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Intermediate for preparing procaterol hydrochloride and preparation method thereof

A technology for procaterol hydrochloride and intermediates, which is applied in the preparation of intermediates of procaterol hydrochloride and the field of preparation thereof, can solve the problems of not being able to obtain key intermediates and the like, and achieve the effects of simple synthesis process and improved efficiency

Active Publication Date: 2022-03-18
四川美域高生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] 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 technical route disclosed by the original research is more suitable for industrial production. The key intermediate 3 cannot be obtained by the reaction under the catalysis of water aluminum trichloride

Method used

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  • Intermediate for preparing procaterol hydrochloride and preparation method thereof
  • Intermediate for preparing procaterol hydrochloride and preparation method thereof
  • Intermediate for preparing procaterol hydrochloride and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1 Synthesis of 5-(2-isopropylaminobutyryl)-8-benzyloxyquinolone

[0079] 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.

[0080] 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 Ben...

Embodiment 2

[0089] Example 2 Synthesis of 5-(2-bromobutyryl)-8-benzyloxyquinolone:

[0090] 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%.

[0091] 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

[0117] Example 3 Synthesis of 5-(1-hydroxyl-2-isopropylaminobutyl)-8-benzyloxyquinolone

[0118] 5A (15.0 g, 0.04 mol) obtained in Example 1 and 150 mL of isopropanol were added to the three-neck flask, sodium borohydride (3.78 g, 0.1 mol) was added three times, and the reaction was stirred at 20° C. for 4 h, and 100.0 mL of water was added to quench the reaction. Extracted twice with 200mL ethyl acetate and combined, concentrated to obtain formula VI (6A: 5-(1-hydroxy-2-isopropylaminobutyl)-8-benzyloxyquinolone), the yield was 91.5%, and the HPLC detection purity was greater than 99%. %.

[0119] The H NMR spectrum of 5-(1-hydroxy-2-isopropylaminobutyl)-8-benzyloxyquinolone: 1 H NMR (400MHz, DMSO-d 6 ), δ / ppm: 10.60(s,1H,H1),8.16(d,J=10.0Hz,1H,H3),7.60–7.50(m,2H,H7),7.41–7.34(m,2H,H8) ,7.34–7.27(m,1H,H9),7.22–7.13(m,2H,H4 and H5),6.55(t,J=8.6Hz,1H,H2),5.29(s,2H,H6),4.92( s,1H,H10),1.42(tdd,J=20.6,12.4,8.4Hz,1H,H16),1.29–1.14(m,2H,H13),0.87(t,J=7.6Hz,3H,H14), 0.80-0.67(m,...

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to an intermediate capable of being used for preparing procaterol hydrochloride and a preparation method of the intermediate. The invention provides an intermediate. The structural formula of the intermediate is shown in the specification. According to the procaterol hydrochloride intermediate and the preparation method thereof, 8-butyryloxyquinolone is taken as a raw material, so that the use of a raw material 2-bromobutyryl chloride or 2-bromobutyryl bromide reagent which is unstable and causes more side reactions is avoided; the problems that the bromine bromination reaction conditions are harsh and difficult to control, the process stability and reproducibility are poor, and the use is inconvenient are solved. When the compound is used for preparing procaterol hydrochloride, the synthesis process is simple and easy to control, the efficiency is improved, and the compound 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 an intermediate capable of preparing Procaterol hydrochloride and a preparation method thereof. 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 bronchial asthma, chronic obstructive pulmonary disease, asthmatic bronchitis, acute bronchitis, chronic bronchitis and other diseases that cause dyspnea. 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 the Class B medical insurance. [0003] There are very few published patent documents about the synthesis process of this product. In 1976, Yoshizaki, S...

Claims

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Application Information

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IPC IPC(8): C07D215/26
CPCC07D215/26Y02P20/55
Inventor 刘治国王春燕随裕敏余乐乐杨梦蝶
Owner 四川美域高生物医药科技有限公司
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