A method for preparing a sitagliptin intermediate using a nitrogen-containing formyl catalyst

Abstract

The present invention provides a method for preparing a sitagliptin intermediate using a nitrogen-containing formyl catalyst, comprising: dissolving a compound shown in formula I in an organic solvent, catalyzing a Lewis base containing a nitrogen formyl group, using chlorosilane as a hydrogen donor to catalytically reduce a mixed product shown in formula II, and then further splitting the mixed product using a D-configuration organic acid resolving agent, alkalizing, and preparing an intermediate shown in formula III, wherein R is hydrogen or a C1-C5 alkyl group. The preparation method provided by the present invention has the characteristics of high yield, relatively mild conditions, simple operation, and relatively low cost, and has good application value in industry.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a method for preparing a sitagliptin intermediate using a nitrogen-containing formyl catalyst. Background Art

[0002] Sitagliptin phosphate is an important drug for the treatment of type 2 diabetes. It is a dipeptidyl peptidase 4 (DPP-4) inhibitor. It can be used alone or in combination with hypoglycemic drugs to treat diabetes.

[0003] The sitagliptin phosphate has the following structural formula:

[0004]

[0005] At present, most of the literature or patents reporting the chemical synthesis methods of sitagliptin mainly involve the construction of chiral carbon atoms with R configuration. There are currently three main methods for preparing the R-configuration chiral carbon in the sitagliptin structure by chemical methods:

[0006] One is to synthesize racemic sitagliptin or its intermediates and then obtain chiral sitagliptin or its key intermediates through chiral resolution. For example, CN101928289A discloses using camphorsulfonic acid or tartaric acid to resolve the racemate to obtain the chiral drug molecule sitagliptin; CN101824037A discloses using a D-configuration organic acid resolution agent to resolve the racemic sitagliptin free base to obtain chiral sitagliptin.

[0007] The second method is to obtain the enamine intermediate through asymmetric hydrogenation reduction. This type of preparation method mainly uses metal catalysts based on precious metals such as ruthenium and rhodium, such as [Rh(cod)2]OTf, [Rh(NBD)2]BF4, [Rh(cod)Cl]2, [Ru(cymene)Cl]2, Ru(OAc)2, and different chiral phosphine ligand combinations, such as (S)-Cy2-p-Tol-Biphemp, (R,S)-p-CF3 Josiphos, R,St-butyl Josiphos, etc., to asymmetric hydrogenate the enamine precursor under the action of H2 to obtain chiral amino groups.

[0008] For example, in WO2009064476, the intermediate β-enamino ester in the synthesis of sitagliptin is subjected to reductive amination, and expensive chiral noble metal ruthenium catalyst and chiral phosphine ligand are also used. In addition, the chiral selectivity in the reaction of introducing chiral amino groups is low (32% ee), the route is long, with a total of five steps, and the yield is low, with a total yield of about 13%. The route is shown below:

[0009]

[0010] The third is to introduce a chiral amino structure through other non-asymmetric hydrogenation reduction chemical synthesis pathways, such as CN105061434A, using S-epichlorohydrin or R-epichlorohydrin to obtain N-arylmethyl-2R-hydroxy-3-cyanopropylamine through multi-step reactions, and then preparing N-arylmethyl-2S-cyanomethylacridine through intramolecular dehydration reaction, thereby constructing the chiral center of sitagliptin. Summary of the invention

[0011] In view of the bottleneck problem currently existing in the art, the preparation route of the key intermediate containing chiral amino group provided by the present invention is to catalytically reduce the compound shown in formula I to obtain a d-product, and then further separate the d-product to prepare a common intermediate compound of sitagliptin containing chiral amino group shown in formula III. The preparation route of the key intermediate containing chiral amino group provided by the present invention is as follows: Figure 1 shown.

