CN102757431A - Novel method for synthesizing sitagliptin - Google Patents
Novel method for synthesizing sitagliptin Download PDFInfo
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- CN102757431A CN102757431A CN2011101091220A CN201110109122A CN102757431A CN 102757431 A CN102757431 A CN 102757431A CN 2011101091220 A CN2011101091220 A CN 2011101091220A CN 201110109122 A CN201110109122 A CN 201110109122A CN 102757431 A CN102757431 A CN 102757431A
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- 0 *N(*)[C@@](CC(O*)=O)Cc(c(F)c1)cc(F)c1F Chemical compound *N(*)[C@@](CC(O*)=O)Cc(c(F)c1)cc(F)c1F 0.000 description 4
- 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
Abstract
The invention discloses a novel method for synthesizing sitagliptin. The method has the advantages of low cost, simplicity in operation, low environmental pollution, high yield and purity of product and the like, and is particularly applicable to industrial production.
Description
Technical field
The present invention relates to the novel method of a kind of synthetic sitagliptin (X).
Background technology
Sitagliptin phosphate monohydrate (Sitagliptin phosphate monohydrate) is the dipeptidyl peptidase-IV that is used to treat type ii diabetes (DDP-4) the suppressor factor class medicine of in October, 2006 first acquisition FDA (Food and Drug Adminstration) (FDA) approval.This medicine is by Merck Co., and Inc. develops, and commodity are called Januvia.Chinese is by name: 7-[(3R)-and 3-amino-1-oxo-4-(2,4, the 5-trifluorophenyl) butyl]-5,6,7,8-tetrahydrochysene-3-(trifluoromethyl)-1,2,4-triazole [4,3-a] pyrazoles phosphoric acid monohydrate; English chemical name is: 7-[(3R)-and 3-Amino-1-oxo-4-(2,4,5-trifluorophenyl) butyl]-5; 6,7,8-tetrahydro-3-(trifluoromethyl)-1; 2,4-triazolo [4,3-a] pyrazine monophosphate monohydrate.Clinical study shows that sitagliptin phosphate can make glycolated hemoglobin (HbA1c) level significantly reduce as single therapy type ii diabetes patient.During with N1,N1-Dimethylbiguanide or TZDs combined utilization, have significant assisting therapy effect, can be directed against three kinds of major defects of type ii diabetes: insulin resistant, the β cell dysfunction, and the α cell dysfunction plays a role.
Known that report the sitagliptin compound method the earliest is Merck & Co., and Inc. describes on basic patent WO2003004498, and its synthetic route is as shown in the formula statement:
This route adopts chiral source to induce the a-amino acid of chirality, and after diazotization reaction generates beta-amino acids, makes up required chiral centre.This route steps is longer, difficult acquisition the in chiral induction source that route is used, and cost is higher.Need to use operations such as n-Butyl Lithium and low temperature, anhydrous and oxygen-free simultaneously in the route, be unfavorable for suitability for industrialized production.
The compound method of disclosed sitagliptin also has several kinds, has described among the WO 2004085661 and has utilized S-benzene G-NH2 to obtain chiral intermediate and further prepare sitagliptin as chiral auxiliary(reagent); Described among the WO 2004087650 and utilized the chiral phosphorus ruthenium catalyst that ketone is carried out asymmetric catalytic hydrogenation, made up chiral secondary alcohol, then chiral secondary alcohol has been converted into Chiral Amine and makes up chiral intermediate and further prepare sitagliptin to reach;
Then another route has been described at patent WO2004085378 by the said firm, and its synthetic route is as shown in the formula statement:
This route synthetic route step is shorter, and it has adopted the chirality rhodium catalyst that the asymmetric catalytic hydrogenation of enamine is made up chiral centre.But this method need be used comparatively expensive chiral catalyst, possibly have scale effect, and the industriallization difficulty is bigger.
