Sitagliptin intermediate and preparation method thereof

Abstract

The invention discloses a novel preparation method of sitagliptin. According to the new route, L-aspartic acid is used as an initial raw material, large steric hindrance amino protection, selective methyl esterification, one-pot acylating chlorination and Friedel-Crafts acylation are performed, benzyl carbonyl is selectively reduced step by step to form methylene, then phthalic anhydride removal, esterification, chlorination, reduction and selective acid amine condensation are performed, and the sitagliptin with high optical purity is prepared. The method has the advantages of simple and efficient reaction steps, high product structure accuracy, strong operability, no need of precious metals, low cost, mild reaction conditions, easy industrialization, and high application value.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a new method for preparing sitagliptin. Background Art

[0002] Sitagliptin is the first oral DPP-4 inhibitor to be marketed, developed by Merck in the United States. It was approved for marketing by the U.S. FDA in October 2006 and can be used alone or in combination with metformin and thiazolidinediones. Route ③ introduces a chiral auxiliary after coupling and amine ester exchange reaction, and then performs an asymmetric catalytic hydrogenation reaction, and finally hydrolyzes to obtain sitagliptin. Patent CN108314688 A (as shown in route ④), through acid amine condensation, amine aldehyde condensation, stereoselective Gernisch reaction, and hydrolysis, sitagliptin is obtained. The above processes all introduce a chiral auxiliary to produce steric hindrance on one side, and introduce chirality by nucleophilic addition reaction or asymmetric hydrogenation on the side with less steric hindrance, and all achieve higher ee values. However, the chiral auxiliary ( R )-(+)-tert-Butylsulfenamide has a high price and high loss.

[0003] .

[0004] Syn.Com .2013, 43(24) , 3281-3286 stereoselective reduction is carried out by NaBH4 / HCOOH instead of expensive, toxic catalysts or ligands, followed by palladium carbon hydrogenation to remove the phenylethyl group and phosphoric acid salt to obtain sitagliptin phosphate. This route uses ( R The price of )-(+)-1-phenylethylamine is significantly lower than that of the other chiral auxiliary agents mentioned above, about 10 to 24 times lower, and expensive noble metal catalysts are avoided, thus reducing production costs. However, the yield of the asymmetric reduction step is 40.9%, which is relatively low, and the palladium carbon residue problem should be paid attention to during the post-treatment of palladium carbon hydrogenation to remove the benzyl group.

[0005] .

[0006] Patent CN107129501 A uses the starting material L-aspartic acid to selectively esterify with benzyl alcohol at the 4th position, triphosgene cyclization, methyl chloroformate protection, Friedel-Crafts acylation, palladium-carbon high-pressure hydrogenation to reduce the carbonyl group, Boc protection, acid-amine condensation, hydrochloric acid hydrolysis and other reactions to obtain sitagliptin. This route not only uses cheap and readily available L-aspartic acid (02) to introduce chirality in advance, but also introduces 1,2,4-trifluorobenzene (06) through Friedel-Crafts acylation, avoiding the Grignard reaction commonly used in previous processes, and is easy to operate. However, the stereoselectivity of the first step of L-aspartic acid esterification is poor, and there will be esterified impurities at the 1st position, which is difficult to separate and purify. In addition, the protecting group is used multiple times in the route, which is cumbersome to operate; the route has a long number of steps and a low total yield of only 24.9%.

[0007] .

[0008] At present, the synthesis process of sitagliptin still has some shortcomings, such as cumbersome reaction steps, high cost of raw materials and low yield, which has an adverse impact on the environment and is not in line with the concept of sustainable development. Therefore, it is of broad social significance to improve the synthesis process route. BRIEF DESCRIPTION OF THE DRAWINGS

[0001] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the intermediate 07 prepared in Example 3 of the present invention.

[0002] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the intermediate 11 prepared in Example 5 of the present invention.

[0003] Figure 3 This is the HPLC spectrum of the intermediate 11 obtained in Example 5 of the present invention.

