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CN107011138B - Preparation method of sitagliptin intermediate - Google Patents

Preparation method of sitagliptin intermediate Download PDF

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CN107011138B
CN107011138B CN201710254023.9A CN201710254023A CN107011138B CN 107011138 B CN107011138 B CN 107011138B CN 201710254023 A CN201710254023 A CN 201710254023A CN 107011138 B CN107011138 B CN 107011138B
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CN107011138A (en
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潘庆华
周熹
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Jiangsu Hankuo Biological Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/0827—Syntheses with formation of a Si-C bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a preparation method of a sitagliptin intermediate VI, which takes 2,4, 5-trifluorophenylacetaldehyde and acetone as raw materials, performs asymmetric Aldol reaction under the induction catalysis of L-proline, and then obtains the intermediate VI through hydroxyl protection, Baeyer-Villiger reaction, deprotection and ester hydrolysis.

Description

Preparation method of sitagliptin intermediate
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a sitagliptin intermediate for diabetes.
Background
Sitagliptin (Sitagliptin) is an important diabetes drug, has definite and obvious clinical effect and drug safety, is one of the current and future serious drugs for treating diabetes, and has the following four routes for synthesizing the important drug.
Route one:
Figure BDA0001272868090000011
this route was the first preparation route developed by merck corporation, and is not suitable for large scale production due to the use of expensive reagents, harsh reaction conditions, and difficult isolation of intermediates.
And a second route:
Figure BDA0001272868090000021
compared with the first route, the cost of raw materials of the route is greatly reduced, the operability is greatly improved, but in the key asymmetric catalysis step, the used ligand and noble metal have a great influence on the cost. In addition, in the first step of the reaction in this route, the use of anhydrous oxygen-free environment and pressurized hydrogen atmosphere is also required, which increases the cost and greatly reduces the operability of large-scale industrialization (org. Proc. Res. Dev, 20059 (5) 634-639.).
And a third route:
Figure BDA0001272868090000031
the route developed by merck corporation has the obvious disadvantages that asymmetric catalytic catalysts and platinum oxide used as a catalyst for double bond hydrogenation are expensive, and the stability of the intermediate is poor, the quality is poor, and the operation space is reduced.
Route four
Figure BDA0001272868090000041
The route is a new route disclosed by merck corporation in 2005, and is characterized in that chiral rhodium of ferrocene ligand is used as a catalyst, the catalyst is efficient and low in price, but the ligand has high instability, and the reaction is required to be carried out in an oxygen-free and water-free system, so that great difficulty is generated in large-scale use.
In the preparation of sitagliptin, (S) - (2,4, 5-trifluorophenyl) -3-hydroxy-butanoic acid (VI) is a very important intermediate. However, as shown in the second route, the existing preparation method of (S) - (2,4, 5-trifluorophenyl) -3-hydroxy-butyric acid has various defects, and the large-scale production of the (S) - (2,4, 5-trifluorophenyl) -3-hydroxy-butyric acid is greatly restricted.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention discloses a novel preparation method of a sitagliptin intermediate VI, which is implemented by the following technical scheme:
Figure BDA0001272868090000051
the preparation method of the sitagliptin intermediate VI comprises the following steps:
1) dissolving 2,4, 5-trifluoro-phenylacetaldehyde II and acetone in a solvent, and carrying out an asymmetric Aldol reaction under the induction catalysis of L-proline to generate a chiral intermediate III;
2) reacting the chiral intermediate III with a hydroxyl protecting agent and an optional alkaline auxiliary agent in an aprotic solvent to protect hydroxyl and generate an intermediate IV;
3) enabling the intermediate IV to generate Baeyer-Villiger oxidation reaction in a peroxide system to generate an intermediate V;
4) removal of the hydroxy protecting group is accompanied by hydrolysis and subsequent neutralization to yield intermediate VI.