Then, the said firm has described elder generation and has made up chiral centre with the asymmetric catalytic hydrogenation of enamine on WO2009064476, then and pyrazine carry out the route that coupling prepares sitagliptin.The key of this route is to be chiral ligand, [Ru (COD) Cl with BINAP
2]
nBe metal catalyst, enamine is carried out asymmetric hydrogenation.Its synthetic route is as shown in the formula statement:
In the above-described several kinds of methods that prepare sitagliptin, all without exception application chiral precurser, chiral auxiliary(reagent) or expensive chiral catalyst, cost is too high, is unfavorable for suitability for industrialized production.
Summary of the invention
The method that the purpose of this invention is to provide a kind of synthetic sitagliptin newly.
First aspect of the present invention provides a kind of method through the synthetic sitagliptin of reactions formula,
In the above-mentioned formula (I), R
1Be benzyl or substituted benzyl; R
2, R
3Be selected from respectively: hydrogen, benzyl and substituted benzyl, wherein substituted benzyl are meant that containing 1-3 on the phenyl is selected from halogen, nitro, C
1-C
12Alkyl and C
1-C
12The substituting group of alkoxyl group.Wherein preferred scheme is: compound (I) obtains compound (VII) through catalytic hydrogenation.
Second aspect of the present invention provides the method for a kind of synthetic compound (I),
Comprise following steps:
(a), be raw material with compound shown in the formula (II), obtain corresponding compounds (III) with benzylalcohol or the reaction of substituted benzylalcohol;
(b), resulting (III) is with ammonia, ammonium formiate, ammonium acetate or R
2R
3NH handles and obtains corresponding compounds (IV);
(c), compound (IV) obtains corresponding compounds (V) with the reductive agent reduction;
(d), compound (V) with the chiral selectors fractionation, obtains the salt (VI) that corresponding chipal compounds is become with resolution reagent in solvent;
(e), compound (VI) obtains compound (I) with alkaline purification;
Above-mentioned formula (I), (III), (IV), (V), (VI) and R
2R
3Among the NH, R
1Be benzyl or substituted benzyl; R
2, R
3Be selected from respectively: hydrogen, benzyl and substituted benzyl, wherein substituted benzyl are meant that containing 1-3 on the phenyl is selected from halogen, nitro, C
1-C
12Alkyl and C
1-C
12The substituting group of alkoxyl group.
According to concrete technical scheme of the present invention, wherein be preferably:
The mol ratio of compound (II) and benzylalcohol or substituted benzyl alcohol is between 1: 1～1: 20 in the step (a).
Temperature of reaction in the step (a) is 20～110 ℃.
Step (a) reaction is carried out under appropriate solvent, and described solvent is selected from: toluene, acetonitrile, trichloromethane and THF wherein are preferably toluene.
Compound (III) and ammonia, ammonium formiate, ammonium acetate, R in the step (b)
2R
3The mol ratio of NH further was preferably 1: 1～1: 5 between 1: 1～1: 20.
Temperature of reaction in the step (b) is 20～110 ℃.
Step (b) reaction is carried out under appropriate solvent, and described solvent is selected from: toluene, acetonitrile, trichloromethane and THF wherein are preferably acetonitrile.
Reaction in the step (c) is carried out under the reductive agent effect, and described reductive agent is selected from: Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, lithium borohydride, three acetic acid Peng Qinghuanas, sodium cyanoborohydride and TERTIARY BUTYL AMINE borine; Further be preferably the TERTIARY BUTYL AMINE borine.
The mol ratio of compound (IV) and reductive agent wherein was preferably 1: 1～1: 3 in the step (c) between 1: 1～1: 6.
Temperature of reaction in the step (c) is 0～110 ℃, wherein is preferably 0～20 ℃.
Step (c) reaction is carried out under appropriate solvent, and described solvent is selected from: toluene, acetonitrile, trichloromethane and THF wherein are preferably THF.