[0004] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of sitagliptin prepared in Example 7 of the present invention. Summary of the invention

[0009] In order to achieve the technical purpose of the present invention, the technical solution provided by the present invention is: The present invention provides a method for preparing a sitagliptin intermediate, comprising the following steps: S1: Compound A is subjected to carbonyl reduction reaction to prepare compound B; S2: Compound B is subjected to chlorination reaction to obtain chlorinated compound C; S3: The chlorinated compound C is dechlorinated to obtain the sitagliptin intermediate D; The reaction equation is: , Wherein, R is a carboxyl protecting group or H, and preferably the carboxyl protecting group is one of C1-C4 alkyl or substituted alkyl, benzyl, diphenylmethyl, p-nitrobenzyl and p-methoxybenzyl.

[0010] Most preferably, the compound of formula A has the structural formula: .

[0011] Or the reaction equation is: , R is defined as above, and R1 is an amino protecting group.

[0012] A preferred embodiment of the present invention is: .

[0013] The present invention provides a method for preparing sitagliptin and its intermediates, and another preferred embodiment is: , Specifically: The method comprises: (a) reducing the carbonyl group of intermediate 07 to a hydroxyl group in the presence of a reducing agent and then removing phthalic anhydride to obtain intermediate 08; (b) isopropylating intermediate 08 to obtain intermediate 09; (c) chlorinating intermediate 09 with a chlorinating agent to obtain intermediate 10; and (d) reducing intermediate 10 with a reducing agent to obtain intermediate 11.

[0014] In one embodiment, the intermediate 07 in the above step (a) can be prepared according to the following reaction, which comprises the following steps: the chiral source L-aspartic acid (02) is subjected to cyclization dehydration via phthalic anhydride (03) to obtain the intermediate 04; the intermediate 04 is selectively methylated under the catalysis of thionyl chloride to obtain the intermediate 05; and the intermediate 05 is subjected to acyl chlorination and Friedel-Crafts acylation to obtain the intermediate 07.

[0015] In another embodiment, sitagliptin is obtained by subjecting the intermediate 11 obtained in the above steps (a) to (b) to hydrolysis reaction with an alkaline reagent to obtain intermediate 12, and then intermediate 12 is subjected to condensation reaction with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride to obtain compound 01.

[0016] Intermediate 8 , intermediate 9 , intermediate 10 , .

[0017] The overall reaction equation of the method of the present invention is as follows: .

[0018] Hereinafter, the method of the present invention will be described in detail with reference to the corresponding steps of the above reaction scheme.

[0019] The present invention provides a novel method for preparing sitagliptin, which comprises the steps of (a) reducing the carbonyl group of an intermediate 07 to a hydroxyl group and then removing phthalic anhydride to obtain an intermediate 08; (b) isopropylating the intermediate 08 to obtain an intermediate 09; (c) chlorinating the intermediate 09 to obtain an intermediate 10; and (d) reducing the intermediate 10 to obtain an intermediate 11.

[0020] In the method of the present invention, the reaction of step (a) is reduction first and then dephthalanhydride. The reducing agent may be selected from one or more of sodium borohydride, potassium borohydride and triethylsilane. Preferably, the reducing agent may be sodium borohydride. The reducing agent may be used in an amount of 1.5 to 2.0 eq, preferably 1.7 eq, per 1 eq of intermediate 07, but the amount may vary according to the reducing agent. The solvent used in the reaction may be selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ethyl acetate and dichloromethane. Preferably, the solvent may be methanol. The reagent used in the dephthalanhydride reaction is 85% hydrazine hydrate, and the amount may be 1.5 to 2.0 eq, preferably 1.6 eq. The reaction temperature may be carried out in the range of 0 to 55 °C, preferably 0 to 30 °C.

[0021] The reaction of step (b) is an esterification reaction. The reaction is carried out in a solvent under the catalytic condition of a chlorination agent, and the chlorination agent can be selected from one of oxalyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, NCS, dichlorohydantoin, TCT, sulfuryl chloride, TCCA and triphosgene. Preferably, the catalyst can be thionyl chloride. The reaction solvent can be one or more of methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 1,2-propylene glycol, 1,3-propylene glycol and 1-butanol, isopropanol, preferably isopropanol.

[0022] The reaction of step (c) is a chlorination reaction. The chlorination agent may be thionyl chloride. The chlorination agent may be used in an amount of 0.5 to 1.5 eq, preferably 1.2 eq, per 1 eq of intermediate 09, but the amount may vary depending on the chlorination agent. The solvent used in the reaction may be selected from one or more of toluene, tetrahydrofuran, ethyl acetate, dichloromethane, and dichloroethane, preferably toluene. The solvent dosage is 2 to 10 V, preferably 5 V.

