Novel synthesis process of procaterol hydrochloride

A technology of procaterol hydrochloride and synthetic method, which is applied in the field of drug synthesis, can solve problems such as inability to obtain key intermediates, and achieve the effect of simple synthesis process and improved efficiency

Active Publication Date: 2022-03-22
四川美域高生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The two synthetic processes have their own advantages and disadvantages. Considering the relative simplicity of the process and the source of raw materials, the author believes that the techn

Method used

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  • Novel synthesis process of procaterol hydrochloride
  • Novel synthesis process of procaterol hydrochloride
  • Novel synthesis process of procaterol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1 Synthesis of 5-(2-bromobutyryl)-8-benzyloxyquinolone

[0077] In the reaction flask, add 8-butyryloxyquinolone (54.43g, 0.26mol) shown in formula I, 350.0mL of chloroform and anhydrous aluminum chloride (103.81g, 0.78mol) in turn, stir at room temperature and then add dropwise Butyryl chloride (33.25g, 0.32mol), then heated up to 80°C and reacted for 8h, slowly added the reactant to frozen hydrochloric acid (300.0mL, 5mol / L), filtered, washed with 300mL deionized water, and dried to obtain formula II The shown substance (the mixture of 2A and 2B, the next step reaction is not separated), the yield is 96.0%, and the [M+H] of the two substances by LC-MS at 2.67min and 3.17min + The nucleoplasmic ratio was both 232.1.

[0078] Add water 215.0mL and potassium carbonate (63.45g, 0.46mol) to the reaction flask successively, add acetonitrile 325.0mL and the mixture of 2A and 2B shown in formula II (54.00g, 0.23mol) under stirring, heat to 80 ℃ and drop Benzyl bromi...

Embodiment 2

[0083] Example 2 Synthesis of 5-(2-bromobutyryl)-8-benzyloxyquinolone:

[0084] Add 8-butyryloxyquinolone shown in formula I (54.43g, 0.26mol), dichloroethane 450.0mL and anhydrous aluminum chloride (109.1g, 0.82mol) in the reaction flask in sequence, and stir evenly at room temperature Afterwards, butyryl chloride (37.41g, 0.36mol) was added dropwise, and then the temperature was raised to 85°C for 9h, and the reactant was slowly added to frozen hydrochloric acid (300.0mL, 5mol / L), filtered, washed with 300mL deionized water, and dried Formula II (mixture of 2A and 2B, proceed to the next reaction without separation) was obtained with a yield of 96.5%.

[0085] Add water 215.0mL and potassium carbonate (63.45g, 0.46mol) in turn to the reaction flask, add acetonitrile 325.0mL and the mixture of 2A and 2B shown in formula II (54.00g, 0.23mol) under stirring, heat to 80°C and add dropwise Benzyl bromide (51.37g, 0.30mol) was reacted for 5h. Add 100.0 mL of water to the reactan...

Embodiment 3

[0103] Example 3 Synthesis of 5-(2-isopropylaminobutyryl)-8-benzyloxyquinolone

[0104] Add formula IV (30.00g, 0.075mol) obtained in Example 1, 300.0mL tetrahydrofuran and isopropylamine (88.50g, 1.5mol) to the reaction flask in sequence, stir and react at 50°C for 8h, concentrate, and use n-hexane 180.0mL and methyl tertiary A mixed solvent composed of 60.0 mL of butyl ether was crystallized, filtered, and dried to obtain 25.3 g of formula V (5-(2-isopropylaminobutyryl)-8-hydroxyquinolone), with a yield of 89.2% and a purity of greater than 97% by HPLC. %.

[0105] 5-(2-isopropylaminobutyryl)-8-benzyloxyquinolone H NMR spectrum: 1 H NMR (400MHz, DMSO-d 6 )δ: 11.22 (s, 1H, H1), 8.57 (d, J = 10.0Hz, 1H, H3), 8.11 (d, J = 8.7Hz, 1H, H4), 7.68–7.55 (m, 2H, H7) ,7.44–7.37(m,2H,H8),7.36–7.30(m,2H,H9 and H5),6.74(t,J=8.9Hz,1H,H2),5.50–5.37(m,2H,H6), 4.02(q,J=7.1Hz,1H,H10),3.27(s,1H,H14),1.98(s,1H,H13),1.29(dt,J=28.9,14.4Hz,6H,H15),1.20– 1.13 (m, 2H, H11), 0.77 (t, J=7.5Hz, 3H,...

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis process of procaterol hydrochloride. The invention provides a synthesis method of procaterol hydrochloride. The method sequentially comprises the following steps: step 1, carrying out Fries rearrangement reaction on 8-butyryloxy quinolone and butyryl chloride to obtain a mixture; 2, directly reacting the mixture obtained in the step 1 with a benzyl compound and alkali to obtain a mixture; step 3, enabling the mixture obtained in the step 2 to react with pyridinium tribromide in tetrahydrofuran to obtain 5-(2-bromobutyryl)-8-benzyloxy quinolone; step 4, carrying out ammonolysis reaction on the product in the step 3 and isopropylamine in tetrahydrofuran; 5, the product in the step 4 is subjected to a reduction reaction in an alcohol solvent, and 5-(2-isopropylamine-1-hydroxybutyl)-8-benzyloxy quinolone is obtained; and 6, carrying out hydrogenation reduction reaction on the product obtained in the step 5 under the catalysis of a catalyst, and carrying out salt forming reaction with hydrochloric acid to obtain procaterol hydrochloride.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a synthesis process of Procaterol Hydrochloride. Background technique [0002] The chemical name of Procaterol Hydrochloride is 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxyquinolone, and its hydrochloride acts as a selective β2 receptor agonist bronchodilator , for the treatment of diseases that cause dyspnea due to bronchial asthma, chronic obstructive pulmonary disease, asthmatic bronchitis, acute bronchitis, chronic bronchitis, etc. Since 1980, dosage forms such as tablets, oral liquids, powder sprays and aerosols have been approved for marketing. In the 2019 edition of the National Medical Insurance, granules, oral liquids, tablets and capsules are included in Class B medical insurance. [0003] The open patent literature about this product synthetic technique is seldom, and in 1976, Yoshizaki, Shiro etc. disclosed the original research synthetic route o...

Claims

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Application Information

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IPC IPC(8): C07D215/26
CPCC07D215/26Y02P20/584
Inventor 刘治国王春燕随裕敏余乐乐
Owner 四川美域高生物医药科技有限公司
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