WO2015123998A1

WO2015123998A1 - Method for synthesizing vildagliptin

Info

Publication number: WO2015123998A1
Application number: PCT/CN2014/089248
Authority: WO
Inventors: 彭学东; 张梅; 赵金召; 闫勇义
Original assignee: 张家港威胜生物医药有限公司
Priority date: 2014-02-21
Filing date: 2014-10-23
Publication date: 2015-08-27
Also published as: CN103804267B; CN103804267A

Abstract

The present invention is a method for synthesizing vildagliptin. The method comprises: performing a condensation reaction of raw materials (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile or (S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile and 3-hydroxyl-amantadine in a mixed system of an organic solvent and water under the effect of a catalyst; and after the reaction, performing extraction separation, concentration and crystallization to obtain a product with a high content, high purity and high yield. The method is concise in process, simple to operate, green and environmentally-friendly, and suitable for industrial mass production.

Description

Synthetic method of vildagliptin

Technical field

The invention relates to a synthesis of a diabetes drug, vildagliptin.

Background technique

Vidastatin, English name: Vildgliptin, also known as vildagliptin Is a new oral therapeutic diabetes drug marketed by Novartis Pharmaceuticals in 2008. Its mechanism of action is effective, selective, competitive and reversible inhibition of dipeptidyl peptidase IV, which enhances glucagon-like peptide I. Activity and reduce hyperglycemia symptoms in patients with type 2 diabetes. Vigletine inhibits the activity of the enzyme by binding to dipeptidyl peptidase IV to form a dipeptidyl peptidase IV complex, which increases the concentration of glucagon-like polypeptide 1 and promotes insulin production by islet B cells. Glucagon concentration, which lowers blood sugar. Studies have shown that vildagliptin, whether used alone or in combination with other anti-diabetic drugs, can significantly reduce the level of clinically meaningful glycosylated hemoglobin, has good tolerance, and has no adverse effects such as weight gain and edema. The incidence of adverse reactions such as hypoglycemia and gastrointestinal tract is also low. It is especially effective in combination with metformin hydrochloride.

The main routes of vildagliptin are as follows:

The first route is to use L-valine as a raw material, first to protect the amine group of L-valine, then synthesize amide and deprotect to obtain L-prolinamide. The amine group is then chloroacetylated and then dehydrated under the action of trifluoroacetic anhydride to give the key intermediate (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile, followed by 3-hydroxy-gold The alkylamine reaction gives vildagliptin (Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.; Burkey, B. F.; Dunning, B. E.; Prasad, K.; Mangold, B. L.; Russel, M. E.; Hughes, T. E. J. Med. Chem. 2003, 46, 2774–2789. Fukushima, H.; Hiratate, A.; Takahashi, M.; Saito, M.; Munetomo, E.; Kitano, K.; Saito, H.; Takaoka, Y.; Yamamoto, K. Bioorg. Med. Chem. 2004, 12, 6053–6061. Shekhar, R.; Girgis, M. J. Process for producing amino acid amides. US Patent Application US 6,271,394 B1, August 7, 2001.).

The second route is to use L-valine as raw material, first carry out amine chloroacetylation, react with ammonium bicarbonate under the catalysis of carbon-carbon dicyclohexylimine to obtain amide and then synthesize amide, and then under the action of trifluoroacetic anhydride Dehydration to give the key intermediate (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile, and then react with 3-hydroxy-adamantanamine to give vedaglietine (Fedorov, A. E.; Shestopalov, A. M.; Belyakov, P. A. Russ. Chem. Bull. 2003, 52, 2197–2202. Santosh K. Singh, Narendra Manne and Manojit Pal. Synthesis of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile: A key intermediate for Dipeptidyl peptidase IV inhibitors. Beilstein Journal of Organic Chemistry, 2008, 4, (20): 1-5. Ulrich Hassiepen, Lorrach; Matthias Kittelmann US 8252751 B2.)

The other routes are also mainly the preparation of the intermediate (S)-1-(2-chloroacetyl)pyrrolidine-2-cyanide and 3-hydroxy-adamantanamine or the starting materials are different. It has been reported in the literature that 1-(2-chloroacetyl)-prolinamide is directly prepared from L-prolinamide, and then intermediate (S)-1-(2-chloroacetyl) is prepared by reacting with different dehydrating reagents. Pyrrolidine-2-methicone (Halama Ales; K Olsine. WO 2010/022690 A2). The preparation method of 3-hydroxy-adamantanamine is based on the reaction of amantadine hydrochloride as a raw material, nitration in nitric acid and concentrated sulfuric acid system, and reduction by strong alkali (checking, preparation of vildagliptin and synthesis of its derivatives) Research, Chongqing Medical University Master's Thesis, 2011.).