[0012] In view of the lack of an efficient and green catalytic reduction method for the compound shown in formula I in the above preparation route in the prior art, the present invention provides a preparation method of a sitagliptin intermediate using a Lewis base catalyst containing a nitrogen formyl group, and the preparation method creatively provides a catalytic system using a Lewis base containing a nitrogen formyl group as a catalyst and chlorosilane as a hydrogen donor, and the efficient and selective reduction of the compound shown in formula I is achieved under the catalytic system. At the same time, the present invention further discloses a method for resolving the mixed compound shown in formula II obtained after catalytic reduction, which can simply and efficiently separate the target product. The preparation method of the sitagliptin intermediate provided by the present invention has the characteristics of high yield, relatively mild conditions, simple operation, and relatively low cost, and has good application value in industry.

[0013] The invention provides a method for preparing a sitagliptin intermediate by using a nitrogen-containing formyl catalyst.

[0014] A method for preparing a sitagliptin intermediate using a nitrogen-containing formyl catalyst, wherein the structure of the sitagliptin intermediate is as shown in Formula III, and the preparation method comprises:

[0015] (1) The compound represented by formula I is dissolved in an organic solvent, and under the catalysis of a Lewis base containing a nitrogen formyl group, trichlorosilane is used as a hydrogen donor to carry out a reduction reaction of the carbon-carbon double bond to obtain a sitagliptin intermediate. The chemical reaction equation is as follows:

[0016]

[0017] In the formula, R is a C1-C5 alkyl group;

[0018] The Lewis base catalyst containing nitrogen formyl group is one of N,N-dimethylformamide, N,N-diethylformamide, N,N-di-n-propylformamide, N-formylpiperidine and 1-formylpyrrolidone;

[0019] The temperature of the reduction reaction is -78°C to 35°C;

[0020] (2) The mixed sitagliptin intermediate obtained in step (1) is resolved using a D-configuration organic acid resolution agent and alkalized to obtain a chiral sitagliptin intermediate represented by formula III. The chemical reaction equation is as follows:

[0021]

[0022] The D-configuration organic acid resolving agent is D-tartaric acid or D-camphorsulfonic acid.

[0023] The preparation method provided by the present invention comprises the step (1) catalytic reduction of the compound shown in formula I and the step (2) separation of the mixed compound shown in formula II, thereby realizing the efficient preparation of the key intermediate of sitagliptin containing chiral amino group shown in formula III. In step (1) of the preparation method, the present invention creatively adopts a catalytic system with a Lewis base containing a nitrogen formyl group as a catalyst and a chlorosilane as a hydrogen donor to carry out efficient selective reduction of the carbon-carbon double bond in the enamine, thereby realizing the efficient reduction of the compound shown in formula I, and achieving the beneficial technical effect of obtaining the target product in high yield (>95%), which is significantly better than the general catalytic system with chlorosilane as a hydrogen donor. This study found that specific Lewis bases containing nitrogen formyl groups and chlorosilanes can realize the efficient reduction of carbon-carbon double bonds in enamines, and the specific Lewis bases containing nitrogen formyl groups include N,N-dimethylformamide, N,N-diethylformamide, N,N-di-n-propylformamide, N-formylpiperidine and 1-formylpyrrolidone.

[0024] Preferably, in step (1), the Lewis base catalyst containing a nitrogen formyl group is N,N-dimethylformamide.

[0025] Preferably, in step (1), the chlorosilane is trichlorosilane (SiHCl3), methyldichlorosilane (MeSiHCl2), dichlorosilane (SiH2Cl2) or dimethylchlorosilane (Me2SiHCl2), diethylchlorosilane (Et2SiHCl2), diphenylchlorosilane (Ph2SiHCl2); more preferably, the chlorosilane is trichlorosilane.

[0026] Preferably, in step (1), the molar ratio of the chlorosilane to the compound represented by formula I is 1:1 to 20:1.

[0027] Preferably, the Lewis base containing nitrogen formyl group is N,N-dimethylformamide, N,N-diethylformamide, N,N-di-n-propylformamide, N-formylpiperidine, 1-formylpyrrolidone, preferably N,N-dimethylformamide.

[0028] Preferably, the molar ratio of the Lewis base catalyst containing a nitrogen formyl group to the compound represented by formula I is 1:1 to 1:10; further preferably, the molar ratio of the chlorosilane to the compound represented by formula I is 3:1 to 10:1.

