CN105315286A - Preparation of Sitagliptin - Google Patents

Preparation of Sitagliptin Download PDF

Info

Publication number
CN105315286A
CN105315286A CN201410369273.3A CN201410369273A CN105315286A CN 105315286 A CN105315286 A CN 105315286A CN 201410369273 A CN201410369273 A CN 201410369273A CN 105315286 A CN105315286 A CN 105315286A
Authority
CN
China
Prior art keywords
preparation
reaction
formula
compound
ammonium
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
CN201410369273.3A
Other languages
Chinese (zh)
Other versions
CN105315286B (en
Inventor
桑光明
赵瑞
张爱明
张喜全
夏春光
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.)
Lianyungang Runzhong Pharmaceutical Co Ltd
Original Assignee
Lianyungang Runzhong Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lianyungang Runzhong Pharmaceutical Co Ltd filed Critical Lianyungang Runzhong Pharmaceutical Co Ltd
Priority to CN201410369273.3A priority Critical patent/CN105315286B/en
Publication of CN105315286A publication Critical patent/CN105315286A/en
Application granted granted Critical
Publication of CN105315286B publication Critical patent/CN105315286B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The invention belongs to the field of medicine synthesis and particularly provides a preparation method for Sitagliptin. According to the method, a cheap metal ruthenium complex and cheap R-BINAP serve as ligands, and the asymmetric hydrogenation reduction of an enamine intermediate is catalyzed, so that R-configuration Sitagliptin can be obtained in a high-selectivity manner; and the reaction time is short, and both the yield of reduction and the ee value of the product are relatively high, so that the method is applicable to industrialized amplified production.