[0023] The reaction of step (d) is a reduction reaction. The reduction can be carried out using a reducing agent, the reducing agent is a metal / acid, and the acid is a Lewis acid. The amount of the acid should be 1.0 to 1.5 eq, preferably 1.2 eq. The metal can be selected from any one of palladium, nickel, zinc, magnesium, and iron. Preferably, it can be any one of the cheap and readily available metals zinc, magnesium, and iron, and more preferably, it can be zinc. The amount of zinc powder is 1.0 to 2.5 eq, preferably 1.7 eq. The reaction can be carried out in one or more reaction solvents, and the one or more solvents can be selected from dimethylformamide, dimethylacetamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, 1,4-dioxane, methanol, and n-butanol. Preferably, the solvent can be tetrahydrofuran and / or ethanol. Moreover, the reaction can be carried out at a temperature in the range of 0 to 100°C, preferably 50 to 65°C.

[0024] In the method of the present invention, the intermediate 07 used in step (a) can be obtained by the following method: subjecting the chiral source L-aspartic acid (02) to phthalic anhydride (03) for cyclization and dehydration to obtain the intermediate 04; and subjecting the intermediate 04 to selective methyl esterification under the catalysis of thionyl chloride to obtain the intermediate 05; and finally subjecting the intermediate 05 to acyl chlorination and Friedel-Crafts acylation reaction.

[0025] The chiral source L-aspartic acid (02) and phthalic anhydride (03) are reacted in the presence of an organic solvent, wherein the solvent is selected from one or more of acetic acid (AcOH), pyridine (Py), dimethyl sulfoxide (DMSO), and N,N-dimethylformamide (DMF). The molar ratio of L-aspartic acid (02) to phthalic anhydride (03) is (1-1.5):1, preferably 1.3:1. The reaction temperature can be in the range of 100-130 °C, preferably 115-120 °C. The reaction time is 2-5 h.

[0026] The esterification reaction of the intermediate 04 is carried out in a solvent under the catalytic condition of a chlorination agent, wherein the chlorination agent may be one or more of thionyl chloride, oxalyl chloride and triphosgene, preferably thionyl chloride; the molar ratio of the intermediate 04 to the chlorination agent is 1:(0.9-1.1), preferably 1:1. The organic solvent for the reaction may be methanol, and the amount used is 5-10 V.

[0027] The reaction of intermediate 05 and intermediate 06 is first carried out in a solvent in the presence of a chlorination agent, and then carried out under Lewis acid catalysis. The chlorination agent in the reaction can be one or more of thionyl chloride, oxalyl chloride and triphosgene, preferably oxalyl chloride. And dimethylformamide (DMF) is used as a catalyst. The reaction solvent can be one or more of dichloromethane, ethyl acetate, and tetrahydrofuran, preferably dichloromethane. The Lewis acid can be one or more of aluminum chloride, ferric chloride, zinc chloride, and phosphoric acid, preferably aluminum chloride. Moreover, 1,2,4-trifluorobenzene (06) in the reaction can be used as both a reactant and a reaction solvent, and the amount used is 5 to 10 eq. The reaction temperature is the solvent reflux temperature. The steps can be carried out using a one-pot method without separating the intermediates. Therefore, the method of the present invention is suitable for large-scale industrial production.

[0028] In the method of the present invention, sitagliptin can be obtained by the following method: (i) reacting the intermediate 11 obtained in the above steps (a) to (d) with an alkaline reagent to obtain an intermediate 12, and (ii) allowing the intermediate 12 to undergo a condensation reaction with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride to obtain the target product sitagliptin, i.e., compound 01.