Chiral separation agent described in the step (d) is D-tartrate and verivate thereof, comprising D-tartrate, D-dibenzoyl tartaric acid, two pairs of toluyl tartrate of D-, D-di-p-methoxy benzoyl tartrate; Wherein preferred D-dibenzoyl tartaric acid.
The mol ratio of compound (V) and chiral separation agent is between 1: 0.5～1: 2 in the step (d), wherein preferred 1: 0.5～1: 1.
Temperature of reaction in the step (d) is 0～80 ℃.
The described solvent of step (d) is selected from: ETHYLE ACETATE, methylene dichloride, chloroform, acetonitrile, acetone, methyl ethyl ketone, THF, dioxane, and their mixed solvent; Further be preferably the mixed solvent of acetonitrile and water, more preferably the volume ratio of the mixed solvent of acetonitrile and water is 3: 1.
Reaction in the step (e) is carried out under the alkali effect, and described alkali is selected from: yellow soda ash, sodium hydrogencarbonate, salt of wormwood, sodium hydroxide, Pottasium Hydroxide and 25-28% ammoniacal liquor.
Step (e) reaction is carried out under appropriate solvent, and described solvent is selected from: methylene dichloride, trichloromethane, ETHYLE ACETATE, THF and toluene.
The third aspect of the invention relates to following three kinds of new midbody compounds:
Compound (IV) has following structure,
Compound (V) has following structure,
Compound (I) has following structure,
Above-mentioned (IV), (V), (I) middle R
1Be benzyl, R
2Be hydrogen or benzyl, R
3Be hydrogen or benzyl.
The method of synthetic sitagliptin provided by the invention, have with low cost, simple to operate, environmental pollution is little, yield is high, the product purity advantages of higher, is particularly suitable for suitability for industrialized production.
Embodiment
Further specify technical scheme of the present invention with specific embodiment below, but protection scope of the present invention is not limited thereto:
Embodiment one: 3-oxo-4-(2,4, the 5-trifluorophenyl) benzyl butyrate synthetic
At room temperature, in eggplant-shape bottle, add 5-[1-hydroxyl-2-(2,4, the 5-trifluorophenyl) ethylidene]-2 successively, 2-dimethyl--1,3-dioxane-4,6-diketone (31.6g), toluene (200mL) and benzylalcohol (10.8g).After system mixed, heat temperature raising refluxed stirring reaction 5-6 hour down.Reaction finishes, and system is cooled to room temperature, adds 100mL water, separatory, and organic phase is with the washing of 100mL saturated common salt, and anhydrous sodium sulfate drying filters, and concentrating under reduced pressure obtains off-white color solid 29g, yield 90%.
1H?NMR(400MHz，CDCl
3)δ3.61(s，2H)，3.84(s，2H)，5.21(s，2H)，6.94-6.98(m，2H)，7.37-7.41(m，5H)。
Embodiment two: 3-amino-4-(2,4, the 5-trifluorophenyl)-2-butylene acid benzyl ester synthetic
At room temperature, in eggplant-shape bottle, add 3-oxo-4-(2,4, the 5-trifluorophenyl) benzyl butyrate (29g), acetonitrile (200mL) and ammonium acetate (35g) successively.After system mixed, heat temperature raising refluxed stirring reaction 5-6 hour down.Reaction finishes, and system is cooled to room temperature, and concentrating under reduced pressure is removed organic solvent, adds 200mL ETHYLE ACETATE and 100mL water then; Separatory, organic phase are with the washing of 100mL saturated common salt, and anhydrous sodium sulfate drying filters; Concentrating under reduced pressure obtains off-white color solid 26g, yield 90%.