[0029] Preferably, in step (1), the molar ratio of the Lewis base catalyst containing a nitrogen formyl group to the compound shown in formula I is 1:1 to 1:10; further preferably, the molar ratio of the Lewis base catalyst containing a nitrogen formyl group to the compound shown in formula I is 1:2.

[0030] Preferably, in step (1), the organic solvent is one or more of toluene, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, acetonitrile and dichloromethane; more preferably, the organic solvent is dichloromethane.

[0031] Preferably, in step (1), the volume mass ratio of the organic solvent to the compound represented by formula I is 1 to 10 mL / g.

[0032] Preferably, in step (1), the temperature of the reduction reaction is -10°C to 35°C; more preferably, the temperature of the reduction reaction is 30°C to 35°C.

[0033] Preferably, in step (2), the D-configuration organic acid resolving agent is D-tartaric acid.

[0034] Preferably, in step (2), the specific method of the splitting is: using a dynamic kinetic splitting method, and the splitting is carried out in the presence of an aromatic aldehyde compound catalyst and a ketone solvent, at a pH of 1 to 3 and a temperature of 0°C to 25°C.

[0035] In a preferred embodiment, the separation is carried out at pH 2-3 and temperature 0°C-10°C.

[0036] Preferably, in step (2), the aromatic aldehyde compound is p-hydroxybenzaldehyde or benzaldehyde; and the ketone solvent is acetone or methyl isobutyl ketone.

[0037] The present invention provides a method for preparing a sitagliptin intermediate using a catalyst containing a nitrogen formyl group. The method avoids the use of noble metal ruthenium and rhodium catalysts in asymmetric reduction, which not only meets the needs of green chemical development, but also reduces costs. The method of the present invention realizes the efficient selective reduction of the important sitagliptin intermediate β-enamine ester with an unprotected amino group using a Lewis base containing a nitrogen formyl group, HSiCl3, which has a simple structure and a low price, with a high yield (>95%), a short reaction time, and simple operation. A method for separating the mixed compound shown in formula II is also provided, which can simply and efficiently separate the target product.

[0038] Compared with the prior art, the present invention has at least the following advantages:

[0039] 1. The preparation route of the present invention avoids the use of precious metal ruthenium and rhodium catalysts in asymmetric reduction, which not only meets the needs of green chemical development, but also reduces costs and is suitable for industrial production.

[0040] 2. The preparation method provided by the present invention has relatively mild conditions and is simple to operate, does not require additional protection and deprotection steps, and has a simple post-processing process.

[0041] 3. The present invention provides a catalytic system using a Lewis base containing a nitrogen carboxylic acid group as a catalyst and chlorosilane as a hydrogen donor, which realizes efficient catalytic reduction of β-enamine, has short reaction time, simple operation and high yield (>95%); and further provides a method for resolving the mixed compound represented by formula II, and the obtained target chiral molecule has high chemical purity and optical purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 The present invention provides a preparation route for the key intermediate of sitagliptin containing a chiral amino group. DETAILED DESCRIPTION

[0043] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are selected according to conventional methods and conditions, or according to the product specifications. Unless otherwise specified, the reagents and raw materials used in the present invention are commercially available.

[0044] Example 1

[0045] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)-2-butenoic acid methyl ester (Formula I)

[0046]

[0047] Add 4-(2,4,5-trifluorophenyl) acetoacetic acid methyl ester (2.50 g, 10.2 mmol) and ammonium acetate (3.85 g, 50 mmol) to methanol (25 mL), stir the reaction at 60 ° C for 12 h, and then concentrate the reaction solution by vacuum vortexing. Add 20 mL of dichloromethane to dissolve the solution, and a large amount of white solid is precipitated. The filtrate is collected by filtration and concentrated by vacuum vortexing. The concentrated solution is dissolved in 3 mL of DCM, and the solution is dropped into 20 mL of n-hexane to precipitate a light yellow solid. The solid is collected by filtration and dried to obtain 2.04 g of 3-amino-4-(2,4,5-trifluorophenyl) but-2-enoic acid methyl ester. The yield is 81%.

