Preparation method of benzochromene derivative

A compound and mixture technology, applied in the field of preparation of benzochromene derivatives, can solve the problems of difficulty in adapting to large-scale industrial production, high price, high production cost, etc.

Active Publication Date: 2016-07-27
ASTATECH CHENGDU BIOPHARM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] But the starting material 7-hydroxyl-3,4-dihydronaphthalene-1 (2 hydrogen)-ketone of the first step of the method is usually all multi-step synthesis, the cost is high, and the catalyst Pd( OPiv) 2 and ligand P(4-F-Ph) 3 is also very expensive
[0009] It can be seen that for the preparation of benzochromene derivatives, the existing methods have high production costs and are difficult to meet the needs of large-scale industrial production.

Method used

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  • Preparation method of benzochromene derivative
  • Preparation method of benzochromene derivative
  • Preparation method of benzochromene derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] The preparation of embodiment 1 compound 2

[0094]

[0095] Under the protection of nitrogen, 14 kg (22.9 mol) of the compound and 20 L of THF were sequentially added into a 50 L reactor, and the temperature was lowered to -70°C. Control the temperature below -70°C and add 6.8 kg of n-BuLi dropwise, and then stir for 0.5 hours below -70°C after the drop. Control the temperature below -70°C and add 4.75kg of triisopropyl borate dropwise. Pour it into 20L (1N) dilute hydrochloric acid, separate the layers, and extract the aqueous phase with EA10L once more. The organic phases were combined, washed once with 10 L of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 22.4 kg of compound with a yield of 85%.

Embodiment 2

[0096] The preparation of embodiment 2 compound 4

[0097] method 1:

[0098]

[0099] Under the protection of nitrogen, 3500g of compound, 3L of THF, 2382g of compound, 626g of potassium carbonate, 3L of deionized water, and 6g of tetrakis(triphenylphosphopalladium) were successively added into a 10L four-necked flask, and the temperature was raised to reflux for overnight reaction. TLC monitors that the reaction is complete (about 16 hours), and then pours into 3L of ice water, separates the liquid, and extracts the aqueous phase once with EA1L. The organic phases were combined, washed once with 2 L of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 4482 g of compound with a yield of 96%.

[0100] HNMR (CDCl 3 ,400MHz):δ7.62(s,1H),7.49-7.11(m,6H),4.69(1H,s),4.50(2H,s).

[0101] Method 2:

[0102]

[0103] Add compound 350g, THF300mL, compound 238.2g, potassium carbonate 62.6g, deionized water 300mL, Pd(dppf)Cl 2 0.6g, heat...

Embodiment 3

[0105] The preparation of embodiment 3 compound 5

[0106] method 1:

[0107]

[0108] Under nitrogen protection, 450 g of the compound, 500 mL of DMSO, and 35.6 g of potassium tert-butoxide were sequentially added into a 1 L four-necked flask, and the temperature was raised to 60° C. for 1 hour. TLC monitors the disappearance of raw materials, pours into 1L of ice water, and extracts with MTBE1Lx3. The organic phases were combined, washed once with 1 L of water and once with 1 L of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 37.5 g of compound with a yield of 82%, HPLC=90%.

[0109] Method 2:

[0110]

[0111] Under nitrogen protection, 450 g of compound, 500 mL of DMF, K 2 CO 3 43.7g, heated up to 60°C and reacted for 1 hour. TLC monitors the disappearance of raw materials, pours into 1L of ice water, and extracts with MTBE1Lx3. The organic phases were combined, washed once with 1 L of water and once with 1 L of satu...

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Abstract

The invention discloses a preparation method of a benzochromene derivative shown as a formula (I). The benzochromene derivative can be taken as a synthesis intermediate of a drug such as a synthesis intermediate of Velpatasvir. Cheap and available 2-fluoro halogenated benzene is taken as a starting material, a brand-new synthetic route for preparing the benzochromene derivative is provided, the total yield of the whole reaction route is high, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of benzochromene derivatives, in particular to a preparation method of a Velpatasvir intermediate. Background technique [0002] Many benzochromene derivatives have a wide range of pharmacological and physiological activities, and some benzochromene derivatives can be used as intermediates for the preparation of medicines, especially the compounds of the following formula (Ia): [0003] [0004] It is an important intermediate for preparing the new hepatitis C drug Velpatasvir. [0005] [0006] Patent WO2013075029 discloses a synthesis method of Velpatasvir, which involves the preparation method of benzochromene derivatives, the main steps are as follows: [0007] [0008] But the starting material 7-hydroxyl-3,4-dihydronaphthalene-1 (2 hydrogen)-ketone of the first step of the method is usually all multi-step synthesis, the cost is high, and the catalyst Pd( OPiv) 2 and ligand P(4-F-Ph) 3 The...

Claims

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Application Information

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IPC IPC(8): C07D311/78C07D311/80C07C29/34C07C33/46
CPCC07C29/34C07C33/46C07D311/78C07D311/80
Inventor 张睿宁兆伦李仟魏庚辉国光波郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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