It has been reported in the literature that the intermediate (S)-1-(2-chloroacetyl)pyrrolidine-2-cyanide and 3-hydroxy-adamantanamine are condensed to give the vildagliptin process in organic solvents such as tetrahydrofuran, N, In a system such as N-dimethylformamide or 2-butanone, the reaction is heated by potassium carbonate or the like 10-30. h, the yield of this step is about 30-50%. The above process for preparing vildagliptin with the intermediate (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile and 3-hydroxy-adamantanamine mainly has the following disadvantages: (1) in organic The solubility of carbonic acid in the solvent is extremely low, so a large excess of potassium carbonate is added to maintain the reaction pH at which condensation amination can be carried out. (2) After adding more potassium carbonate, in order to increase the pH, heating must be promoted to promote the dissolution of potassium carbonate, which leads to possible hydrolysis of the amide bond, and at high temperature, 3-hydroxy-adamantanamine may be combined with two molecules (S) The reaction of 1-(2-chloroacetyl)pyrrolidine-2-carbonitrile produces a large amount of by-products. (3) A large amount of potassium iodide is used in the catalyst of the reaction system, and it becomes one of the main pollutants. (4) Due to the low reaction conversion rate, many by-products, the final yield of vildagliptin is low, the effect of cutting and crystallization separation is poor, and even the column chromatography separation process is too high, which is not conducive to industrialization.

Summary of the invention

In order to solve the above disadvantages of preparing vildagliptin by using (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile and 3-hydroxy-adamantanamine as raw materials, the process route of the present invention is directly (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile or (S)-1-(2-bromoacetyl)pyrrolidine-2-cyanohydrin with 3-hydroxy-adamantanamine The reaction is carried out in a mixed system of an organic solvent and water. The process reduces the use of organic solvent and potassium carbonate catalyst, and the preparation of vildagliptin is low in cost, simple in process, green and environmentally friendly, and has high yield, and has very good application value.

The present invention differs from the above prior art methods in that: (1) a new starting material (S)-1-(2-bromoacetyl)pyrrolidine-2-cyanoic acid and 3-hydroxyl are employed. - Amantadine, the test proved that the reaction conditions are milder, the by-products are less, and the yield is higher. (2) The non-polar organic solvent and water are used as the reaction medium, and the phase transfer catalyst is added to greatly improve the reaction efficiency and the conversion rate. (3) The conversion rate is high, the conditions are mild, the by-products are few, and the product crystal separation is simple. (4) Other raw and auxiliary materials are conventional reaction reagents, which are mild, safe, and free of pollutants, and the process is more green and environmentally friendly. The device is simpler and the operation is more concise. The above is an excellent industrial production route from the perspectives of economy, environment and occupational health.

The technical problem to be solved by the present invention is to overcome the shortcomings of the existing preparation methods, and to provide an environmentally friendly, low-cost, simple and high-yield preparation process of vildagliptin.

The object of the present invention is achieved by the following technical scheme: a method for synthesizing vildagliptin, comprising making a raw material (S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile or (S)-1- (2-Chloroacetyl)pyrrolidine-2-cyanohydrin and 3-hydroxy-adamantanamine are condensed under the action of a catalyst in a mixed system of an organic solvent and water, and the reaction is terminated by extraction and concentration to obtain Vidad The crude product is condensed and the crude product is crystallized to obtain the final product.

The invention provides a simple environmentally friendly synthesis process of vildagliptin, and considers environmental protection and efficiency in the reaction reagents and raw materials. The method has the advantages of high atomic economy, simple equipment, and green production process, and has great economic and social benefits.

BRIEF DESCRIPTION OF THE DRAWINGS:

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a synthetic route diagram of vildagliptin according to the present invention.

detailed description:

The invention is further illustrated in the following examples which are not intended to limit the scope of the invention.

The vildagliptin synthesis route provided by the invention directly adopts (S)-1-(2-chloroacetyl)pyrrolidine-2-cyanohydrin or (S)-1-(2-bromoacetyl)pyrrolidine- 2-Micyanidine is reacted with 3-hydroxy-adamantanamine, and the reaction is terminated by extraction, concentration, and crystallization to obtain a high-content and high-purity product. Specific steps can be referred to as follows:

1. In the No. 1 stainless steel reactor, the reaction raw material (S)-1-(2-chloroacetyl)pyrrolidine-2-cyano or (S)-1-(2-bromoacetyl)pyrrolidine- 2-Micyanidine and 3-hydroxy-adamantanamine were dissolved by stirring at room temperature.

2. Add the neutral base and phase transfer catalyst to the No. 2 stainless steel reactor, and then add an appropriate amount of water to stir the solvent for use.

3, jacket control No. 1 reactor temperature 10 Below °C, stir the aqueous solution containing alkali and phase transfer catalyst in the No. 2 stainless steel reactor slowly into the No. 1 reactor, and maintain the temperature within 30 °C, the reaction 4-16 h, TLC monitoring of the complete reaction of the starting material is considered complete.

4. After the reaction is completed, the reaction solution is transferred to an extraction tank and allowed to stand for stratification. The organic phase was separated and extracted twice with a volume of organic solvent. Concentration under reduced pressure gave a crude product of the Vidastatin oil.

5. The crude product of vildagliptin is heated and dissolved in a certain amount of organic solvent, passed through a fine filter, transferred to a crystallization tank with a concentrator, concentrated under reduced pressure to a certain volume, and stirred and cooled to crystallize. Crystallization is completed, decompression is considered, and the double cone is dried at 50 ° C. h, get qualified vidagliptin products.

