CN107011138B - A kind of preparation method of sitagliptin intermediate - Google Patents

Abstract

The invention discloses a preparation method of a sitagliptin intermediate VI. The method uses 2,4,5-trifluorophenylacetaldehyde and acetone as raw materials, and an asymmetric Aldol reaction occurs under the induction and catalysis of L-proline, followed by hydroxyl protection, Baeyer-Villiger reaction and deprotection and esterification Hydrolysis affords intermediate VI. The method has the advantages of low price and easy availability of raw materials, low cost, few synthesis steps, mild reaction conditions and environmental friendliness, high stereoselectivity, and can be used for industrial production.

Description

A kind of preparation method of sitagliptin intermediate

technical field

The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of an intermediate for diabetes drug sitagliptin.

Background technique

Sitagliptin is an important diabetes drug with clear and significant clinical effects and drug safety. It is one of the current and future blockbuster drugs for the treatment of diabetes. For the synthesis of this important drug, there are currently The following four routes.

Route one:

This route is the earliest preparation route developed by Merck. Since many expensive reagents are used in this route, the reaction conditions are relatively harsh, and the separation of intermediates is difficult. Therefore, this route is not suitable for large-scale production.

Route two:

Compared with Route 1, the raw material cost of this route has been greatly reduced, and the operability has also been greatly improved. However, in the key asymmetric catalytic step, the ligands and precious metals used still contribute to the cost. greater impact. And in the first step reaction of this route, it is also necessary to use an anhydrous and oxygen-free environment and a pressurized hydrogen atmosphere, which also increases the cost and greatly reduces the operability of large-scale industrialization (Org.Proc.Res.Dev, 2005 9(5) 634-639.).

Route three:

This route was developed by Merck, and its obvious drawback is that the catalyst for asymmetric catalysis and the use of platinum oxide as a catalyst for hydrogenation of double bonds are expensive, and the stability of the intermediate is poor and the quality is poor, resulting in a change in operating space. Small.

route four

This route is a new route disclosed by Merck in 2005. It is characterized by using chiral rhodium of ferrocene ligand as the catalyst. The catalyst is highly efficient and inexpensive. However, due to the high instability of the ligand, the reaction must be It is carried out in an oxygen-free and anhydrous system, which makes it difficult to use it on a large scale.

In the preparation of sitagliptin, (S)-(2,4,5-trifluorophenyl)-3-hydroxy-butyric acid (VI) is a very important intermediate. However, as shown in Route 2 above, the existing method for preparing (S)-(2,4,5-trifluorophenyl)-3-hydroxy-butyric acid has many defects, which greatly restrict its large-scale production.

SUMMARY OF THE INVENTION

In view of the above-mentioned problems existing in the prior art, the present invention discloses a new preparation method of sitagliptin intermediate VI, which is implemented by the following technical solutions:

A preparation method of sitagliptin intermediate VI is provided, comprising the steps of:

1) Dissolving 2,4,5-trifluorophenylacetaldehyde II and acetone in a solvent, under the induction and catalysis of L-proline, an asymmetric Aldol reaction occurs to generate a chiral intermediate III;

2) react chiral intermediate III with hydroxyl protecting agent and optional basic auxiliary agent in aprotic solvent to protect hydroxyl to generate intermediate IV;

3) Baeyer-Villiger oxidation reaction is generated in intermediate IV in peroxide system to generate intermediate V;

4) Removal of the hydroxyl protecting group and simultaneous hydrolysis followed by neutralization to generate intermediate VI.

Preferably, the molar ratio of 2,4,5-trifluorophenylacetaldehyde to acetone, solvent and L-proline described in 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 a temperature of -40 to -50°C, and the reaction time is 6 to 10 h, preferably 8 h.

Preferably, the Baeyer-Villiger oxidation reaction in step 3) is carried out at a temperature of 40-60° C., preferably at a temperature of 50° C.; the reaction time is 2-3 hours, preferably 2 hours.

Preferably, the peroxide system in step 3) is an aqueous hydrogen peroxide solution and an acetic acid system, wherein the mass concentration of H ₂ O ₂ in the aqueous hydrogen peroxide solution is 20-50 wt %, preferably 30 wt %; the 2 The molar ratio of ,4,5-trifluorophenylacetaldehyde, aqueous hydrogen peroxide solution and acetic acid is 1:(2.5～5.5):(8～12).