Preferably, the molar ratio of the 2,4, 5-trifluoro-phenylacetaldehyde to the acetone, the solvent and the L-proline in the step 1) is 1 (4-6): (17-23): 1-1.5.
Preferably, the solvent in step 1) is a short-chain alcohol compound, preferably ethanol; the asymmetric Aldol reaction is carried out at the temperature of-40 to-50 ℃, and the reaction time is 6 to 10 hours, preferably 8 hours.
Preferably, the Baeyer-Villiger oxidation reaction in the step 3) is carried out at a temperature of 40-60 ℃, preferably at a temperature of 50 ℃; the reaction time is 2 to 3 hours, preferably 2 hours.
Preferably, the peroxide system in step 3) is an aqueous hydrogen peroxide solution, an acetic acid system, wherein the aqueous hydrogen peroxide solution is H2O2The mass concentration of (A) is 20-50 wt%, preferably 30 wt%; the molar ratio of the 2,4, 5-trifluoro-phenylacetaldehyde to the aqueous hydrogen peroxide to the acetic acid is 1 (2.5-5.5) to (8-12).
Preferably, the molar ratio of the 2,4, 5-trifluoro-phenylacetaldehyde to the hydroxyl protective agent in the step 2) is 1 (1-1.3); the molar ratio of the 2,4, 5-trifluoro-phenylacetaldehyde to the optional alkaline auxiliary agent is 1 (1-1.3); preferably, the basic assistant is pyridine.
Preferably, the hydroxyl protecting group in step 2) is tert-butyldimethylsilyl chloride; preferably, the aprotic solvent is ethyl acetate, toluene, chlorobenzene, and chloroform, more preferably ethyl acetate.
Preferably, the step of deprotecting the hydroxy-protecting group in step 4) is carried out under acidic conditions in a solvent; preferably the acidic conditions are created by the addition of an acid; preferably the acid is hydrochloric acid, acetic acid, sulphuric acid, chlorosulphonic acid, more preferably hydrochloric acid, most preferably concentrated hydrochloric acid; the addition amount of the acid is 1.5 to 3 times of that of 2,4, 5-trifluoro-phenylacetaldehyde by mol.
Preferably, the solvent in step 4) is acetone, and the molar ratio of the acetone to the 2,4, 5-trifluorophenylacetaldehyde is 2.5-3.5.
The term "optional" as used herein refers to the presence or absence of an additive, e.g., "optional basic additive" refers to embodiments that include a basic additive or embodiments that do not include a basic additive.
The short-chain alcohol compound refers to an alcohol compound with 1-7 carbon atoms.
The concentrated hydrochloric acid is a hydrochloric acid aqueous solution with the mass fraction of 36-40%.
The hydroxyl protection and deprotection reaction can be carried out by using a conventional technical method in the field, and the reaction temperature of the hydroxyl protection reaction is preferably-5 ℃ and the reaction time is preferably 1.5-3 h.
The hydrolysis and neutralization reaction of the present invention can be carried out by using a method conventionally used in the art, and preferably, the neutralization step of step 4) is carried out by adding a base conventionally used in the art, and preferably, the base is sodium hydroxide.
The invention has the beneficial effects that:
1) mild reaction conditions
The method of the invention does not relate to anhydrous and anaerobic reaction conditions and pressurized operation (namely, all the steps are operated under normal pressure), and the reaction conditions are milder and are easy to implement.
2) High-efficiency and low-cost reaction method
The method has simple route, starts from the trifluoro-phenylacetaldehyde, can obtain the target product only by four steps of reaction, improves the production efficiency, reduces the loss of raw materials, takes L-proline as a chiral inducing reagent in the key reaction step, has low price, and has extremely obvious reduction in cost compared with the ligand and noble metal of the catalyst used in the route 2.
3) Is environment friendly
The method of the invention has the advantages of reducing the reaction steps, reducing the used reagent amount, reducing the possibility of pollution caused by the reagent, not involving the use of gas in the reaction and reducing the discharge of three wastes.
