CN103910634A - Preparation method of sitagliptin intermediate - Google Patents

Preparation method of sitagliptin intermediate Download PDF

Info

Publication number
CN103910634A
CN103910634A CN201310732949.6A CN201310732949A CN103910634A CN 103910634 A CN103910634 A CN 103910634A CN 201310732949 A CN201310732949 A CN 201310732949A CN 103910634 A CN103910634 A CN 103910634A
Authority
CN
China
Prior art keywords
solvent
compound
carried out
grams
organic solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201310732949.6A
Other languages
Chinese (zh)
Other versions
CN103910634B (en
Inventor
赖金强
梁志广
杨凤智
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong HEC Pharmaceutical
Original Assignee
Guangdong HEC Pharmaceutical
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangdong HEC Pharmaceutical filed Critical Guangdong HEC Pharmaceutical
Priority to CN201310732949.6A priority Critical patent/CN103910634B/en
Publication of CN103910634A publication Critical patent/CN103910634A/en
Application granted granted Critical
Publication of CN103910634B publication Critical patent/CN103910634B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a preparation method of a sitagliptin intermediate. The method utilizes a low-toxicity organic solvent as a reaction solvent, realizes high-yield preparation of a high-purity desired product, is conducive to safe production and is suitable for industrial production.

Description

The preparation method of Xi Gelieting intermediate
Technical field
The present invention relates to the preparation method of medicine and intermediate thereof, belong to pharmaceutical technology field.
Background technology
Xi Gelieting, is a kind of oral hyperglycemia medicine, in diabetes B patient, can improve glycemic control by the level that increases active intestines insulinotropin.
Prepare in the method for Xi Gelieting, need to first prepare a kind of important intermediate, its structure as shown in (I1),
Large-scale industrial production intermediate (I1) safely and efficiently, to industrial production, Xi Gelieting is significant; In the method for preparing Xi Gelieting of many pieces of documents, prepare this intermediate and use acetonitrile, tetrahydrofuran (THF) etc. as reaction solvent.
In preparation technology, the solvent using is according to its toxicity difference, and the toxic healthy to workman is also different, also different on the impact of drug quality.Pharmacopoeia of each country has all carried out strict classification to solvent, according to the toxicity of solvent, common solvent is divided into three classes: wherein first kind solvent refer to known can be carcinogenic and by the strong doubt solvent harmful to human and environment, possible in the situation that, should avoid using this kind solvent, as benzene (2ppm), tetracol phenixin (4ppm) etc.; Equations of The Second Kind solvent refers to without genotoxicity but has the solvent of animal carinogenicity, as acetonitrile (410ppm), methylcyclohexane (1180ppm) etc.; The 3rd kind solvent refers to the solvent to human body low toxicity, and without demonstration in the situation that, the amount of residual solvent can not be accepted higher than 0.5%.According to classification, acetonitrile, tetrahydrofuran (THF) equal solvent all belong to Equations of The Second Kind solvent, and its toxicity is larger, volatile, have intense stimulus smell or easily produce superoxide, unfavorable to environment, operator ' s health and production safety, are unsuitable for industrialized production.
Summary of the invention
Summary of the invention
A kind of method of the Xi Gelieting of preparation intermediate is provided here, by using hypotoxicity reaction solvent, has solved the dysgenic problem of existing method to environment and operator, be suitable for large-scale industrialization and produce; And can prepare to high yield high purity this intermediate.
Detailed Description Of The Invention
Here provide one to prepare the method suc as formula the compound shown in (I1), described method can solve the dysgenic problem of existing method to environment and operator, is suitable for large-scale industrialization and produces; And can prepare this intermediate to high yield high purity, and then suitability for industrialized production is prepared Xi Gelieting.
Intermediate (I1):