[0029] The reaction of step (i) can be carried out in the presence of a base, and the base can be selected from potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate (including monobasic potassium phosphate, dibasic potassium phosphate and tribasic potassium phosphate), sodium phosphate (including monobasic sodium phosphate, dibasic sodium phosphate and tribasic sodium phosphate), preferably sodium hydroxide. The base can be 1.0~1.3 eq, preferably 1.0~1.1 eq, preferably 1.05 eq. The reaction can be carried out in the presence of one or more solvents, and the one or more solvents are selected from tetrahydrofuran, hexamethylphosphoramide, C1~C5 alcohols, dimethyl ether, diethyl ether, diisopropyl ether, ethyl acetate, dimethoxyethane and toluene. Preferably, the solvent can be water, tetrahydrofuran or C1~C5 alcohols (such as methanol, ethanol, propanol, isopropanol, butanol, etc.). More preferably, the solvent may be a mixed solvent of isopropanol and water, with the usage ratio being 2:1, 1:1, 1:2, preferably 1:2.

[0030] Step (ii) (the reaction of intermediate 12 with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride) can be carried out in the presence of a condensing agent, which can be one or more of carbonyl diimidazole, N,N-dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide (DIC), and 1-ethyl-3-dimethylcarbamate (EDCl). The condensing agent can be preferably N,N-dicyclohexylcarbodiimide (DCC), and the amount used is 1.0 to 1.5 eq, preferably 1.1 eq. The reaction can be carried out in the presence of one or more solvents, which can be selected from isopropanol, tetrahydrofuran, n-butanol, ethyl acetate, 1,4-dioxane, toluene, preferably tetrahydrofuran.

[0031] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention has a high accuracy of product structure. The selective methyl esterification of the 4-position carboxylic acid is achieved by utilizing the large steric anhydride protection of the dicarboxylic acid intermediate 04, a lower reaction temperature, a slower drop rate, and the like.

[0032] (2) In the method of the present invention, intermediate 07 is subjected to carbonyl reduction, deprotection of phthalic anhydride, and isopropyl esterification to obtain intermediate 09, which solves the problem that the traditional reduction system (triethylsilane, hydrazine hydrate and its derivatives, sodium borohydride and Lewis acid, etc.) cannot selectively reduce the benzyl carbonyl group in intermediate 07 to methylene; (3) The reaction steps of the present invention are simple and efficient, highly operable, do not require the use of precious metals, are low in cost, have mild reaction conditions, and are easy to industrialize. DETAILED DESCRIPTION

[0033] In order to explain the technical content, structural features, achieved purpose and effect of the technical solution in detail, the following is further described in conjunction with specific embodiments and drawings. This embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation method and specific operation process are given, but the protection scope of the present invention is not limited to the following embodiments.

[0034] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0035] Example 1: Preparation of Intermediate 04 At room temperature 29 ℃, add white powder 02 (23.6 g, 173.78 mmol) and DMSO (30 mL) to a 500 mL three-necked flask, move it into an oil bath and start heating. When the internal temperature reaches 115~120 ℃, start adding 03 (20.0 g, 133.68mmol) to the above system in ten batches every 20 min. After the addition is completed, continue the reaction, and TLC monitors that the raw materials have reacted. Use a constant pressure dropping funnel to slowly add saturated brine (165 mL) to the above system, maintaining the internal temperature at about 95 ℃. After the addition is completed, slowly cool down. When the internal temperature is about 87 ℃, solids begin to precipitate. After keeping warm for 2 h, it naturally drops to room temperature 26 ℃ and stirs overnight. The next day, the filter cake was filtered to obtain a white solid, which was then rinsed twice with water and PE, and then transferred to a 50 °C hot air circulation dryer until constant weight was obtained, yielding 30.62 g of white powder 04 with a yield of 87.1% (based on 03). Structural characterization: Measured mp: 219.6~224.5 °C; [α] D 25 = -49.2 (c 1.0, EtOH); ESI-MS(m / z): 262.0 [MH] - ; 1 H NMR (400 MHz, DMSO- d 6 )δ 12.90 (s, 2H), 7.97 – 7.87 (m, 4H), 5.18 (t, J = 7.2 Hz, 1H), 3.15 (dd, J =16.7, 7.4 Hz, 1H), 2.95 (dd, J = 16.7, 7.0 Hz, 1H).