1H?NMR(400MHz，DMSO-d6)δ3.45(s，2H)，4.24(s，1H)，4.99(s，2H)，7.22(b，1H)，7.29-7.36(m，5H)，7.50-7.56(m，2H)，7.80(b，1H)。
Embodiment three: 3-amino-4-(2,4, the 5-trifluorophenyl) benzyl butyrate synthetic
At room temperature, in there-necked flask, add 3-amino-4-(2,4, the 5-trifluorophenyl)-2-butylene acid benzyl ester (32g), THF (300mL) and TERTIARY BUTYL AMINE borine (8.7g) successively.After system mixed, cooling was cooled to 0-5 ℃.Under 0-5 ℃, in system, slowly be added dropwise to Virahol (60mL) solution of the pre-configured vitriol oil (20g).Dropwise, rise to room temperature naturally, stirring reaction is about 8 hours.Reaction finishes, and adds 200mL water, regulates pH=8-9 with the 2N NaOH aqueous solution; Concentrating under reduced pressure is removed organic solvent, adds 300mL ETHYLE ACETATE and 200mL water then, separatory; Organic phase is with the washing of 200mL saturated common salt, and anhydrous sodium sulfate drying filters; Concentrating under reduced pressure obtains faint yellow oily thing 28g, yield 87%.
1H?NMR(400MHz，CDCl
3)δ1.82(b，2H)，2.35-2.56(m，2H)，2.65-2.73(m，2H)，3.46-3.48(m，1H)，5.13(s，1H)，6.87-6.93(m，1H)，6.99-7.06(m，1H)，7.32-7.41(m，5H)。
Embodiment four: (R)-and 3-amino-4-(2,4, the 5-trifluorophenyl) benzyl butyrate D-dibenzoyl tartaric acid salt synthetic
3-amino-4-(2,4, the 5-trifluorophenyl) benzyl butyrate (32g) is dissolved in acetonitrile (300mL); In the mixed solvent of water (100mL), stir adding D-dibenzoyl tartaric acid (36g) down, have a large amount of white solids to separate out; 0.5 temperature rising reflux after hour, after dissolving fully, cooling crystallization.The solid that filtration is separated out, minor amounts of acetonitrile: water (3: 1) solution washing.With acetonitrile (300mL), the mixed solvent crystallization once more of water (100mL) obtains white solid 28.6g.
Embodiment five: (R)-and 3-amino-4-(2,4, the 5-trifluorophenyl) benzyl butyrate synthetic
(R)-3-amino-4-(2,4, the 5-trifluorophenyl) benzyl butyrate D-dibenzoyl tartaric acid salt (28.6g) is scattered in the ETHYLE ACETATE (300mL); Add 8% sodium bicarbonate aqueous solution (100mL), stir after 0.5 hour, tell organic phase; Organic phase is with the washing of 100mL saturated common salt, and anhydrous sodium sulfate drying filters; Concentrating under reduced pressure obtains colorless oil 13.4g, splits total recovery 42%.Analyze through chirality HPLC, the ee value is 99.5%.
1H?NMR(400MHz，CDCl
3)δ1.82(b，2H)，2.35-2.56(m，2H)，2.65-2.73(m，2H)，3.46-3.48(m，1H)，5.13(s，1H)，6.87-6.93(m，1H)，6.99-7.06(m，1H)，7.32-7.41(m，5H)。
Embodiment six: (R)-and 3-(t-butoxycarbonyl amino)-4-(2,4, the 5-trifluorophenyl) is butyro-synthetic
(R)-3-amino-4-(2,4, the 5-trifluorophenyl) benzyl butyrate (32g) is dissolved in the methyl alcohol (300mL), nitrogen protection adds 7%Pd-C (3.2g) down, and system is replaced into atmosphere of hydrogen, 25-30 ℃ following synthesis under normal pressure 12-16 hour.Reaction finishes, and filters, and uses the small amount of methanol washing leaching cake, filtrate decompression is concentrated obtain white solid.Resulting white solid is scattered in the THF (300mL), adds tert-Butyl dicarbonate (26g) and saturated aqueous sodium carbonate (200mL), 25-30 ℃ following stirring reaction 6-8 hour.Reaction finishes, and separatory extracts water once with ETHYLE ACETATE (200mL) again.Merge organic phase, (200mL) washes with saturated sodium-chloride water solution, and anhydrous sodium sulfate drying filters, and concentrating under reduced pressure obtains white solid 30g, yield 92%.