Description

The preparation of Xi Gelieting
Technical field
The present invention relates to pharmaceutical synthesis field, be specifically related to the preparation method of Xi Gelieting.
Background technology
Xi Gelieting chemical name is 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl) butyl]-5,6,7,8-tetrahydrochysene-3-Trifluoromethyl-1,2,4-triazolo [4,3-a] pyrazine (formula I), has following structural formula.Be a kind of oral DPP-IV inhibitor, be used for the treatment of type ii diabetes.
Xi Gelieting has multiple synthetic method, synthesizes the method for Xi Gelieting disclosed in Chinese patent CN200480007313.4, needs multiple step, and need carry out repeatedly post-reaction treatment.
In addition, there is the chiral carbon atom of a R configuration in Xi Gelieting molecular formula, the chiral purity of medicine directly affects the Absorption and curative effect of medicine, therefore for chiral drug, provides a kind of method preparing pure single configuration to have important effect.
Synthesis R configuration Xi Gelieting mainly contains two kinds of methods, one is after the Xi Gelieting by synthesising racemation, obtaining R configuration Xi Gelieting through chiral separation, obtaining R configuration Xi Gelieting as disclosed in CN200910148240.5 with camphorsulfonic acid or tartrate resolving racemic.The method split not only process is complicated, and need to use a large amount of organic solvent, and S configuration Xi Gelieting cannot re-use, cause wastage of material, cost is high, is unfavorable for suitability for industrialized production.
Another kind method is obtained through asymmetric hydrogenation reduction by enamine intermediates.The key of its synthesis is enamine intermediates (2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo [4,3-a] pyrazine-7 (8H)-Ji]-1-(2,4,5-trifluorophenyl) but-2-ene-2-amine (formula II) asymmetric hydrogenation reduction, wherein enamine intermediates structure is as follows.
This kind of method enamine intermediates formula II, after asymmetric reduction, directly can obtain R configuration Xi Gelieting.As disclosed by the method for enamine intermediates formula II asymmetric synthesis Xi Gelieting in Chinese patent CN200480007313.4 and CN200580010669.8, metal precursor used is rhodium or iridium complex, as [Rh (COD) Cl] 2, part is chiral ferrocene base biphosphine ligand.But the price of metal rhodium used or iridium, Ferrocenyl diphosp hine ligand is all very expensive, and the hydrogenation time is longer, is not suitable for amplifying and produces.
Summary of the invention
On the one hand, the invention provides the preparation method of a kind of Xi Gelieting, comprising: under the existence of Chiral stationary phase and ammonium salt, formula II compound carries out hydrogenation in suitable alcoholic solvent.
Wherein Chiral stationary phase is selected from ruthenium complex Ru (R-BINAP) (O 2cCH 3) 2.
Described ammonium salt is selected from ammonium chloride, Salicylate ammonium, ammonium acetate, preferred Salicylate ammonium.
Suitable alcoholic solvent is selected from methyl alcohol, ethanol, trifluoroethanol, particular methanol.
In some embodiments, the mass volume ratio (grams per milliliter) of formula II compound and alcoholic solvent is 1:5-40; In some embodiments, calculate according to mol ratio, formula II compound: ammonium salt=1:1-7.
In some embodiments, the pressure of hydrogenation is 2-4MPa.In some embodiments, temperature of reaction is 60-90 DEG C; In some preferred embodiments, temperature of reaction is 75-85 DEG C.
In some embodiments, the time of hydrogenation is 4-13 hour; In some preferred embodiments, the time of hydrogenation is 4-8 hour.
On the other hand, the invention provides the preparation method of enamine intermediates formula II compound, comprising:
(a) 2,4,5-trifluoro benzene acetic acid in a solvent, react under the existence of DMAP, Maxwell acid, pivalyl chloride and diisopropyl ethyl amine (DIEA), prepare formula IV compound, reaction solution drops into next step reaction without separation;
The reaction solution of (b) step (a) and 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride, under organic acid exists, reaction, prepares formula III compound, and reaction solution drops into next step reaction without separation;
C the reaction solution of () step (b) and ammonia source reagent react, obtain formula II compound.
Wherein, the solvent selected from methanol of step (a), ethanol, acetonitrile or DMAC; Preferred acetonitrile.
Step (b) organic acid is selected from formic acid, acetic acid, trifluoroacetic acid; Preferred trifluoroacetic acid.
The ammonia source reagent of step (c) is selected from ammoniacal liquor and ammonium acetate.
Again on the one hand, the invention provides the preparation method of a kind of Xi Gelieting, comprise the following steps:
(a) 2,4,5-trifluoro benzene acetic acid in a solvent, react under the existence of DMAP, Maxwell acid, pivalyl chloride and diisopropyl ethyl amine (DIEA), prepare formula IV compound, reaction solution drops into next step reaction without separation;
The reaction solution of (b) step (a) and 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride, under organic acid exists, reaction, prepares formula III compound, and reaction solution drops into next step reaction without separation;
C the reaction solution of () step (b) and ammonia source reagent react, obtain formula II compound;
D (), under the existence of Chiral stationary phase and ammonium salt, formula II compound carries out hydrogenation in suitable alcoholic solvent, obtains Xi Gelieting.
Wherein, the solvent selected from methanol of step (a), ethanol, acetonitrile or DMAC; Preferred acetonitrile.
The organic acid of step (b) is selected from formic acid, acetic acid, trifluoroacetic acid; Preferred trifluoroacetic acid.
The ammonia source reagent of step (c) is selected from ammoniacal liquor and ammonium acetate.
In step (d), Chiral stationary phase is selected from ruthenium complex Ru (R-BINAP) (O 2cCH 3) 2; Ammonium salt is selected from ammonium chloride, Salicylate ammonium, ammonium acetate, preferred Salicylate ammonium; Suitable alcoholic solvent is selected from methyl alcohol, ethanol, trifluoroethanol, particular methanol; In some embodiments, the mass volume ratio (grams per milliliter) of formula II compound and alcoholic solvent is 1:5-40; In some embodiments, calculate according to mol ratio, formula II compound: ammonium salt=1:1-7; In some embodiments, the pressure of hydrogenation is 2-4MPa; In some embodiments, temperature of reaction is 60-90 DEG C; In some preferred embodiments, temperature of reaction is 75-85 DEG C; In some embodiments, the time of hydrogenation is 4-13 hour; In some preferred embodiments, the time of hydrogenation is 4-8 hour.
Use cheap metal Ru complex compound and cheap R-BINAP as part in preparation method of the present invention, the asymmetric hydrogenation reduction of catalysis enamine intermediates formula II compound, R configuration Xi Gelieting can be obtained by highly selective, reaction times is short, and the ee value of reduction yield and product is all higher, be applicable to industrial amplification production.
In addition, in the process of preparation formula II compound, all intermediates directly drop into the next step without the need to being separated, and contriver surprisingly finds the selection by ammonia source in the selection of acidic conditions in step (b) and step (c), make the easier crystallization of reaction product formula II compound, obtain highly purified formula II compound, thus aftertreatment is more simple, there is synthesis step short, the advantage that reaction yield is high.
Embodiment
Below in conjunction with embodiment, the invention will be further described, but the present invention is not limited to following embodiment.The reaction raw materials used in the present invention, solvent etc. are all the unprocessed direct use in commercially available prod if no special instructions, Chiral stationary phase Ru (R-BINAP) (O 2cCH 3) 2method preparation in reference EP272787.Abbreviation letter used herein has definition conventional in this area, such as:
BINAP:2,2 '-bis-(diphenylphosphine base)-1,1 '-dinaphthalene
COD:1,5-cyclooctadiene
DMAP:N, N dimethylamine yl pyridines
DIEA:N, N-diisopropyl ethyl amine
DMAC:N, N-N,N-DIMETHYLACETAMIDE
(S, S)-JOSIPHOS has following structure:
The synthesis of embodiment 1 formula IV compound
2,4,5-trifluorophenyl acetic acid (5.5kg, 28.93mol), Maxwell acid (4.62kg, 31.8mol), DMAP (0.283kg, 2.3mol) and acetonitrile (16.5L) is added respectively in 100L reactor.In above-mentioned suspension liquid, drip DIEA (11L, 62.2mol), then slowly drip t-BuCOCl (3.92L, 31.8mol), dropwise temperature and keep 45 ~ 50 DEG C of reactions 2 ~ 3 hours.Reaction terminates to continue next step synthesis without the need to process.
The synthesis of embodiment 2 formula III compound
In the reaction system (embodiment 1) of previous step, add 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene [1,2,4] triazolo [4,3-a] pyrazine hydrochloride (6.62kg, 29.04mol), then slowly drip CF 3cOOH (0.66L, 8.69mol), dropwises under temperature of reaction being set to 50 ~ 55 DEG C of conditions and reacts 6 hours, continues next step synthesis after reaction terminates without the need to process.
Embodiment 3
(2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo [4,3-a] pyrazine-7 (8H)-Ji] synthesis of-1-(2,4,5-trifluorophenyl) but-2-ene-2-amine (formula II)