In general formula (I1), R 1, R 2, R 3, R 4, R 5be selected from hydrogen, halogen, the alkyl of C1-C6, the alkoxyl group of C1-C6 separately identical or differently; R 7be selected from hydroxyl, the alkoxyl group of C1-C6, halogen, CH 2ph or OCH 2ph; Wherein " C1-C6 " refers to 1 to 6 carbon, and " Ph " refers to phenyl.
The method of preparing compound (I1) comprises by compound (01) and compound (02) in hypotoxicity organic solvent, prepares through serial reaction; Compound (01) and compound (02) structure are respectively as shown in the formula shown in (01) and formula (02):
Wherein, R 6be selected from hydroxyl, halogen; M is alkalimetal ion; R 1, R 2, R 3, R 4, R 5, R 7definition is identical with definition in general formula (I1).
In some embodiments, R 1, R 4for hydrogen; R 2, R 3, R 5for fluorine.
In some embodiments, R 7be selected from methoxyl group, oxyethyl group, tert.-butoxy.
In some embodiments, M is sodium ion, potassium ion.
Wherein, described hypotoxicity organic solvent refers to oral medium lethal dose (oral LD50, mouse (rat)) higher than 2900mg/Kg, 3000mg/Kg, 3500mg/Kg, 4000mg/Kg, 4500mg/Kg, the organic solvent of 5000mg/Kg or 5500mg/Kg (mg/kg).
In some embodiments, described hypotoxicity organic solvent easily produces the solvent of superoxide not included in air.
In some embodiments, hypotoxicity organic solvent is esters solvent.
In some embodiments, compound (01) and compound (02), in hypotoxicity organic solvent, comprise the steps: through the method for compound shown in serial reaction preparation formula (I1)
Step (a) and step (b) are in no particular order, after step (a) and step (b) react completely, the product of step (a) and step (b) is carried out to step (c), prepare compound (I1); Step (a), step (b) and step (c) are carried out in identical or different low-toxic solvent, preferred identical low-toxic solvent;
MgCl in step (b) 2for Magnesium Chloride Anhydrous, step (b) is carried out under alkali exists, and described alkali is triethylamine or N, N-diisopropyl ethyl amine or its combination, and in some embodiments, alkali is triethylamine;
Step (c) is included in reaction and then the reaction of process acid decarboxylation under alkaline condition, obtains compound (I1), and described alkali is triethylamine or N, N-diisopropyl ethyl amine or its combination, and described acid is mineral acid, organic acid or its combination; In some embodiments, described acid is hydrochloric acid, sulfuric acid, phosphoric acid, citric acid or its combination; Described alkali is triethylamine in some embodiments, and described acid is hydrochloric acid.
In some embodiments, hypotoxicity organic solvent is ethyl acetate, isopropyl acetate or its combination.
In some embodiments, shown in preparation formula (I1), the method for compound comprises: compound shown in compound shown in formula (01) and formula (02) through serial reaction, prepares compound shown in formula (I1) in hypotoxicity organic solvent; Wherein, R 1, R 4for hydrogen, R 2, R 3, R 5for fluorine, R 6for hydroxyl or halogen, R 7as defined in general formula (I1).
In some embodiments, shown in preparation formula (I1), the method for compound comprises: compound shown in compound shown in formula (01) and formula (02) through serial reaction, prepares compound shown in formula (I1) in esters solvent; Wherein, R 1, R 4for hydrogen, R 2, R 3, R 5for fluorine, R 6for hydroxyl, R 7for oxyethyl group, M is potassium ion.
In some embodiments, shown in preparation formula (I1), the method for compound comprises following reaction:
Wherein, step (a), step (b) and step (c) are carried out in identical or different low-toxic solvent, preferred identical low-toxic solvent, MgCl in step (b) 2for Magnesium Chloride Anhydrous, K is potassium ion, and step (b) is carried out under alkali exists, and first reaction and then the reaction of process acid decarboxylation under alkaline condition of step (c), prepares compound (I1); In some embodiments, step (a), step (b) and step (c) are carried out in esters solvent; In some embodiments, step (a), step (b) and step (c) are carried out in ethyl acetate or isopropyl acetate, step (b) alkali used is triethylamine, in step (c), first under triethylamine exists, reaction, then through persalt effect, prepares compound (I1): 3-carbonyl-4-(2,4,5-trifluorophenyl) ethyl butyrate.
Embodiment
In order to make those skilled in the art understand better technical scheme of the present invention, below further disclose some unrestricted embodiment the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can obtain by method preparation described in the invention.