4) Higher product purity
The sitagliptin intermediate prepared according to the method of the invention has higher ee value (95% and above).
Detailed Description
The reagents used in the invention are commercially available and have chemical purity, wherein the sources of the main raw materials are as follows:
l-proline, analytically pure, 500g, Shanghai Si Xin Biotech limited;
2,4, 5-trifluorophenylacetaldehyde, analytically pure, 150g, shangzhou shangjie chemical ltd;
30 wt% of aqueous hydrogen peroxide, Hangzhou Jingxin chemical Co.
The instrument used in the embodiment of the invention is as follows:
1h NMR spectrometer, Varian 400 MR;
mass spectrometer, Agilent 5975E;
a micro melting point apparatus RT 3-03C; SGW-2 automatic polarimeters, shanghai precision instruments ltd;
gas Chromatography (GC) instrument: agilent 7890A.
Example 1
Step 1 preparation of (S) - (2,4, 5-trifluorophenyl) -3-hydroxy-pentanone (compound III):
adding 298g of acetone, 800g of ethanol and 115g of L-proline into a reaction bottle, stirring and dissolving, slowly cooling to-40-50 ℃, dropwise adding 174.1g of 2,4, 5-trifluorophenylacetaldehyde, completing the dropwise addition within about two hours, continuing the reaction for about 8 hours, monitoring by gas chromatography GC until the content of the 2,4, 5-trifluorophenylacetaldehyde system is less than 1%, heating the system to-5 ℃, adding 600ml of water and 700ml of ethyl acetate, separating an organic layer, adding magnesium sulfate for drying, filtering, and directly using the obtained filtrate after subtracting the ethyl acetate solvent from the filtrate to obtain the compound III with the GC detection purity of 94% for the next reaction.
Step 2 preparation of (S) - (2,4, 5-trifluorophenyl) -3-tert-butyldimethylsilyloxy-butanone (compound IV):
cooling the ethyl acetate solution obtained in the step 1 to 0 ℃, adding 79.0g of pyridine, dropwise adding 151.0g of tert-butyldimethylsilyl chloride while stirring, keeping the temperature of the system not more than 5 ℃, continuing the reaction for 2 hours, filtering to remove the generated pyridine hydrochloride, evaporating the solvent under reduced pressure at the temperature not higher than 35 ℃, detecting the purity of the remaining light yellow oily compound IV by GC to be 95%, and directly using the product in the next reaction.
Step 3 preparation of (S) - (2,4, 5-trifluorophenyl) -3-tert-butyldimethylsilyloxy-butyric acid methyl ester (compound V):
and (3) adding the oily substance obtained in the step (2) into 600ml of acetic acid, heating to 50 ℃ under stirring, slowly dropwise adding 350ml of 30% aqueous hydrogen peroxide, reacting for two hours, evaporating the acetic acid under reduced pressure at the temperature of not more than 50 ℃, and directly using the residual oily substance without impurity for the next reaction.
