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Preparation method of procaterol hydrochloride

A technology of procaterol hydrochloride and procaterol, which is applied in the direction of organic chemistry, can solve the problems of high production cost, achieve the effects of low price, save preparation time, and improve preparation efficiency

Active Publication Date: 2020-06-02
佛山市隆信医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The invention provides a preparation method of Procaterol hydrochloride, which solves the problem of high production cost of the existing Procaterol hydrochloride

Method used

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  • Preparation method of procaterol hydrochloride
  • Preparation method of procaterol hydrochloride
  • Preparation method of procaterol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The preparation of the present embodiment 5-(2-bromobutyryl)-8-hydroxyquinolone

[0050] Add carbon disulfide (600mL), 8-hydroxyquinoline nitrogen oxide (79.59g, 0.5mol), 2-bromobutyryl bromide (344.85g, 1.50mol) and aluminum trichloride ( 133.34g, 1.00mol), reacted for 3 hours at 25°C, filtered, recrystallized and dried with 800ml 95% ethanol to obtain yellow crystal 5-(2-bromobutyryl)-8-hydroxyquinolone (100.8g), yield 78%, Its purity was greater than 98% by HPLC.

[0051] The detection result of 5-(2-bromobutyryl)-8-hydroxyquinolone proton NMR spectrum is: 1 HNMRδ: 7.93~7.96(d, J=12Hz, 1H, ArH), 7.72~7.74(d, J=8Hz, 1H, ArH), 7.27~7.30(d, J=12Hz, 1H, ArH), 6.71~6.73 (d, J=8Hz, 1H, ArH), 11.27(s, 1H, NH), 12.28(s, 1H, OH), 5.70~5.74(t, J=8Hz, 1H, CH), 1.95~2.20(m ,2H,CH2 ), 1.02~1.06(t, J=8Hz, 3H, CH 3 )

Embodiment 2

[0053] This embodiment is the preparation of 5-(2-bromobutyryl)-8-hydroxyquinolone

[0054] Add nitrobenzene (550mL), 8-hydroxyquinoline nitrogen oxide (79.59g, 0.5mol), 2-bromobutyryl chloride (278.18g, 1.50mol) and aluminum trichloride to a 1000mL there-necked flask with mechanical stirring (133.34g, 1.00mol), reacted at 70°C for 6 hours, filtered, recrystallized from 700ml 95% ethanol and dried to obtain yellow crystal 5-(2-bromobutyryl)-8-hydroxyquinolone (96.15g), yield 75% , and its purity was greater than 98% as detected by HPLC.

Embodiment 3

[0056] Preparation of 5-(2-methylisopropylaminobutyryl)-8-hydroxyquinolone

[0057] Add methanol (600mL), 5-(2-bromobutyryl)-8-hydroxyquinolone (92.97g, 0.3mol) prepared in Example 1, isopropylamine (26.60g, 0.45 mol), be warming up to 60 DEG C and react for 8 hours, be down to room temperature, the pH of the reaction solution is adjusted to 2 with hydrochloric acid, and the solid is precipitated, filtered and washed with water to obtain 5-(2-methylisopropylaminobutyryl)-8-hydroxyquinolone ( 77.85g), its purity was greater than 99% as detected by HPLC, and its yield was 90%.

[0058] The detection result of 5-(2-methylisopropylamine butyryl)-8-hydroxyquinolone proton NMR spectrum is: 1 HNMRδ: 8.24~8.21(d, J=12Hz, 1H, ArH), 7.18~7.16(d, J=8Hz, 1H, ArH), 6.95~6.93(d, J=8Hz, 1H, ArH), 6.79~6.77 (d,J=8Hz,1H,ArH),11.43(s,1H,NH),4.13~4.11(m,1H,CH),3.98~3.66(q,J=4Hz,1H,CH),1.58~1.75 (m,2H,CH 2 ), 1.51~1.54 (t, J=8Hz, 6H, CH 3 ),0.71~0.74(t,J=8Hz,3H,CH 3 )

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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of procaterol hydrochloride. The invention discloses a preparation method of procaterolhydrochloride. The preparation method comprises the following steps of: reacting 8-hydroxyquinoline nitrogen oxide with 2-bromobutyryl halide to obtain 5-(2-bromobutyryl)-8-hydroxyquinolone, then carrying out aminolysis to obtain 5-(2-methylisopropylamine butyryl)-8-hydroxyquinolone, then carrying out hydrogenation reduction to obtain procaterol, and then conducting salifying on procaterol and hydrochloric acid to obtain procaterol hydrochloride. According to the preparation method of procaterol hydrochloride provided by the invention, cheap and easily available 8-hydroxyquinoline nitrogen oxide is used as a starting raw material to prepare procaterol hydrochloride, the production cost of procaterol hydrochloride is reduced, the preparation steps of 8-acetoxyquinolone and 8-hydroxyquinolone in a conventional route are omitted, the preparation steps of procaterol hydrochloride are simplified, and the reduction stereoselectivity is improved, so that the preparation time is saved, the preparation efficiency is improved, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of Procaterol Hydrochloride. Background technique [0002] Procaterol hydrochloride was invented and manufactured by Otsuka Pharmaceutical Co., Ltd., Japan, and is a bronchodilator. It is suitable for bronchial asthma, asthmatic bronchitis, acute bronchitis with increased bronchial reactivity, and chronic obstructive pulmonary disease. [0003] There are few published patent documents about the preparation of this product. The original Japanese Otsuka patent US4026897 describes the use of 2,8-dihydroxyquinoline as a starting material to prepare Procaterol hydrochloride through rearrangement, condensation, hydrogenation reduction, and salification. This preparation route adopts 2,8-dihydroxyquinoline with high cost as the starting material, and the hydrogenation selectivity is not high, resulting in high production cost of procaterol hydroc...

Claims

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Application Information

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IPC IPC(8): C07D215/26
CPCC07D215/26
Inventor 封康黄绍智陈奕文石磊何衍健
Owner 佛山市隆信医药科技有限公司
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