[0036] Example 2: Preparation of Intermediate 05 At room temperature of 28 °C, add white powder 04 (40.0 g, 152.07 mmol) and methanol (200 mL) to a 500 mL three-necked flask. Transfer to a 0 °C low-temperature reactor, use a constant pressure dropping funnel to drop thionyl chloride (11.16 mL, 152.07 mmol) into the above reaction system at a rate of 8-10 s / d, and maintain the internal temperature at 0-3 °C. After the drop, continue to maintain the internal temperature at 0 °C for the reaction, and monitor the complete reaction of the raw materials by TLC. Add water to quench the reaction, and connect the alkaline cylinder to absorb the acidic gas at the same time, and the system pH = 3. The diaphragm pump is used to spin-dry methanol at 45 °C, and a large amount of white solid precipitates in the system. After spinning, continue stirring at room temperature for 2 h, filter and rinse with water twice, and discard the filtrate. The filter cake is placed in a 50 °C hot air circulation dryer until constant weight, and 38.33 g of white solid 05 is obtained, with a yield of 91% (based on 04). Structural characterization: Measured mp: 161.0~162.9 ℃; ESI-MS (m / z): 300.0 [M+Na] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.51 (s, 1H), 7.96 – 7.87 (m, 4H), 5.19 (t, J = 7.3 Hz,1H), 3.60 (s, 3H), 3.22 (dd, J = 16.6, 7.4 Hz, 1H), 3.04 (dd, J = 16.6, 7.2 Hz,1H).

[0037] Example 3: Preparation of Intermediate 07 Step 1: Add white powder 05 (30.0 g, 108.30 mmol), DCM (150 mL) and DMF (1.5 mL) to a 500 mL single-mouth bottle at room temperature of 29 °C. Transfer to a 0 °C low-temperature reactor and use a constant pressure dropping funnel to drop oxalyl chloride (11.22 mL, 129.93 mmol) at a rate of 2-3 s / d, maintaining the internal temperature below 5 °C. After the drop is completed, transfer to room temperature 29 °C for reaction, and TLC monitors the complete reaction of the raw material. The dichloromethane is dried by a 40 °C diaphragm pump to obtain an orange-yellow oily acid chloride intermediate. Step 2: Add transparent liquid 06 (60 mL, 574.20 mmol) to the above system, and then slowly add yellow block solid aluminum chloride (65.7 g, 487.26 mmol) in batches under an ice bath. After the addition is completed, reflux in an oil bath at 95 °C, and the reaction of the raw material is monitored by TLC. In an ice bath, water was slowly added to quench the reaction. The quenching process was highly exothermic, and the system pH = 2~3. The aqueous phase was extracted twice with EA (100 mL), and the combined organic phases were washed with water and saturated brine until neutral, dried over anhydrous magnesium sulfate, filtered and evaporated to obtain 33.3 g of crude yellow solid. The system was moved into an ice bath with an internal temperature of 3 °C, toluene and ethanol were added to slurry for 3 h, filtered, and the filtrate was discarded. The filter cake was placed in a hot air circulation drying at 50 °C to constant weight to obtain 21.03 g of white powder 07, with a yield of 51.5% (based on 05). Structural characterization: Measured mp: 177.4~181.3 °C; [α] D 25 = -6.1 (c 1.0, MeOH); ESI-MS(m / z): 400.0408 [M+Na] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.49 (s, 1H), 7.96 – 7.83 (m, 5H), 7.77 (td, J = 10.7, 6.4 Hz, 1H), 5.44 (t, J = 6.6 Hz, 1H), 3.97 (dd, J = 18.5, 6.4, 2.5 Hz,1H), 3.68 (dd, J = 18.5, 6.8, 2.5 Hz, 1H).