Preferably, in step 2), the molar ratio of 2,4,5-trifluorophenylacetaldehyde to hydroxyl protective agent is 1:(1-1.3); the 2,4,5-trifluorophenylacetaldehyde and The molar ratio of the optional alkaline auxiliary agent is 1:(1-1.3); preferably, the alkaline auxiliary agent is pyridine.

Preferably, the hydroxyl protecting group in step 2) is tert-butyldimethylchlorosilane; preferably, the aprotic solvent is ethyl acetate, toluene, chlorobenzene and chloroform, more preferably ethyl acetate.

Preferably, the step of removing the hydroxyl protecting group in step 4) is carried out in a solvent under acidic conditions; the acidic conditions are preferably generated by adding an acid; preferably the acid is hydrochloric acid, acetic acid, sulfuric acid, chlorosulfonic acid, more preferably Hydrochloric acid, most preferably concentrated hydrochloric acid; the added amount of the acid is 1.5-3 times that of 2,4,5-trifluorophenylacetaldehyde in moles.

Preferably, the solvent in step 4) is acetone, and the molar ratio of the acetone to 2,4,5-trifluorophenylacetaldehyde is 2.5-3.5.

The term "optional" in the present invention refers to the case of inclusion or exclusion, for example, "optional alkaline auxiliary agent" refers to the technical solution including alkaline auxiliary agent, or the technical solution not including alkaline auxiliary agent.

The short-chain alcohol compounds referred to in the present invention refer to alcohol compounds having 1 to 7 carbon atoms.

The concentrated hydrochloric acid of the present invention is an aqueous hydrochloric acid solution with a mass fraction of 36-40%.

The hydroxyl protection and deprotection reactions of the present invention can be carried out using conventional technical methods in the art. Preferably, the reaction temperature of the hydroxyl protection reaction is -5-5°C, and the reaction time is 1.5-3h.

The hydrolysis and neutralization reactions of the present invention can be carried out using conventional technical methods in the art, preferably, the neutralization step in step 4) is carried out by adding a conventionally used alkali in the art, preferably the alkali is sodium hydroxide .

The beneficial effects of the present invention are:

1) Mild reaction conditions

The method of the present invention does not involve anhydrous and oxygen-free reaction conditions and pressurized operation (that is, each step is operated under normal pressure), and the reaction conditions are milder and easy to implement.

2) Efficient and low-cost reaction method

In the traditional method, the preparation of the target intermediate product from trifluorophenylacetaldehyde often requires a reaction process of more than five steps; the method route of the present invention is simple, and starting from trifluorophenylacetaldehyde, the target product can be obtained by only four steps of reaction , improve the production efficiency and reduce the loss of raw materials. In addition, the raw material L-proline used in the key reaction steps of the present invention is a chirality inducing reagent, and the price is low. Compared with the ligands and precious metals of the catalyst used in route 2, the cost is extremely significantly reduced.

3) Environmentally friendly

In the method of the invention, the number of reaction steps is reduced, the amount of reagents used is also reduced, the possibility of pollution caused by the reagents is reduced, the use of gas is not involved in the reaction, and the discharge of three wastes is reduced.

4) Higher product purity

The sitagliptin intermediate prepared according to the method of the present invention has a higher ee value (95% and above).

Detailed ways

The reagents used in the present invention are all commercially available, and the specifications are chemically pure, and the sources of the main raw materials are:

L-Proline, analytical grade, 500g, Shanghai Sixin Biotechnology Co., Ltd.;

2,4,5-Trifluorophenylacetaldehyde, analytical grade, 150g, Hangzhou Shangjie Chemical Co., Ltd.;

Aqueous hydrogen peroxide solution, 30wt%, Hangzhou Jingxin Chemical Co., Ltd.

The instruments used in the embodiments of the present invention are:

¹ H NMR spectrometer, Varian 400MR;

Mass spectrometer, Agilent 5975E;

Micro melting point apparatus RT3-03C; SGW-2 automatic polarimeter, Shanghai Precision Instrument Co., Ltd.;

Gas Chromatograph (GC) Apparatus: Agilent 7890A.