Step 4 preparation of (S) - (2,4, 5-trifluorophenyl) -3-hydroxy-butanoic acid (compound VI):
adding the oily substance obtained in the step 3 into 500ml of 15% hydrochloric acid and 200ml of acetone, stirring for 24 hours at about 55 ℃, monitoring by T L C until the material point disappears, namely after the reaction is finished, adding 40% sodium hydroxide aqueous solution to adjust the pH to be neutral, distilling the solvent under reduced pressure until the internal temperature is 40-45 ℃, adding 400ml of water and 500ml of methyl tert-butyl ether for extraction, separating out an organic layer, distilling the methyl tert-butyl ether under reduced pressure, adding 230ml of toluene into the system, crystallizing for 8 hours at 0 ℃, filtering and drying to obtain 113g of white-like crystals, wherein the yield is 48 percent based on 2,4, 5-trifluorophenylacetaldehyde, the melting point is 82-83 ℃, the ee value is 95 percent and the yield is α percent]D＝6.94°(C＝1.0，CHCl3)，1HNMR(400Mz,CDCl3):7.1(m 1H),6.16(m,1H),4.28(m1H),2.82(d 2H),2.60(dd 1H),2.55(dd 1H)。
Example 2
Step 1 preparation of (S) - (2,4, 5-trifluorophenyl) -3-hydroxy-pentanone (compound III):
298g of acetone, 1000g of ethanol and 170g of L-proline are added into a reaction bottle, after stirring and dissolving, the temperature is slowly reduced to-40 to-50 ℃, 174.1g of 2,4, 5-trifluorophenylacetaldehyde is dripped in, the dripping is finished within about two hours, the reaction is continued for about 10 hours, GC monitors that the content of the 2,4, 5-trifluorophenylacetaldehyde system is less than 1 percent, the system is heated to-5 ℃, 600ml of water and 700ml of ethyl acetate are added, an organic layer is separated, magnesium sulfate is added for drying and filtering, the GC detection purity of the compound III is 95 percent after the solvent ethyl acetate is subtracted from the obtained filtrate, and the compound III is directly used for the next reaction.
And 2-4.
The steps of example 1 were followed in steps 2-4 except that the starting reactants were replaced with the product of step 1 of this example.
105g of off-white crystals were finally obtained in a yield of 45% based on 2,4, 5-trifluorophenylacetaldehyde, a melting point of 82-83 ℃ and an ee value of 95% [ α ]]D＝6.94°(C＝1.0，CHCl3)，1H NMR(400Mz,CDCl3):7.1(m 1H),6.16(m,1H),4.28(m1H),2.82(d 2H),2.60(dd 1H),2.55(dd 1H)。
Example 3
Adding 240g of acetone, 700g of methanol and 140g of L-proline into a reaction bottle, stirring and dissolving, slowly cooling to-45 to-50 ℃, dropwise adding 174.1g of 2,4, 5-trifluorophenylacetaldehyde, completing the dropwise addition within about two hours, continuously reacting for about 10 hours, monitoring by GC until the content of the 2,4, 5-trifluorophenylacetaldehyde system is less than 1%, heating the system to-5 ℃, adding 500ml of water and 700ml of ethyl acetate, separating an organic layer, adding magnesium sulfate, drying, filtering, subtracting the ethyl acetate solvent from the obtained filtrate, detecting the purity of the compound III by GC, and directly using the compound III in the next reaction.
And 2-4.
The steps of example 1 were followed in steps 2-4 except that the starting reactants were replaced with the product of step 1 of this example.
110g of white-like crystals were finally obtained in a yield of 47% based on 2,4, 5-trifluorophenylacetaldehyde, a melting point of 82-83 ℃ and an ee value of 95% [ α ]]D＝6.93°(C＝1.0，CHCl3)，1H NMR(400Mz,CDCl3):7.1(m 1H),6.16(m,1H),4.28(m1H),2.82(d 2H),2.60(dd 1H),2.55(dd 1H)。

Claims (18)

1. A preparation method of sitagliptin intermediate VI comprises the following steps:
1) dissolving 2,4, 5-trifluoro-phenylacetaldehyde II and acetone in a solvent, and carrying out an asymmetric Aldol reaction under the induction catalysis of L-proline to generate a chiral intermediate III;
Figure FDA0002391766040000011
2) reacting the chiral intermediate III with a hydroxyl protecting agent and an optional alkaline auxiliary agent in an aprotic solvent to protect hydroxyl and generate an intermediate IV;
Figure FDA0002391766040000012
3) enabling the intermediate IV to generate Baeyer-Villiger oxidation reaction in a peroxide system to generate an intermediate V;
Figure FDA0002391766040000013
4) removing the hydroxyl protecting group and simultaneously hydrolyzing, then carrying out neutralization reaction to generate an intermediate VI,
Figure FDA0002391766040000014
2. the method as claimed in claim 1, wherein the molar ratio of the 2,4, 5-trifluorophenylacetaldehyde to acetone, the solvent and the L-proline in step 1) is 1 (4-6) to (17-23) to (1-1.5).