[0038] Example 4: Preparation of Intermediate 09 Step 1: Add white powder 07 (20.0 g, 53.04 mmol) and MeOH (120 mL) to a 500 mL three-necked flask at room temperature of 28 °C. Transfer to a 0 °C low-temperature reactor and add sodium borohydride (3.2 g, 84.86 mmol) in batches, maintaining the internal temperature no higher than 2 °C. Move to room temperature of 28 °C to continue the reaction, and monitor the complete reaction of the raw material by TLC. Transfer to a 0 °C low-temperature reactor and add 85% mass fraction of hydrazine hydrate (3.30 mL, 90.16 mmol) dissolved in methanol (10 mL) through a constant pressure dropping funnel at a rate of 3 s / d. Transfer to room temperature of 28 °C to continue the reaction, and monitor the complete reaction of the raw material by TLC. Under ice bath, add water (120 mL) to the above system, slowly add 12 mol / L hydrochloric acid (9.5 mL) to adjust the pH of the aqueous phase to 2~3. Remove methanol by rotary evaporation with a 45 ℃ diaphragm pump, then filter, rinse the filter cake twice with water (20 mL), and discard the filter cake (impurity phthaloyl hydrazide). Wash the aqueous phase twice with EA (60 mL) to remove impurities, and spin dry the aqueous phase with a 60 ℃ diaphragm pump to obtain a light yellow gel-like solid. Add toluene (50 mL) in batches and spin dry with water to constant weight to obtain 20.80 g crude product (mixed with various salts) of light yellow solid 08 hydrochloride, which is directly put into the next step. Step 2: At room temperature 28 ℃, add the above light yellow solid 08 hydrochloride (20.80 g) and isopropanol (140 mL) to a 500 mL three-necked flask, and the system is a light yellow-white turbid solution. Transfer to an ice bath, add thionyl chloride (10.24 mL, 132.60 mmol) through a constant pressure dropping funnel at a rate of 4-5 s / d, and maintain the internal temperature not higher than 5 °C. Transfer to a 95 °C oil bath for reflux reaction, and monitor the complete reaction of the raw material by TLC. Transfer the system to an ice bath, add saturated sodium bicarbonate aqueous solution (100 mL) to quench and adjust the system pH to 8-9. The aqueous phase is extracted twice with EA (100 mL), and the organic phases are combined and washed once with water (100 mL) and saturated brine (100 mL). Add anhydrous magnesium sulfate to dry for 0.5 h and then filter. The organic phase is rotated to constant weight by a 45 °C diaphragm pump to obtain 13.40 g of brown liquid oil. The total crude yield from 07 to 09 is 86.8% (based on 07). No further purification is required, and it can be directly put into the next step and stored in a 0 °C refrigerator. Structural characterization: [α] D 25 = +13.7 (c 1.0, MeOH); ESI-MS(m / z): 292.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.47 (dq, J= 9.3, 6.1 Hz, 2H), 4.98(dd, J = 9.3, 3.3 Hz, 1H), 4.90 (dq, J = 12.5, 6.2 Hz, 1H), 3.44 (t, J = 6.7 Hz,1H), 1.89 (dd, J = 13.5, 5.9, 3.8 Hz, 1H), 1.69 (dd, J = 13.7, 9.2, 7.4 Hz, 1H),1.20 (dd, J = 6.2, 3.3 Hz, 6H).

[0039] Example 5: Preparation of Intermediate 11 Step 1: At room temperature of 30 °C, add brown liquid oil 09 (20.0 g, 68.70 mmol) and toluene (140 mL) to a 500 mL three-necked flask. Transfer to a -1 °C low-temperature reactor, and begin to drop thionyl chloride (5.55 mL, 75.57 mmol) through a constant pressure dropping funnel, maintaining the internal temperature at no more than 3 °C. Transfer to a 45 °C oil bath for reaction, maintain the internal temperature at 43 °C, TLC monitors that the raw material has reacted, stop heating and naturally cool to room temperature. Saturated sodium bicarbonate aqueous solution (120 mL) is slowly added to the system under an ice bath to quench thionyl chloride, and the system pH = 8. Collect the toluene phase, extract the aqueous phase twice with EA (60 mL), combine the organic phases, dry them over anhydrous magnesium sulfate, and rotary evaporate to obtain an orange-yellow oil. 16.88 g of yellow transparent liquid (S, R)-10 and (S, S)-10 mixture were separated by column chromatography, with a yield of 79.5% (based on 09). Step 2: At room temperature of 30 °C, add yellow transparent liquid (S, R)-10 and (S, S)-10 mixture (14.0 g, 45.30 mmol), acetic acid (3.14 mL, 54.36 mmol) and THF (90 mL) to a 250 mL three-necked flask. Transfer to a -1 °C low-temperature reactor and add black granular zinc powder (5.04 g, 77.01 mmol, 1.7 eq) in batches. Transfer to a 65 °C oil bath, maintain the internal temperature at 63 °C, TLC monitors that the raw material has reacted, stop heating and naturally cool to room temperature. Filter to remove solid impurities such as zinc powder, transfer to a 200 mL single-necked bottle, and spin dry THF at 45 °C with a diaphragm pump to obtain a brown oil. Water (80 mL) and 12 mol / L hydrochloric acid (3.8 mL) were added to adjust the system pH to 3, and then the aqueous phase was washed twice with PE (60 mL). White powdered sodium carbonate (7.2 g) was added to the aqueous phase to adjust the system pH to 9. The aqueous phase was extracted twice with EA (70 mL), and the organic phases were combined and washed once with saturated brine (100 mL). Anhydrous magnesium sulfate was added to the organic phase and stirred for 0.5 h, then filtered and rotated to constant weight with a diaphragm pump at 45 °C to obtain 11.50 g of brown transparent liquid 11, with an ee value of 99.95% and a yield of 92.3% (based on the mixture of (S, R)-10 and (S, S)-10). Structural characterization: ESI-MS (m / z): 276.1 [M+H] + ; 1 HNMR (400 MHz, DMSO- d 6 ) δ 7.44 (dt, J = 18.6, 9.2 Hz, 2H), 4.93 – 4.82 (m, 1H), 3.28 – 3.18 (m, 1H), 2.67 (dd, J= 13.4, 5.6 Hz, 1H), 2.61 – 2.53 (m, 1H), 2.32(dd, J = 15.2, 5.2 Hz, 1H), 2.23 (dd, J = 15.2, 7.9 Hz, 1H), 1.55 (s, 2H) 1.17(dd, J = 6.0, 3.7 Hz, 6H).

