CN110759914A

CN110759914A - Preparation method of medicine for treating diabetes

Info

Publication number: CN110759914A
Application number: CN201910109121.2A
Authority: CN
Inventors: 林岱宗; 贾世哲; 柏煦; 王进基
Original assignee: Meihua Dongjin International Biomedical Research Institute Co ltd
Current assignee: Shenyang Meihua Dongjin Biopharmaceutical Co ltd
Priority date: 2019-02-03
Filing date: 2019-02-03
Publication date: 2020-02-07

Abstract

A process for preparing the medicine to treat diabetes features that the chiral reduction and amino protection are combined into one-step reaction. The method combines the steps of chiral reduction and amino protection into one-step reaction, not only well solves a large number of problems in the prior art, but also uses the chiral ligand which is cheap and easy to obtain, and has simple and convenient operation and high yield.

Description

Preparation method of medicine for treating diabetes

Background

The invention provides a preparation method of a medicine for treating diabetes, belonging to the field of medicine preparation.

Diabetes mellitus

Diabetes Mellitus (DM) is a syndrome with chronic hyperglycemia and glucose tolerance as main characteristics and combined with disturbance of fat and protein metabolism caused by insufficient insulin or impaired action in vivo, along with the prolongation of the diabetic course, patients are prone to complication of chronic progressive diseases of heart, brain, kidney, retina and nervous system, the World Health Organization (WHO) classifies Diabetes Mellitus into type I Diabetes Mellitus (T1DM), type II Diabetes Mellitus (T2DM), gestational Diabetes Mellitus and special type 4 Diabetes Mellitus in 1999, wherein the type I Diabetes Mellitus is an autoimmune system disease and shows impaired insulin secretion function of insulin β cells, and absolute deficiency of insulin in vivo, the type II Diabetes Mellitus is also called non-insulin dependent Diabetes Mellitus and is caused by insulin resistance of tissue cells, functional decline of insulin β cells and other various reasons.

Worldwide, 4.22 million adults were estimated to have diabetes in 2014, in contrast to 1.08 million people in 1980. Global diabetes (age-normalized) prevalence has increased nearly doubled since 1980, rising from 4.7% to 8.5% in adults. The rate of increase in the prevalence of diabetes in low-income and medium-income countries has outpaced high-income countries over the last decade. Diabetes in 2012 directly caused the death of 150 million people. While overproof blood glucose caused another 220 million deaths by increasing the risk of cardiovascular and other diseases. 43% of these 370 ten thousand deaths occur before the age of 70. The percentage of hyperglycemia or diabetes deaths occurring before the age of 70 in low-and medium-income countries is higher than in high-income countries. It is predicted that diabetes will become the seventh leading cause of death worldwide by 2030.

The basic treatment measures for diabetes today include diet control, exercise and drug therapy, and are dominated by drug therapy, wherein type I diabetes is mainly treated by injection of insulin or its analogues, while type II diabetes patients do not need to rely on insulin and can use oral hypoglycemic drugs to control blood glucose.

1.2 dipeptidyl peptidase IV (DPP-4) inhibitors

Two major insulinotropic hormones are glucagon-like peptide (GLP-1) and glucose-dependent insulin-releasing peptide (GIP). when fed, the gastrointestinal tract is stimulated to secrete incretins which act with specific GPCRs on the surface of β cells to induce secretion of insulin in the pancreas, GLP-1 inhibits glucagon secretion, reduces appetite and slows gastric emptying, and may exert its effect on β cell proliferation and differentiation and normal function of β cells.GLP-17-36, which is rapidly degraded to GLP-19-36 by a serine protease, while GLP-19-36 cannot promote insulin secretion.DPP-4 can also be cleaved by other DPP, DPP-Y, DPP-2, or DPP-Y2.

Currently marketed DPP-4 inhibitors are Sitagliptin (the first marketed oral DPP-4 inhibitor), Vildagliptin (Vildagliptin), Saxagliptin (Saxagliptin), Alogliptin (Alogliptin), Linagliptin (Linagliptin), terliptin (Teneligliliptin), Omarigliptin (Omargigliptin), and the structural formula is shown in FIG. 6.

1.3 discovery of sitagliptin

Sitagliptin (Sitagliptin) is the first oral DPP-4 inhibitor to be marketed, developed by us majorit, us FDA approval for Sitagliptin alone or in combination with metformin, thiazolidinediones, for improving glycemic control in type II diabetic patients was obtained in 2006 month 10, FDA approval for Sitagliptin in combination with metformin for initial treatment of diabetes and as an additional therapy for failure of sulfonylureas or sulfonylurea + metformin to control blood glucose, in 2010 month 2, FDA approval for Sitagliptin as an additional agent for hyperlipidemia, in 2011 month 5, in japan approval for Sitagliptin in combination with α -glucosidase inhibitor, in 2011 month 9, in japan approval for Sitagliptin combination with insulin, in 2011 month 10, in 2011 month FDA-Sitagliptin + simvastatin compound formulation for patients with both diabetes and simvastatin, in 3 in year 3, in japan approval for severe renal insufficiency type II diabetes treatment, in 2014 month 5, in combination with other drugs for oral therapy of Sitagliptin type II.

The sale amount of sitagliptin is successfully broken billion (6.68 billion dollars in sale amount in 2007), the sale amount successfully breaks through 10 billion dollars in the third year of sale (nearly 14 billion dollars in sale amount in 2008), and the annual sale amount of sitagliptin is over 40 billion dollars after the sale amount breaks through 40 billion dollars in 2012, so that the sale amount is relatively stable. According to the Thomson Louvre, the 2021 year sales of sitagliptin will break through $ 50 billion and later decline.

1. Existing synthetic route and process

In the early days, researchers in Mushadong reacted benzyl bromide SM-2 with SM-1 to obtain an intermediate M-1, which was protected with Boc and hydrolyzed to obtain M-2. The intermediate M-2 is subjected to an Arndt-Eistert reaction to obtain a homolog M-3, then the homolog M-3 is reacted with SM-3 to generate amide, and salt formation is performed to obtain Sitagliptin (Sitagliptin), as shown in FIG. 7.

The starting material SM-3 is obtained by reacting hydrazine hydrate with 2-chloropyrazine to obtain M-4. M-4 and trifluoroacetic anhydride form M-5, and M-6 is obtained under the action of polyphosphoric acid. Hydrogenation of M-6 provided starting material SM-3, as shown in FIG. 8.

In the above synthetic route, the only chiral center in the Sitagliptin (Sitagliptin) structure is introduced by chiral prosthetic group control, in the subsequent synthesis, the use of protecting groups is involved, the operation steps are added, from the viewpoint of green chemistry and atom economy, in the subsequent process development, the researchers of Merck tried asymmetric catalytic hydrogenation to introduce chirality β -keto ester 31 obtained by conversion of acid 30 under Masamune conditions, asymmetric hydrogenation of β -keto ester 31 was carried out with modified (S) -binaphthylphenyl-phosphate catalyst, hydrolysis of the obtained chiral ester to obtain acid 32 with excellent yield, and ee value of 94%, coupling of acid 32 and o-benzylhydroxylamine under EDC as catalyst to obtain hydroxamic acid 33. hydroxamic acid 33 obtained by mitsunobu reaction ring closure of β -lactam 34, recrystallization from methanol to obtain 34% yield (from compound 32), while improving optical purity, ee value up to 99, hydrolysis of β -lactam 34 with triazole, coupling of Sitagliptin, and salt formation of Sitagliptin (Sitagliptin), and recrystallization of Sitagliptin (fig. 9).

The total yield of Sitagliptin (Sitagliptin) synthesized from acid 30 was 45%. The route is rather long, but the yield per step is relatively high, and Merck made about 100kg of API with this route for early safety evaluation and clinical trials. However, from a green chemistry perspective, there are several disadvantages:

the use of high molecular weight reagents to convert hydroxyl groups to amino groups is a cumbersome route;

masamune requires very high dilution rate, which reaches 30L/kg, and limits the production capacity of the process;

the two-step coupling reaction uses a reagent EDC with low atom economy;

the Mitsunobu reaction produces a large amount of by-products and has low atomic availability.

In view of the above drawbacks, the Merck company decided to develop a new process route by introducing Meldrum's acid on the substrate acid 30 to give

adducts

37, 37 which can be reacted with triazole without purification to give β -ketoamide 38.38 or without purification, by adding a methanolic solution of ammonium acetate to convert to enamine 39. the overall yield from acid 30 to enamine 39 is 84%.

After many screening attempts, Merck researchers have found that enamines 39 can undergo asymmetric hydrogenation by [ Rh (COD) Cl ]2 and t-BuJosiphos. In this transformation, very good ee values can be achieved without the use of protecting groups. After the reaction is finished, 90-95% of rhodium is recovered by Ecosorb C-941 adsorbent and salified to obtain Sitagliptin (Sitagliptin), and the figure 10 shows.

A novel asymmetric hydrogenation technology is introduced into a Sitagliptin (Sitagliptin) production process, so that the industrial waste is reduced by 80%, and the cost is reduced by 70%. Likewise, only 44 kg of industrial waste is generated when 1 kg of sitagliptin raw material drug is produced, and the industrial waste water is reduced to 0! Every 1000 kg of sitagliptin raw material medicine is produced, 220000 kg of industrial garbage is generated for the earth. For this reason, the chemical processing team of the Merck company sitagliptin honors the "Presidental Green Chemistry Challenge reward (manufactured)" in 2006.

Although the asymmetric hydrogenation route can reduce the waste generated in the production, there is also a significant environmental disadvantage. Rhodium is a very rare metal and is present in the earth's crust only in an amount of 4. mu.g/kg. Due to this scarcity, the market price of rhodium fluctuates considerably: from early 2006 to 7 months 2008 (before global economic decline), the price of rhodium rose from $ 3000 per ounce to $ 10000 per ounce. The nonrenewability of rhodium leads to a yearly increase in the production cost of Sitagliptin (Sitagliptin).

Disclosure of Invention

The purpose of the invention is as follows:

the invention provides a preparation method of a medicine for treating diabetes, and aims to solve the problems in the prior art.

The technical scheme is as follows:

a preparation method of a medicine for treating diabetes is characterized by comprising the following steps: the method combines the steps of chiral reduction and amino protection into one-step reaction.