Embodiment 1
17.85 grams of potassium ethyl malonate salt, 11.97 grams of 22 milliliters of triethylamines and Magnesium Chloride Anhydrouss join respectively in the anhydrous ethyl acetate of 120 milliliters of stirrings, stirring at room temperature 2 hours; By 9.5 grams of 2,4,5-trifluoro benzene acetic acids and N, 9.73 grams of N '-carbonyl dimidazoles stir 0.5 hour in 50 milliliters of ethyl acetate, and this mixed solution is joined in previous reaction liquid; Mixed reaction solution, 50 ℃ of-60 ℃ of stirring reactions 6 hours-8 hours, is cooled to 15 ℃-25 ℃, adds 10% aqueous hydrochloric acid, regulate pH to pH to be less than 3, layering, saturated common salt water washing 3 times for organic layer, concentrated evaporate to dryness after anhydrous sodium sulfate drying for organic layer, obtains 13.2 grams of oily matter.
Embodiment 2
17.85 grams of potassium ethyl malonate salt, 11.97 grams of 22 milliliters of triethylamines and Magnesium Chloride Anhydrouss join respectively in the isopropyl acetate of 120 milliliters of stirrings, stirring at room temperature 2 hours, by 2, 4, 9.5 grams of 5-trifluoro benzene acetic acids and N, 9.73 grams of N '-carbonyl dimidazoles stir 0.5 hour in 50 milliliters of isopropyl acetates, this mixed solution is joined in previous reaction liquid, mixed reaction solution was 50 ℃ of-60 ℃ of stirring reactions 6 hours-8 hours, be cooled to 15 ℃-25 ℃, add 10% aqueous hydrochloric acid, regulate pH to pH to be less than 3, layering, saturated common salt water washing 3 times for organic layer, concentrated evaporate to dryness after anhydrous sodium sulfate drying for organic layer, obtain 13.1 grams of oily matter.
Embodiment 3
20.82 grams of propanedioic acid list tert-butyl ester sylvite, N, 11.97 grams of 27.5 milliliters of N-diisopropyl ethyl amines and Magnesium Chloride Anhydrouss join respectively in the ethyl acetate of 120 milliliters of stirrings, stirring at room temperature 2 hours, by 2, 4, 9.5 grams of 5-trifluoro benzene acetic acids and N, 9.73 grams of N '-carbonyl dimidazoles stir 0.5 hour in 50 milliliters of ethyl acetate, this mixed solution is joined in previous reaction liquid, mixed reaction solution is at 50 ℃ of-60 ℃ of stirring reaction 6-8 hour, be cooled to 15 ℃-25 ℃, add 10% aqueous hydrochloric acid, regulate pH to pH to be less than 3, layering, saturated common salt water washing 3 times for organic layer, concentrated evaporate to dryness after anhydrous sodium sulfate drying for organic layer, obtain 15.1 grams of oily matter.
Embodiment 4
24.39 grams of propanedioic acid list benzene methyl sylvite, 11.97 grams of 22 milliliters of triethylamines and Magnesium Chloride Anhydrouss join respectively in the isopropyl acetate of 120 milliliters of stirrings, stirring at room temperature 2 hours, by 2, 4, 9.5 grams of 5-trifluoro benzene acetic acids and N, 9.73 grams of N '-carbonyl dimidazoles stir 0.5 hour in 50 milliliters of isopropyl acetates, this mixed solution is joined in previous reaction liquid, mixed reaction solution was 50 ℃ of-60 ℃ of stirring reactions 6 hours-8 hours, be cooled to 15 ℃-25 ℃, add 10% aqueous hydrochloric acid, regulate pH to pH to be less than 3, layering, saturated common salt water washing 3 times for organic layer, concentrated evaporate to dryness after anhydrous sodium sulfate drying for organic layer, obtain 16.28 grams of oily matter.
Embodiment 5
20.82 grams of propanedioic acid list tert-butyl ester sylvite, 11.97 grams of 22 milliliters of triethylamines and Magnesium Chloride Anhydrouss join respectively in the isopropyl acetate of 120 milliliters of stirrings, stirring at room temperature 3 hours, by 2, 4, 10.43 grams of 5-trifluoro-benzene Acetyl Chloride 98Min.s and N, 9.73 grams of N '-carbonyl dimidazoles stir 0.5 hour in 50 milliliters of isopropyl acetates, this mixed solution is joined in previous reaction liquid, mixed reaction solution was 50 ℃ of-60 ℃ of stirring reactions 6 hours-8 hours, be cooled to 15 ℃-25 ℃, add 10% aqueous hydrochloric acid, regulate pH to pH<3, layering, saturated common salt water washing 3 times for organic layer, concentrated evaporate to dryness after anhydrous sodium sulfate drying for organic layer, obtain 15.0 grams of oily matter.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and apply the technology of the present invention.Those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.

