.100 g/ml.
[00118] In yet another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having a bulk density of about 0.200 g/ml to about 0.700 g/ml.
[00119] In yet another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having tapped density of about 0.300 g/ml to about 0.900 g/ml, after micronization.
[00120] In yet another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having bulk density of about 0.2 00 g/ml to about 0.800 g/ml, after micronization.
[00121] In yet another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, characterized by X-ray Powder Diffraction (XRPD) pattern with reflections at about: 4.68, 9.33, 14.00, 15.04,18.29,18.68, 19.13, 19.49, 22.1 1, 24.13, 32.97 and 33.52 + 0.2 degrees 2 theta, which is substantially in accordance with Fig. 3.
[00122] In yet another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, characterized by differential scanning calorimetry (DSC) thermogram with sharp endotherm at about 218.38°C with onset at about 216.65°C and endset at about 220.68°C, which is substantially in accordance with Fig. 4.
[00123] In another embodiment, the present invention provides R-sitagliptin phosphate obtained by the processes herein described, having residual organic solvent less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. Pharmacopoeia; the recommended amount is less than 5000 ppm for acetone, ethanol, ethyl acetate and methyl tert-butyl ether; less than 3880 ppm for cyclohexane; less than 3000 ppm for methanol; less than 890 ppm for toluene; less than 720 ppm for tetrahydrofuran; less than 600 ppm for methylene chloride; less than 410 ppm for acetonitrile; less than 250 ppm for diisopropyl ether.
[00124] The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state sitagliptin phosphate into any of the foregoing desired particle size range. One common technique to decrease particle size is by micronization. Micronization is a mechanical process that involves the application of force to a particle, thereby resulting in the break-up of the particle. Such force may applied by collision of particles at high speeds. Micronization may be carried out, for example, by grinding or by air-jet micronizer.
[00125] In yet another embodiment, the present invention provides pharmaceutical compositions comprising sitagliptin or pharmaceutically acceptable salt thereof obtained
by the processes herein described, having a D50 and Ό90 particle size of less than about 200 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns.
[00126] In yet another embodiment, the present invention provides pharmaceutical compositions comprising sitagliptin or pharmaceutically acceptable salt thereof obtained by the processes herein described, having a D50 and D90 particle size after micronization less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns.
[00127] While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
[00128] Example 1: Preparation of 5-[l-hydroxy-2-(2, 4, 5-trifluorophenyl) ethylidene]-2, 2-dimethyl-l, 3-dioxane-4, 6-dione (Formula X)
300 gm of 2, 4, 5-trifluorophenyl acetic acid, 240 gm of oxalic acid, 15 ml of dimethylformamide (DMF) and 1500 ml of methylenedichloride were charged into a clean and dry round bottom flask by stirring at about 25-30°C for about 2-3 hours, the progress of the reaction was monitored by thin layer chromatography (TLC) including high performance liquid chromatography (HPLC), after the completion of the reaction, the reaction mass was cooled to about -5°C. Pre-reacted solution of 385.2 gm of 4- dimethylamino pyridine and 341 gm of 2, 2-dimethyl-l, 3-dioxane-4, 6-dione in 1500 ml of methylenedichloride was added to reaction mass between the temperature of about -5°C and maintained the reaction mixture at the same temperature until the completion of reaction, which was monitored by TLC or HPLC. 420 gm of dried product of 5-[l- hydroxy-2-(2,4,5-trifluorophenyl)ethylidene]-2,2-dimethyl-l ,3-dioxane-4,6-dione (Formula X) was obtained by the acidic aqueous workup followed by solid precipitation with diisopropyl ether. The isolated compound has been characterized by Melting points, Mass, 'HNMR and HPLC purity.
Mass : 315.31 [M-H]~
' H NMPV(300 MHz,CDC13 ) : 7.1,6.9 (2 H,m), 4.43 (2 H,s), 1.7(6 H,s)
Melting point : [86.44 - 109.5]°C
HPLC purity NLT = 98 %.