Example 1 Synthesis of vildagliptin 1

In a No. 1 500 L stainless steel autoclave, add (S)-1-(2-chloroacetyl)pyrrolidine-2-cyanide 20.0 2 kg of kg and 3-hydroxy-adamantanamine were dissolved by stirring with 160 L of dichloromethane. Add neutral alkali potassium carbonate 10.0 kg and tetrabutylammonium bromide 1.1 in stainless steel reactor No. Kg, re-dissolved with water 80.0 kg. The jacketed cold brine is used to control the temperature of No. 1 reactor below 10 °C, and slowly enter the No. 2 reactor aqueous solution, and the addition is completed in about 2 hours. Then slowly warm to room temperature and continue to stir the reaction 10 h, to the thin layer chromatography to monitor the starting material (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile complete reaction, the reaction was terminated.

The reaction solution was transferred to an extraction tank and allowed to stand for separation. The methylene chloride layer was separated, and then extracted with 50 L of dichloromethane. Combine methylene chloride total about 260 L, anhydrous sodium sulfate 10.0 kg was added to dry overnight, and then concentrated under reduced pressure to remove methylene chloride to give a crude product of vistastatin 38.7 kg. Add 95% ethanol 300 L is heated to dissolve the crude vedagliptin, finely filtered, and transferred to a concentrated crystallization tank. About 180 L of ethanol was concentrated under reduced pressure, and the mixture was cooled to about 10 ° C to be stirred and crystallized for 2 h to precipitate white vildagliptin crystals. Pumping, double cone drying temperature control 50 Drying within °C for 3 h, the qualified vildagliptin 31.3 kg, yield 88.9%, high performance liquid phase detection, area normalization purity 99.0%, external standard method content 99.1%.

Example 2 Synthesis of vildagliptin 2

In a No. 1 500 L stainless steel autoclave, add (S)-1-(2-bromoacetyl)pyrrolidine-2-cyanide 21.5 2 kg of kg and 3-hydroxy-adamantanamine were dissolved by stirring with 160 L of dichloromethane. Add neutral acid sodium carbonate 9.0 kg and tetrabutylammonium bromide 1.2 kg in the No. 2 stainless steel reactor, re-water 80.0 Kg stirred to dissolve. The jacketed cold brine is used to control the temperature of No. 1 reactor below 10 °C, and slowly enter the No. 2 reactor aqueous solution, and the addition is completed in about 2 hours. Then slowly heat up to 20-22 ° C, continue to stir the reaction 5 h, to the thin layer chromatography to monitor the starting material (S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile complete reaction, the reaction was terminated.

The reaction solution was transferred to an extraction tank and allowed to stand for separation. The methylene chloride layer was separated, and then extracted with 50 L of dichloromethane. Combine methylene chloride total about 260 L, anhydrous sodium sulfate 10.0 kg was added to dry overnight, and then concentrated under reduced pressure to remove methylene chloride to give the crude product of vdastatin oil 39.1 kg. Add 95% ethanol 300 L is heated to dissolve the crude vedagliptin, finely filtered, and transferred to a concentrated crystallization tank. About 180 L of ethanol was concentrated under reduced pressure, and the mixture was cooled to about 10 ° C to be stirred and crystallized for 2 h to precipitate white vildagliptin crystals. Pumping, double cone drying temperature control 50 Drying within °C for 3 h, qualified Verdagliptin 32.1 kg, yield 91.2%, high performance liquid phase detection, area normalization purity 99.3%, external standard method content 99.5%.

Claims

1. A method for synthesizing vildagliptin, which comprises the steps of: (S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile or (S)-1-(2-chloro) Acetyl)pyrrolidine-2-cyanohydrin and 3-hydroxy-adamantanamine are condensed under the action of a catalyst in a mixed system of an organic solvent and water, and the reaction is terminated by extraction and concentration to obtain a crude product of vildagliptin, crude product Crystallization gives the final product.

2. The method according to claim 1, wherein the organic solvent is dichloromethane, which is used in an amount of 5 to 10 times, preferably 8 times, that of 3-hydroxy-adamantanamine.

3. The method according to claim 1, wherein the catalyst is one of potassium carbonate or sodium carbonate in an amount of from 0.1 to 0.8 times the amount of 3-hydroxy-adamantanamine.

4. The method according to claim 1, characterized in that tetrabutylammonium bromide is also used as a phase transfer catalyst in the reaction in an amount of from 0.01 to 0.2 times the amount of 3-hydroxy-adamantanamine.

5. The method of claim 1 wherein the catalyst is slowly added as an aqueous solution and is controlled at 2-4 The addition was completed in an hour, and the temperature of the mixture was kept within 10 ° C during the addition of the catalyst, the reaction temperature was maintained at 10-30 ° C, and the reaction time was 4-16 hours.

6. The method according to claim 1, characterized in that the crude vedaglutine is thermally dissolved in anhydrous ethanol, the amount of anhydrous ethanol is 6-12 times the volume of the crude product, and then 2/3 volume of ethanol is concentrated under reduced pressure, and the temperature is lowered to 10 The crystals were stirred under °C.