1H?NMR(400MHz，CDCl
3)δ1.38(s，9H)，2.59(m，2H)，2.96(m，2H)，4.15(m，1H)，5.03(b，1H)，6.89-6.93(m，1H)，6.97-7.04(m，1H)。
Embodiment seven: 7-[(3R)-3-(t-butoxycarbonyl amino)-1-oxo-4-(2,4, the 5-trifluorophenyl) butyl]-5,6,7,8-tetrahydrochysene-3-(trifluoromethyl)-1,2,4-triazole [4,3-a] pyrazoles synthetic
With (R)-3-(t-butoxycarbonyl amino)-4-(2,4, the 5-trifluorophenyl) butyric acid (26.6g), 2,6-lutidine (18g) and 3-(trifluoromethyl)-5; 6,7,8-tetrahydrochysene-[1,2; 4] triazolo [4,3-a] pyrazine hydrochlorides (17.3g) add in the methylene dichloride (300mL) successively, are cooled to 0-5 ℃; Stir adding TBTU (28.2g) down, return to room temperature naturally, continue reaction 8-10 hour.Reaction finishes, and organic phase is used 1N HCl (200mL), water (200mL), 5% aqueous sodium carbonate (200mL), saturated sodium-chloride water solution (200mL) washing, anhydrous sodium sulfate drying successively; Filter; Concentrating under reduced pressure obtains white foam shape solid 36g, yield 90%.
1H?NMR(400MHz，CDCl
3)δ1.39(s，9H)，2.59-2.72(m，2H)，2.79-2.96(m，2H)，3.96-4.38(m，5H)，4.95(s，1H)，4.98-5.10(m，1H)，5.31(b，1H)，6.89-6.93(m，1H)，6.97-7.06(m，1H)。
Embodiment eight: 7-[(3R)-3-amino-1-oxo-4-(2,4, the 5-trifluorophenyl) butyl]-5,6,7,8-tetrahydrochysene-3-(trifluoromethyl)-1,2,4-triazole [4,3-a] pyrazoles synthetic
With 7-[(3R)-3-(t-butoxycarbonyl amino)-1-oxo-4-(2,4, the 5-trifluorophenyl) butyl]-5; 6,7,8-tetrahydrochysene-3-(trifluoromethyl)-1; 2,4-triazole [4,3-a] pyrazoles (25g) add in the isopropyl ether solution of 4N HCl; Under the room temperature stirring reaction 6-8 hour, in the system slowly the adularescent solid separate out.Reaction finishes, and nitrogen protection is filtered down, and a small amount of isopropyl ether washing obtains white solid (being prone to suction).Resulting white solid is scattered in the ETHYLE ACETATE (200mL), adds 8% sodium bicarbonate aqueous solution (150mL), stir after 0.5 hour; Tell organic phase, organic phase is with the washing of 100mL saturated common salt, anhydrous sodium sulfate drying; Filter; Concentrating under reduced pressure obtains colorless oil 18.8g, yield 92%.
1H?NMR(400MHz，CDCl
3)δ1.86(b，2H)，2.59-2.72(m，2H)，2.79-2.96(m，2H)，3.96-4.38(m，5H)，4.95(s，1H)，4.98-5.10(m，1H)，6.89-6.93(m，1H)，6.97-7.06(m，1H)。
Claims (10)
1. method through the synthetic sitagliptin of reactions formula,
In the above-mentioned formula (I), R
1Be benzyl or substituted benzyl; R
2, R
3Be selected from respectively: hydrogen, benzyl and substituted benzyl, wherein substituted benzyl are meant that containing 1-3 on the phenyl is selected from halogen, nitro, C
1-C
12Alkyl and C
1-C
12The substituting group of alkoxyl group.