[00129] Example 2: Preparation of 3(S)-2, 4, 5-trifluoro-3-hydroxy benzenebutanoic acid [1-6] (Formula VII) (see Scheme 1)
400 gm of compound of formula (X) was refluxed with 2000 ml methanol, followed by sodium bicarbonate workup gives compound of formula (IX), which further converted into 3(S)-2,4,5-trifluoro-3-hydroxy benzenebutanoic acid methyl ester of formula (VIII) by asymmetric hydrogenation, by charging 1400 ml of methanolic solution of formula (IX) into 1000 L hydrogenation reactor followed by the addition of (S)-BINAP RuCl2 -triethylamine complex (prepared by adding 1.81 gm of S-BINAP, 0.7 gm of 1,5-cycloocatdine Ruthenium chloride and 30.05 gm of triethylamine into 1400 ml of methanolic reflux for about 20 hours). Asymmetric hydrogenation was carried out with about 6 to 6.5 kg/cm2 of hydrogen pressure and about 80-85°C, and the progress of reaction was monitored by HPLC. Reaction was completed at about 5- 7 hours and purity of formula (VIII) by Chiral HPLC was 98.28% ee. Formula (VIII) was converted into 3(S)-2,4,5-trifluoro-3-hydroxybenzenebutanoic acid of formula (VII) by adding aqueous sodium hydroxide solution (made by dissolving 67.2 gm of sodium hydroxide in to 280 ml of water) followed by refluxing the reaction mass by heating at about 65 - 70°C for about 3-5 hours. 190 gm of formula (VII) was isolated form 1400 ml of cyclohexane crystallization or isolated from toluene. Purity of formula (VII) by Chiral HPLC: 99.35 % ee.
[00130] Example 3: Preparation of (35)-N-(benzyloxy)-3-hydroxy-4-(2,4,5- trifluorophenyl) butanamide (Formula VI) (see Scheme 1)
200 gm of 3(S)-2,4,5-trifluoro-3-hydroxy benzenebutanoic acid of formula (VII), 1000 ml of tetrahydrofuran (THF), 1000 ml of water were charged into a clean and dry round bottom flask containing the mixture 164 gm of o-benzylhydroxylamine hydrochloride and 43 gm of lithium hydroxide, at about 25-30°C. 246 gm of l -ethyl-(3- dimethylaminopropyl) carbodiimide HC1 (EDAC.HC1) was added to solution and reaction was maintained at about 25-30°C for about 3-4 hours, the progress of the reaction was monitored by HPLC. THF was distilled out under vacuum at about 40-45
°C, followed by the acidification of the reaction mass by charging 60 ml of con. HC1 (35- 36%). 255 gm of (3S)-N-(benzyloxy)-3-hydroxy-4-(2,4,5-trifluorophenyl) butanamide of formula (VI) was isolated and dried the isolated product under vacuum. The isolated compound was characterized by Mass, 1HNMR, melting points and HPLC purity.
Mass : 340.5 [ M+l]
Ή NMR(300 MHz,DMSO ) : 2.09 [2 H,d], 2.5 [lH,s],2.6~2.75 [lH,m],4.08 [lH,bs],
4.7[2H,s],5.0[lH,bs],7.3~7.5 [7 H, m],l 1.02[lH,s] Melting point : 87 - 91 °C by DSC.
HPLC purity : NLT = 97.5 %.
[00131] Example 4: Preparation of (3tf)-3-[(benzyloxy) amino]-4-(2,4,5- trifluorophenyl) butanoic acid tert-butylamine (Formula IV)
1500 ml of tetrahydrpfuran (THF), 289.45 gm of triphenylphosphine were charged into a clean and dry round bottom flask (RBF) followed by stirring for about 25- 30°C for about 15 minutes. Cool the reaction mass at about -5°C. Charge the THF solution of diisopropyl azodicarboxylate (DIAD) (made by dissolving 223.44 gm of DIAD in 500 ml of THF) to the reaction mass, followed by addition of THF solution of (35 -N-(benzyloxy)-3-hydroxy-4-(2,4,5-trifluorophenyl) butanamide of formula (VI) (made by dissolving 250 gm of formula VI in 1000 ml of THF) followed by stirring for about 5°C for about 3 hours. The progress of reaction of was monitored by HPLC. To the formed intermediate (4R)-l-(benzyloxy)-4-(2,4,5-trifluoro benzyl)azitidine-2-one of formula (V), solution of sodium hydroxide (made by dissolving 44.24 gm of sod. hydroxide in 1250 ml of water) was added without isolating formula (V), followed by heating the reaction mass at about 65-70°C for about 2-3 hours, then completion of reaction was monitored by HPLC. Distilled out the THF under vacuum at about 45-50°C, followed by addition of 3750 ml of water and stirred the reaction mass to about 5 hours. Triphenylphosphine oxide was filter out as solid (side product), washed the solid with water and add 1250 ml of MTBE to the filtrate under stirring for about 30°C for about 20 to 30 minutes and separate out the MTBE, followed by acidification of aqueous layer to pH of 1.5 to 2.5 using 36% HC1, extracted the aqueous layer twice with 1250 ml of methyl dichloride and to the MDC layer of 5% sodium chloride solution was added.