[0048] 1H NMR (400MHz, CDCl3), δ7.85(s,1H),7.09(dd,J=17.9,7.9Hz,1H),6.95(dd,J=16.1,9.5Hz,1H),4.57(s,1H),3.65(s,3H),3.41(s,2H).

[0049] Example 2

[0050] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester (Formula II)

[0051]

[0052] 49.0 mg (0.2 mmol) of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester, 3.6 uL (0.2 mmol) of water, 3 uL (0.04 mmol) of DMF, and 120 uL (0.6 mmol) of HSiCl3 were added to dichloromethane (2 mL) in sequence. After stirring at 0°C for 36 h, 2 mL of saturated NaHCO3 was added to quench the reaction. The filtrate was collected by filtration and extracted three times with 10 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by vacuum column purification (petroleum ether: ethyl acetate: triethylamine = 5:1:5%) to obtain 43 mg of colorless oily liquid with a yield of 87%.

[0053] 1H NMR(400MHz, CDCl3), δ7.04(ddd,J=10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J=9.0,8.6,7.1 Hz,1H),2.73(dd,J=13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J=16.0,4.1Hz,1H),2.32(dd,J=16.0,8.7Hz,1H).

[0054] Example 3

[0055] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester (Formula II)

[0056]

[0057] 49.0 mg (0.2 mmol) of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester, 3.6 uL (0.2 mmol) of water, 3 uL (0.04 mmol) of DMF, and 120 uL (0.6 mmol) of HSiCl3 were added to dichloromethane (2 mL) in sequence. After stirring and reacting for 24 h at 10 ° C, 2 mL of saturated NaHCO3 was added to quench the reaction. The filtrate was collected by filtration and extracted with 10 mL of ethyl acetate three times. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by rotation. Purification by column (petroleum ether: ethyl acetate: triethylamine = 5:1:5%) gave 45 mg of colorless oily liquid with a yield of 91%.

[0058] 1H NMR(400MHz, CDCl3), δ7.04(ddd,J=10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J=9.0,8.6,7.1 Hz,1H),2.73(dd,J=13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J=16.0,4.1Hz,1H),2.32(dd,J=16.0,8.7Hz,1H).

[0059] Example 4

[0060] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester (Formula II)

[0061]

[0062] 49.0 mg (0.2 mmol) of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester, 3.6 uL (0.2 mmol) of water, 3 uL (0.04 mmol) of DMF, and 120 uL (0.6 mmol) of HSiCl3 were added to dichloromethane (2 mL) in sequence. After stirring at 30 ° C for 12 h, 2 mL of saturated NaHCO3 was added to quench the reaction. The filtrate was collected by filtration, extracted with 10 mL of ethyl acetate 3 times, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by rotation. Purification by column (petroleum ether: ethyl acetate: triethylamine = 5:1:5%) gave 47 mg of colorless oily liquid with a yield of 98%.

[0063] 1H NMR(400MHz, CDCl3), δ7.04(ddd,J=10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J=9.0,8.6,7.1 Hz,1H),2.73(dd,J=13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J=16.0,4.1Hz,1H),2.32(dd,J=16.0,8.7Hz,1H).

[0064] Example 5

[0065] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester (Formula II)

[0066]

[0067] 49.0 mg (0.2 mmol) of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester, 3.6 uL (0.2 mmol) of water, 3 uL (0.04 mmol) of DMF, and 120 uL (0.6 mmol) of HSiCl3 were added to acetonitrile (2 mL) in sequence. After stirring the reaction at 30 ° C for 12 h, 2 mL of saturated NaHCO3 was added to quench the reaction. The filtrate was collected by filtration, extracted 3 times with 10 mL of ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by rotation. Purification by column (petroleum ether: ethyl acetate: triethylamine = 5: 1: 5%) gave 40 mg of colorless oily liquid with a yield of 81%.