2. method according to claim 1 is characterized in that: compound (I) obtains compound (VII) through catalytic hydrogenation.
3. the method for a synthetic compound (I),
Comprise following steps:
(a), be raw material with compound shown in the formula (II), obtain corresponding compounds (III) with benzylalcohol or the reaction of substituted benzylalcohol;
(b), resulting (III) handles with ammonia, ammonium formiate, ammonium acetate or R2R3NH and obtains corresponding compounds (IV);
(c), compound (IV) obtains corresponding compounds (V) with the reductive agent reduction;
(d), compound (V) with the chiral selectors fractionation, obtains the salt (VI) that corresponding chipal compounds is become with resolution reagent in solvent;
(e), compound (VI) obtains compound (I) with alkaline purification;
Above-mentioned formula (I), (III), (IV), (V), (VI) and R
2R
3Among the NH, R
1Be benzyl or substituted benzyl; R
2, R
3Be selected from respectively: hydrogen, benzyl and substituted benzyl, wherein substituted benzyl are meant that containing 1-3 on the phenyl is selected from halogen, nitro, C
1-C
12Alkyl and C
1-C
12The substituting group of alkoxyl group.
4. method according to claim 3, it is characterized in that the reductive agent described in the step (c) is selected from: Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, lithium borohydride, three acetic acid Peng Qinghuanas, sodium cyanoborohydride and TERTIARY BUTYL AMINE borine are preferably the TERTIARY BUTYL AMINE borine.
5. in the method according to claim 3, it is characterized in that the resolving agent described in the step (d) is selected from D-tartrate, D-dibenzoyl tartaric acid, two pairs of toluyl tartrate of D-and D-di-p-methoxy benzoyl tartrate; Further be preferably the D-dibenzoyl tartaric acid.
6. method according to claim 3 is characterized in that the described solvent of step (d) is selected from: ETHYLE ACETATE, methylene dichloride, chloroform, acetonitrile, acetone, methyl ethyl ketone, THF, dioxane, water, and their mixed solvent; Further be preferably the mixture of acetonitrile and water.
7. method according to claim 6, the volume ratio of acetonitrile and water are 3: 1.
8. compound (IV),
R wherein
1Benzyl, R
2Be hydrogen or benzyl, R
3Be hydrogen or benzyl;
9. compound (V),
R wherein
1Benzyl, R
2Be hydrogen or benzyl, R
3Be hydrogen or benzyl.
10. compound (I),
R wherein
1Benzyl, R
2Be hydrogen or benzyl, R
3Be hydrogen or benzyl.
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Cited By (8)
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| CN102363599A (en) * | 2011-10-09 | 2012-02-29 | 浙江华海药业股份有限公司 | Chiral resolution method of sitagliptin intermediate |
| CN103923087A (en) * | 2014-04-21 | 2014-07-16 | 南京靖龙药物研发有限公司 | Method for preparing deuterium-labeled sitagliptin |
| CN104193744A (en) * | 2014-07-15 | 2014-12-10 | 上海应用技术学院 | Preparation method of sitagliptin intermediate |
| CN104447374A (en) * | 2013-09-17 | 2015-03-25 | 深圳翰宇药业股份有限公司 | Preparation method of sitagliptin and intermediate thereof |
| CN112209931A (en) * | 2019-07-10 | 2021-01-12 | 浙江昌海制药有限公司 | Process method for improving yield and purity of sitagliptin |
| CN112341332A (en) * | 2020-11-11 | 2021-02-09 | 浙江昌明药业有限公司 | Recycling method of sitagliptin key intermediate degradation waste |
| CN115819258A (en) * | 2022-12-13 | 2023-03-21 | 浙江大学 | Preparation method of sitagliptin intermediate by using phosphine-oxygen double bond-containing catalyst |
| CN115960007A (en) * | 2022-12-13 | 2023-04-14 | 浙江大学 | Preparation method of sitagliptin intermediate by using nitrogen-containing formyl catalyst |
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