Separate out MDC layer and distilled out the MDC under vacuum at about 30-35°C for about 2-3 hours. Degas the reaction mass (oily product) under vacuum at about 30-35°C and add MTBE. Cool the reaction mass at about 25-30°C and then add 107.8 gm of tert- butylamine, maintain the reaction by stirring for about 2-3 hours and filter out (3/?)-3- [(benzyloxy)amino]-4-(2,4,5-trifluorophenyl)butanoic acid tert-butylamine of formula (IV), dried the product under vacuum at about 50-55°C for about 12 hours.
The isolated compound of formula (IV) was characterized by HNMR, Mass, Melting point and tert-butylamine (TBA) assay, SOR.
Mass 340.1 1 [M+l] as Free acid & 412.77 [M+] as TBA salt.
Melting point 126 to 130.5 °C by DSC
NMR [300 MH,CdC13] 1.3[9H,s],2.2[2H,m],2.7[l H,m],2.9[lH,m],4.7[2H,t],
6.2 [ 4 H ,b],6.8[l H,m] ,7[l H,m],7.3[5H,m]
TBA assay 17.29
SOR 2.5° (1 % in methanol)
Chemical purity by HPLC 98.47 %
Stereochemical purity by 98.8 % ee.
Chiral HPLC
[00132] Example 5: Preparation of (/?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[ 1,2,4] triazolo[4,3-<3]pyrazin-7(8H)-yI]-l -(2,4,5-trifluorophenyI)butan-2-amine (Formula I)
64 gm of 3-trifluromentyl 5,6,7,8-tetrahydro (1,2,4) triazolo[4,3-a] pyrazine HQ of formula (III), 55 ml of triethylamine, 500 ml of methylenedichloride (MDC) were charged into a clean and dry round bottom flask followed by stirring for about 30 minutes, to this reaction mass 64 gm of l-ethyl-(3-dimethylaminopropyl) carbodiimide EDAC.HC1, 39.09 gm of anhydrous 1 -hydroxylbenzotriazole were added and maintained the reaction mass for about 10-20 minutes followed by the addition of (5R)-3- [(benzyloxy)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (made separately by charging 100 gm of (3i?)-3-[(benzyloxy)amino]-4-(2,4,5-trifluorophenyl)butanoic acid tert- butylamine of formula (IV), suspended in 700 ml of methylenedichloride (MDC) and 500 ml of water, to that 27 ml of acetic acid was added and stirred for about 15 minutes,
separated out the MDC layer and washed with 5% sodium chloride solution followed by drying with anhydrous sodium sulfate). Maintain the reaction mass at about 20-25°C for about 3 hours, completion of the reaction was monitored by HPLC, washed the reaction mass with 500 ml 5% sodium bicarbonate solution (twice), followed by washed with 5 % sodium chloride solution. MDC layer was distilled out under vacuum at about 30-35°C followed by dissolving in 1400 ml of methanol, charged into 2000 ml hydrogenation reactor. Hydrogenation was carried out with 18 gm of 10% Pd/C, about 3.5 kg/Cm2 of hydrogen pressure and at about 50-55°C temperature for about 10-12 hours. Filter out the reaction mass by hyflobed followed by evaporation of methanol under vacuum and degassed completely and dissolved with 500 ml of MDC and 1500 ml of water, 28 gm of 85% orthophosphoric acid was added and maintained the stirring for about 2 hours, separate the MDC layer, wash the aqueous layer with 500 ml of MDC, extract the aqueous layer with 1000 ml of MDC (twice) by adjusting the pH to about 10- 12 using 10% Sodium hydroxide solution. Wash the MDC layer with 5% sodium chloride solution. Evaporated the MDC under vacuum followed by degassing and dissolved with 500 ml of methyl-t-butyl ether and crystallized out 60 gm of crude (Λ)-4-οχο-4-[3- (trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l -(2,4,5- trifluorophenyl)butan-2-amine at about 55-65°C followed by the filtration at about 20- 25°C, dried the product under vacuum for about 12 hours, the chemical purity by HPLC and stereo chemical purity by chiral HPLC was analyzed and the result showed that 95.5% and 99.5% respectively. Chemical and stereochemical purity of formula (I) was further enhanced by dissolving it with 1500 ml of toluene at about 70-80°C and cool to about 0-5°C for about 5 hours. Filter out the solid under vacuum washed with toluene, again recrystallized the wet cake with 1000 ml of toluene by dissolving at about 70-80°C and charcoalised with 15 gm of activated charcoal at about 65-70°C, followed by the filtration through hyflobed and crystallized the solid by stirring at about 0-5°C for about 5 hours. Filter out the solid under vacuum washed with toluene, 500 ml of methyl-t-butyl ether (MTBE) was added to the filtered wet cake and dried under vacuum at about 55- 60°C for about 12 hours to achieve loss on drying to below 0.5 % w/w. After drying 45 gm of pure (#)-4-oxo-4-[3-(trifluoromethyl) -5,6-dihydro [1 ,2,4] triazolo[4,3-o]pyrazin- 7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine was obtained.