[0040] Example 6: Preparation of Intermediate 12 At room temperature of 26 °C, add brown transparent liquid 11 (10.0 g, 36.35 mmol) and IPA (15 mL) to a 250 mL three-necked flask, and the system is a yellow transparent solution. Transfer to a -1 °C low-temperature reactor, and begin to drop sodium hydroxide (1.56 g, 38.17 mmol) dissolved in water (30 mL) through a constant pressure dropping funnel, maintaining the internal temperature no higher than 5 °C. Transfer to a 32 °C oil bath for reaction, and TLC monitors that the raw material has reacted completely. At room temperature of 26 °C, add concentrated hydrochloric acid (3.2 mL), the system pH = 6~7, and white solids are obviously precipitated. Add water (15 mL), maintain the system IPA:H2O (1:3), and then transfer to 0 °C and stir for 2 h. Then quickly filter and rinse twice with acetone (10 mL). The filter cake was placed in a hot air circulation drying at 50 °C until constant weight was obtained, and 8.15 g of white powder 12 was obtained, with a yield of 96.2% (based on 11). Structural characterization: Measured mp: 210.1~210.8 °C; ESI-MS (m / z): 234.1 [M+H] + .

[0041] Example 7: Preparation of Sitagliptin (01) At room temperature 24 ℃, add white powder 12 (5.0 g, 21.45 mmol), white granular solid 13 hydrochloride (5.88 g, 25.74 mmol) and THF (25 mL) to a 100 mL three-necked flask. Transfer to a -1 ℃ low-temperature reactor and slowly add white liquid DCC (5.33 g, 25.74 mmol) dissolved in THF (10 mL). Transfer to a 50 ℃ oil bath for reaction, and TLC monitors that the raw material has reacted completely. Stop heating and naturally cool to room temperature, transfer the system to a 200 mL single-necked flask, and spin dry THF with a 45 ℃ diaphragm pump to obtain a white viscous substance. At room temperature, add water (40 mL) and 12 mol / L hydrochloric acid (1.8 mL) to the system and adjust the system pH to 3. Stir at room temperature for 1 h, filter, and rinse three times with 1% hydrochloric acid aqueous solution, and discard the white filter cake (DCU). Add an appropriate amount of sodium carbonate solid to the aqueous phase to adjust the system pH to 8. The aqueous phase was extracted with EA (40 mL) three times, combined, washed with saturated brine and dried with an appropriate amount of anhydrous magnesium sulfate, and then rotary evaporated to obtain a white oil. 7.40 g of white solid 01 was obtained by column chromatography, with a yield of 84.8% (based on 12). Structural characterization: [α] D 20 = -22.3 (c 1.0, CHCl3); measured mp: 116.4~117.9 ℃; ESI-MS (m / z): 408.1256 [M+H] + ; 1 H NMR (600 MHz, CDCl3) δ 7.01 (dd, J = 16.8, 8.9 Hz, 1H), 6.85(dd, J = 16.2, 9.2 Hz, 1H), 5.06 – 4.82 (m, 2H), 4.19 – 3.85 (m, 4H), 3.51 (s,1H), 2.73 (dd, J = 13.6, 5.6 Hz, 1H, 2.61 (dd, J = 13.7, 7.7 Hz, 1H), 2.47 (dd, J = 16.0, 3.3 Hz, 1H), 2.38 (dd, J = 16.0, 8.7 Hz, 1H).

