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A kind of preparation method of avastatin

An intermediate and palladium catalyzed technology, which is applied in the preparation of Avastin intermediates and the field of Avastin preparation, can solve the problems of unsatisfactory product yield and purity, danger, and difficult control of industrial batch production, and achieve high efficiency. Preparation route, risk reduction, short time effect

Active Publication Date: 2017-05-31
CHONGQING HUAPONT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] However, dangerous n-butyl lithium is used in the above synthetic methods, which is not easy to control in industrial batch production, which brings great danger to the production factory, and is not ideal in product yield and purity.

Method used

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  • A kind of preparation method of avastatin
  • A kind of preparation method of avastatin
  • A kind of preparation method of avastatin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0034] Preparation of Example 14-methyl-N'-(3-(pyrrolidin-1-yl)-1-(p-tolyl)propylene)benzenesulfonylhydrazone

[0035] In a three-necked reaction flask, add 100 g (460 mmol) of 3-(pyrrolidin-1-yl)-1-(p-tolyl)propan-1-one, 102.8 g (552 mmol) of p-toluenesulfonyl hydrazide, and Add 7.9 g (46 mmol) of toluenesulfonic acid, add 120 ml of tetrahydrofuran, stir and reflux, react for 2.5 hours, monitor by TLC spotting, if the reaction is not complete, continue to heat and reflux. After the reaction was completed, the crude product was evaporated to dryness under reduced pressure, then added n-hexane and stirred into a slurry, filtered and dried to obtain 4-methyl-N'-(3-(pyrrolidin-1-yl)-1-(p Tolyl)propylene)benzenesulfonylhydrazone 168.5g, yield 95%.

Embodiment 2

[0036] The preparation of embodiment 2 Avastin

[0037] In a three-necked reaction flask, add 25.0 liters of 4-methyl-N'-(3-(pyrrolidin-1-yl)-1-(p-tolyl)propylene)benzenesulfonylhydrazone prepared in Example 1 g (64.9mmol), (E)-ethyl 3-(6-bromopyridin-2-yl) ethyl acrylate 17.4g (68.1mmol), Pd 2 (dba) 3 1.2g (1.3mmol), Xphos1.2g (2.6mmol), potassium tert-butoxide 9.5g (84.3mmol), stir and mix well, add dry 1,4-dioxane 150ml, pass into N 2 After two gas replacements, continue to feed N 2 protection, the reaction system was heated to 80°C and reacted at this temperature for 5 hours. HPLC and TLC monitor the reaction. After completion, cool to room temperature and filter. The filter cake is washed twice with 25 ml of tetrahydrofuran. 20.7 g of ethyl 3-(pyrrolidin-1-yl)-1-(p-tolyl)prop-1-en-1-yl)pyridin-2-yl)acrylate, with a purity of 98.9% and a yield of 85%.

[0038]In a three-necked reaction flask, add (E)-ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-(p-tolyl)prop-1-ene-1- Base) ...

Embodiment 3

[0039] The preparation of embodiment 3 Avastin

[0040] In a three-necked reaction flask, add 4-methyl-N'-(3-(pyrrolidin-1-yl)-1-(p-tolyl)propylene)benzenesulfonylhydrazone 30.0 prepared in Example 1 g (77.8mmol), (E)-ethyl 3-(6-bromopyridin-2-yl) ethyl acrylate 19.9g (77.8mmol), Pd 2 (dba) 3 4.2g (4.7mmol), Xphos4.4g (9.3mmol), lithium tert-butoxide 18.6g (233.4mmol), stir and mix evenly, add dry 1,4-dioxane 150ml, pass into N 2 After two gas replacements, continue to feed N 2 protection, the reaction system was heated to 90°C and reacted at this temperature for 6 hours. HPLC and TLC monitor the reaction. After completion, cool to room temperature and filter. The filter cake is washed twice with 25 ml of tetrahydrofuran. 23.7g of ethyl 3-(pyrrolidin-1-yl)-1-(p-tolyl)prop-1-en-1-yl)pyridin-2-yl)acrylate, purity 98.7%, yield 81.0% .

[0041] In a three-necked reaction flask, add (E)-ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-(p-tolyl)prop-1-ene-1- Base) pyridin-2-yl) ethyl ac...

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Abstract

The invention belongs to the field of organic chemical synthesis and specifically relates to a preparation method of acrivastine. The preparation method comprises the following steps: by taking p-methyl benzoyl hydrazone and alpha-halogenated pyridine as raw materials, carrying out palladium-catalyzed coupling reaction to obtain an intermediate for synthesizing acrivastine; and further preparing acrivastine. By carrying out non-palladium borate-catalyzed coupling reaction, the preparation method is mild in reaction condition; dangerous butyl lithium is not used, so that the risk in plant production is reduced; the reaction is short in time required and high in efficiency; and the raw materials are cheap and easily available and the cost is lowered. The preparation method provided by the invention provides a novel safe, economic and efficient preparation path for preparation of acrivastine.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and in particular relates to a method for preparing an avastatin intermediate and a method for preparing avastatin using the intermediate. Background technique [0002] Acrivastine, alias name: Avastin, chemical name: (E,E)-3-[6-[1-(p-tolyl)-3-pyrrolidin-1-yl-1- Propyl]-2-pyridyl]acrylic acid, the structural formula shown below, belongs to the class of antihistamine clemastine, which is used to treat nasal sensitivity and inflammation such as sneezing and runny nose, and relieve itching and hay fever. [0003] [0004] The preparation method of Avastatin is more classically a five-step synthesis method, namely: successively by preparing 2,6-dibromopyridine (2), 2-bromo-6-(4-toluoyl)pyridine (3), 2-(6-Bromo-2-pyridyl)-2-(4-methylphenyl)-1,3-dioxolane(4), (E)-3-[6-[(4-methylphenyl) Carbonyl]-2-pyridyl]ethyl acrylate (5) to finally give Avastatin (1). Its reaction formula is as follow...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/55
CPCC07D213/55
Inventor 许华侨周春燕许佳黄真
Owner CHONGQING HUAPONT PHARMA
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