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Trelagliptin and preparation method of succinate thereof

A technology of troxagliptin succinate and succinic acid, which is applied in the field of preparation of troxagliptin and troxagliptin succinate, can solve the problems of low yield, high production cost, and complicated operation of the preparation method, and achieve The effect of reducing the content of impurities, low production cost, simple and safe process operation

Active Publication Date: 2016-06-15
上海新礼泰药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is in order to overcome the complex operation of the preparation method of troxagliptin succinate in the prior art, high requirements for production equipment, low yield, cumbersome post-treatment process, high impurity content of the obtained product, low A kind of preparation method of Trexagliptin and its succinate is provided due to defects such as easy purification, high production cost and unsuitability for industrialized production

Method used

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  • Trelagliptin and preparation method of succinate thereof
  • Trelagliptin and preparation method of succinate thereof

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Experimental program
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Effect test

Embodiment 1

[0039] Embodiment 1: Preparation of Trexagliptin Intermediate II (with reference to the method reported by CN101573351A)

[0040]

[0041] 3.0 Kg of 4-fluoro-2-methylbenzonitrile was added to 23.7 Kg of acetonitrile, and then 4.0 Kg of N-bromosuccinimide and 0.15 Kg of azobisisobutyronitrile were added. Heated to 70°C for 8 hours. Concentrate under reduced pressure to remove acetonitrile, add 25Kg of dichloromethane and stir, filter and wash the filter cake with 12Kg of dichloromethane. Wash the filtrate three times with 15Kg of 7% sodium bisulfite solution; add 15Kg of N-methylpyrrolidone after concentrating the organic phase to remove dichloromethane, then add 3.03Kg of 6-chloro-3-methyluracil and 2.91Kg of potassium carbonate . Heated to 60°C for 5 hours. Cool to 35°C, add 45Kg of water, cool to 10°C, stir, and filter. Add 19Kg of n-heptane to the filter cake, stir, filter, and air-dry at 50-55°C to obtain trexagliptin intermediate II, 4.49Kg, yield: 68.9%, HPLC puri...

Embodiment 2

[0042] Embodiment 2: the preparation of trexagliptin succinate I '

[0043]

[0044] Trexagliptin intermediate II 4.49Kg is added isopropanol 35.5Kg, then adds trexagliptin intermediate III ((R)-3-aminopiperidine dihydrochloride) 2.91Kg, potassium phosphate 8.1Kg and four 11 g of n-propylammonium bisulfate was heated to 40°C to 50°C for 4 to 5 hours. After concentration under reduced pressure, 30 Kg of dichloromethane and 22.5 Kg of water were added to separate layers, and the organic phase was washed three times with water. The aqueous phase was extracted once with 12Kg of dichloromethane. Combine the organic phases, add 0.9 Kg of anhydrous sodium sulfate and let stand for 3 hours, filter, and concentrate under reduced pressure to obtain 4.48 Kg of trexagliptin crude product. Add 21.6Kg of methanol to the whole batch of troxagliptin crude product, raise the temperature to 60°C-65°C to clarify the solution, cool to 20°C-25°C and stir for 1 hour to 2 hours at a stirring ra...

Embodiment 3

[0046] Embodiment 3: the preparation of trexagliptin succinate I '

[0047] Add 10.0 g of trexagliptin intermediate II to 79 g of isopropanol, then add 9.4 g of trexagliptin intermediate III, 30.7 g of anhydrous sodium phosphate and 116 mg of tetra-n-butylammonium bisulfate, and heat to 30°C to 40°C. ℃ for 7 hours to 9 hours. After concentration under reduced pressure, 50 mL of dichloromethane and 50 mL of water were added to separate layers, and the organic phase was washed twice with water. The aqueous phase was extracted twice with 20 mL of dichloromethane. The organic phases were combined, 2 g of anhydrous magnesium sulfate was added and allowed to stand for 5 hours, filtered, and concentrated under reduced pressure to obtain 10.1 g of crude trexagliptin. Add 60mL of ethanol to the whole batch of crude trexagliptin, heat to 60°C-65°C and stir until clear, cool to 20°C-25°C and stir for 1 hour to 2 hours, filter, and use ethanol cooled to 10°C-15°C 5 mL was washed three ...

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Abstract

The invention discloses a trelagliptin and a preparation method of succinate thereof. The preparation method includes the following steps that a trelagliptin intermediate II and a trelagliptin intermediate III perform nucleophilic substitution reaction in an organic solvent in the presence of phosphate and a phase transfer catalyst to obtain trelagliptin I, and then trelagliptin I reacts with the succinate to produce salt. The operation process of the preparation method is simple and safe, special devices are not needed, the impurity contents of bis-substituted and primary amine substituted isomers can significantly reduced, only one-time recrystallization is needed, the purity of the obtained trelagliptin succinate I' can be above 99.5%, the impurity contents of the bis-substituted and primary amine substituted isomers are both below 0.05%, the contents of all the other impurities are all below 0.05%, the prepared trelagliptin succinate I' is high in purity, the production cost is low, and the trelagliptin and the preparation method are suitable for industrialized production.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to a preparation method of trexagliptin and trexagliptin succinate. Background technique [0002] The Chinese name of troxagliptin succinate is 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine -1-ylmethyl]-4-fluoro-benzonitrile succinate, the English name is 2-({6-[(3(R)-3-aminopiperidin-1-yl]-3-methyl-2, 4-dioxo-3,4-dihydro-pyrimidin-1(2H)-yl}methyl)-4-fluorobenzonitrolemonosuccinate), Chemical Abstracts (CAS) No. 1029877-94-8, was developed by Takeda Pharmaceutical Co., Ltd. of Japan for the treatment of A new drug for type II diabetes, the structure of which is shown in formula I': [0003] [0004] Trexagliptin succinate was approved for marketing in Japan on March 26, 2015 based on the efficacy and safety data of multiple phase III clinical trials conducted in Japan. The drug's efficacy has been confirmed in all trials, a...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C51/41C07C55/10
CPCC07B2200/07C07D401/04
Inventor 黄俊柴雨柱徐丹朱春霞田舟山刘振峰周军全陈建
Owner 上海新礼泰药业有限公司
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