CN101824037B - Preparation method of Januvia free base - Google Patents
Preparation method of Januvia free base Download PDFInfo
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- CN101824037B CN101824037B CN2010101264314A CN201010126431A CN101824037B CN 101824037 B CN101824037 B CN 101824037B CN 2010101264314 A CN2010101264314 A CN 2010101264314A CN 201010126431 A CN201010126431 A CN 201010126431A CN 101824037 B CN101824037 B CN 101824037B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention relates to a preparation method of Januvia free base which takes 7-[3-amino-1- oxygen-4-(2,4,5-trifluorophenyl)-2-butenyl)]-5,6,7,8-tetralin-3-(1-trifluoromethyl)-1,2,4- triazole[4,3-alpha]benzopyrazine as an initial raw material. The method comprises the following steps: (1) enabling the 7-[3-amino-1- oxygen-4-(2,4,5-trifluorophenyl)-2-butenyl)]-5,6,7,8-tetralin-3-(1-trifluoromethyl)-1,2,4- triazole[4,3-alpha]benzopyrazine to perform a catalytic hydrogenation reaction to generate mixed spiral Januvia free base in the presence of a Pd-C catalyst or hydroboron; (2) splitting the spiral Januvia free base by using an organic acid spitting agent with D configuration to obtain R-Januvia organic acid salt; and (3) neutralizing the R-Januvia organic acid salt to obtain the Januvia free base. The invention provides a new path for synthesizing the Januvia free base without expensive metallic catalysts, has lower cost and is applicable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of Januvia free base.
Background technology
Sitagliptin (sitagliptin) is a kind of novel anti type ii diabetes medicine of FDA approval listing, is first dipeptidyl peptidase-iv inhibitor medicine that is used to treat the type ii diabetes medicine.The OHA that the sitagliptin mechanism of action is different from the past, it increases secretion of insulin through improving the ability that diabetic subject self beta Cell of islet produces Regular Insulin when blood sugar increasing, thus control of diabetes patient's glucose level.Clinical study show sitagliptin be one oral effectively, the medicine of good market prospects, single with or share with N1,N1-Dimethylbiguanide, pioglitazone significant hypoglycemic activity all arranged, and it is few to take safety, better tolerance, untoward reaction.Sitagliptin (sitagliptin) structural formula is following:
About the synthetic especially synthetic defectives such as cost height, complicated operation that exist of its free alkali of sitagliptin, can't realize scale operation at present.The Januvia free base structural formula is following:
WO2004085378, WO2005020920 and WO2005097733 disclose with 7-[3-amino-1-oxygen-4-(2,4, the 5-trifluorophenyl)-crotyl]-5; 6,7,8-tetrahydrochysene-3-(1-trifluoromethyl)-1; 2,4-triazole [4,3-α] and pyrazine are raw material; Ligand complex with precious metals such as rhodium and iridium is that chiral catalysis reagent carries out catalytic hydrogenating reduction to two keys, can obtain the Januvia free base of high chiral purity, and reaction equation is following:
This method is simple, and is easy to operate, but expensive metal catalyst is difficult for reclaiming, can not applying mechanically, and causes the production cost of Januvia free base very high, is inappropriate for suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention is in order to overcome the deficiency of prior art, a kind of preparation method who is suitable for the Januvia free base of suitability for industrialized production to be provided.
For solving above technical problem, the present invention takes following technical scheme:
A kind of preparation method of Januvia free base is with 7-[3-amino-1-oxygen-4-(2,4, the 5-trifluorophenyl)-crotyl]-5; 6,7,8-tetrahydrochysene-3-(1-trifluoromethyl)-1,2; 4-triazole [4,3-α] and pyrazine are starting raw material, and said method comprises the steps:
(1), makes said-[3-amino-1-oxygen-4-(2,4, the 5-trifluorophenyl)-crotyl]-5; 6,7,8-tetrahydrochysene-3-(1-trifluoromethyl)-1; 2, the Januvia free base that catalytic hydrogenation reaction generates DL takes place in 4-triazole [4,3-α] and pyrazine in the presence of Pd-C catalyzer or hydroborate;
(2), adopt the organic acid resolving agent of D configuration, the Januvia free base of step (1) gained DL is split, obtain R-sitagliptin organic acid salt;
(3), neutralization procedure (2) gained R-sitagliptin organic acid salt obtains said Januvia free base.
Above-mentioned preparation method representes as follows with chemical equation:
According to further embodiment of the present invention: in the step (1), said hydrogenation reaction is carried out down and in the alcoholic solvent for 5 ℃～60 ℃ in temperature, and alcoholic solvent can be for being selected from one or more the mixture in methyl alcohol, ethanol and the Virahol.Reaction is preferably carried out under 25 ℃～30 ℃.