Ammonium acetate (2kg is added respectively in 200L reactor, 26mol), ammoniacal liquor (4L) and methyl alcohol (59.4L), by this solution warms to 45 DEG C, the previous step reaction solution (embodiment 2) getting 10% volume dropwise joins in above-mentioned solution.Dropping terminates rear maintenance 45 DEG C reaction 2.5 hours.Continue the reaction solution dripping remaining 90%.Dropping terminates rear continuation reaction 3 hours, then drips methyl alcohol (26.4L).Dropwise and be slowly cooled to 0 ~ 5 DEG C to system afterwards.And continue stirring 1 hour at this temperature, rear rejection filter.Filter cake is joined in 100L reactor, add purified water stirring to pulp 1 hour, then rejection filter.Filter cake is continued join in 100L reactor, add methyl alcohol stirring to pulp 1 hour, then rejection filter, filter cake vacuum 50 DEG C of dryings 6 hours.Obtain white powder solid 8.5kg, productive rate 75%.
1H-NMR(400MHz,DMSOd6):δ8.48(s,br,1H),7.50(m,2H),6.82(s,br,1H),4.90(s,1H),4.85(s,2H),4.14(t,J＝5.1Hz,2H),3.90(t,J＝5.1Hz,2H),3.44(s,2H).
13C-NMR(100MHz,CDCl3):δ168.9,160.1,155.6(ddd,J＝243.7,10.0,1.7Hz),151.4,148.1(dt,J＝247.4,13.9Hz),145.9(ddd,J＝241.5,12.1,3.3Hz),142.4(q,J＝38.9Hz),121.9(ddd,J＝18.6,6.3,4.2Hz),118.6(dd,J＝19.7,5.5Hz),118.5(q,270.6Hz),105.6(dd,J＝28.9,21.4Hz),81.0,43.5,34.1.
Embodiment 4
7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl) butyl]-5,6,7,8-tetrahydrochysene-3-Trifluoromethyl-1s, the preparation of 2,4-triazolo [4,3-a] pyrazine (formula I)
(2Z)-4-oxo-4-[3-(trifluoromethyl)-5 is added in 5L hydrogenation reaction cauldron, 6-dihydro-[1,2,4] triazolo [4,3-a] pyrazine-7 (8H)-Ji]-1-(2,4,5-trifluorophenyl) but-2-ene-2-amine (200g, 0.49mol), Salicylate ammonium (380g, 2.45mol), catalyzer Ru (R-BINAP) (O 2cCH 3) 2(4.1g, 4.9mmol) and 2L anhydrous methanol, reaction system nitrogen replacement 5 times, then use hydrogen exchange 3 times, pressurized with hydrogen is to 3Mpa, system is warming up to 75 DEG C ~ 80 DEG C stirring reactions 7 hours, and HPLC monitoring reaction lower than 3% (normalization method), stops heating to raw material, system is cooled to room temperature, feed liquid activated carbon decolorizing 10min, suction filtration, filtrate is concentrated into dry.
1NHCl (3L) stirring and dissolving is added to enriched material, filter, filtrate is washed by ethyl acetate, slowly adds sodium carbonate (371g in aqueous phase, 3.5mol), aqueous phase is extracted with ethyl acetate twice, merges organic phase, organic phase anhydrous sodium sulfate drying, suction filtration, concentrate to obtain white solid sitagliptin base 176.4g, yield 88.4%, ee>99%.
1H-NMR(300MHz,D 2O):δ7.32(m,1H),7.16(m,1H),5.03(s,1H),4.97(s,1H),4.37-4.22(m,2H),4.11-4.05(m,3H),3.22-2.89(m,4H)；
13C-NMR(300MHz,D 2O):171.60(s,1C),159.47(m,1C),156.14(m,1C),152.57(m,1C),149.43(m,1C),146.20(m,1C),144.91(m,1C),120.47(m,1C),120.15(q,1C),107.20(dd,1C),49.69(s,1C),44.93(s,1C),42.69(s,1C),40.22(s,1C),35.24(s,1C),32.46(s,1C).
MS:[M+H] +:408.1266。
Embodiment 5 (comparative example)
In reactor, add ammonium acetate (2kg, 26mol) and methyl alcohol (59.4L) respectively, by this solution warms to 45 DEG C, the reaction solution that the embodiment 2 of getting 10% volume finally prepares dropwise joins in above-mentioned solution.Dropping terminates rear maintenance 45 DEG C reaction 1.5 hours, then adds crystal seed, and 45 DEG C are continued reaction 0.5 hour.Continue the reaction solution (3 ~ 6 hours) dripping remaining 90%.Dropping terminates rear continuation reaction 3 hours, then drips methyl alcohol (26.4L).Dropwise and to be slowly cooled to 0 ~ 5 DEG C (3 ~ 4 hours) to system afterwards.And continue stirring 1 hour at this temperature, then rejection filter.Yield is 30%.
Embodiment 6
The condition changing into the high performance liquid chromatography (HPLC) of product percentages is measured as follows in embodiment 4:
Instrument: ThermoU3000 high performance liquid chromatograph, Chromeleon7 chromatographic working station, chromatographic column: PLATISIL tMoDS (150*4.6mm5 μ); Determined wavelength: 215nm, flow velocity: 1.0ml/min, column temperature: 23 DEG C, sample size: 10 μ l,
Sample concentration: 1.0mg/ml (first use a small amount of methyl alcohol clearly molten, then add mobile phase A dilution)
Method: mobile phase A: 1.21gTris adds 800ml water dissolution, then adds 200ml methyl alcohol and 90 μ l concentrated hydrochloric acids
B:1.21gTris adds 200ml water dissolution, then adds 800ml methyl alcohol and 90 μ l concentrated hydrochloric acids
(Tris: Tutofusin tris)
The condition measuring the high performance liquid chromatography (HPLC) that polarimetry purity uses in embodiment 4 is as follows:
Instrument: ThermoU3000 high performance liquid chromatograph, Chromeleon7 chromatographic working station, chromatographic column: CHIRALPAKAD-H (250*4.6mm5 μ),
Determined wavelength: 268nm, flow velocity: 0.8ml/min, column temperature: 35 DEG C, sample size: 10 μ l,
Sample concentration: 1.0mg/ml, sample solvent methyl alcohol: water=9: 1,
Method: moving phase ethanol: normal hexane: diethylamine: water=600: 400: 1: 1.