[0068] 1H NMR(400MHz, CDCl3), δ7.04(ddd,J=10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J=9.0,8.6,7.1 Hz,1H),2.73(dd,J=13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J=16.0,4.1Hz,1H),2.32(dd,J=16.0,8.7Hz,1H).

[0069] Example 6

[0070] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester (Formula II)

[0071]

[0072] 49.0 mg (0.2 mmol) of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester, 3.6 uL (0.2 mmol) of water, 3 uL (0.04 mmol) of DMF, and 120 uL (0.6 mmol) of HSiCl3 were added to toluene (2 mL) in sequence. After stirring the reaction at 30 ° C for 12 h, 2 mL of saturated NaHCO3 was added to quench the reaction. The filtrate was collected by filtration, extracted 3 times with 10 mL of ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by rotation. Purification by column (petroleum ether: ethyl acetate: triethylamine = 5:1:5%) gave 48 mg of colorless oily liquid with a yield of 93%.

[0073] 1H NMR(400MHz, CDCl3), δ7.04(ddd,J=10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J=9.0,8.6,7.1 Hz,1H),2.73(dd,J=13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J=16.0,4.1Hz,1H),2.32(dd,J=16.0,8.7Hz,1H).

[0074] Example 7

[0075] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester (Formula II)

[0076]

[0077] 49.0 mg (0.2 mmol) of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester, 3.6 uL (0.2 mmol) of water, 3 uL (0.04 mmol) of DMF, and 120 uL (0.6 mmol) of HSiCl3 were added to ethyl acetate (2 mL) in sequence. After stirring the reaction at 30 ° C for 12 h, 2 mL of saturated NaHCO3 was added to quench the reaction. The filtrate was collected by filtration, extracted with 10 mL of ethyl acetate 3 times, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by vacuum column purification (petroleum ether: ethyl acetate: triethylamine = 5:1:5%) to obtain 44 mg of colorless oily liquid with a yield of 89%.

[0078] 1H NMR(400MHz, CDCl3), δ7.04(ddd,J=10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J=9.0,8.6,7.1 Hz,1H),2.73(dd,J=13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J=16.0,4.1Hz,1H),2.32(dd,J=16.0,8.7Hz,1H).

[0079] Comparative Example 1

[0080] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester (Formula II)

[0081]

[0082] 49.0 mg (0.2 mmol) of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester, 3.6 uL (0.2 mmol) of water, 4.1 mg (0.04 mmol) of 1-formylpyrrolidone, and 120 uL (0.6 mmol) of HSiCl3 were added to dichloromethane (2 mL) in sequence. After stirring at 30 ° C for 12 h, 2 mL of saturated NaHCO3 was added to quench the reaction. The filtrate was collected by filtration, extracted with 10 mL of ethyl acetate 3 times, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by vacuum column purification (petroleum ether: ethyl acetate: triethylamine = 5:1:5%) to obtain 38 mg of colorless oily liquid with a yield of 78%.

[0083] The characterization data of the product prepared in this example are as follows:

[0084] 1H NMR(400MHz, CDCl3), δ7.04(ddd,J=10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J=9.0,8.6,7.1 Hz,1H),2.73(dd,J=13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J=16.0,4.1Hz,1H),2.32(dd,J=16.0,8.7Hz,1H).

[0085] Comparative Example 2

[0086] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester (Formula II)

[0087]

[0088] 49.0 mg (0.2 mmol) of 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester, 3.6 uL (0.2 mmol) of water, 4.1 mg (0.04 mmol) of triethylamine, and 120 uL (0.6 mmol) of HSiCl3 were added to dichloromethane (2 mL) in sequence. After stirring at 30 ° C for 12 h, 2 mL of saturated NaHCO3 was added to quench the reaction. The filtrate was collected by filtration, extracted with 10 mL of ethyl acetate 3 times, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by vacuum column purification (petroleum ether: ethyl acetate: triethylamine = 5:1:5%) to obtain 5 mg of colorless oily liquid with a yield of 10%.