According to an aspect of the present invention, the organic acid resolving agent of D configuration described in the step (2) can be D-tartrate or D-camphorsulfonic acid etc., wherein preferred D-tartrate.Said fractionation can be adopted various known disassemble techniques, preferably adopts the kinetic resolution method, more preferably, adopts the Dynamic Kinetic Resolution method.According to a concrete aspect, said fractionation is being carried out in the presence of the aromatic aldehyde based compound catalyzer and under 0 ℃～60 ℃ of the ketones solvents, pH1～5, temperature.Preferably, said fractionation is at pH 2～4, carries out under 0 ℃～10 ℃ of the temperature, and said ketones solvent can be acetone or MIBK.Said aromatic aldehyde based compound is preferably PARA HYDROXY BENZALDEHYDE, phenyl aldehyde etc.Said pH can regulate through adding formic acid or acetate.
According to another aspect of the invention, in the step (3), preferably use 25wt%～28wt% ammoniacal liquor to be neutralization reagent.
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
The invention provides the variation route of synthetic Januvia free base, need not to adopt expensive metal catalyst, cost is lower, is suitable for suitability for industrialized production.
Embodiment
Embodiment below in conjunction with concrete does further detailed description to the present invention, but the present invention is not limited to this embodiment.
Embodiment 1
Present embodiment provides a kind of preparation method of Januvia free base of DL, and is specific as follows: with 7-[3-amino-1-oxygen-4-(2,4, the 5-trifluorophenyl)-crotyl]-5; 6,7,8-tetrahydrochysene-3-(1-trifluoromethyl)-1,2; 4-triazole [4,3-α] and pyrazine (60g, 148mmol), methyl alcohol 600ml and 10g 3%Pd/C join in the 1000ml reaction kettle, uses nitrogen, hydrogen exchange 3 times respectively; Hydrogenation finishes to inhaling hydrogen under temperature 20-25 ℃, normal pressure, inhales about 10-15h of hydrogen time, and reaction is complete, discharging; Reactant filtered and recycled Pd/C, reaction solution filter after adding 6g activated carbon decolorizing 10min; Filtrate decompression is concentrated into dried, gets the colourless thick material of 58g, the i.e. Januvia free base of DL.Yield 96%, HPLC purity 99.5%.
Embodiment 2
Present embodiment provides a kind of preparation method of Januvia free base of DL, and is specific as follows: with 7-[3-amino-1-oxygen-4-(2,4, the 5-trifluorophenyl)-crotyl]-5; 6,7,8-tetrahydrochysene-3-(1-trifluoromethyl)-1,2; 4-triazole [4,3-α] and pyrazine (60g, 148mmol); Methyl alcohol 600ml, adds KBH in batches by in the maintenance warm 10-15 ℃
4(40g, 740mmol), reinforced finishing is in 20-25 ℃ of stirring reaction 3h; After keeping 20-25 ℃ of Dropwise 5 0ml concentrated hydrochloric acid, add the 500ml ether, 250ml water cools to 5 ℃ and uses strong aqua conditioned reaction liquid PH to be 8-9; After layering, ether layer are used and are washed twice, anhydrous magnesium sulfate drying 5h, drying finishes; Filter, filtrate decompression is concentrated into dried, gets the colourless thick material of 58g, the i.e. Januvia free base of DL.Yield 96%, HPLC purity 99.2%.
Embodiment 3
Present embodiment provides a kind of preparation method of R-sitagliptin tartrate, and step is following:
(1), according to preparing the Januvia free base of DL with embodiment 1 identical method.
(2), with D-tartrate (22g 147mmol) stirs down and is dissolved in fully in the 500ml acetone, add again catalytic amount PARA HYDROXY BENZALDEHYDE (0.1g, 0.735mmol), stir down dropping Glacial acetic acid min. 99.5 conditioned reaction pH=3 after, reacting liquid temperature is reduced to 0 ℃.Januvia free base (60g with step (1) gained DL; After 147mmol) being dissolved in the 200ml acetone; Januvia free base acetone soln with the DL for preparing under 0-5 ℃ of stirring is added drop-wise in the tartaric acid solution, and the adularescent solid is separated out in the dropping process.Dropwise, keep 5 ℃ of stirred crystallization 10h.Filter, filter cake acetone is washed after drying and is got white crystals 67g, i.e. R-sitagliptin tartrate.Yield 82%, ee%=99.7%.
Embodiment 4
Present embodiment provides a kind of preparation method of R-sitagliptin tartrate, and step is following:
(1), according to preparing the Januvia free base of DL with embodiment 1 identical method.
