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Process for production of dibenzoxepin compound

A manufacturing method and technology of diphenyl, which is applied in the direction of organic chemistry, etc., can solve the problem of not finding the target of the efficient Z type.

Active Publication Date: 2014-07-23
SUMITOMO CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, no more efficient method for obtaining Z-shaped targets has been found

Method used

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  • Process for production of dibenzoxepin compound
  • Process for production of dibenzoxepin compound
  • Process for production of dibenzoxepin compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 11-Hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]oxa -Manufacture of 2-tert-butyl acetate

[0044] 143 g of water, 110 ml of toluene, and 146.4 g of 25% aqueous sodium hydroxide solution were added to 121.4 g (0.5 mol) of a 65.1% aqueous solution of 3-dimethylaminopropyl chloride hydrochloride, and stirred at about 25° C. for 30 minutes. 16.8 g of potassium carbonate was added to the separated organic layer, dehydrated, filtered, washed with 60 ml of toluene, and the filtrate and washing liquid were combined to prepare a toluene solution of 3-dimethylaminopropyl chloride.

[0045] 10 ml of tetrahydrofuran (THF) and 0.73 g of magnesium were mixed, and 0.1 g of 1,2-dibromoethane was added to activate the magnesium. To this, 11.6 g of toluene solutions of 3-dimethylaminopropyl chloride were dripped at 37-39 degreeC over 30 minutes. The mixture was stirred at 50° C. for 1 hour to prepare a Grignard reagent.

[0046] In dissolved with (11-oxo-6,11-dihydrodib...

Embodiment 2

[0049] (Z)-11-oxo-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxa -Manufacture of 2-acetic acid hydrochloride (olopatadine hydrochloride)

[0050] Charge the flask with 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]oxa - 10.0 g (0.0243 mol) of tert-butyl 2-acetate and 20 ml of toluene, and 3.8 g (0.03645 mol) of 35% hydrochloric acid were added. The ratio of Form E:Form Z in the reaction solution was 85:15. The reaction solution was stirred for 14 hours at a bath temperature of 100-105°C. (The internal temperature starts to reflux at 88°C, and the temperature rises to 95°C). At this moment, the E-type:Z-type ratio is 66:33. Then, a Dean-Stark apparatus was installed, and water was azeotropically distilled off (distillation removal amount: about 10 ml of toluene and about 1 ml of water). The reaction liquid was cooled to room temperature, and the solvent was removed. 100 ml of acetone and 1 ml of water were added to the residue, followed by stir...

Embodiment 3

[0060] (Z)-11-(3-Dimethylaminopropylidene)-6,11-dihydrodibenzo[b,c]oxa -2-Acetic acid hydrochloride (olopatadine hydrochloride)

[0061] In a Teflon-coated reaction kettle with a capacity of 100 ml, 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo[b,c]oxa - 5.0 g (0.0122 mol) of tert-butyl 2-acetate and 10 ml of toluene, and 0.63 g (0.0173 mol) of hydrogen chloride gas was added by bubbling at 20°C. Then, after sealing and stirring at a temperature from 90°C to 97°C for 8 hours, the reaction solution was cooled to 25°C. At this moment, the E type: Z type is 3.5:96.5. After adding 10 ml of toluene to dilute the reaction solution, the crystal was washed with 20 ml of toluene and further with 10 ml of acetone. It was dried at 50° C. to obtain 3.8 g (0.0101 mol) of olopatadine hydrochloride. The apparent yield was 83%, and the purity measured by HPLC was 97.5% for type Z and 1.1% for type E.

[0062] 1 H NMR (400MHz, DMSO-d 6 )δ2.73(s, 6H), 2.77(td, J=7.6, 7.2Hz,...

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Abstract

The present invention provides a method for producing a dibenzoxe compound. In a solvent, in the presence of an acid, the dibenzoyl compound represented by the formula (I) (in the formula, Me represents a methyl group, and R1, R2 and R3 each independently represent an alkyl group having 1 to 4 carbon atoms) is Olopatadine useful as a pharmaceutical can be produced efficiently and industrially advantageously by heating the oxa derivative or its salt.

Description

technical field [0001] The present invention relates to a method for producing olopatadine useful as a pharmaceutical. Background technique [0002] Olopatadine ((Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxa -2-acetic acid) (11-((Z)-3-(Dimethyl-amino)propylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid) is a compound represented by formula (II) , is a pharmaceutical compound useful as an antiallergic drug for allergic rhinitis, urticaria, and the like. [0003] [0004] In the manufacture of (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxa by chemical synthesis - In the case of 2-acetic acid, the E-form as an isomer is generally produced at the same time, so isomerization from the E-form to the Z-form is necessary in order to obtain more of the target Z-form. [0005] In Japanese Patent Publication No. 5-86925 and Japanese Patent Publication No. 7-116174, it is described that when the target object is obtained by E / Z mixture, it c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D313/12
CPCC07D313/12C07B49/00
Inventor 林健人桂正小松庆田中正英
Owner SUMITOMO CHEM CO LTD
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