Claims (10)

1. the preparation method of Xi Gelieting, comprising:
Under the existence of Chiral stationary phase and ammonium salt, formula II compound carries out hydrogenation in suitable alcoholic solvent.
2. the preparation method of claim 1, wherein metal complex is Ru (R-BINAP) (O 2cCH 3) 2.
3. the preparation method of claim 1, wherein ammonium salt is selected from ammonium chloride, Salicylate ammonium, ammonium acetate.
4. the preparation method of claim 3, wherein ammonium salt is selected from Salicylate ammonium.
5. the preparation method of claim 1, wherein suitable alcoholic solvent is selected from methyl alcohol, ethanol, trifluoroethanol.
6. the preparation method of claim 5, wherein suitable alcoholic solvent is selected from methyl alcohol.
7. the preparation method of claim 1, the preparation method of its compound of formula H comprises:
(a) 2,4,5-trifluoro benzene acetic acid in a solvent, react under the existence of DMAP, Maxwell acid, pivalyl chloride and diisopropyl ethyl amine (DIEA), prepare formula IV compound, reaction solution drops into next step reaction without separation;
The reaction solution of (b) step (a) and 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride, under organic acid exists, reaction, prepares formula III compound, and reaction solution drops into next step reaction without separation;
C the reaction solution of () step (b) and ammonia source reagent react, obtain formula II compound.
8. the preparation method of claim 7, in step (b), organic acid is selected from formic acid, acetic acid, trifluoroacetic acid.
9. the preparation method of claim 8, in step (b), organic acid is selected from trifluoroacetic acid.
10. the preparation method of claim 7, the ammonia source reagent of step (c) is selected from ammoniacal liquor and ammonium acetate.
CN201410369273.3A 2014-07-30 2014-07-30 The preparation of Xi Gelieting Active CN105315286B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410369273.3A CN105315286B (en) 2014-07-30 2014-07-30 The preparation of Xi Gelieting

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410369273.3A CN105315286B (en) 2014-07-30 2014-07-30 The preparation of Xi Gelieting

Publications (2)

Publication Number Publication Date
CN105315286A true CN105315286A (en) 2016-02-10
CN105315286B CN105315286B (en) 2018-08-17

Family

ID=55243680

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410369273.3A Active CN105315286B (en) 2014-07-30 2014-07-30 The preparation of Xi Gelieting

Country Status (1)

Country Link
CN (1) CN105315286B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN111712500A (en) * 2018-02-13 2020-09-25 意大利合成制造有限公司 Novel efficient process for the preparation of sitagliptin
CN111875607A (en) * 2016-06-16 2020-11-03 正大天晴药业集团股份有限公司 Preparation method of chiral pyrrolopyrimidine compound
CN115894198A (en) * 2022-11-04 2023-04-04 浙江永太科技股份有限公司 Preparation method of key intermediate 1- (2, 3, 6-trifluorophenyl) propane-2-ketone of Qulipta

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0272787A2 (en) * 1986-11-14 1988-06-29 Takasago International Corporation Catalytic production of optically active carboxylic acid
CN1072898A (en) * 1991-10-15 1993-06-09 米德公司 Panel interlocking means
WO2004087650A2 (en) * 2003-03-27 2004-10-14 Merck & Co. Inc. Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors
CN1761642A (en) * 2003-03-19 2006-04-19 麦克公司 The method for preparing chiral beta amino acid derivatives by asymmetric hydrogenation
CN101175714A (en) * 2005-01-24 2008-05-07 默克公司 Process to chiral beta amino acid derivatives by asymmetric hydrogenation
WO2009064476A1 (en) * 2007-11-13 2009-05-22 Teva Pharmaceutical Industries Ltd. Preparation of sitagliptin intermediate
CN103058888A (en) * 2011-10-21 2013-04-24 上海朴颐化学科技有限公司 Preparation method of (R)-3-t-butyloxycarboryl-amino-4-(2, 4, 5-trifluorobenzene) butyric acid
CN103232455A (en) * 2013-05-14 2013-08-07 聊城九州和谷生物科技有限公司 Industrial production method of sitagliptin