3. The method according to claim 1, wherein the solvent in step 1) is a short chain alcohol compound; the asymmetric Aldol reaction is carried out at the temperature of-40 to-50 ℃, and the reaction time is 6 to 10 hours.
4. The method according to claim 3, wherein the solvent in step 1) is ethanol.
5. The process according to claim 3, wherein the asymmetric Aldol reaction in step 1) has a reaction time of 8 h.
6. The method according to claim 1, wherein the Baeyer-Villiger oxidation reaction in step 3) is carried out at a temperature of 40-60 ℃; the reaction time is 2-3 hours.
7. The process according to claim 6, wherein the Baeyer-Villiger oxidation reaction in step 3) is carried out at a temperature of 50 ℃.
8. The method of claim 1, wherein the peroxide system in step 3) is an aqueous hydrogen peroxide solution, an acetic acid system, wherein the aqueous hydrogen peroxide solution is H2O2The concentration is 20-50 wt%; the molar ratio of the 2,4, 5-trifluoro-phenylacetaldehyde to the aqueous hydrogen peroxide to the acetic acid is 1 (2.5-5.5) to (8-12).
9. The method of claim 8, wherein the aqueous hydrogen peroxide solution is H2O2The concentration was 30 wt%.
10. The method as claimed in claim 1, wherein the molar ratio of the 2,4, 5-trifluorophenylacetaldehyde to the hydroxyl protecting agent in the step 2) is 1 (1-1.3); the molar ratio of the 2,4, 5-trifluoro-phenylacetaldehyde to the optional alkaline auxiliary agent is 1 (1-1.3).
11. The method according to claim 1 or 10, wherein the basic auxiliary in step 2) is pyridine.
12. The method of claim 1, wherein the hydroxyl protecting group in step 2) is tert-butyldimethylsilyl chloride; the aprotic solvent is ethyl acetate, toluene, chlorobenzene and chloroform.
13. The process of claim 1, wherein the step of removing the hydroxyl protecting group in step 4) is carried out under acidic conditions in a solvent.
14. The method of claim 13 wherein said acidic conditions are created by the addition of an acid in an amount of 1.5 to 3 times by mole the amount of 2,4, 5-trifluorophenylacetaldehyde.
15. The method of claim 14, wherein the acid is hydrochloric acid, acetic acid, sulfuric acid, chlorosulfonic acid.
16. The process of any one of claims 13-15, wherein the solvent in step 4) is acetone and the molar ratio of acetone to 2,4, 5-trifluoroacetaldehyde is 2.5-3.5.
17. The method according to claim 1, wherein the neutralization step in step 4) is performed by adding a base.
18. The method of claim 17, wherein the base is sodium hydroxide.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103755596A (en) * 2013-09-30 2014-04-30 浙江工业大学 Preparation method of sitagliptin intermediate
CN103819475A (en) * 2014-02-11 2014-05-28 浙江新和成股份有限公司 Synthetic method of sitagliptin and salt thereof
CN105968030A (en) * 2016-05-10 2016-09-28 浙江工业大学 Preparation method of Sitagliptin midbody of beta-amino acid

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EP2609099A2 (en) * 2010-08-27 2013-07-03 USV Limited Sitagliptin, salts and polymorphs thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103755596A (en) * 2013-09-30 2014-04-30 浙江工业大学 Preparation method of sitagliptin intermediate
CN103819475A (en) * 2014-02-11 2014-05-28 浙江新和成股份有限公司 Synthetic method of sitagliptin and salt thereof
CN105968030A (en) * 2016-05-10 2016-09-28 浙江工业大学 Preparation method of Sitagliptin midbody of beta-amino acid

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