The step of combining the chiral reduction and the amino protection into one step is as follows:

hydrogenation:

adding trifluoroethanol into a reaction kettle, and sequentially adding 3-amino-4- (2,4, 5-trifluorophenyl) -2-methyl crotonate, a (cyclooctyl-1, 5-diene) ruthenium dichloride polymer, (R) - (+) - (1,1 '-binaphthyl-2, 2' -diyl) bis (diphenylphosphine) and di-tert-butyl carbonate into the reaction kettle; replacing with nitrogen, stirring at room temperature, replacing the atmosphere in the kettle with hydrogen, pressurizing, heating at the internal temperature, reacting for a while, stopping the reaction, detecting by TLC (DCM, product Rf is 0.6), passing through a kieselguhr funnel, rotatably evaporating the filtrate to dryness, dissolving the obtained residue in methanol, adding water, precipitating a large amount of white solid, and standing; performing suction filtration, wherein a filter cake is gray solid, and a crude product, namely (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

and (3) recrystallization:

dissolving crude (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate in methanol to prepare a methanol solution, heating to a specified temperature, preserving the temperature until the solid is completely dissolved, dropwise adding water, adding seed crystals, naturally cooling to room temperature, and standing; the mixture is filtered, and a filter cake is washed to obtain white needle-shaped solid (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate.

To obtain white needle-shaped solid (R) -methyl 3-amino-4- (2,4, 5-trifluorophenyl) butyrate: optical purity>99.8 percent. ee value>99.8％，¹H NMR(300MHz,CDCl₃)δ7.07-7.03(m,1H),6.94-6.85(m,1H),5.12(d,J＝9.0Hz,1H), 4.15-4.12(m,1H),3.71(s,3H),2.85(d,J＝9.0Hz,2H),2.58-2.54(m,2H),1.38(s,9H).

in the hydrogenation step:

trifluoroethanol: 120-200 mL, reaction vessel volume: 500mL, methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate: 10g,0.04mol, ruthenium (cyclooctyl-1, 5-diene) dichloride polymer: 101 to 124mg, 0.009 to 0.011 equivalents, (R) - (+) - (1,1 '-binaphthyl-2, 2' -diyl) bis (diphenylphosphine) 225 to 274mg,0.009 to 0.011 equivalents, di-tert-butyl carbonate: 9.0 to 10.9g,0.9 to 1.1 equivalent; replacing with nitrogen for 2-3 times; stirring for 15-45 min at room temperature; replacing the atmosphere in the kettle with hydrogen for 3-5 times; pressurizing to 0.4-1.2 MPa; the internal temperature rises to 50-90 ℃; reacting for 8-24 hours; dissolving the obtained residue in 100-150 mL of methanol, adding 240-400 mL of water, precipitating a large amount of white solid, and standing for 4-8 h; performing suction filtration, wherein a filter cake is gray solid, and a crude product, namely (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

in the recrystallization step:

dissolving 10-15 g of crude (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate in methanol to prepare a methanol solution with the concentration of 0.2-0.5 g/mL, heating to 50-60 ℃, preserving the temperature until the solid is completely dissolved, dropwise adding 15-30 mL of water, adding seed crystals, naturally cooling to room temperature, and standing for 10-20 hours; the mixture is filtered, and the filter cake is washed with 20-40 mL (methanol/water: 1/1-1/1.5) to obtain white needle-shaped solid methyl (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyrate.

The method comprises the following steps:

the first step is as follows:

adding analytically pure acetonitrile into a three-neck bottle, connecting with a mechanical stirrer, starting the stirrer to a certain degreeSequentially reacting 2,4, 5-trifluorophenylacetic acid, Meldrum's acid, DMAP (A), (B), (C)4-dimethylaminopyridineEnglish name: 4-dimethylaminopyrdine; DMAP) is added into a reaction bottle through a charging hole, and the system is white turbid liquid;

DIPEA (N, N-Diisopropylethylamine) Dripping into the system through a constant-pressure dropping funnel, wherein the system is a yellow transparent solution after the dripping is finished;

diluting pivaloyl chloride with acetonitrile, slowly dripping into the system through a constant-pressure dropping funnel, after dripping, moving the system into an oil bath for heating, wherein the system is brownish yellow and reacts for a certain time;

cooling the system, dropping 1N HCl into the system through a constant-pressure dropping funnel, keeping the temperature of the system, separating out a large amount of white solids in the dropping process after the dropping is finished, filtering, washing a filter cake to be white by using acetonitrile/water mixed liquor, and drying in vacuum to obtain a product 5- (1-hydroxy-2- (2,4, 5-trifluorophenyl) ethylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone;

¹H NMR(300MHz,CDCl₃)δ7.19-7.10(m,1H),7.00-6.91(m,1H),4.44(s,2H),1.76(s,6H).

the second step is that:

adding analytically pure methanol into a three-neck flask, and adding a compound 5- (1-hydroxy-2- (2,4, 5-trifluorophenyl) ethylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone into the reaction flask from a feeding port to obtain a turbid liquid; heating in oil bath until the system refluxes; the system gradually changes from a turbid state to a yellow transparent liquid;

the reaction is evaporated to dryness by rotation and the residue is taken up in MTBE: (Methyl tert-butyl ether) Dissolving, washing organic phase with 1N HCl, and NaHCO₃Washing with water solution, collecting organic phase, drying with anhydrous sodium sulfate, filtering, and spin drying; obtaining a crude product, adding isopropanol, heating to a temperature not higher than 35 ℃ to completely dissolve the crude product, dripping water into the system, stirring for 12-20 hours, separating out solids, filtering, and washing a filter cake with water to obtain a product, namely methyl 3-oxo-4- (2,4, 5-trifluorophenyl) butyrate;

¹H NMR(300MHz,DMSO-d6)δ7.57-7.46(m,1H),7.45-7.35(m,1H),3.96(s,br,2H),3.75(s, 2H),3.64(s,3H)

the third step:

placing 3-oxo-4- (2,4, 5-trifluorophenyl) methyl butyrate into a round-bottom flask, adding methanol, stirring at room temperature until all solids are dissolved, adding ammonium acetate, heating the system to reflux, dissolving all solids, and clarifying the system; cooling to room temperature, rotating the reaction system to evaporate to dryness to obtain a white solid, adding ethyl acetate into the white solid, fully stirring, filtering, and leaching a filter cake with ethyl acetate; heating the filtrate, adding petroleum ether, cooling to room temperature, adding petroleum ether, stirring and standing; filtering the system to obtain a filter cake which is a white solid and is methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate;

¹H NMR(300MHz,CDCl₃)δ6.97-6.95(m,1H),6.94-6.93(m,1H),4.56(s,1H),3.65(s,3H), 3.41(s,2H).

the fourth step:

hydrogenation:

adding trifluoroethanol into a reaction kettle, and sequentially adding 3-amino-4- (2,4, 5-trifluorophenyl) -2-methyl crotonate, a (cyclooctyl-1, 5-diene) ruthenium dichloride polymer, (R) - (+) - (1,1 '-binaphthyl-2, 2' -diyl) bis (diphenylphosphine) and di-tert-butyl carbonate into the reaction kettle; replacing with nitrogen, stirring at room temperature, replacing the atmosphere in the kettle with hydrogen, pressurizing a, heating the inner temperature, stopping the reaction, detecting by TLC (DCM, product Rf is 0.6), passing through a kieselguhr funnel, rotatably evaporating the filtrate to dryness, dissolving the obtained residue in methanol, adding water, precipitating a large amount of white solid, and standing; performing suction filtration, wherein a filter cake is gray solid, and a crude product, namely (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

and (3) recrystallization:

dissolving crude (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate in methanol to prepare a methanol solution, heating to a certain temperature, keeping the temperature until the solid is completely dissolved, dropwise adding water, adding seed crystals, naturally cooling to room temperature, and standing; filtering the mixture, and washing a filter cake to obtain white needle-shaped solid (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

the fifth step:

adding a mixed solution of tetrahydrofuran and water into a single-mouth bottle, adding (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate into the mixed solution, and then adding lithium hydroxide monohydrate, wherein the reaction solution is white turbid; stirring, changing the reaction solution into a clear solution, monitoring by TLC, stopping the reaction, adding a saturated sodium bicarbonate aqueous solution into the system, spinning to dry tetrahydrofuran, adjusting the system by using a potassium bisulfate aqueous solution, separating out a white solid, and filtering to obtain a white solid (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid;

and a sixth step:

adding acetonitrile into a three-necked bottle, starting stirring, and adding (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid and 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride to finish; cooling, and adding N-methylmorpholine and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in sequence when the temperature in the reactor is reduced; after the addition, controlling the temperature of a reaction system at a certain temperature, and determining that the reaction raw material (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid is completely consumed, and finishing the reaction; adding purified water and methyl tert-butyl ether into the reaction system, and stirring; standing and separating, and stirring and washing an organic phase with a potassium bicarbonate solution and a NaCl solution; separating liquid and discarding the water phase; drying the organic phase, filtering and spin-drying the organic phase, and directly using the organic phase in the next step;

the seventh step:

adding HCl/EtOH solution into the crude product in the previous step, and starting stirring; clarifying the reaction solution, stirring for reaction, and after the reaction is completed, spin-drying the solvent; adding the oily matter into a reaction bottle, adding purified water into the reaction bottle under stirring, and adjusting the pH value by using a NaOH solution; adding isopropyl acetate, extracting, stirring, standing and layering; separating liquid, discharging water phase, adding isopropyl acetate into the water phase, extracting, standing, layering, and collecting organic phase; combining the organic phases extracted twice, extracting and washing with purified water, standing, and separating liquid; discarding the aqueous phase, drying the organic phase, filtering and spin-drying; pulping the oily substance with methyl tert-butyl ether, and stirring; filtering and filtering to dryness; washing the filter cake with methyl tert-butyl ether, and filtering to dryness; collecting the filter cake to obtain sitagliptin;

eighth step:

adding isopropanol and purified water into a three-mouth bottle, adding sitagliptin under stirring, heating the system, and clarifying the mixture; filtering out the solid, heating the filtrate, and slowly adding phosphoric acid; when the internal temperature is a certain temperature, a large amount of white solid is separated out, the internal temperature is raised, and the reaction liquid is clarified; slowly cooling, cooling the temperature in the system, controlling the temperature, stirring and reacting to naturally cool the reaction system to room temperature;

from the room temperature, performing timed crystallization, adding isopropanol, pulping and stirring; and (3) carrying out suction filtration, leaching the filter cake with isopropanol, carrying out suction drying, collecting the filter cake, placing the filter cake in a hot air circulation oven, and drying at room temperature to obtain solid sitagliptin phosphate monohydrate.