Claims (9)

1. a method of preparing suc as formula compound shown in (I1), comprise: the compound (01) being shown below and compound (02) are in hypotoxicity organic solvent, prepare compound (I1) through serial reaction
Wherein, R 1, R 2, R 3, R 4, R 5be selected from hydrogen, halogen, the alkyl of C1-C6, the alkoxyl group of C1-C6; R 6be selected from hydroxyl, halogen; R 7be selected from hydroxyl, the alkoxyl group of C1-C6, halogen, CH 2ph or OCH 2ph; M is selected from sodium ion, potassium ion; " C1-C6 " refers to 1 to 6 carbon, and " Ph " refers to phenyl.
2. method according to claim 1, described hypotoxicity organic solvent be oral medium lethal dose higher than 2900mg/Kg, 3000mg/Kg, 3500mg/Kg, 4000mg/Kg, 4500mg/Kg, the organic solvent of 5000mg/Kg or 5500mg/Kg.
3. method claimed in claim 1, comprises the steps:
Wherein, step (a) and step (b) in no particular order, step (a), step (b) and step (c) are carried out in identical or different low-toxic solvent, MgCl in step (b) 2for Magnesium Chloride Anhydrous.
4. method claimed in claim 3, wherein step (b) is carried out under alkali exists, and step (c) is included under alkaline condition reaction and then through peracid effect.
5. method claimed in claim 4, wherein R 1, R 4for hydrogen, R 2, R 3, R 5for fluorine.
6. method claimed in claim 5, step (a) (b), (c) is carried out in identical esters solvent.
7. method claimed in claim 4, wherein R 1, R 4for hydrogen, R 2, R 3, R 5for fluorine, R 6for hydroxyl, R 7for oxyethyl group, M is potassium ion.
8. method claimed in claim 4, the alkali in step (b) is triethylamine, and the alkali in step (c) is triethylamine, and acid is hydrochloric acid.
9. the arbitrary described method of claim 3-8, step (a) (b), (c) is carried out in ethyl acetate or isopropyl acetate or its combination.
CN201310732949.6A 2012-12-29 2013-12-25 The preparation method of sitagliptin intermediate Active CN103910634B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310732949.6A CN103910634B (en) 2012-12-29 2013-12-25 The preparation method of sitagliptin intermediate

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
CN201210587903 2012-12-29
CN201210587903.5 2012-12-29
CN2012105879035 2012-12-29
CN201310117110 2013-04-04
CN2013101171101 2013-04-04
CN201310117110.1 2013-04-04
CN201310732949.6A CN103910634B (en) 2012-12-29 2013-12-25 The preparation method of sitagliptin intermediate

Publications (2)

Publication Number Publication Date
CN103910634A true CN103910634A (en) 2014-07-09
CN103910634B CN103910634B (en) 2018-04-27

Family

ID=51036685

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310732949.6A Active CN103910634B (en) 2012-12-29 2013-12-25 The preparation method of sitagliptin intermediate

Country Status (1)