[0089] The characterization data of the product prepared in this example are as follows:

[0090] 1H NMR(400MHz, CDCl3), δ7.04(ddd,J=10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J=9.0,8.6,7.1 Hz,1H),2.73(dd,J=13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J=16.0,4.1Hz,1H),2.32(dd,J=16.0,8.7Hz,1H).

[0091] Example 8

[0092] This embodiment provides a method for preparing 3R-amino-4-(2,4,5-trifluorophenyl)-2-butyrate tartrate, and the steps are as follows: racemic 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester is prepared in the same manner as in Example 2. D-tartaric acid (1.5 g, 10 mmol) is completely dissolved in 40 ml of acetone under stirring, and then a catalytic amount of p-hydroxybenzaldehyde (6.1 mg, 0.05 mmol) is added, and glacial acetic acid is added dropwise under stirring to adjust the reaction pH to 3, and then the reaction liquid temperature is reduced to 0°C. After dissolving the obtained racemic 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester (2.45g, 10mmol) in 20ml acetone, the prepared racemic 3-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester acetone solution was added dropwise to the tartaric acid solution under stirring at 0-5℃. White solid precipitated during the addition. After the addition was completed, the mixture was stirred at 5℃ for 10h for crystallization. Filter, wash the filter cake with acetone and dry to obtain 1.5g of white solid, i.e., 3R-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid ester tartrate. The yield was 78%, and the ee% was 99%.

[0093] Example 9

[0094] This embodiment provides a method for preparing 3R-amino-4-(2,4,5-trifluorophenyl)-2-butyrate, and the steps are as follows: 1.5g 3R-amino-4-(2,4,5-trifluorophenyl)-2-butyrate tartrate, 18mL ether and 12mL pure water are stirred and mixed for 30min, and the temperature is lowered to below 5°C. Concentrated ammonia water is added dropwise at 0-5°C, and the pH of the reaction solution is adjusted to 8-9. The layers are separated, and the ether layer is washed twice with water and dried with anhydrous magnesium sulfate for 5h. Filter, and the filtrate is concentrated to dryness under reduced pressure to obtain 0.87g of colorless oily liquid, i.e., 3R-amino-4-(2,4,5-trifluorophenyl)-2-butyric acid methyl ester. The yield is 91%, and ee%=99%.

[0095] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing a sitagliptin intermediate using a nitrogen-containing formyl catalyst, characterized in that: The structural formula of the sitagliptin intermediate is shown in Formula III, and the preparation method comprises: (1) The compound represented by formula I is dissolved in an organic solvent, and the carbon-carbon double bond is reduced by trichlorosilane as a hydrogen donor under the catalysis of a Lewis base containing a nitrogen formyl group to obtain a compound represented by formula II. The chemical reaction equation is as follows: ， In the formula, R is a C1-C5 alkyl group; The organic solvent is dichloromethane; The Lewis base catalyst containing nitrogen formyl group is N,N-dimethylformamide; The temperature of the reduction reaction is 30°C to 35°C; (2) using a D-configuration organic acid resolving agent to resolve the chromatic compound of formula II obtained in step (1), and alkalizing to obtain a chiral sitagliptin intermediate of formula III. The reaction equation is as follows: ； The D-configuration organic acid resolving agent is D-tartaric acid or D-camphorsulfonic acid.

2. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of trichlorosilane to the compound represented by formula I is 1:1 to 20:

1.

3. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of the Lewis base catalyst containing a nitrogen formyl group to the compound represented by formula I is 1:1 to 1:

10.

4. The preparation method according to claim 1, characterized in that: The volume mass ratio of the organic solvent to the compound represented by formula I is 1-10 mL / g.

5. The preparation method according to claim 1, characterized in that: In step (2), the specific method of the splitting is: using a dynamic kinetic splitting method, and the splitting is carried out in the presence of an aromatic aldehyde compound catalyst and a ketone solvent, at a pH of 1-3 and a temperature of 0°C-25°C.

6. The preparation method according to claim 5, characterized in that: In step (2), the aromatic aldehyde compound is p-hydroxybenzaldehyde or benzaldehyde; and the ketone solvent is acetone or methyl isobutyl ketone.

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