Chemical purity by HPLC : 99.21 %
Stereochemical purity by : 99.9 % ee.
Chiral HPLC
[00133] Example 6: Preparation of (7?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[ 1 ,2,4] triazolo[4,3-o]pyrazin-7(8H)-yl]- 1 -(2,4,5-trifluorophenyl)butan-2-amine (Formula I)
64 gm of 3-trifluromentyl 5,6,7,8-tetrahydro ( 1 ,2,4) triazolo[4,3-a] pyrazine. HCl of formula (III), 55 ml of triethylamine, 500 ml of methylenedichloride (MDC) were charged into a clean and dry round bottom flask followed by stirring for about 30 minutes, to this reaction mass 79.3 gm of DCC (NN'-Dicyclohexylcarbodiimide), 39.09 gm of anhydrous 1 -hydroxylbenzotriazole were added and maintained the reaction mass for about 10-20 minutes followed by the addition of (3i?)-3-[(benzyloxy)amino]-4- (2,4,5-trifluorophenyl)butanoic acid (made separately by charging 100 gm of (3R)-3- [(benzyloxy)amino]-4-(2,4,5-trifluorophenyl)butanoic acid tert-butylamine of formula (IV), suspended in 700 ml of methylenedichloride (MDC) and 500 ml of water, to that 27 ml of acetic acid was added and stirred for about 15 minutes, separated out the MDC layer and washed with 5% sodium chloride solution followed by drying with anhydrous sodium sulfate). Maintain the reaction mass at about 20-25°C for about 3 hours, completion of the reaction was monitored by HPLC, washed the reaction mass with 500 ml 5% sodium bicarbonate solution (twice), followed by washed 5 % sodium chloride solution. MDC layer was distilled out under vacuum at about 30-35°C followed by dissolving in 1400 ml of methanol, charged into 2000 ml hydrogenation reactor. Hydrogenation was carried out with 18 gm of 10% Pd/C, about 3.5 kg/Cm2 of hydrogen pressure and at about 50-55°C temperature for about 10-12 houfs. Filter out the reaction mass by hyflobed followed by evaporation of methanol under vacuum and degassed completely and dissolved with 500 ml of MDC and 1500 ml of water, 28 gm of 85% orhtophospharic acid was added and maintained the stirring for about 2 hours, separate the MDC layer, wash the aqueous layer with 500 ml of MDC, extract the aqueous layer with 1000 ml of MDC (twice) by adjusting the pH to about 10-12 using 10% Sodium hydroxide solution. Wash the MDC layer with 5% sodium chloride solution. Evaporated
the MDC under vacuum followed by degassing and dissolved with 500 ml of methyl-t- butyl ether and crystallized out 60 gm of crude (i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3-o]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2 -amine at about 55-65°C followed by the filtration at about 20-25°C, dried the product under vacuum for about 12 hours, purity of formula (I) was further enhanced by dissolving it with 1500 ml of toluene at about 70-80°C and cool to about 0-5°C for about 5 hours. Filter out the solid under vacuum washed with toluene, again recrystallized the wet cake with 1000 ml of toluene by dissolving at about 70-80°C and charcoalised with 15 gm of activated charcoal at about 65-70°C, followed by the filtration through hyflobed and crystallized the solid by stirring at about 0-5°C for about 5 hours. Filter out the solid under vacuum washed with toluene, 500 ml of methyl -t-butyl ether (MTBE) was added to the filtered wet cake and dried under vacuum at about 55-60°C for about 12 hours to achieve loss on drying to below 0.5 % w/w. After drying 35-45 gm of pure ( ?)-4-oxo-4- [3-(trifluoromethyl) -5,6-dihydro [1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl]-l -(2,4,5- trifluorophenyl)butan-2 -amine was obtained.