The method comprises the following steps:

the first step is as follows:

adding 500-600 mL of analytically pure acetonitrile (> 99%) into a 5L three-necked bottle, connecting mechanical stirring, starting stirring, and sequentially adding 2,4, 5-trifluorophenylacetic acid: 180g,1 equivalent, Meldrum's acid: 122.8-150.1 g, 0.9-1.1 equivalent), DMAP: 5.78g to 11.6g,0.05 equivalent to 0.1 equivalent, and adding the mixture into a reaction bottle through a feed inlet to obtain a white turbid liquid;

mixing DIPEA: 219.9g to 244.7g,1.8 to 2.0 equivalent weight, and dripping into the white turbid liquid system through a constant pressure dropping funnel, wherein the system is a yellow transparent solution after dripping for 20 to 40 minutes, and the internal temperature is 35 to 40 ℃;

reacting pivaloyl chloride: 102.7-125.6 g, 0.9-1.1 equivalent weight, acetonitrile: diluting by 50-100 mL, slowly dropping the yellow transparent solution system through a constant-pressure dropping funnel, and after dropping is finished within 45-75 minutes, keeping the internal temperature at 0-45 ℃; moving the system to an oil bath for heating, keeping the internal temperature at 30-45 ℃, and reacting for 1-2 hours, wherein the system is changed into brown yellow;

cooling the brown-yellow system to 0-5 ℃, and adding 1N HCl: 1.8 ~ 2.2L drop into this system, keep this system temperature to be 0 ~ 5 ℃,1 ~ 2 hours of dropwise add finishes, and it has a large amount of white solids to precipitate to drop into the in-process, filters this white solid, obtains the filter cake, and the filter cake is with the mixed solution of acetonitrile/water 1/4 (volume ratio): washing the mixture by 3-3.3L to white, and drying the mixture in vacuum at 40-50 ℃ to obtain a product 5- (1-hydroxy-2- (2,4, 5-trifluorophenyl) ethylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone;

¹H NMR(300MHz,CDCl₃)δ7.19-7.10(m,1H),7.00-6.91(m,1H),4.44(s,2H),1.76(s,6H).

the second step is that:

adding 1.0-1.2L of analytically pure methanol into a 2L three-necked bottle, and adding 245g,0.77mol and 1.0 equivalent of the compound 5- (1-hydroxy-2- (2,4, 5-trifluorophenyl) ethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone in the first step into the reaction bottle through a feeding port to obtain a turbid liquid; heating in an oil bath at the oil temperature of 80-90 ℃ until the system flows back; the system gradually changes from a turbid state to a yellow transparent liquid;

rotating and evaporating the yellow transparent liquid reaction system to dryness, adding 400-500 mL of MTBE into the residue until the residue is completely dissolved, washing the dissolved organic phase with 1N HCl for 250-300 mL/time, washing for 3 times, and then using NaHCO with the mass concentration of 5-7%₃Washing with the aqueous solution for 250-300 mL/time and 3 times, collecting an organic phase, drying with anhydrous sodium sulfate, filtering, and spin-drying; obtaining a crude product, adding 600-700 mL of isopropanol, heating to a temperature not higher than 35 ℃ to completely dissolve the isopropanol, dripping 1.2-1.4L of water into the completely dissolved system at a temperature of 20-35 ℃, stirring for 16 hours, separating out solids, filtering to obtain a filter cake, and washing the filter cake with 200-250 mL of water to obtain a product of methyl 3-oxo-4- (2,4, 5-trifluorophenyl) butyrate;

the third step:

placing 10g,0.041mol and 1 equivalent of methyl 3-oxo-4- (2,4, 5-trifluorophenyl) butyrate in the second step into a round-bottom flask, adding the round-bottom flask into 100-150 mL of methanol, stirring at room temperature until all solids are dissolved, adding 12.5-15.6 g and 4-5 equivalents of an ammonium acetate ready-made system, heating the system to reflux, and dissolving all solids to clarify the system; cooling to room temperature (15-25 deg.C), and rotary evaporating the reaction system to obtain white solid. Adding 10-15 mL of ethyl acetate into the white solid, fully stirring, filtering, and leaching a filter cake with 5-10 mL of ethyl acetate; mixing all filtrates, heating to 50 ℃, adding 40-60 mL of petroleum ether with a boiling range of 60-90 ℃, cooling to room temperature, adding 100-120 mL of petroleum ether, stirring and standing for 3-5 h; filtering the system after stirring the petroleum ether to obtain a filter cake which is white solid and 3-amino-4- (2,4, 5-trifluorophenyl) -2-methyl crotonate;

the fourth step:

hydrogenation:

adding 120-200 mL of trifluoroethanol into a 500mL reaction kettle, and sequentially adding 10g of methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate, 0.04mol of methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate, 101-124 mg of (cyclooctyl-1, 5-diene) ruthenium dichloride polymer, 0.009-0.011 equivalent of (R) - (+) - (1,1 '-binaphthyl-2, 2' -diyl) bis (diphenylphosphine), 225-274 mg of 0.009-0.011 equivalent of (diphenyl-phosphine), 9.0-10.9 g of di-tert-butyl carbonate and 0.9-1.1 equivalent of (di-tert-butyl carbonate) into the reaction kettle; replacing 2-3 times with 99.5% nitrogen (the oxygen content is less than or equal to 0.5%), stirring at room temperature for 15-45 min, replacing the atmosphere in a kettle with hydrogen for 3-5 times, pressurizing to 0.4-1.2 MPa, raising the internal temperature to 50-90 ℃, stopping the reaction after reacting for 8-24 hours, detecting by TLC (DCM, the product Rf is 0.6), passing through a kieselguhr funnel, rotatably evaporating the filtrate to dryness, dissolving the obtained residue in 100-150 mL of methanol, adding 240-400 mL of water, precipitating a large amount of white solid, and standing for 4-8 hours; performing suction filtration, wherein a filter cake is gray solid, and a crude product, namely (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

and (3) recrystallization:

dissolving 10-15 g of crude (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate in the hydrogenation step into methanol to prepare a methanol solution with the concentration of 0.2-0.5 g/mL, heating to 50-60 ℃, preserving the temperature until the solid is completely dissolved, dropwise adding 15-30 mL of water, adding 50-100mg of seed crystal, naturally cooling to room temperature, and standing for 10-20 hours; filtering the mixture to obtain a filter cake, and washing the filter cake with 20-40 mL of a solution of methanol/water (1/1-1/1.5) to obtain a white acicular solid (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

ee value > 99.8%

¹H NMR(300MHz,CDCl₃)δ7.07-7.03(m,1H),6.94-6.85(m,1H),5.12(d,J＝9.0Hz,1H), 4.15-4.12(m,1H),3.71(s,3H),2.85(d,J＝9.0Hz,2H),2.58-2.54(m,2H),1.38(s,9H).

The fifth step:

adding a mixed solution of 3-5mL of tetrahydrofuran and 3-5mL of water into a 25mL single-neck bottle, adding 200mg and 0.58mmol of (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate obtained in the fourth step into the mixed solution, and then adding 24-120 mg and 1.0-5.0 equivalents of lithium hydroxide monohydrate, wherein the reaction liquid is white turbid; stirring the mixture at 15-30 ℃ for 1-20 hours until the reaction solution becomes a clear solution, stopping the reaction by TLC (monitoring that the PE: EA is 5:1 and the raw material (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate is completely converted), adding 2-5 mL of saturated sodium bicarbonate aqueous solution into the system after the reaction is stopped, carrying out rotary drying on tetrahydrofuran at 35-40 ℃, adjusting the pH of the system to be 2-3 by 10-30 mg/L of potassium bisulfate aqueous solution to precipitate a white solid, and filtering to obtain white solid (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid;

¹H NMR(300MHz,CDCl₃)δ7.10-7.01(m,1H),6.92-6.88(m,1H),5.06(s,br,1H),4.13(s,br, 1H),2.87(d,J＝9.0Hz,2H),2.62-2.60(m,2H),1.38(s,9H).

and a sixth step:

adding 30-50 mL of acetonitrile into a three-necked bottle, starting stirring, and adding 15g and 1eq of (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid and 10.1-12.3 g and 1.0-1.2 eq of 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride in the fifth step, and finishing; cooling, and sequentially adding 4.2-5.0 g and 0.9-1.1 eq of N-methylmorpholine and 8.6-17.2 g and 1.0-2.0 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride when the internal temperature is reduced to 0-5 ℃; after the addition, controlling the temperature of a reaction system at 0-10 ℃, and determining that the reaction raw material (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid is completely consumed, and finishing the reaction; adding 70-100 mL of purified water and 150-200 mL of methyl tert-butyl ether into the reaction system, and stirring for 20-40 minutes; standing and separating, and stirring and washing 70-100 mL of 10-15% potassium bicarbonate solution and 70-100 mL of 10-20% NaCl solution in an organic phase; separating liquid and discarding the water phase; drying the organic phase, filtering and spin-drying to obtain a crude product which is directly used in the next step;

the seventh step:

adding 100-200 g of 2-4 mol/L HCl/EtOH solution into the crude product in the previous step, and starting stirring; the reaction temperature is 25-30 ℃, the reaction solution is clarified, stirred and reacted, after the reaction is completed, the solvent is dried in a spinning mode to obtain oily matter, the oily matter is added into a reaction bottle, 100-200 mL of purified water is added into the reaction bottle under stirring, and the pH value is adjusted to 10-12 by using 2-3 mol/L NaOH solution; adding 200-400 mL of isopropyl acetate, extracting and stirring for 10-20 minutes, and standing and layering for 10-15 minutes; separating liquid, discharging a water phase to obtain an organic phase, adding 200-400 mL of isopropyl acetate into the discharged water phase, extracting, standing, layering, and collecting the organic phase; combining the organic phases extracted twice, extracting and washing for 15-20 minutes by using 100-200 mL of purified water, standing for 10-20 minutes, and separating liquid; discarding the water phase to obtain an organic phase, drying the organic phase, and filtering and spin-drying; obtaining oily matter, pulping and stirring the oily matter for 8-12 hours by using 100-200 mL of methyl tert-butyl ether; filtering and filtering to dryness; washing a filter cake with 20-40 mL of methyl tert-butyl ether, and performing suction filtration until the filter cake is dry; collecting the filter cake to obtain sitagliptin; (in the case of the organic phase of the two extractions: the first is the organic phase obtained after the aqueous phase was discharged, and the second is the organic phase obtained after the extraction and the standing for the separation in this case)

¹H NMR(300MHz,D₂O)δ7.27-7.17(m,1H),7.13-7.02(m,1H),5.04(s,1H),4.94(d,J＝3.9 Hz,1H),4.36-4.25(m,2H),4.07-4.04(m,2H),3.55-3.50(m,1H),2.80-2.60(m,4H).