(2), with D-tartrate (22g 147mmol) stirs down and is dissolved in fully in the 500ml acetone, add again catalytic amount phenyl aldehyde (0.015g, 0.147mmol), stir down dropping Glacial acetic acid min. 99.5 conditioned reaction PH=3 after, reacting liquid temperature is reduced to 0 ℃.Will be according to the Januvia free base (60g of the DL of implementing row one preparation; After 147mmol) being dissolved in the 200ml acetone; Januvia free base acetone soln with the DL for preparing under 0-5 ℃ of stirring is added drop-wise in the tartaric acid solution, and the adularescent solid is separated out in the dropping process.Dropwise, keep 5 ℃ of stirred crystallization 10h.Filter, filter cake acetone is washed after drying and is got white crystals 70g, i.e. R-sitagliptin tartrate.Yield 85%, ee%=99.8%.
Embodiment 5
Present embodiment provides a kind of preparation method of Januvia free base, and it comprises the steps:
(1), the Januvia free base of preparation DL
With 7-[3-amino-1-oxygen-4-(2,4, the 5-trifluorophenyl)-crotyl]-5,6,7; 8-tetrahydrochysene-3-(1-trifluoromethyl)-1,2,4-triazole [4,3-α] and pyrazine (60g; 148mmol), methyl alcohol 600ml and 10g 5%Pd/C join in the 1000ml reaction kettle, uses nitrogen, hydrogen exchange 3 times respectively, hydrogenation finishes to inhaling hydrogen under temperature 20-25 ℃, normal pressure, inhales about 2-3h of hydrogen time; Reaction is finished, and discharging is after reactant filtered and recycled Pd/C, reaction solution add 6g activated carbon decolorizing 10min; Filter, filtrate decompression is concentrated into dried, gets the colourless thick material of 60g, the i.e. Januvia free base of DL.Yield 99.5%, HPLC purity 99.7%.
(2), preparation R-sitagliptin tartrate
With D-tartrate (22g 147mmol) stirs down and is dissolved in fully in the 500ml acetone, add again catalytic amount PARA HYDROXY BENZALDEHYDE (0.02g, 0.147mmol), stir down dropping Glacial acetic acid min. 99.5 conditioned reaction pH=3 after, reacting liquid temperature is reduced to 0 ℃.Januvia free base (60g with the DL of step (1) preparation; After 147mmol) being dissolved in the 200ml acetone; Januvia free base acetone soln with the DL for preparing under 0-5 ℃ of stirring is added drop-wise in the tartaric acid solution, and the adularescent solid is separated out in the dropping process.Dropwise, keep 5 ℃ of stirred crystallization 10h.Filter, filter cake acetone is washed after drying and is got white crystals 68g, i.e. R-sitagliptin tartrate.Yield 83%, ee%=99.7%.
(3), preparation Januvia free base
68g step (2) gained R-sitagliptin tartrate, 300ml ether and 200ml pure water stirred mix 30min down, cool to below 5 ℃ after.Keep 0-5 ℃ to drip strong aqua, conditioned reaction liquid pH=8-9, layering, ether layer is used anhydrous magnesium sulfate drying 5h after washing twice.Filter, filtrate decompression is concentrated into dried, gets the colourless thick material of 48g, i.e. Januvia free base.Yield 96%, ee%=99.8%.
Embodiment 6
Present embodiment provides a kind of preparation method of Januvia free base, and it comprises the steps:
(1), according to preparing the Januvia free base of DL with embodiment 5 identical methods.
(2), preparation R-sitagliptin tartrate
With the D-camphorsulfonic acid (34g 147mmol) stirs down and is dissolved in fully in the 500ml acetone, add again catalytic amount PARA HYDROXY BENZALDEHYDE (0.02g, 0.147mmol), stir down dropping Glacial acetic acid min. 99.5 conditioned reaction pH=3 after, reacting liquid temperature is reduced to 0 ℃.Januvia free base (60g with the DL of step (1) preparation; After 147mmol) being dissolved in the 200ml acetone; Januvia free base acetone soln with the DL for preparing under 0-5 ℃ of stirring is added drop-wise in the tartaric acid solution, and the adularescent solid is separated out in the dropping process.Dropwise, keep 5 ℃ of stirred crystallization 10h.Filter, filter cake acetone is washed after drying and is got white crystals 75g, i.e. R-sitagliptin tartrate.Yield 80%, ee%=99.8%.