Example 1

Step 1. Preparation of (S)-(2,4,5-trifluorophenyl)-3-hydroxy-pentanone (Compound III):

Add 298g of acetone, 800g of ethanol, and 115g of L-proline into the reaction flask, stir and dissolve, slowly cool down to -40～-50℃, add 174.1g of 2,4,5-trifluorophenylacetaldehyde dropwise, about two After dripping for 8 hours, the reaction was continued for about 8 hours. The 2,4,5-trifluorophenylacetaldehyde system content was monitored by gas chromatography to be less than 1%. The organic layer was dried by adding magnesium sulfate, and filtered. The obtained filtrate, after deducting the solvent ethyl acetate, had a GC detection purity of 94% of compound III, which was directly used in the next reaction.

Step 2. Preparation of (S)-(2,4,5-trifluorophenyl)-3-tert-butyldimethylsiloxy-butanone (Compound IV):

The ethyl acetate solution obtained in step 1 was cooled to 0 °C, 79.0 g of pyridine was added, 151.0 g of tert-butyldimethylsilyl chloride was added dropwise with stirring, and the temperature of the system was kept not higher than 5 °C, the reaction was continued for 2 hours, and the generated chloroform was removed by filtration. Pyridine hydrochloride, the solvent was evaporated under reduced pressure not higher than 35°C, and the remaining pale yellow oily compound IV was 95% pure as detected by GC, which was directly used in the next step.

Step 3. Preparation of (S)-(2,4,5-trifluorophenyl)-3-tert-butyldimethylsiloxy-butyric acid methyl ester (compound V):

The oil obtained in step 2 was added to 600 ml of acetic acid, and the temperature was raised to 50 ° C under stirring, and 350 ml of 30% aqueous hydrogen peroxide solution was slowly added dropwise. The material was directly used in the next step without purification.

Step 4. Preparation of (S)-(2,4,5-trifluorophenyl)-3-hydroxy-butyric acid (Compound VI):

The oil obtained in step 3 was added to 500ml of 15% hydrochloric acid and 200ml of acetone, stirred at about 55°C for 24 hours, and monitored by TLC until the starting point disappeared, that is, after the reaction was completed, 40% aqueous sodium hydroxide solution was added to adjust pH to neutrality. The solvent was distilled under reduced pressure to an internal temperature of 40-45°C, then 400ml of water and 500ml of methyl tert-butyl ether were added for extraction, the organic layer was separated, and the methyl tert-butyl ether was evaporated under reduced pressure. Crystallize for 8 hours, filter and dry to obtain 113 g of off-white crystals, yield 48% based on 2,4,5-trifluorophenylacetaldehyde, melting point: 82-83°C, ee value 95%, [α] _D = 6.94° (C=1.0, CHCl ₃ ), ¹ H NMR (400Mz, CDCl ₃ ): 7.1 (m 1H), 6.16 (m, 1H), 4.28 (m 1H), 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):

Add 298g acetone, 1000g ethanol, 170g L-proline into the reaction flask, stir to dissolve, slowly cool down to -40--50°C, drop 174.1g 2,4,5-trifluorophenylacetaldehyde, about two After dripping for 1 hour, the reaction was continued for about 10 hours. GC monitoring showed that the content of the 2,4,5-trifluorophenylacetaldehyde system was less than 1%, the temperature of the system was -5 °C, 600 ml of water and 700 ml of ethyl acetate were added, and the organic layer was separated. , adding magnesium sulfate to dry, and filtering, the obtained filtrate, after deducting the solvent ethyl acetate, has a GC detection purity of 95% of compound III, which is directly used in the next reaction.

Steps 2 to 4.

Except for replacing the starting reactant with the product of step 1 of this example, the remaining steps are carried out according to steps 2 to 4 of embodiment 1.

Finally, 105 g of off-white crystals were obtained, with a yield of 45% based on 2,4,5-trifluorophenylacetaldehyde, melting point: 82-83 °C, ee value of 95%, [α] _D = 6.94 ° (C = 1.0, CHCl ₃ ), ¹ H NMR (400 Mz, CDCl ₃ ): 7.1 (m 1H), 6.16 (m, 1H), 4.28 (m 1H), 2.82 (d 2H), 2.60 (dd 1H), 2.55 (dd 1H).

