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Vildagliptin, vildagliptin analogues and vildagliptin intermediate, and preparation methods of three and application

An analog and reaction technology, applied in the field of vildagliptin and its analogs, can solve the problems of low conversion rate, many reaction by-products, low yield and the like

Active Publication Date: 2014-07-16
CHEMVON BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The technical problem to be solved by the present invention is to overcome defects such as many reaction by-products in the existing vildagliptin preparation method, conversion rate is low, post-treatment operation is loaded down with trivial details, yield is low, product purity is low and provides vildagliptin and Its analogue, intermediate and its preparation method and application

Method used

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  • Vildagliptin, vildagliptin analogues and vildagliptin intermediate, and preparation methods of three and application
  • Vildagliptin, vildagliptin analogues and vildagliptin intermediate, and preparation methods of three and application
  • Vildagliptin, vildagliptin analogues and vildagliptin intermediate, and preparation methods of three and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0212] Preparation of the amino acid fragment 2a of embodiment 1N-Boc protection

[0213]

[0214] Weigh 50.0 g of hydroxyamantadine, suspend in 700 ml of ethyl acetate, add 55.3 g of ethyl bromoacetate under mechanical stirring, cool in an ice bath, add 68.5 g of anhydrous K in batches 2 CO 3 powder. After half an hour, the temperature was raised to 45° C., and after 5 hours of reaction, TLC detection showed that the reaction was basically complete. The reaction mixture was cooled to room temperature, filtered to remove most of the solids, adjusted to pH 3-4 with 2N dilute hydrochloric acid, separated to remove the organic phase, and then adjusted to pH 10 with 2N NaOH in the aqueous phase, and 200 mL×3 ethyl acetate Extraction product. Dried over anhydrous sodium sulfate and concentrated to give 49.2 g of oily product 5a (R 14 is hydroxyl, R 15 For ethyl), the yield is 65%.

[0215] Take 40g of the above-mentioned oil, dissolve it in 300ml of tetrahydrofuran and 60m...

Embodiment 2

[0218] The preparation of the amino acid fragment 2b' of embodiment 2N-Boc protection

[0219]

[0220] Weigh 50.0 g of amantadine, suspend in 700 mL of ethyl acetate, add 55.3 g of ethyl bromoacetate under mechanical stirring, cool in an ice bath, add 68.5 g of anhydrous K in batches 2 CO 3 powder. Half an hour later, the temperature was raised to 45°C for reaction, and after 5 hours, TLC detection showed that the reaction was basically complete. Cool the reaction mixture to room temperature, remove most of the solids by filtration, adjust the pH value to 3-4 with 2N dilute hydrochloric acid, separate the organic phase, adjust the pH value of the aqueous phase to 10 with 2N NaOH, and use ethyl acetate 200mL×3 Extraction product. Drying over anhydrous sodium sulfate and concentrating gave 55.0 g of oily product 5b (R 14 for hydrogen, R 15 For ethyl), the yield is 70%.

[0221] Take 50g of the above-mentioned oil, dissolve it in 400ml of tetrahydrofuran and 70ml of N,N...

Embodiment 3

[0224] The preparation of the amino acid fragment 2c of embodiment 3N-Cbz protection

[0225]

[0226] Weigh 5.0g compound 5a (R 14 is hydroxyl, R 15 ethyl), dissolved in 40ml of anhydrous tetrahydrofuran, added diisopropylethylamine (5.1g, 2eq.) and benzyl chloroformate (5.05g, 1.5eq) successively under ice-cooling, and raised to room temperature after half an hour The reaction was stirred for 3.5 hours, and the conversion of the starting material was detected by TLC. The system was diluted with 100 mL of ethyl acetate, and washed with saturated ammonium chloride solution and saturated sodium chloride solution once. After drying over anhydrous sodium sulfate, the solvent was removed to obtain compound 6c (R 3 is benzyloxycarbonyl, R 14 is hydroxyl, R 15 Ethyl) was directly used in the next reaction without further purification.

[0227] The above intermediate 6c (R 3 is benzyloxycarbonyl, R 14 is hydroxyl, R 15 is ethyl) dissolved in 50mL THF, added 2.49g, 3eq.LiO...

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Abstract

The invention discloses vildagliptin, vildagliptin analogues and a vildagliptin intermediate, and preparation methods of the above compounds and application. The invention provides the vildagliptin analogues shown as a general formula 10, wherein R1 is triethylsilyloxy group, trifluoroacetoxy group, benzyloxy group, tert-butyldimethylsiloxy group, and R2 is cyano group or formamido group. The provided preparation method for the anti-diabetic medicine vildagliptin and the vildagliptin analogues is mild in reaction conditions, less in by-products, high in conversion rate, simple in post-treatment operation, high in product yield, good in purity, low in production cost and good in industrialization prospect. The invention provides a key intermediate N-substituted pyrrolidine compound 1 for preparing the anti-diabetic medicine vildagliptin and the vildagliptin analogues, and a preparation method of the intermediate. The synthetic method is simple in reaction conditions, cheap and easily available in raw materials, relatively high in both conversion rate and yield, low in cost, friendly in environment and suitable for industrial production. The general formula 10 is shown in the specification.

Description

technical field [0001] The invention relates to vildagliptin and its analogs, intermediates, preparation methods and applications thereof. Background technique [0002] Diabetes mellitus (Diabetes mellitus) is a series of clinical syndromes caused by absolute or relative insufficiency of insulin in the body. At present, the clinically used antidiabetic drugs mainly include insulin, metformin, sulfonylurea drugs, thiazolidinedione drugs, and α-glucosidase inhibitors. Completely controlling the level of glycosylated hemoglobin makes it difficult to maintain long-term curative effect, cannot effectively alleviate the disease according to the cause, and has many problems such as poor safety, easy liver toxicity, and weight gain. [0003] The newly developed dipeptidyl peptidase IV (dipeptidyl-peptidase IV, DPP-IV) inhibitor has been medically proven to be a new type of effective diabetes treatment drug. Clinical results show that this type of drug has a good hypoglycemic effec...

Claims

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Application Information

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IPC IPC(8): C07D207/16C07C271/24C07C229/14C07C227/18C07F7/18C07C233/83
CPCY02P20/55C07D207/16C07C229/14C07C233/83C07C271/24C07F7/1804
Inventor 王猛王东蔡茂军王方道周杰
Owner CHEMVON BIOTECH CO LTD
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