(3), preparation Januvia free base
75gR-sitagliptin tartrate, 300ml ether and 200ml pure water stirred mix 30min down, cool to below 5 ℃ after.Keep 0-5 ℃ to drip strong aqua, conditioned reaction liquid PH=8-9, layering, ether layer is used anhydrous magnesium sulfate drying 5h after washing twice.Filter, filtrate decompression is concentrated into dried, gets the colourless thick material of 46g, i.e. Januvia free base.Yield 96%, ee%=99.9%.
More than the present invention has been done detailed description; Its purpose is to let the personage that is familiar with this art can understand content of the present invention and implements; Can not limit protection scope of the present invention with this; All equivalences of doing according to spirit of the present invention change or modify, and all should be encompassed in protection scope of the present invention.
Claims (6)
1. the preparation method of a Januvia free base is with 7-[3-amino-1-oxygen-4-(2,4, the 5-trifluorophenyl)-crotyl]-5; 6,7,8-tetrahydrochysene-3-(1-trifluoromethyl)-1,2; 4-triazole [4,3-α] and pyrazine are starting raw material, and it is characterized in that: said method comprises the steps:
(1), makes said 7-[3-amino-1-oxygen-4-(2,4, the 5-trifluorophenyl)-crotyl]-5; 6,7,8-tetrahydrochysene-3-(1-trifluoromethyl)-1; 2, the Januvia free base that hydrogenation reaction generates DL takes place in 4-triazole [4,3-α] and pyrazine in the presence of Pd-C catalyzer or hydroborate;
(2), adopt the organic acid resolving agent of D configuration; Januvia free base to step (1) gained DL splits, and obtains R-sitagliptin organic acid salt, wherein; The Dynamic Kinetic Resolution method is adopted in said fractionation; Specifically be in the presence of PARA HYDROXY BENZALDEHYDE or phenyl aldehyde and ketones solvent, pH2～4, carry out under 0 ℃～10 ℃ of the temperature that said ketones solvent is acetone or MIBK;
(3), neutralization procedure (2) gained R-sitagliptin organic acid salt obtains said Januvia free base.
2. preparation method according to claim 1; It is characterized in that: in the step (1); Said hydrogenation reaction is carried out down and in the alcoholic solvent 5 ℃～60 ℃ of temperature, and said alcoholic solvent is one or more the mixture that is selected from methyl alcohol, ethanol and the Virahol.
3. preparation method according to claim 2 is characterized in that: in the step (1), said hydrogenation reaction is carried out under 25 ℃～30 ℃ of temperature.
4. preparation method according to claim 1 is characterized in that: the organic acid resolving agent of D configuration described in the step (2) is D-tartrate or D-camphorsulfonic acid.
5. preparation method according to claim 1 is characterized in that: in the step (2), use formic acid or acetate to regulate said pH.
6. preparation method according to claim 1 is characterized in that: in the step (3), use 25wt%～28wt% ammoniacal liquor as neutralization reagent.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102757431B (en) * | 2011-04-24 | 2016-03-30 | 浙江华海药业股份有限公司 | A kind of novel method of synthesizing sitagliptin |
| EP2527320A1 (en) * | 2011-05-27 | 2012-11-28 | LEK Pharmaceuticals d.d. | Preparation of Sitagliptin Intermediates |
| CN104418861B (en) * | 2013-09-10 | 2017-11-10 | 浙江医药股份有限公司新昌制药厂 | A kind of preparation method of Xi Gelieting midbody compound |
| CN107428761B (en) * | 2015-01-08 | 2019-11-05 | 李氏制药有限公司 | The method for preparing dipeptidyl peptidase-4 (DPP-4) inhibitor |
| CN110857303A (en) * | 2018-08-24 | 2020-03-03 | 江苏瑞科医药科技有限公司 | Preparation method of sitagliptin free base monomer |
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| US20080227786A1 (en) * | 2004-01-16 | 2008-09-18 | Ferlita Russell R | Novel Crystalline Salts of a Dipeptidyl Peptidase-IV Inhibitor |
| JP4980358B2 (en) * | 2005-09-19 | 2012-07-18 | アロー セラピューティクス リミテッド | Benzodiazepine derivatives for treating hepatitis C infection |
| WO2009084024A2 (en) * | 2007-11-02 | 2009-07-09 | Glenmark Generics Limited | A process for the preparation of r-sit agliptin and its pharmaceutically acceptable salts thereof |
| EP2599781A1 (en) * | 2007-12-20 | 2013-06-05 | Dr. Reddy's Laboratories Ltd. | Processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof |
| CN101928289A (en) * | 2009-06-19 | 2010-12-29 | 北京海步国际医药科技发展有限公司 | Method for preparing dipeptidyl peptidase-IV inhibitor |
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