Method for preparing sartan antihypertensive drug side-chain

An anti-hypertensive and sartan-like technology, which is applied in the field of preparation of pharmaceutical intermediates, can solve problems such as difficult purification and difficult control of bromination depth, and achieve the effects of less dibrominated by-products, high purity and high yield

Inactive Publication Date: 2012-07-11
YICHANG HEC CHANGJIANG PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] 1) In the bromination process, the bromination depth is difficult to control, and more dibromine by-products are generated;
[0004] 2) Since there are unreacted raw materials and dibromo by-products in the product, and the polarities of the three are similar, it is difficult to purify by recrystallization

Method used

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  • Method for preparing sartan antihypertensive drug side-chain
  • Method for preparing sartan antihypertensive drug side-chain
  • Method for preparing sartan antihypertensive drug side-chain

Examples

Experimental program
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preparation example Construction

[0018] A preparation method for the side chain of sartan antihypertensive drugs, comprising: 4'-bromomethylbiphenyl-2-carbonitrile, 4'-bromomethylbiphenyl-2-carboxylate methyl ester, 5-[2 -(4'-Bromomethylbiphenyl)]-2-H-imidazole, 5-[2-(4'-Bromomethylbiphenyl)]-2-triphenylmethyl-imidazole are sartan drugs Synthetic, it is characterized in that: II (4'-methylbiphenyl-2-carbonitrile, 4'-methylbiphenyl-2-carboxylate methyl ester, 5-[2-(4'-methylbiphenyl) ]-2-H-imidazole, 5-[2-(4'-methylbiphenyl)]-2-triphenylmethyl-imidazole) dissolved in an aprotic organic solvent, adding 0.5 to 0.8 equivalents of brominated Then add the initiator, react for 1 to 6 hours, add the brominated agent and the initiator in stages, and add 0.02 to 0.2 equivalents of the brominated agent each time, until the basic reaction of the raw materials is complete, cool down to room temperature, wash and separate , reclaim the reaction solvent, add crystallization solvent in the raffinate and stir crystallization...

Embodiment I4

[0027] Embodiment 1 The synthesis of 4'-bromomethyl biphenyl-2-carbonitrile

[0028] In a 500ml flask, add 4'-methylbiphenyl-2-carbonitrile (38.7g, 0.2mol), 400ml of dichloromethane, and then dibromohydantoin (17.2g, 0.06mol), azobisisobutyronitrile 1.0g was heated up to reflux for 6 hours, cooled to 30-35°C, and dibromohydantoin and azobisisobutyronitrile were added in portions, adding dibromohydantoin (2.9g, 0.01mol) each time, azobis Isobutyronitrile 0.2g, after each reaction for 3 hours, stop the reaction until the HPLC of the raw material for phase detection is 96%, the dibromo product is <2%, and the raw material is < 1%.

Embodiment II4

[0029] Synthesis of embodiment II 4'-bromomethyl biphenyl-2-methyl carboxylate

[0030] In a 500ml flask, add 4'-methylbiphenyl-2-carboxylate methyl ester (45.3g, 0.2mol), ethyl acetate 400ml, add NBS (21.4g, 0.12mol), benzoyl peroxide 0.5 g, heat up to reflux for 6 hours, cool down to 62-67°C, add NBS and benzoyl peroxide in portions, add NBS (3.6g, 0.02mol) each time, benzoyl peroxide 0.2g, each time After reacting for 3 hours, stop the reaction until the HPLC of the phase detection material is 96%, dibromo products <2%, and raw materials <1%.

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Abstract

The invention relates to a method for preparing a sartan antihypertensive drug side-chain. The method comprises the following steps of: dissolving (4'-methylbiphenyl-2-nitrile, 4'-methylbiphenyl-2-carboxylic methyl, 5-[2-(4'-methylbiphenyl)]-2-H-imidazole and 5-[2-(4'-methylbiphenyl)]-2-triphenylmethyl-imidazole) into an aprotic organic solvent, adding 0.5-0.8 of brominated agent with equivalent weight, and then adding a small quantity of initiators; raising temperature until backflow reaction is performed for 3-6 hours, and then dropping temperature by 5-10 DEG C; and refilling the brominated agent and a small quantity of initiators for several times, adding 0.02-0.2 of brominated agent with equivalent weight in every time, and refilling every 3-5 hours. The temperature is dropped to the room temperature after raw materials are basically reacted, water washing and layering are carried out, a reaction solvent is recovered, a fining solvent is added into exhaust liquor for agitated crystallization, cooling and filtering, and the sartan antihypertensive drug side-chain is obtained. The yield is 90 percent, the purity is more than 96 percent, and the dibromo products are less than 2 percent.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation process of a side chain of a sartan antihypertensive drug. Background technique [0002] 4'-Bromomethylbiphenyl-2-carbonitrile, 4'-Bromomethylbiphenyl-2-carboxylate methyl ester, 5-[2-(4'-Bromomethylbiphenyl)]-2-H- Imidazole and 5-[2-(4'-bromomethylbiphenyl)]-2-triphenylmethyl-imidazole are key intermediates for the synthesis of sartan drugs, but the current synthesis process has the following disadvantages: [0003] 1) In the bromination process, the bromination depth is difficult to control, and more dibromine by-products are generated; [0004] 2) Since there are unreacted raw materials and dibromo by-products in the product, and the polarities of the three are similar, it is difficult to purify by recrystallization. Contents of the invention [0005] The purpose of the present invention is to provide a method for preparing the side cha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/50C07C253/30C07C69/78C07C67/307C07D233/64
Inventor 查高峰覃鹏唐金龙张艳飞
Owner YICHANG HEC CHANGJIANG PHARMA CO LTD
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