Eighth step:

adding 30-50 mL of isopropanol and 5-10 mL of purified water into a three-neck flask, adding 14g of sitagliptin in the seventh step under stirring, and clarifying a mixture when the temperature of a system is raised to 39-41 ℃; filtering out solids, heating the filtrate to 78-80 ℃, and slowly adding 1-1.1 equivalent of analytically pure phosphoric acid; when the internal temperature is 51-53 ℃, a large amount of white solid is separated out, and when the internal temperature is increased to 75-80 ℃, the reaction liquid is clarified; slowly cooling, cooling the temperature in the system from 75 ℃ to 66-68 ℃ within 1-2 hours, controlling the temperature at 66-68 ℃, stirring and reacting for 2-3 hours, and naturally cooling the reaction system to room temperature;

from the room temperature, performing timed crystallization for 10-12 hours, adding 50-80 mL of isopropanol, pulping and stirring for 1-3 hours; and (3) carrying out suction filtration to obtain a filter cake, leaching the filter cake with 20-40 mL of isopropanol, carrying out suction drying, collecting the filter cake, placing the filter cake in a hot air circulation oven, drying at room temperature for 1-2 hours, and drying at 40-45 ℃ for 3-5 hours to obtain the final solid sitagliptin phosphate monohydrate.

¹H NMR(300MHz,D₂O)δ7.33-7.25(m,1H),7.20-7.12(m,1H),4.99-4.95(m,2H),4.36-4.27 (m,2H),4.07-3.97(m,3H),3.12-2.92(m,4H).

In the first step, after the DIPEA is dripped, the temperature is obviously increased in the dripping process, the internal temperature of the system is controlled to be lower than 40 ℃, the system is yellow transparent solution, and the internal temperature is 36 ℃.

In the first step, after the t-BuCOCl is dripped, the temperature is obviously increased in the dripping process, the internal temperature is controlled to be lower than 50 ℃ and is 44 ℃; the system is moved to an oil bath for heating, the internal temperature is kept at 45 ℃, the system is changed into brown yellow, and the reaction lasts for 2 hours.

The solvent used was: the methanol, ethanol, isopropanol, acetonitrile, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, tetrahydrofuran and trifluoroethanol are analytically pure, and the purity is more than 99 percent; the petroleum ether is analytically pure boiling range of 60-90 ℃; the purity of the reagent used is greater than 95%.

The advantages and effects are as follows: the invention provides a preparation method of a medicine for treating diabetes, which combines the steps of chiral reduction and amino protection into one-step reaction, not only well solves a large number of problems in the past, but also uses a chiral ligand which is cheap and easy to obtain, is simple and convenient to operate and has high yield.

The method has the advantages that: the chiral ligand is cheap and easy to obtain, and the cost is low.

The method has the advantages that: the amino protection is directly carried out in an asymmetric catalytic hydrogenation system, thereby reducing the occurrence of side reactions, improving the reaction yield and being beneficial to the purification of products.

The advantages are that: the two-step reaction is combined into one step, and the operation is simple and convenient.

Drawings

FIG. 1 shows HPLC purity > 99% in the chemical analysis results of the final product sitagliptin phosphate monohydrate;

FIG. 2 is optical purity chiral HPLC;

FIG. 3 is also an optical purity chiral HPLC; in fig. 2 and 3, optical purity chiral HPLC > 99.5%;

FIG. 4 is a HNMR map;

FIG. 5 is a mass spectrometry profile;

FIG. 6 is a drawing of the background art;

FIG. 7 is a drawing of the background art;

FIG. 8 is a background art drawing;

FIG. 9 is a background art drawing;

FIG. 10 is a background art drawing;

FIG. 11 is a diagram of commercial production of Sitagliptin (Sitagliptin) using a transaminase route instead of an asymmetric hydrogenation route;

FIG. 12 is a synthetic route diagram for sitagliptin according to the present invention;

FIG. 13 is a schematic diagram of the first synthesis step in the process;

FIG. 14 is a schematic diagram of the second synthesis step in the process;

FIG. 15 is a schematic diagram of the third synthesis step;

FIG. 16 is a schematic diagram of the fourth synthesis step;

FIG. 17 is a schematic diagram of the fifth synthesis step;

FIG. 18 is a schematic diagram of the sixth synthesis step;

FIG. 19 is a schematic diagram of the seventh synthesis step;

FIG. 20 is a schematic diagram of the eighth synthesis step.

Detailed Description

hydrogenation:

and (3) recrystallization:

To obtain white needle-shaped solid (R) -methyl 3-amino-4- (2,4, 5-trifluorophenyl) butyrate: ee value>99.8％，¹HNMR(300 MHz,CDCl₃)δ7.07-7.03(m,1H),6.94-6.85(m,1H),5.12(d,J＝9.0Hz,1H),4.15-4.12(m,1H), 3.71(s,3H),2.85(d,J＝9.0Hz,2H),2.58-2.54(m,2H),1.38(s,9H).

in the hydrogenation step:

in the recrystallization step:

In summary, the method comprises the following specific steps:

the first step is as follows:

cooling the brown-yellow system to 0-5 ℃, and adding 1N HCl: 1.8 ~ 2.2L instils into this system, keeps this system temperature to be 0 ~ 5 ℃,1 ~ 2 hours of dropwise add finishes, instils into the in-process and has a large amount of white solids to separate out, filters this white solid, obtains the filter cake, and the filter cake is with 20% acetonitrile/water mixed liquid: washing the mixture by 3-3.3L to white, and drying the mixture in vacuum at 40-50 ℃ to obtain a product 5- (1-hydroxy-2- (2,4, 5-trifluorophenyl) ethylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone;

¹H NMR(300MHz,CDCl₃)δ7.19-7.10(m,1H),7.00-6.91(m,1H),4.44(s,2H),1.76(s,6H).

the second step is that:

rotating the yellow transparent liquid reaction system to evaporate to dryness, adding 400-500 mL of MTBE into the residue to dissolve, washing the dissolved organic phase with 1N HCl for 250-300 mL/time, washing for 3 times, and then using 5-7% NaHCO₃Washing with the aqueous solution for 250-300 mL/time and 3 times, collecting an organic phase, drying with anhydrous sodium sulfate, filtering, and spin-drying; obtaining a crude product, adding 600-700 mL of isopropanol, heating to a temperature not higher than 35 ℃ to completely dissolve the isopropanol, dripping 1.2-1.4L of water into the completely dissolved system at a temperature of 20-35 ℃, stirring overnight, separating out solids, filtering to obtain a filter cake, and washing the filter cake with 200-250 mL of water to obtain a product of methyl 3-oxo-4- (2,4, 5-trifluorophenyl) butyrate;

the third step:

placing 10g,0.041mol and 1 equivalent of methyl 3-oxo-4- (2,4, 5-trifluorophenyl) butyrate in the second step into a round-bottom flask, adding the round-bottom flask into 100-150 mL of methanol, stirring at room temperature until all solids are dissolved, adding 12.5-15.6 g and 4-5 equivalents of an ammonium acetate ready-made system, heating the system to reflux, and dissolving all solids to clarify the system; cooling to room temperature (15-25 ℃), carrying out rotary evaporation to dryness on the reaction system cooled to room temperature to obtain a white solid, adding 10-15 mL of ethyl acetate into the white solid, fully stirring, filtering, and leaching a filter cake with 5-10 mL of ethyl acetate; heating the filtrate to 50 ℃, adding 40-60 mL of petroleum ether with a boiling range of 60-90 ℃, cooling to room temperature, adding 100-120 mL of petroleum ether, stirring and standing for 3-5 hours; filtering the system after stirring the petroleum ether to obtain a filter cake which is white solid and 3-amino-4- (2,4, 5-trifluorophenyl) -2-methyl crotonate;

the fourth step:

hydrogenation:

adding 120-200 mL of trifluoroethanol into a 500mL reaction kettle, and sequentially adding 10g of methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate, 0.04mol of methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate, 101-124 mg of (cyclooctyl-1, 5-diene) ruthenium dichloride polymer, 0.009-0.011 equivalent of (R) - (+) - (1,1 '-binaphthyl-2, 2' -diyl) bis (diphenylphosphine), 225-274 mg of 0.009-0.011 equivalent of (diphenyl-phosphine), 9.0-10.9 g of di-tert-butyl carbonate and 0.9-1.1 equivalent of (di-tert-butyl carbonate) into the reaction kettle; replacing 2-3 times with nitrogen, stirring at room temperature for 15-45 min, replacing the atmosphere in the kettle with hydrogen for 3-5 times, pressurizing to 0.4-1.2 MPa, raising the internal temperature to 50-90 ℃, reacting for 8-24 hours, stopping the reaction, detecting by TLC (DCM, with the Rf being 0.6), passing through a kieselguhr funnel, rotatably evaporating the filtrate to dryness, dissolving the obtained residue in 100-150 mL of methanol, adding 240-400 mL of water, precipitating a large amount of white solid, and standing for 4-8 hours; performing suction filtration, wherein a filter cake is gray solid, and a crude product, namely (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

