Preparation method of Anagliptin intermediate

A technology of intermediates and compounds, which is applied in the field of drug synthesis, can solve the problems that pyrimidine-6-carboxamide is not easy to obtain, and achieve the effects of no environmental pollution, simple operation, and cheap and easy-to-obtain raw materials

Inactive Publication Date: 2016-02-10
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0007] In the above synthetic route, 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxamide is not easy to obtain, so in the field of chemical industry, there is an urgent need for an intermediate that can effectively prepare alogliptin. A New Method for 2-Methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic Acid

Method used

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  • Preparation method of Anagliptin intermediate
  • Preparation method of Anagliptin intermediate
  • Preparation method of Anagliptin intermediate

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preparation example Construction

[0033] The preparation method of alalogliptin intermediate 1 comprises the following steps:

[0034]

[0035] In the first step, in the ether solution containing compound 5, a strong base was slowly added under ice bath conditions, then ethyl formate was added and stirred overnight at room temperature to obtain compound 4;

[0036] In the second step, compound 4 and compound 3 were added into the acidic solution, and stirred at 120° C. for 3 h to obtain compound 2;

[0037] The third step is to concentrate the above reaction solution, add ethanol and alkaline aqueous solution, heat to 70° C., and stir for 1 h to obtain compound 1.

[0038] In the first step, the volume molar ratio of ether to compound 5 is 2L / mol-3L / mol, and the strong base is 1.8-2 times the molar amount of compound 5. The temperature of the nucleophilic substitution reaction is -10°C-40°C, more preferably -5°C-15°C.

[0039] In the second step, the volume molar ratio of the acidic solution to the compou...

Embodiment 1

[0042] The synthesis of embodiment 1.2-formyl-3-oxopropionic acid ethyl ester

[0043]

[0044] Weigh 3,3-diethoxy ethyl propionate (10g, 52.57mmol), add diethyl ether (300ml), slowly add sodium hydride (4.2g, 105mmol) under ice-bath stirring conditions, then weigh ethyl formate Ester (39 g, 526 mmol) was added to the above reaction solution and stirred at room temperature overnight. After TLC (petroleum ether: ethyl acetate = 3:1) monitors the end of the reaction, transfer the reaction solution into a separatory funnel, add water (200ml), separate the water layer, adjust the pH of the water layer to 1 with hydrochloric acid, and then transfer to the separatory funnel. In a liquid funnel, extract with ether, wash the organic layer with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain an orange-red oily liquid. The obtained crude product can be directly put into the next reaction without purification.

Embodiment 2

[0045] The synthesis of embodiment 2.2-methyl-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid ethyl ester

[0046]

[0047] Weigh 2-formyl-3-oxopropionic acid ethyl ester (3.2g, 32.95mmol) and 3-amino-5-methyl-1H-pyrazole (compound 4, 4.99g, 34.60mmol) in a three-necked flask In, acetic acid (40ml) was added, heated to 120°C and stirred for 3h. After the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1), the heating was stopped, and the reaction solution was concentrated under reduced pressure to obtain the title crude product; the crude product could be directly put into the next reaction without purification.

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Abstract

The invention provides a preparation method of an Anagliptin intermediate. The preparation method comprises following steps: (1) in the presence of an alkali, 3,3-diethoxy propionate (compound 5) is reacted with a formate (HCOOR1) so as to obtain a compound 4; (2) the compound 4 and 3-amino-5-methyl-1H-pyrazole (compound 3) are subjected to cyclization reaction in an acid solvent so as to obtain a compound 2; and (3) the compound 2 is subjected to esterolysis in the presence of an alkali so as to obtain 2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (compound 1); wherein R is used for representing a group selected from methyl, ethyl, propyl, or benzyl, and R1 is used for representing a group selected from methyl, ethyl, propyl, or benzyl. Operation of the preparation method is simple; the raw materials are cheap and easily available; the preparation method is suitable for industrialized large-scale production, and is green and friendly to the environment; and no environmental pollution is caused.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of anagliptin (Anagliptin) intermediate 2-methyl-pyrazolo[15-a,]pyrimidine-6-carboxylic acid. Background technique [0002] [0003] Alagliptin [0004] Alalogliptin, chemical name N-[2-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-2-methylpropanyl ]-2-Methyl-6-pyrazolo[1,5-a]pyrimidinecarboxamide, trade name Suiny, is a DPP-IV inhibitor jointly developed by Japan Kowa Pharmaceutical Company and Japan Sanwa Chemical Research Institute, For the treatment of type 2 diabetes. [0005] 2-Methyl-pyrazolo[15-a,]pyrimidine-6-carboxylic acid is an important intermediate for the preparation of alalogliptin, which reacts with (2S)-1-(2-chloroacetyl )-2-pyrrolidinecarbonitrile is spliced ​​to obtain alalogliptin through connecting chains. The synthetic route reported in the literature is as follows: [0006] [0007] In the above synthetic route, 2-methyl-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 王悦郭珩岑均达
Owner SHANGHAI INST OF PHARMA IND CO LTD
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