Country Link
CN (1) CN103910634B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105949072A (en) * 2016-05-10 2016-09-21 苏州敬业医药化工有限公司 Preparation method and intermediate of beta-substituted amino-gamma-substituted aryl butyric acid
CN106831783A (en) * 2017-01-10 2017-06-13 苏利制药科技江阴有限公司 A kind of synthetic method of phosphoric acid sitagliptin intermediate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1449388A (en) * 2000-08-31 2003-10-15 艾博特公司 Process and intermediates for preparing retroviral protease inhibitors
CN101417999A (en) * 2007-10-25 2009-04-29 上海恒瑞医药有限公司 Piperazines derivates, preparation method thereof and application thereof in medicine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1449388A (en) * 2000-08-31 2003-10-15 艾博特公司 Process and intermediates for preparing retroviral protease inhibitors
CN101417999A (en) * 2007-10-25 2009-04-29 上海恒瑞医药有限公司 Piperazines derivates, preparation method thereof and application thereof in medicine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
刘伟等: "异丁酰乙酸乙酯的合成", 《化学试剂》 *
王建塔等: "磷酸西他列汀的合成", 《中国医药工业杂志》 *
王斌等: "2, 3, 4, 5 -四氟苯甲酰乙酸乙酯的合成", 《化学试剂》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105949072A (en) * 2016-05-10 2016-09-21 苏州敬业医药化工有限公司 Preparation method and intermediate of beta-substituted amino-gamma-substituted aryl butyric acid
CN106831783A (en) * 2017-01-10 2017-06-13 苏利制药科技江阴有限公司 A kind of synthetic method of phosphoric acid sitagliptin intermediate
CN106831783B (en) * 2017-01-10 2019-02-22 苏利制药科技江阴有限公司 A kind of synthetic method of phosphoric acid sitagliptin intermediate

Also Published As

Publication number Publication date
CN103910634B (en) 2018-04-27

Similar Documents

Publication Publication Date Title
Li et al. Regioselective and stereoselective sulfonylation of alkynylcarbonyl compounds in water
CN103058989B (en) Method for preparing alpha-lipoic acid
JP5979376B2 (en) Highly soluble pyrroloquinoline quinone salt and method for producing the same
CA2956554A1 (en) Preparation of cationic lipid compounds and their salts as nucleic acid carriers
CN113666824B (en) Cannabidiol-2-propionate and application thereof
CN108349943A (en) Heterocycle is limited tricyclic sulfonamide as antitumor and anticancer agent
CN104628773B (en) (R)-9-&amp;#91;2- (phosphinylidyne phenol ylmethoxy) propyl;The preparation method of adenine
CN113735709B (en) Cannabidiol-2-butyrate and application thereof
JP2018501272A (en) Method for preparing sixth crystalline form of sofosbuvir
CN103910634A (en) Preparation method of sitagliptin intermediate
CN102786431A (en) Preparation method of propacetamol hydrochloride
CN106146560B (en) A kind of refining methd of high-purity phosphoric acid specially azoles amine
CA3221027A1 (en) Cyclohexane lipidoids for nucleic acid transfection and use thereof
CN103819379A (en) Cholestanol co crystal of vitamin D3 and its preparation method and application
CN105732754B (en) Synthesis method of alkyl acid testosterone compound
CN103936809A (en) Improved preparation method of dexamethasone sodium phosphate intermediate
CN103483255A (en) Fluorinated isoquinoline compounds and preparation method thereof
CN107235853B (en) A kind of synthetic method being used to prepare Canton love-pea vine A prime and its isomers
CN103113408B (en) A kind of novel method preparing phosphonomycin fosfomycin phenylethylamine calt
CN103360310B (en) The preparation method of a kind of Sitafloxacin intermediate, Sitafloxacin and sitafloxacin medicine composition
CN104530088A (en) Tert-butyl 2-amino-6,7-dihydro-5H-thiazolo[5,4-b]pyridyl-4-carboxylate and derivatives thereof, and their synthesis method
CN100556889C (en) N-replaces-2,4-two chloro-5-fluorobenzamides and preparation thereof and application
CN106748942A (en) Doxercalciferol analog WXFQ 65 and its synthetic method
CN104151396A (en) Method for catalyzing and synthesizing S-acetyl-L-glutathione from mixed solvent
CN108586429A (en) The purifying process for purification of r-lipoic acid cholinester halide

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CP03 Change of name, title or address

Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province

Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd.

Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei

Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd.

CP03 Change of name, title or address