and (3) recrystallization:

dissolving 10-15 g of crude (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate in the hydrogenation step into methanol to prepare a methanol solution with the concentration of 0.2-0.5 g/mL, heating to 50-60 ℃, preserving the temperature until the solid is completely dissolved, dropwise adding 15-30 mL of water, adding seed crystals, naturally cooling to room temperature, and standing for 10-20 hours; filtering the mixture to obtain a filter cake, and washing the filter cake with 20-40 mL of a solution of methanol/water (1/1-1/1.5) to obtain a white acicular solid (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

ee value > 99.8%

The fifth step:

and a sixth step:

the seventh step:

adding 100-200 g of 2-4 mol/L HCl/EtOH solution into the crude product in the previous step, and starting stirring; the reaction temperature is 25-30 ℃, the reaction solution is clarified, stirred and reacted, after the reaction is completed, the solvent is dried in a spinning mode to obtain oily matter, the oily matter is added into a reaction bottle, 100-200 mL of purified water is added into the reaction bottle under stirring, and the pH value is adjusted to 10-12 by using 2-3 mol/L NaOH solution; adding 200-400 mL of isopropyl acetate, extracting and stirring for 10-20 minutes, and standing and layering for 10-15 minutes; separating liquid, discharging a water phase to obtain an organic phase, adding 200-400 mL of isopropyl acetate into the discharged water phase, extracting, standing, layering, and collecting the organic phase; combining the organic phases extracted twice, extracting and washing for 15-20 minutes by using 100-200 mL of purified water, standing for 10-20 minutes, and separating liquid; discarding the water phase to obtain an organic phase, drying the organic phase, and filtering and spin-drying; obtaining oily matter, pulping and stirring the oily matter for 8-12 hours by using 100-200 mL of methyl tert-butyl ether; filtering and filtering to dryness; washing a filter cake with 20-40 mL of methyl tert-butyl ether, and performing suction filtration until the filter cake is dry; collecting the filter cake to obtain sitagliptin;

eighth step:

adding 30-50 mL of isopropanol and 5-10 mL of purified water into a three-neck flask, adding 14g of sitagliptin in the seventh step under stirring, and clarifying a mixture when the temperature of a system is raised to 39-41 ℃; filtering out solids, heating the filtrate to 78-80 ℃, and slowly adding 1-1.1 equivalent of phosphoric acid; when the internal temperature is 51-53 ℃, a large amount of white solid is separated out, and when the internal temperature is increased to 75-80 ℃, the reaction liquid is clarified; slowly cooling, cooling the temperature in the system from 75 ℃ to 66-68 ℃ within 1-2 hours, controlling the temperature at 66-68 ℃, stirring and reacting for 2-3 hours, and naturally cooling the reaction system to room temperature;

Example 1:

the first step is as follows:

acetonitrile (540mL) was added to a 5L three-necked flask, mechanical stirring was connected, stirring was turned on, and S.M-1(180 g), Meldrum's acid (128.4g), and DMAP (7.92g) were added to the reaction flask in this order from the addition port at room temperature, and the system was a white turbid liquid.

DIPEA (219.9g) is dripped into the system through a constant-pressure dropping funnel, and the dripping is finished for about 30min (the dripping process has obvious temperature rise, the temperature in the system is controlled to be lower than 40 ℃), the system is a yellow transparent solution, and the internal temperature is 36 ℃.

t-BuCOCl (107.5g) was diluted with acetonitrile (60mL), and the mixture was slowly dropped into the system through a constant pressure dropping funnel over about 1 hour (the temperature was remarkably increased during the dropping, the internal temperature was controlled to be lower than 50 ℃ C.), and the internal temperature was 44 ℃. The system was moved to an oil bath and heated, the internal temperature was maintained at 45 ℃ and the system became brown yellow, reacted for about 2 hours, and detected by TLC (PE: EA 3:1, 1 drop of acetic acid was added, and Rf of the product was 0.3).

Cooling the system to 0 ℃, dropping 1N HCl (2160mL) into the system through a constant pressure dropping funnel, keeping the system temperature at 0 ℃, dropping the system for about 2 hours, separating out a large amount of white solids in the dropping process, filtering, washing the filter cake to white with 20% acetonitrile/water mixed solution (3.3L), and drying in vacuum at 40 ℃ to obtain 245g of a product, yield: 81.8 percent

Second step of

Methanol (1.1L) was added to a 2L three-necked flask, and the product of the first step (245g,0.77mol) was added to the reaction flask through the addition port, and the system was a turbid liquid. Heating in oil bath at 85 deg.C until the system refluxes. The system gradually changes from a turbid state to a yellow transparent liquid.

Refluxing for 3h, TLC detecting (PE: EA is 3:1, 1 drop acetic acid is dropped, and development is carried out for 2 times, product Rf is 0.7)

The methanol was spin dried, the residue was dissolved in MTBE (500mL), and the organic phase was washed with 1N HCl300 mL/sec, then 7% NaHCO₃The aqueous solution (300 mL/time) was washed, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and spin-dried. To give 174g of crude product, isopropanol (696mL) was added, and the mixture was heated to 30 ℃ to dissolve all of it, water (1392mL) was added dropwise to the system at 20 ℃ and stirred for 16 hours, a solid precipitated, filtered, and the filter cake was washed with water (200mL) to give 154g of product, yield: 80.7 percent, extracting the mother liquor by DCM, collecting the organic phase, and spin-drying to obtain 13g of crude product.

¹H NMR(CDCl3)d 7.08(m,1H),6.94(m,1H),3.85(s,2H),3.77(s,3H),3.55(s,2H)；

The third step

The product of the second step (10g,0.041mol) was placed in a round bottom flask, methanol (120mL) was added and stirred at room temperature until the solid was completely dissolved, ammonium acetate (15.6g,4 equiv.) was added and the system was heated to reflux and the solid was completely dissolved and the system was clear. After stirring at reflux for 3 hours, the starting material was completely reacted by TLC (DCM, product Rf ═ 0.8, bright blue under uv lamp long irradiation) and the product formed a single spot.

And cooling to room temperature of 15-25 ℃, carrying out rotary evaporation on the reaction system to dryness to obtain a white solid, adding 15mL of ethyl acetate into the white solid, fully stirring, filtering, and washing a filter cake with 5mL of ethyl acetate. And heating the filtrate to 50 ℃, adding 40mL of petroleum ether, cooling to room temperature, adding 120mL of petroleum ether, stirring and standing for 3 h.

The system was filtered to give 9.1g of filter cake as a white solid in 90% yield, m.p.:70-72 ℃.

¹H-NMR(300NHz，CDCl3)：δ7.13-7.04(m,1H),6.99-6.90(m,1H),4.56(s,1H),3.65(s,3H), 3.41(s,br,2H)

The fourth step

The method is characterized in that: the chiral reduction and the amino protection are combined into one-step reaction, and the used chiral ligand is cheap and easy to obtain, the operation is simple and convenient, and the yield is high.

Hydrogenation:

trifluoroethanol (150mL) was added to a 500mL reaction vessel, and the three step products (10g,0.04mol), [ Ru (cod) Cl2] n (112mg, 0.4mmol), (R) -BINAP (249mg,0.4mmol), and Boc2O (9.8g,0.044mol) were added to the reaction vessel in that order. After the reaction was stopped after the internal temperature was raised to 70 ℃ and the reaction was carried out for 15 hours by replacing the atmosphere in the autoclave with nitrogen gas for 3 times, stirring the mixture at room temperature for 30min and replacing the internal atmosphere with hydrogen gas four times, the reaction was stopped, the mixture was subjected to TLC detection (DCM, product Rf ═ 0.6), the mixture was passed through a celite funnel and evaporated to dryness by rotation, and the obtained residue was dissolved in MeOH (120mL), 240mL of water was added thereto, a large amount of white solid was precipitated, and the mixture was allowed to stand for 4 hours. The crude product was filtered off with suction and the filter cake was 12g (crude purity 96%, ee 91%) as a grey solid.

And (3) recrystallization:

and (3) dissolving 12g of the sample in the hydrogenation step in 60mL of methanol, heating to 60 ℃ to completely dissolve the sample, dropwise adding 25mL of water, adding 50mg of seed crystal, naturally cooling to room temperature, and standing for 10 hours. The mixture was filtered and the filter cake was washed with 20mL (methanol/water-1/1) to give 10g of a white needle solid in 71% yield with 98.5% purity of the product and an ee of greater than 99%. MP: 90-91 ℃ 1H-NMR (300NHz, CDCl 3): δ 7.07-7.02(m,1H),6.94-6.86(m,1H),5.11(d, J ═ 9.0Hz,1H), 4.18-4.08(m,1H),3.71(s,3H),2.88-2.80(m,2H),2.60-2.50(m,2H),1.38(s,9H)

The fifth step

A mixed solution of THF (3mL) and water (3mL) was charged into a 25mL one-necked flask, four steps (200mg,0.58mmol) were added to the system, and LiOH. H.₂O (72mg,1.73mmol) was added to the system, which was cloudy. After stirring at room temperature (about 26 ℃) for 16 hours, the system became a clear solution, TLC monitoring (PE: EA ═ 5:1, product at origin) stopped the reaction, saturated aqueous sodium bicarbonate (2mL) was added to the system, THF was spun dry at 40 ℃, KHSO was added₄(200mg,20mL of water) was added to adjust the pH of the system to 2-3, and a white solid was precipitated and filtered to give 6(153mg, yield 80%)

The sixth step

Adding into a three-mouth bottleAcetonitrile (30mL), stirring was started, and the product of the fifth step (15g,1eq.) and SM2(12.3g, 1.2eq.) were added, complete. The temperature was initially reduced and, after the internal temperature had dropped to 0 ℃, N-methylmorpholine (4.2g, 0.9eq.) and EDCI hydrochloride (12.9g, 1.5eq.) were added in succession. And after the addition is finished, controlling the temperature of the reaction system at 8 ℃, and determining that the product in the fifth reaction step is completely consumed, and finishing the reaction. Purified water (70mL) and methyl t-butyl ether (150mL) were added to the reaction system, and the mixture was stirred for 20 minutes. Standing for separating, and using 10% KHCO for organic phase₃The solution (70mL), 20% NaCl solution (70mL) was washed with stirring. The liquid was separated and the aqueous phase was discarded. The organic phase was dried, filtered and then spin dried and used directly in the next step.