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0272787A2 (en) * 1986-11-14 1988-06-29 Takasago International Corporation Catalytic production of optically active carboxylic acid
CN1072898A (en) * 1991-10-15 1993-06-09 米德公司 Panel interlocking means
CN1761642A (en) * 2003-03-19 2006-04-19 麦克公司 The method for preparing chiral beta amino acid derivatives by asymmetric hydrogenation
WO2004087650A2 (en) * 2003-03-27 2004-10-14 Merck & Co. Inc. Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors
CN101175714A (en) * 2005-01-24 2008-05-07 默克公司 Process to chiral beta amino acid derivatives by asymmetric hydrogenation
WO2009064476A1 (en) * 2007-11-13 2009-05-22 Teva Pharmaceutical Industries Ltd. Preparation of sitagliptin intermediate
CN103058888A (en) * 2011-10-21 2013-04-24 上海朴颐化学科技有限公司 Preparation method of (R)-3-t-butyloxycarboryl-amino-4-(2, 4, 5-trifluorobenzene) butyric acid
CN103232455A (en) * 2013-05-14 2013-08-07 聊城九州和谷生物科技有限公司 Industrial production method of sitagliptin

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DIETRICH STEINHUEBEL ET AL.: "Direct asymmetric reductive amination", 《J.AM.CHEM.SOC》 *
KARL B.HANSEN ET AL.: "Highly efficient asymmetric synthesis of sitagliptin", 《J.AM.CHEM.SOC》 *
MELISSA BIRCH ET AL.: "A simplified process for the manufacture of imagabalin hydrochloride (PD-0332334),an α2δ-ligand for the treatment of generalized anxiety disorder", 《ORG.PROCESS.RES.DEV.》 *
董建霞等: "钌-手性膦配体催化剂在不对称催化氢化反应中的应用", 《江苏化工》 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111875607A (en) * 2016-06-16 2020-11-03 正大天晴药业集团股份有限公司 Preparation method of chiral pyrrolopyrimidine compound
CN111875607B (en) * 2016-06-16 2021-12-03 正大天晴药业集团股份有限公司 Preparation method of chiral pyrrolopyrimidine compound
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
CN111712500A (en) * 2018-02-13 2020-09-25 意大利合成制造有限公司 Novel efficient process for the preparation of sitagliptin
CN111712500B (en) * 2018-02-13 2023-07-11 意大利合成制造有限公司 Efficient process for the preparation of sitagliptin
CN115894198A (en) * 2022-11-04 2023-04-04 浙江永太科技股份有限公司 Preparation method of key intermediate 1- (2, 3, 6-trifluorophenyl) propane-2-ketone of Qulipta

Also Published As

Publication number Publication date
CN105315286B (en) 2018-08-17

Similar Documents

Publication Publication Date Title
JP5923105B2 (en) Chiral spiro-pyridylamidophosphine ligand compound, synthesis method thereof and use thereof
CN105315286A (en) Preparation of Sitagliptin
TW200932749A (en) Process improvement using TMEDA
CN106366022A (en) Intermediate used for AZD9291 preparation, and preparation method and application thereof
CN106831550A (en) A kind of optical activity two（It is miscellaneous）Aryl methyl alcohol and its method of asymmetric synthesis
CN112062767B (en) Preparation method and intermediate of rumepilone
JP4718452B2 (en) Optically active transition metal-diamine complex and method for producing optically active alcohols using the same
CN103467528A (en) Preparation method of lobaplatin
CN101830891A (en) Synthesizing method of piribedil
CN102627648A (en) Preparation method of sitagliptin
EP3156391B1 (en) Method for preparing sitagliptin intermediate via asymmetrical reduction method
CN102503883A (en) Method for selectively preparing isoindoline-1-ketone derivative or isoquinoline-1-ketone derivative
CN113896728A (en) Synthetic preparation method of rotundine
CN104876929B (en) The synthetic method of a kind of 1,2,3,4-Tetrahydronaphthyridderivates compounds and application
EP2547683B1 (en) Method of preparing sitagliptin
CN102532106A (en) Synthesis method of crizotinib serving as antitumor molecular targeting medicament
CN109879800B (en) Preparation process of bepotastine drug intermediate
CN102050748B (en) Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol
CN113979983B (en) Asymmetric synthesis method of fidarestat key intermediate
CN103387577A (en) Asymmetric synthesis method of sitagliptin base
CN107298683A (en) A kind of synthetic method of chiral benzodiazepine * compounds
CN105254668A (en) New preparation method for fosaprepitant and pharmaceutically acceptable salt thereof
CN101768116B (en) Preparation method for Ivabradine
CN102260255B (en) Simple and convenient synthesis method of 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-3-isobutyl-2H-benzo[a] quinolizidine-2-ketone
CN102316862A (en) The method for preparing S1P receptor stimulating agent or antagonist

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