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Stable carteolol hydrochloride, its preparation method and ophthalmic pharmaceutical composition

A technology of hydrochloric acid card and reactants, applied in the field of medicine, can solve problems such as difficult removal of imine products, easy excessive dehydrogenation, harsh operating conditions, etc.

Active Publication Date: 2020-04-10
深圳市瑞霖医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

5-Hydroxy-3,4-dihydro-2(1H)-quinolone can be obtained by amination of 1,3-cyclohexanedione, condensation with allyl acid, and dehydroaromatization [Shono T, Matsumura Y, Kashimura S.A new practical synthesis of 5-hydroxy-3,4-dihydrocarbostyril and 5-hydroxycarbostyril[J].J Org Chem,1981,46(18):3719-3721; Tamura Y,Terashima M,Higuchi Y,et al.Synthesis of 5-hydroxy and alkoxy-3,4-dihydrocarbostyils[J].Chem Ind(London), 1970,7(45):1435], the operating conditions of this method are relatively harsh, and it is necessary to use liquid ammonia for ammoniation and noble metal catalysts for high temperature removal Hydroaromatization, and easily over-dehydrogenated to obtain by-products
There are literature [Huang YH, Hartmann RW.The improved preparation of 7,8-dihydroquinoline-5(6H)-one and 6,7-dihydro-5H-1-pyrindin-5-one[J].Synth Commun,1998,28 (7): 1197-1200] Using 1,3-cyclohexanedione and ammonium acetate to reflux ammoniation in benzene can avoid the use of liquid ammonia, but the solvent is highly toxic; it was later reported [Wang GW, MiaoCB. Environmentally benign one -pot multi-component approaches to the synthesis of novel unsymmetrical 4-arylacridinediones [J]. Green Chem, 2006, 8: 1080-1085] changed to hydrogenation and dehydroaromatization under solvent-free conditions, which simplifies the operation , but will generate imine products that are not easy to remove

Method used

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  • Stable carteolol hydrochloride, its preparation method and ophthalmic pharmaceutical composition
  • Stable carteolol hydrochloride, its preparation method and ophthalmic pharmaceutical composition
  • Stable carteolol hydrochloride, its preparation method and ophthalmic pharmaceutical composition

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] Embodiment 1: preparation carteolol hydrochloride

[0119] This embodiment adopts the following reaction scheme

[0120]

[0121]

[0122] Step a: Preparation of 3-amino-2-cyclohexenone

[0123] Add 1,3-cyclohexanedione (3.36g, 0.03mol) and ammonium acetate (3.23g, 0.042mol) into a 100ml three-neck flask, stir well, and react in an oil bath at 100°C for 20min, remove the oil bath Natural cooling, during which the reaction solution solidified, cooled to room temperature, added ethyl acetate (10ml), heated to dissolve, cooled to 0 ° C, filtered, and the filter cake was dried to obtain yellow crystals as 3-amino-2-cyclohexenone ( 3.09g, yield 93.2%), mp 132~134℃ (document [Wang GW, Miao CB. Environmentally benign one-pot multi-component approaches to the synthesis of novelunsymmetrical 4-arylacridinediones [J]. Green Chem, 2006,8: 1080-1085]: yield 90%, mp 133-134°C).

[0124] Step b: Preparation of 3,4,7,8-tetrahydro-2,5(1H,6H)-quinolinedione

[0125] Add 3-am...

Embodiment 2

[0133] Embodiment 2: preparation carteolol hydrochloride

[0134] Step a: Preparation of 3-amino-2-cyclohexenone

[0135] Add 1,3-cyclohexanedione (0.03mol) and ammonium acetate (0.042mol) into a 100ml three-neck flask, stir well, react in an oil bath at 100°C for 20min, remove the oil bath and cool naturally, during which the reaction liquid Solidify, add ethyl acetate (10ml) after cooling to room temperature, heat to dissolve and then cool to 0°C, filter, and dry the filter cake to obtain yellow crystals as 3-amino-2-cyclohexenone (yield 93.2%), mp 132-133°C.

[0136] Step b: Preparation of 3,4,7,8-tetrahydro-2,5(1H,6H)-quinolinedione

[0137] Add 3-amino-2-cyclohexenone (0.02mol) and acrylic acid (0.03mol) into a 100ml three-necked flask, heat up to reflux for 4 hours with stirring, cool to room temperature, the reaction solution solidifies to obtain a reddish-brown solid, add Water ethanol (5ml), heated to dissolve and then cooled to room temperature, filtered, and th...

Embodiment 3

[0144] Embodiment 3: preparation carteolol hydrochloride

[0145] Step a: Preparation of 3-amino-2-cyclohexenone

[0146] Add 1,3-cyclohexanedione (0.03mol) and ammonium acetate (0.039mol) into a 100ml three-neck flask, stir well, react in an oil bath at 110°C for 15min, remove the oil bath and cool naturally, during which the reaction liquid After solidification, add ethyl acetate (10ml) after cooling to room temperature, heat to dissolve, then cool to 0°C, filter, and dry the filter cake to obtain yellow crystals as 3-amino-2-cyclohexenone (yield 93.6%). mp 132-133°C.

[0147] Step b: Preparation of 3,4,7,8-tetrahydro-2,5(1H,6H)-quinolinedione

[0148] Add 3-amino-2-cyclohexenone (0.02mol) and acrylic acid (0.032mol) into a 100ml three-necked flask, heat up to reflux for 3 hours with stirring, cool to room temperature, the reaction solution solidifies to obtain a reddish-brown solid, add Water ethanol (5ml), heated to dissolve and then cooled to room temperature, filter...

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Abstract

The invention relates to stable carteolol hydrochloride, a preparation method thereof and an eye medicine combination, in particular to a method for preparing carteolol hydrochloride. The method comprises the following steps of preparing 3-amino-2-cyclohexenone, tetrahydro-2,5(1H, 6H)-quinolinone, 5-hydroxy-3,4-dihydro-2(1H)-carbostyril and 5-(2,3-epoxypropoxy)-3,4-dihydro-2(1H)-carbostyril, and then the carteolol hydrochloride is obtained. Furthermore, the invention provides the carteolol hydrochloride crude medicine obtained according to the method, the eye medicine combination prepared by using the obtained carteolol hydrochloride as the crude medicine, and applications of the obtained carteolol hydrochloride to preparation of drugs for treating or preventing glaucoma or ocular hypertension. The method has excellent pharmaceutical characteristics, for example, the obtained crude medicine and a preparation has excellent stability.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a beta-adrenergic receptor blocker, its preparation method and eye drop pharmaceutical composition containing it, in particular to carteolol hydrochloride, its preparation method and its containing Eye drops pharmaceutical composition. The carteolol hydrochloride prepared by the invention has excellent medicinal properties. Background technique [0002] Carteolol (Carteolol), clinically used as its hydrochloride, also known as carteolol, is a β-adrenergic receptor blocker developed by Otsuka Pharmaceutical Company of Japan. Launched under the trade name Milelan. On January 22, 1997, with the approval of the State Food and Drug Administration, China Otsuka Pharmaceutical Co., Ltd. began to produce carteolol hydrochloride eye drops with the trade name "Mekailang". So far, the domestic clinical use is mainly the carteolol hydrochloride eye drops produced by China Otsuka Pharmaceut...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/227A61K31/4704A61P27/02A61P27/06A61K9/08
CPCA61K9/0048A61K9/08A61K31/4704A61K47/02A61K47/12A61K47/186C07D215/227
Inventor 张静刘丰华方子华刘瑄杨玲
Owner 深圳市瑞霖医药有限公司
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