Seventh step

To the crude product in the previous step was added 4mol/L HCl/EtOH solution (105g) and stirring was started. The reaction temperature is 30 ℃, the reaction liquid is clarified and stirred for reaction, and after the reaction is completed, the solvent is dried by spinning. The oil was added to a reaction flask, purified water (150mL) was added to the flask with stirring, and the pH was adjusted to 10 with 3mol/L NaOH solution. Isopropyl acetate (200mL) was added, stirred for 15 minutes, and allowed to stand for 10 minutes. Separating, discharging the water phase, and collecting the organic phase. The organic phases were combined, washed with purified water (100mL) for 15 minutes, allowed to stand for 10 minutes, and separated. The aqueous phase was discarded and the organic phase was dried and filtered to dryness. The oil was slurried with methyl tert-butyl ether (100mL) and stirred for 8 hours. Filtering and filtering to dryness. The filter cake was washed with methyl tert-butyl ether (20mL) and filtered to dryness with suction. The filter cake was collected to give 814 g of intermediate (two step yield 76.3%).

Eighth step

Isopropanol (30mL) and purified water (5mL) were added to a three-necked flask, and the product of the seventh step (14g) was added with stirring, and when the system was warmed to 39 ℃, the mixture was clear. 5.6g of solid was filtered off, the filtrate was warmed to 78 ℃ and phosphoric acid (2.4g) was slowly added. When the internal temperature was 51 ℃, a large amount of white solid precipitated, and when the internal temperature rose to 75 ℃, the reaction solution was clear. Slowly cooling, cooling the temperature in the system from 75 ℃ to 68 ℃ within 1 hour, controlling the temperature at 68 ℃, stirring and reacting for 2 hours, and naturally cooling the reaction system to room temperature.

After the mixture reached room temperature, the mixture was crystallized for 12 hours while being counted, isopropyl alcohol (50mL) was added, and the mixture was stirred for 1 hour. And (3) carrying out suction filtration, leaching the filter cake with isopropanol (20mL), draining, collecting the filter cake, placing the filter cake in a hot air circulation oven, drying at room temperature for 1 hour, and drying at 45 ℃ for 5 hours to obtain 9.4g of solid with the yield of 87.1%. And obtaining a final product.

¹H-NMR(300NHz，D2O)：δ7.27-7.17(m,1H),7.13-7.02(m,1H),5.04(s,1H),4.94(d,J＝6.0 Hz,1H),4.36-4.20(m,2H),4.08-4.04(m,2H),3.57-3.47(m,1H),2.85-2.57(m,4H)

Example 2

The first step is as follows:

analytically pure acetonitrile (> 99%) 500mL was added to a 5L three-necked flask, mechanical stirring was connected, stirring was turned on, and 2,4, 5-trifluorophenylacetic acid: 180g,1 equivalent, Meldrum's acid: 122.8g, 0.9eq, DMAP: 5.78g, 0.05 equivalent, adding into a reaction bottle through a charging hole, wherein the system is white turbid liquid;

mixing DIPEA: 244.7g,2.0 equivalent, and dripping into the white turbid liquid system through a constant pressure dropping funnel, wherein the system is a yellow transparent solution after the dripping is finished for 20 minutes, and the internal temperature is 35 ℃;

reacting pivaloyl chloride: 102.7g g,0.9 eq, acetonitrile: diluting by 50mL, slowly dropping the yellow transparent solution system through a constant-pressure dropping funnel, and after dropping for 45 minutes, keeping the internal temperature at 0 ℃; the system is moved to an oil bath for heating, the internal temperature is kept at 30 ℃, the system is changed into brown yellow, and the reaction lasts for 1 hour;

the above brown system was cooled to 5 ℃ and 1N HCl: 1.8L drop into this system, keep this system temperature at 5 ℃,1 hour dropwise add finishes, and it has a large amount of white solids to separate out to drop into the in-process, filters this white solid, obtains the filter cake, and the filter cake is with 20% acetonitrile/water mixed solution: washing 3L to white, and vacuum drying at 50 ℃ to obtain a product 5- (1-hydroxy-2- (2,4, 5-trifluorophenyl) ethylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone;

the second step is that:

adding 1.2L of analytically pure methanol into a 2L three-neck flask, and adding 245g,0.77mol and 1.0 equivalent of the compound 5- (1-hydroxy-2- (2,4, 5-trifluorophenyl) ethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone in the first step into the reaction flask through a feeding port to obtain a turbid liquid; heating in oil bath at 80 deg.C until the system flows back; the system gradually changes from a turbid state to a yellow transparent liquid;

the yellow clear liquid reaction was evaporated to dryness by rotary evaporation, the residue was dissolved in 400mL of MTBE, and the dissolved organic phase was washed with 1N HCl 250 mL/time, 3 times and then with 5% NaHCO₃Washing with the aqueous solution for 250 mL/time and 3 times, collecting an organic phase, drying with anhydrous sodium sulfate, filtering, and spin-drying; obtaining a crude product, adding 600mL of isopropanol, heating to a temperature not higher than 35 ℃ to completely dissolve the crude product, dripping 1.2L of water into the completely dissolved system at the temperature of 35 ℃, stirring for 20 hours, separating out solids, filtering to obtain a filter cake, and flushing the filter cake with 250mL of water to obtain a product of methyl 3-oxo-4- (2,4, 5-trifluorophenyl) butyrate;

the third step:

placing 10g,0.041mol and 1 equivalent of methyl 3-oxo-4- (2,4, 5-trifluorophenyl) butyrate in the second step into a round-bottom flask, adding the round-bottom flask into 100mL of methanol, stirring at room temperature until all solids are dissolved, adding 12.5-15.6 g of ammonium acetate ready-made system with 4-5 equivalents, heating the system to reflux, and dissolving all solids to clarify the system; cooling to room temperature (25 ℃), rotating and evaporating the reaction system cooled to room temperature to dryness to obtain white solid, adding 10mL of ethyl acetate into the white solid, fully stirring, filtering, and leaching the filter cake with 10mL of ethyl acetate; heating the filtrate to 50 ℃, adding 60mL of petroleum ether with the boiling range of 60 ℃, cooling to room temperature, adding 100mL of petroleum ether, stirring and standing for 5 hours; filtering the system after stirring the petroleum ether to obtain a filter cake which is white solid and 3-amino-4- (2,4, 5-trifluorophenyl) -2-methyl crotonate;

the fourth step:

hydrogenation:

adding 120mL of trifluoroethanol into a 500mL reaction kettle, and sequentially adding 10g of methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate, 0.04mol of methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate, 101mg of (cyclooctyl-1, 5-diene) ruthenium dichloride polymer, 0.009 equivalents of (R) - (+) - (1,1 '-binaphthyl-2, 2' -diyl) bis (diphenylphosphine), 0.009 equivalents of (diphenylphosphine), 9.0g of di-tert-butyl carbonate and 0.9 equivalents into the reaction kettle in the third step; replacing 2 times with nitrogen, stirring at room temperature for 15min, replacing the atmosphere in the kettle with hydrogen for 3 times, pressurizing to 0.4MPa, raising the internal temperature to 50 ℃, stopping the reaction after 8 hours of reaction, detecting by TLC (DCM, product Rf is 0.6), passing through a kieselguhr funnel, evaporating filtrate in a rotary manner to dryness, dissolving the obtained residue in 100mL of methanol, adding 240mL of water, precipitating a large amount of white solid, and standing for 4 hours; performing suction filtration, wherein a filter cake is gray solid, and a crude product, namely (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

and (3) recrystallization:

dissolving 10g of crude (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate in the hydrogenation step into methanol to prepare a methanol solution with the concentration of 0.2g/mL, heating to 50 ℃, preserving the temperature until the solid is completely dissolved, dropwise adding 15mL of water, adding 10mg of seed crystal, naturally cooling to room temperature, and standing for 20 hours; filtering the mixture to obtain a filter cake, and washing the filter cake with 40mL of a solution of methanol/water (1/1) to obtain white needle-shaped solid methyl (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyrate;

the fifth step:

adding a mixed solution of 5mL of tetrahydrofuran and 5mL of water into a 25mL single-neck bottle, adding 200mg and 0.58mmol of (R) -methyl 3-amino-4- (2,4, 5-trifluorophenyl) butyrate in the fourth step into the mixed solution, and adding 24mg of lithium hydroxide monohydrate by 1.0 equivalent, wherein the reaction solution is white turbid; stirring at 15 ℃ for 20 hours until the reaction solution becomes a clear solution, stopping the reaction by TLC monitoring (PE: EA: 5:1, complete conversion of the raw material (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate), adding 5mL of saturated aqueous sodium bicarbonate solution into the system after the reaction is stopped, spinning off tetrahydrofuran at 35 ℃, adjusting the pH of the system to 3 by 10mg/L of aqueous potassium hydrogen sulfate solution to precipitate a white solid, and filtering to obtain white solid (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid;

and a sixth step:

adding 50mL of acetonitrile into a three-necked bottle, starting stirring, and adding 15g,1eq and 10.1g,1.0eq of the (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid and 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride in the fifth step, and finishing; cooling, and when the internal temperature is reduced to 5 ℃, sequentially adding 5.0g of N-methylmorpholine, 1.1eq and 8.6g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1.0 eq; after the addition, controlling the temperature of a reaction system at 10 ℃, and determining that the reaction raw material (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid is completely consumed, and finishing the reaction; adding 100mL of purified water and 200mL of methyl tert-butyl ether into the reaction system, and stirring for 40 minutes; standing, separating, and stirring and washing an organic phase by using 100mL of 15% potassium bicarbonate solution and 100mL of 10% NaCl solution; separating liquid and discarding the water phase; drying the organic phase, filtering and spin-drying to obtain a crude product which is directly used in the next step;

the seventh step:

adding 100g of 2mol/L HCl/EtOH solution into the crude product in the previous step, and starting stirring; the reaction temperature is 25 ℃, the reaction solution is clarified, the stirring reaction is carried out, after the reaction is completed, the solvent is dried by spinning to obtain oily matter, the oily matter is added into a reaction bottle, 100mL of purified water is added into the reaction bottle under the stirring, and the pH value is adjusted to be 12 by using 2mol/L NaOH solution; adding 400mL of isopropyl acetate, extracting and stirring for 10 minutes, standing and layering for 15 minutes; separating liquid, discharging a water phase to obtain an organic phase, adding 400mL of isopropyl acetate into the discharged water phase, extracting, standing, layering, and collecting the organic phase; combining the organic phases extracted twice, extracting and washing with 200mL of purified water for 20 minutes, standing for 20 minutes, and separating liquid; discarding the water phase to obtain an organic phase, drying the organic phase, and filtering and spin-drying; obtaining an oily substance, pulping and stirring the oily substance for 12 hours by using 200mL of methyl tert-butyl ether; filtering and filtering to dryness; washing a filter cake with 40mL of methyl tert-butyl ether, and performing suction filtration until the filter cake is dry; collecting the filter cake to obtain sitagliptin;

eighth step:

adding 50mL of isopropanol and 10mL of purified water into a three-neck flask, adding 14g of sitagliptin in the seventh step under stirring, and clarifying the mixture when the temperature of the system is raised to 41 ℃; filtering out the solid, heating the filtrate to 80 ℃, and slowly adding 1 equivalent of phosphoric acid; when the internal temperature is 53 ℃, a large amount of white solid is separated out, and when the internal temperature is raised to 80 ℃, the reaction solution is clear; slowly cooling, cooling the temperature in the system from 75 ℃ to 66 ℃ within 2 hours, controlling the temperature at 66 ℃, stirring and reacting for 3 hours, and naturally cooling the reaction system to room temperature;

from the room temperature, timing and crystallizing for 10 hours, adding 80mL of isopropanol, pulping and stirring for 3 hours; and (3) carrying out suction filtration to obtain a filter cake, leaching the filter cake with 40mL of isopropanol, carrying out suction drying, collecting the filter cake, placing the filter cake in a hot air circulation oven, drying the filter cake for 2 hours at room temperature, and drying the filter cake for 3 hours at 40 ℃ to obtain the final solid sitagliptin phosphate monohydrate.

Example 3

The first step is as follows:

add analytically pure acetonitrile (> 99%) 600mL into a 5L three-necked flask, couple mechanical stirring, turn on stirring, and sequentially add 2,4, 5-trifluorophenylacetic acid: 180g,1 equivalent, Meldrum's acid: 150.1g,1.1 equivalents), DMAP: 11.6g,0.1 equivalent, adding into a reaction bottle through a charging hole, wherein the system is white turbid liquid;

mixing DIPEA: 219.9g,1.8 equivalent, and dripping into the white turbid liquid system through a constant pressure dropping funnel, wherein the system is a yellow transparent solution after dripping for 40 minutes, and the internal temperature is 40 ℃;

reacting pivaloyl chloride: 125.6g,1.1 equivalents, reaction with acetonitrile: diluting by 100mL, slowly dropping the yellow transparent solution system through a constant-pressure dropping funnel, and after 75 minutes of dropping, keeping the internal temperature at 45 ℃; the system is moved to an oil bath for heating, the internal temperature is kept at 35 ℃, the system is changed into brown yellow, and the reaction lasts for 1.5 hours;

the above brown system was cooled to 3 ℃ and 1N HCl: 2.2L of the system is dripped into the solution, the temperature of the system is kept at 3 ℃, the dripping is finished within 1.5 hours, a large amount of white solid is separated out in the dripping process, the white solid is filtered to obtain a filter cake, and the filter cake is mixed with 20 percent acetonitrile/water solution: washing 3.1L to white, and vacuum drying at 45 deg.C to obtain product 5- (1-hydroxy-2- (2,4, 5-trifluorophenyl) ethylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone;

¹H NMR(300MHz,CDCl₃)δ7.19-7.10(m,1H),7.00-6.91(m,1H),4.44(s,2H),1.76(s,6H).

the second step is that:

adding 1.1L of analytically pure methanol into a 2L three-neck flask, and adding 245g,0.77mol and 1.0 equivalent of the compound 5- (1-hydroxy-2- (2,4, 5-trifluorophenyl) ethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone in the first step into the reaction flask through a feeding port to obtain a turbid liquid; heating in oil bath at 90 deg.C until the system flows back; the system gradually changes from a turbid state to a yellow transparent liquid;

the yellow clear liquid reaction was evaporated to dryness by rotary evaporation, the residue was dissolved in 450mL of MTBE, and the dissolved organic phase was washed with 280 mL/time 1N HCl, 3 times and then with 6% NaHCO₃Washing with aqueous solution for 280 mL/time and 3 times, collecting organic phase, drying with anhydrous sodium sulfate, filtering, and spin-drying; obtaining a crude product, adding 700mL of isopropanol, heating to a temperature not higher than 35 ℃ to completely dissolve the crude product, dripping 1.4L of water into the completely dissolved system at a temperature of 30 ℃, stirring for 12 hours, separating out solids, filtering to obtain a filter cake, and washing the filter cake with 230mL of water to obtain a product, namely methyl 3-oxo-4- (2,4, 5-trifluorophenyl) butyrate;

the third step:

placing 10g,0.041mol and 1 equivalent of methyl 3-oxo-4- (2,4, 5-trifluorophenyl) butyrate in the second step into a round-bottom flask, adding 150mL of methanol, stirring at room temperature until all solids are dissolved, adding 12.5g and 5 equivalents of an ammonium acetate ready-made system, heating the system to reflux, and dissolving all solids to ensure that the system is clear; cooling to room temperature (15-25 ℃), rotatably evaporating the reaction system cooled to room temperature to dryness to obtain white solid, adding 12mL of ethyl acetate into the white solid, fully stirring, filtering, and leaching a filter cake with 8mL of ethyl acetate; heating the filtrate to 50 ℃, adding 50mL of petroleum ether with the boiling range of 90 ℃, cooling to room temperature, adding 110mL of petroleum ether, stirring and standing for 4 hours; filtering the system after stirring the petroleum ether to obtain a filter cake which is white solid and 3-amino-4- (2,4, 5-trifluorophenyl) -2-methyl crotonate;

the fourth step:

hydrogenation:

adding 200mL of trifluoroethanol into a 500mL reaction kettle, and sequentially adding 10g of methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate, 0.04mol of methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate, 124mg of (cyclooctyl-1, 5-diene) ruthenium dichloride polymer, 0.011 equivalent of (R) - (+) - (1,1 '-binaphthyl-2, 2' -diyl) bis (diphenylphosphine) 274mg,0.011 equivalent of, 10.9g of di-tert-butyl carbonate and 1.1 equivalent of the di-tert-butyl carbonate into the reaction kettle; replacing with nitrogen for 3 times, stirring at room temperature for 45min, replacing the atmosphere in the kettle with hydrogen for 5 times, pressurizing to 1.2MPa, raising the internal temperature to 90 ℃, stopping the reaction after 24 hours of reaction, detecting by TLC (DCM, product Rf is 0.6), passing through a kieselguhr funnel, rotating and evaporating filtrate to dryness, dissolving the obtained residue in 150mL of methanol, adding 400mL of water, precipitating a large amount of white solid, and standing for 8 hours; performing suction filtration, wherein a filter cake is gray solid, and a crude product, namely (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

and (3) recrystallization:

dissolving 15g of crude (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate in the hydrogenation step in methanol to prepare a methanol solution with the concentration of 0.5g/mL, heating to 55 ℃, preserving the temperature until the solid is completely dissolved, dropwise adding 30mL of water, adding 80 mg of seed crystal, naturally cooling to room temperature, and standing for 15 hours; filtering the mixture to obtain a filter cake, and washing the filter cake with 30mL of a solution of methanol/water (1/1.5) to obtain white needle-shaped solid methyl (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyrate;

ee value > 99.8%;

the fifth step:

adding a mixed solution of 4mL of tetrahydrofuran and 4mL of water into a 25mL single-neck bottle, adding 200mg and 0.58mmol of (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate obtained in the fourth step into the mixed solution, and then adding 24-120 mg and 1.0-5.0 equivalents of lithium hydroxide monohydrate, wherein the reaction solution is white turbid; stirring at 30 ℃ for 1 hour to ensure that the reaction solution becomes a clear solution, stopping the reaction by TLC monitoring (PE: EA: 5:1, complete conversion of the raw material (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate), adding 3mL of saturated aqueous sodium bicarbonate solution into the system after the reaction is stopped, spinning off tetrahydrofuran at 38 ℃, adjusting the pH of the system to 2 by 30mg/L of aqueous potassium hydrogen sulfate solution to precipitate a white solid, and filtering to obtain white solid (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid;

and a sixth step:

adding 40mL of acetonitrile into a three-necked bottle, starting stirring, and adding 15g,1eq and 10.1g,1.0eq of the (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid and 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride in the fifth step, and finishing; cooling, and sequentially adding 4.5g of N-methylmorpholine, 1.1eq and 17.2g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 2.0eq when the internal temperature is reduced to 3 ℃; after the addition, controlling the temperature of a reaction system at 0 ℃, and determining that the reaction raw material (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid is completely consumed, and finishing the reaction; adding 80mL of purified water and 180mL of methyl tert-butyl ether into the reaction system, and stirring for 30 minutes; standing, separating, and stirring and washing an organic phase by using 80mL of 12% potassium bicarbonate solution and 80mL of 15% NaCl solution; separating liquid and discarding the water phase; drying the organic phase, filtering and spin-drying to obtain a crude product which is directly used in the next step;

the seventh step:

adding 200g of 3mol/L HCl/EtOH solution into the crude product in the previous step, and starting stirring; the reaction temperature is 28 ℃, the reaction solution is clarified, the reaction is carried out under stirring, after the reaction is completed, the solvent is dried by spinning to obtain oily matter, the oily matter is added into a reaction bottle, 200mL of purified water is added into the reaction bottle under stirring, and the pH value is adjusted to be between 11 by using 3mol/L NaOH solution; adding 300mL of isopropyl acetate, extracting and stirring for 20 minutes, and standing and layering for 12 minutes; separating liquid, discharging a water phase to obtain an organic phase, adding 300mL of isopropyl acetate into the discharged water phase, extracting, standing, layering and collecting the organic phase; combining the organic phases extracted twice, extracting and washing with 150mL of purified water for 18 minutes, standing for 15 minutes, and separating liquid; discarding the water phase to obtain an organic phase, drying the organic phase, and filtering and spin-drying; obtaining oily matter, pulping the oily matter by using 150mL of methyl tert-butyl ether and stirring for 10 hours; filtering and filtering to dryness; washing a filter cake with 30mL of methyl tert-butyl ether, and performing suction filtration until the filter cake is dry; collecting the filter cake to obtain sitagliptin;

eighth step:

adding 40mL of isopropanol and 8mL of purified water into a three-neck flask, adding 14g of sitagliptin in the seventh step under stirring, and clarifying the mixture when the temperature of the system is raised to 40 ℃; filtering out the solid, heating the filtrate to 79 ℃, and slowly adding 1.1 equivalent of phosphoric acid; when the internal temperature is 52 ℃, a large amount of white solid is separated out, and when the internal temperature is raised to 78 ℃, the reaction solution is clear; slowly cooling, cooling the temperature in the system from 75 ℃ to 67 ℃ within 1.5 hours, controlling the temperature at 67 ℃, stirring and reacting for 2.5 hours, and naturally cooling the reaction system to room temperature;

from the room temperature, performing timed crystallization for 12 hours, adding 70mL of isopropanol, pulping and stirring for 2 hours; and (3) carrying out suction filtration to obtain a filter cake, leaching the filter cake with 30mL of isopropanol, carrying out suction drying, collecting the filter cake, placing the filter cake in a hot air circulation oven, drying the filter cake for 1.5 hours at room temperature, and drying the filter cake for 4 hours at 42 ℃ to obtain the final solid sitagliptin phosphate monohydrate.

The sitagliptin diabetes mouse model experiment of the invention

Type ii diabetes model, ob/ob mice, were purchased from changzhou cavens laboratory animals ltd, four groups of five mice (a, B, C, D) and were dosed by drinking water for sitagliptin synthesized in this way for one week (7D). Group A: purified water, 50mg/kg/D for group B, 100mg/kg/D for group C, and D: 200 mg/may g/d. Immediately after the fasting tail vein blood was taken before the start of the experiment (0d) and after the end of the administration (7d), blood glucose was measured with a glucometer, and the results were as follows:

TABLE-experimental mice fasting blood glucose

Sitagliptin dosage	A is purified water 0	B:50mg/kg/d	C:100mg/kg/d	C:200mg/Kg/d
					0d	22.5+/-0.2mM	23.1+/-0.4mM	21.5+/-0.3mM	20.8+/-0.1mM
7d	21.9+/-0.5mM	17.2+/-0.7mM	14.2+/-0.4mM	10.2+/-0.6mM
					The blood sugar level is reduced%	2.7％	25.5％	34.0％	51％

The experimental result shows that the sitagliptin synthesized by the method can reduce the blood sugar amount of a mouse, the reduced level is in direct proportion to the administration amount, and the sitagliptin has normal biological activity.

Claims

1. A preparation method of a medicine for treating diabetes is characterized by comprising the following steps: the method combines the steps of chiral reduction and amino protection into one-step reaction.

2. The method for preparing a medicament for treating diabetes according to claim 1, wherein the method comprises the following steps: the step of combining the chiral reduction and the amino protection into one step is as follows:

hydrogenation:

and (3) recrystallization:

3. The method for preparing a medicament for treating diabetes according to claim 1, wherein the method comprises the following steps: the step of combining the chiral reduction and the amino protection into one step is as follows:

in the hydrogenation step:

in the recrystallization step:

4. The method for preparing a medicament for treating diabetes according to claim 3, wherein the method comprises the following steps: the method comprises the following steps:

the first step is as follows:

adding analytically pure acetonitrile into a three-neck flask, connecting mechanical stirring, starting stirring, and sequentially adding 2,4, 5-trifluorophenylacetic acid, Meldrum's acid and DMAP into the reaction flask from a feeding port at a certain temperature to obtain a white turbid liquid;

dripping DIPEA into the system through a constant-pressure dropping funnel, wherein the system is a yellow transparent solution after dripping is finished;

the second step is that:

the reaction was evaporated to dryness by rotation, the residue was taken up in MTBE and the organic phase was washed with 1N HCl and then with NaHCO₃Washing with water solution, collecting organic phase, drying with anhydrous sodium sulfate, filtering, and spin drying; obtaining a crude product, adding isopropanol, heating to a temperature not higher than 35 ℃ to completely dissolve the crude product, dripping water into the system, stirring for 12-20 hours, separating out solids, filtering, and washing a filter cake with water to obtain a product, namely methyl 3-oxo-4- (2,4, 5-trifluorophenyl) butyrate;

the third step:

¹H NMR(300MHz,CDCl₃)δ6.97-6.95(m,1H),6.94-6.93(m,1H),4.56(s,1H),3.65(s,3H),3.41(s,2H).

the fourth step:

hydrogenation:

and (3) recrystallization:

dissolving crude (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate in methanol to prepare a methanol solution, heating to a certain temperature, keeping the temperature until the solid is completely dissolved, dropwise adding water, adding 60 mg of seed crystal, naturally cooling to room temperature, and standing; filtering the mixture, and washing a filter cake to obtain white needle-shaped solid (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

the fifth step:

and a sixth step:

the seventh step:

eighth step:

5. The method for preparing a medicament for treating diabetes according to claim 4, wherein the method comprises the following steps: the method comprises the following steps:

the first step is as follows:

the second step is that:

rotating and evaporating the yellow transparent liquid reaction system to dryness, adding 400-500 mL of MTBE into the residue until the residue is completely dissolved, washing the dissolved organic phase with 1N HCl for 250-300 mL/time, washing for 3 times, and then using NaHCO with the mass concentration of 5-7%₃Washing with the aqueous solution for 250-300 mL/time and 3 times, collecting an organic phase, drying with anhydrous sodium sulfate, filtering, and spin-drying; obtaining a crude product, adding 600-700 mL of isopropanol, heating to a temperature not higher than 35 ℃ to completely dissolve the crude product, dripping 1.2-1.4L of water into the completely dissolved system at a temperature of 20-35 ℃, stirring for 12-20 hours, separating out solids, filtering to obtain a filter cake, and washing the filter cake with 200-250 mL of water to obtain a product of methyl 3-oxo-4- (2,4, 5-trifluorophenyl) butyrate;

¹H NMR(300MHz,DMSO-d6)δ7.57-7.46(m,1H),7.45-7.35(m,1H),3.96(s,br,2H),3.75(s,2H),3.64(s,3H)

the third step:

the fourth step:

hydrogenation:

adding 120-200 mL of trifluoroethanol into a 500mL reaction kettle, and sequentially adding 10g of methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate, 0.04mol of methyl 3-amino-4- (2,4, 5-trifluorophenyl) -2-butenoate, 101-124 mg of (cyclooctyl-1, 5-diene) ruthenium dichloride polymer, 0.009-0.011 equivalent of (R) - (+) - (1,1 '-binaphthyl-2, 2' -diyl) bis (diphenylphosphine), 225-274 mg of 0.009-0.011 equivalent of (diphenyl-phosphine), 9.0-10.9 g of di-tert-butyl carbonate and 0.9-1.1 equivalent of (di-tert-butyl carbonate) into the reaction kettle; replacing 2-3 times with 99.5% nitrogen, stirring for 15-45 min at room temperature, replacing the atmosphere in a kettle with hydrogen for 3-5 times, pressurizing to 0.4-1.2 MPa, raising the internal temperature to 50-90 ℃, stopping the reaction after reacting for 8-24 hours, detecting by TLC (DCM, with the Rf being 0.6), passing through a kieselguhr funnel, rotatably evaporating the filtrate to dryness, dissolving the obtained residue in 100-150 mL of methanol, adding 240-400 mL of water, precipitating a large amount of white solid, and standing for 4-8 hours; performing suction filtration, wherein a filter cake is gray solid, and a crude product, namely (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate;

and (3) recrystallization:

the fifth step:

¹H NMR(300MHz,CDCl₃)δ7.10-7.01(m,1H),6.92-6.88(m,1H),5.06(s,br,1H),4.13(s,br,1H),2.87(d,J＝9.0Hz,2H),2.62-2.60(m,2H),1.38(s,9H).

and a sixth step:

the seventh step:

¹H NMR(300MHz,D₂O)δ7.27-7.17(m,1H),7.13-7.02(m,1H),5.04(s,1H),4.94(d,J＝3.9Hz,1H),4.36-4.25(m,2H),4.07-4.04(m,2H),3.55-3.50(m,1H),2.80-2.60(m,4H).

eighth step:

¹H NMR(300MHz,D₂O)δ7.33-7.25(m,1H),7.20-7.12(m,1H),4.99-4.95(m,2H),4.36-4.27(m,2H),4.07-3.97(m,3H),3.12-2.92(m,4H)。

6. The method for preparing a medicament for treating diabetes according to claim 4 or 5, wherein: in the first step, after the DIPEA is dripped, the temperature is obviously increased in the dripping process, the internal temperature of the system is controlled to be lower than 40 ℃, the system is yellow transparent solution, and the internal temperature is 36 ℃.

7. The method for preparing a medicament for treating diabetes according to claim 6, wherein the method comprises the following steps: in the first step, after the t-BuCOCl is dripped, the temperature is obviously increased in the dripping process, the internal temperature is controlled to be lower than 50 ℃ and is 44 ℃; the system is moved to an oil bath for heating, the internal temperature is kept at 45 ℃, the system is changed into brown yellow, and the reaction lasts for 2 hours.

8. The method for preparing a medicament for treating diabetes according to claim 6, wherein the method comprises the following steps: the solvent used was: the methanol, ethanol, isopropanol, acetonitrile, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, tetrahydrofuran and trifluoroethanol are analytically pure, and the purity is more than 99 percent; the petroleum ether is analytically pure boiling range of 60-90 ℃; the purity of the reagent used is greater than 95%.