[0042] It should be noted that, although the above embodiments have been described in this article, the patent protection scope of the present invention is not limited thereby. Therefore, the innovative concept of the present invention, the changes and modifications made to the embodiments described herein, or the equivalent structure or equivalent process transformation made by using the contents of the present specification and drawings, and the direct or indirect application of the above technical solutions in other related technical fields are all included in the protection scope of the present invention.

Claims

1. A method for preparing a sitagliptin intermediate, characterized in that: include: S1: The compound represented by formula A-1 is subjected to carbonyl reduction reaction to obtain the compound represented by formula B-1; S2: subjecting the compound represented by formula B-1 to chlorination reaction to obtain the compound represented by formula C-1; S3: The compound represented by formula C-1 is dechlorinated to obtain the sitagliptin intermediate D-1. The reaction equation is as follows: ， Wherein, R is a carboxyl protecting group or H, and R1 is an amino protecting group.

2. A method for preparing a sitagliptin intermediate, characterized in that: include: S1: The compound represented by formula A is subjected to carbonyl reduction reaction to obtain the compound represented by formula B; S2: The compound represented by formula B is subjected to chlorination reaction to obtain the compound represented by formula C; S3: The compound represented by formula C is dechlorinated to obtain the sitagliptin intermediate D. The reaction equation is as follows: , wherein R is a carboxyl protecting group or H.

3. The preparation method according to claim 1 or 2, characterized in that: The carboxyl protecting group is one of C1-C4 alkyl or substituted alkyl, benzyl, diphenylmethyl, p-nitrobenzyl and p-methoxybenzyl.

4. The preparation method according to claim 1 or 2, characterized in that: In step S1, the reducing agent is one of sodium borohydride, potassium borohydride and triethylsilane.

5. The preparation method according to claim 1 or 2, characterized in that: In step S1, the solvent is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, and dichloromethane.

6. The preparation method according to claim 1 or 2, characterized in that: In step S1, the reaction temperature is 0-55°C.

7. The preparation method according to claim 1 or 2, characterized in that: In step S2, the chlorination agent is one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, N-chlorosuccinimide (NCS), dichlorohydantoin, cyanuric chloride (TCT), sulfuryl chloride, trichloroisocyanuric acid (TCCA), and triphosgene, and the amount of the chlorination agent is 0.5~1.5eq.

8. The preparation method according to claim 1 or 2, characterized in that: In step S2, the solvent is one or more of toluene, tetrahydrofuran, ethyl acetate, and dichloromethane, and the amount of the solvent is 4-6 V.

9. The preparation method according to claim 1 or 2, characterized in that: In step S3, the reduction is performed using a reducing agent, and the reducing agent is a metal / acid system.

10. The preparation method according to claim 1 or 2, characterized in that: In step S3, the solvent is one or more of dimethylformamide, dimethylacetamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, 1,4-dioxane, methanol, and n-butanol.

11. The preparation method according to claim 1 or 2, characterized in that: The compound of formula A is prepared by the following method: L-aspartic acid (02) is subjected to cyclization dehydration with phthalic anhydride (03) to obtain intermediate 04. , and the intermediate 04 is selectively methylated under the catalysis of thionyl chloride to obtain the intermediate 05, Intermediate 05 was chlorinated and acylated to give intermediate 07. .

12. The preparation method according to claim 1 or 2, characterized in that: Further preparing sitagliptin comprises the following steps: (i) reacting the compound of formula D obtained in S1 to S3 with an alkaline reagent to obtain intermediate 12, , and (ii) intermediate 12 undergoes condensation reaction with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine or a salt thereof to obtain sitagliptin, i.e. compound 01, .

13. The preparation method according to claim 1 or 2, characterized in that: The steps include: .

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