[00134] Example 7: Preparation of (i?)-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-amine phosphate (1 : 1)
38 gm of (i?)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[4,3- o]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine charged into the 1000 ml round bottom flask containing 218.8 ml of ethanol and 68.02 ml of water under stirring at about 20-25°C for about 15°C to get clear solution. 1 1.84 gm of 85% phosphoric acid was added to clear solution and heat the reaction mass to about 75-85°C, while heating the reaction mass white solid formed and then dissolved upon reflux , and reflux maintained for about 2 hours, then cool to about 65-70°C and the temperature maintained the reaction mass at about 5 hours. Cool the reaction mass slowly to about 25- 30°C for about 8-12 hours, maintained the stirring at about 25-30°C for about 12 hours, then 174.8 ml of ethanol was added and maintained the stirring for about 2 hours at about 25-30°C. Filter out solid and washed with 57 ml of ethanol (twice), dried the solid under vacuum for about 24 hours. 42 gm of (i?)-4-oxo-4-[3-(trifluoromethyl)-5,6-
dihydro[l,2,4]triazolo[4,3-o]pyrazin-7(8H)-yl]-l -(2,4,5-trifluorophenyl)butan-2-amine phosphate (1 : 1) was obtained.
Chemical purity by HPLC: 99.87%; Stereochemical purity by: 100% ee, by chiral HPLC
Specific optical rotation (SOR): -21.43 ° [1 % in water]
Melting point by DSC: 218. 41°C [range between 216 to 220 °C]
Particle size: di0: 23.450 μπι; d50: 78.254 μιη; d90: 193.089 μηι
Particle size after micronization: d)0: 6.999 μηι; d50: 35.620 μπι; d90: 89.703 μm
Surface area: 10.76 m2/g
Bulk density: 0.39 g/ml; Tapped density: 0.62 g/ml
Bulk density after micronization: 0.42g/ml; Tapped density after micronization: 0.69g
Claims
1. An isolated compound of formula IV)
(IV)
or an amine salt thereof.
2. The salt of claim 1, wherein said salt is selected from the group consisting of methylamine, ethylamine, isopropylamine, tert-butylamine (TBA), tris(hydroxymethyl) methylamine, cyclohexyamine, benzylamine, 4-methoxybenzylamine ethanolamine, diethanolamine, piperazine, tromethamine.
3. The salt of claim 2, wherein said salt is tert-butylamine (TBA).
4. A process for the preparation of tert-but lamine salt of formula (IV),
a) reacting compound of formula (VI)
with azodicarboxylate, a phosphine to form (4R)-l-(benzyloxy)-4-(2,4,5-trifluoro benzyl)azitidine-2-one of formula V);
(V)
b) reacting the compound of formula (V) with a base or an acid to form a reaction mass; c) adding the tert-butyl amine (TBA) to the reaction mass of (b); and
d) isolating the compound of formula (IV) as TBA salt.
5. The process of claim 4, wherein the organic solvent is selected from tetrahydrofuran, 1,4-dioxane methylene chloride, ethylene chloride, cyclohexane, toluene, ethyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether.
6. The process of claim 4 a), wherein the amount of azodicarboxylate is used from about 1 mole to about 5 moles per mole of the compound of formula VI.
7. The process of claim 4 a), wherein the amount of phosphine is used from about 1 mole to about 5 moles per mole of the compound of formula VI.
8. The process of claim 4 c), wherein addition of tert-butyl amine is carried out at room temperature.
9. A process for the preparation of amine salt of formula (IV), comprising:
a) reacting compound of formula (VI), with an azodicarboxylate, a phosphine and solvent to form (4R)-l-(benzyloxy)-4-(2,4,5-trifluoro benzyl)azitidine-2-one of formula (V); b) reacting compound of formula (V) with base or an acid to form a reaction mass;
c) adding the amine to the reaction mass of step b); and
d) isolating the compound of formula (IV) as a salt.
10. A process for the preparation of sitagliptin of formula (I), or pharmaceutically acceptable salt thereof,
(I) salt of compound of formula IV
(IV)
with compound of formula III, or its salt,
(III)
to form a compound of formula II; and
(Π)
b) debenzylating the compound of formula II.
1 1. The process of claim 14, wherein amine salt is tert-butylamine (TBA).
12. The process of claim 14, wherein reaction is carried out in presence of coupling agent, selected from the group consisting of N,N'-diethylcarbodiimide, Ν,Ν'-dipropyl carbodiimide N,N'-diisopropylcarbodiimide, Ν,Ν'-dicyclohexylcarbodiimide, N-ethyl-N'- [3-(dimethylamino) propyl]carbodiimide, Ν,Ν'-carbonyldiimidazole.
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