Example 3

Add 240g acetone, 700g methanol, and 140g L-proline into the reaction flask, stir to dissolve, slowly cool down to -45--50°C, drop 174.1g 2,4,5-trifluorophenylacetaldehyde, about two After dripping for 10 hours, the reaction was continued for about 10 hours. GC monitoring showed that the content of the 2,4,5-trifluorophenylacetaldehyde system was less than 1%. The system was heated to -5 °C, 500 ml of water and 700 ml of ethyl acetate were added, and the organic layer was separated. , adding magnesium sulfate to dry, filtering, the obtained filtrate after deducting the solvent ethyl acetate, the GC detection purity of compound III is 94%, which is directly used in the next reaction.

Steps 2 to 4.

Except for replacing the starting reactant with the product of step 1 of this example, the remaining steps are carried out according to steps 2 to 4 of embodiment 1.

Finally, 110 g of off-white crystals were obtained, with a yield of 47% based on 2,4,5-trifluorophenylacetaldehyde, melting point: 82-83°C, ee value of 95%, [α] _D = 6.93° (C = 1.0, CHCl ₃ ), ¹ H NMR (400 Mz, CDCl ₃ ): 7.1 (m 1H), 6.16 (m, 1H), 4.28 (m 1H), 2.82 (d 2H), 2.60 (dd 1H), 2.55 (dd 1H).

Claims (18)

1. a preparation method of sitagliptin intermediate VI, the step that comprises is: 1) Dissolving 2,4,5-trifluorophenylacetaldehyde II and acetone in a solvent, under the induction and catalysis of L-proline, an asymmetric Aldol reaction occurs to generate a chiral intermediate III;

2) react chiral intermediate III with hydroxyl protecting agent and optional basic auxiliary agent in aprotic solvent to protect hydroxyl to generate intermediate IV;

3) Baeyer-Villiger oxidation reaction is generated in intermediate IV in peroxide system to generate intermediate V;

4) remove hydroxyl protecting group and hydrolyze simultaneously, then carry out neutralization reaction, thereby generate intermediate VI,

2. method according to claim 1 is characterized in that, the mol ratio of 2,4,5-trifluorophenylacetaldehyde described in step 1) and acetone, solvent, L-proline is=1:( 4~6):(17~23):(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 a temperature of -40 to -50 °C, and the reaction time is 6 ~ 10h. 4. The method according to claim 3, wherein the solvent described in step 1) is ethanol. 5. The method according to claim 3, wherein the reaction time of the asymmetric Aldol reaction described in step 1) is 8h. 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° C.; the reaction time is 2-3 hours. 7 . 7. The method according to claim 6, wherein the Baeyer-Villiger oxidation reaction described in step 3) is carried out at a temperature of 50°C. 8. The method according to claim 1, wherein the peroxide system in step 3) is an aqueous hydrogen peroxide solution and an acetic acid system, wherein the H2O2 concentration in the aqueous _hydrogen peroxide solution is ₂₀ ～20 50wt%; the molar ratio of the 2,4,5-trifluorophenylacetaldehyde, the aqueous hydrogen peroxide solution and the acetic acid is 1:(2.5-5.5):(8-12). 9 . The method according to claim 8 , wherein the concentration of H ₂ O ₂ in the aqueous hydrogen peroxide solution is 30 wt %. 10 . 10. The method according to claim 1, wherein the molar ratio of 2,4,5-trifluorophenylacetaldehyde to hydroxyl protective agent in step 2) is 1:(1～1.3); the The molar ratio of 2,4,5-trifluorophenylacetaldehyde to the optional alkaline auxiliary agent is 1:(1-1.3). 11. The method according to claim 1 or 10, characterized in that, in step 2), the basic auxiliary agent is pyridine. 12. The method according to 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 method according to claim 1, wherein the step of removing the hydroxyl protecting group in step 4) is carried out in a solvent under acidic conditions. 14. The method according to claim 13, wherein the acidic condition is generated by adding an acid, and the amount of the acid added is 1.5-3 times that of 2,4,5-trifluorophenylacetaldehyde in moles . 15. The method according to claim 14, wherein the acid is hydrochloric acid, acetic acid, sulfuric acid, and chlorosulfonic acid. 16. The method according to any one of claims 13-15, wherein the solvent in step 4) is acetone, and the molar ratio of the acetone to 2,4,5-trifluorophenylacetaldehyde is 2.5 -3.5. 17. The method according to claim 1, wherein the neutralization step in step 4) is performed by adding alkali. 18. The method of claim 17, wherein the alkali is sodium hydroxide.