Method for synthesizing intermediate of 17-hydroxy acylated cortical hormone steroid medicament

A technology of corticosteroid and synthesis method, applied in the field of green new process of corticosteroid, can solve the problems of unrecoverable acid catalyst and multiple pollutants, and achieve the effect of simplifying post-processing, prolonging reaction time, improving purity and yield

Inactive Publication Date: 2013-07-10
SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the second step of hydrolysis reaction, a serious side reaction is the side reaction of 21-hydroxyl ester group protection, which needs to use weak acid aqueous solution to catalyze the reaction, and needs to use a large amount of water in the reaction and washing process, and the acid catalyst used at the same time cannot Recycling, resulting in the generation of more pollutants

Method used

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  • Method for synthesizing intermediate of 17-hydroxy acylated cortical hormone steroid medicament
  • Method for synthesizing intermediate of 17-hydroxy acylated cortical hormone steroid medicament
  • Method for synthesizing intermediate of 17-hydroxy acylated cortical hormone steroid medicament

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The synthesis of embodiment 1 methylprednisolone ethyl cypionate 2-1

[0030]

[0031] Suspend 8.0 g of methylprednisolone 1-1 in 120 mL of dichloromethane, add 8 mL of triethyl orthopropionate, and add 200 mg of p-toluenesulfonic acid at room temperature. After stirring for 5 minutes, the system is completely clear, and TLC shows that the reaction is basically complete. To ensure complete reaction, the reaction was continued for 30 minutes. The solvent was removed to obtain a viscous oil. Add 100mL of petroleum ether and stir at room temperature. The solid gradually precipitated, filtered with suction, washed twice with petroleum ether (25mL), and the obtained solid 2-1 was drained to obtain 8.6g of pure product.

[0032] Compound 2-1: molecular weight, 458.59; 1 H NMR (400MHz, CDCl 3 )δ7.29(d,J=10.1Hz,1H),6.26(dd,J=10.1,1.2Hz,1H),6.01(s,1H),4.55–4.26(m,1H),4.14(d,J =16.6Hz,1H),3.91(d,J=16.6Hz,1H),3.51–3.35(m,2H),1.75(q,J=7.5Hz,3H),1.44(s,3H),1.10(d ,J=7.5Hz,3H)...

Embodiment 2

[0033] The synthesis of embodiment 2 methylprednisolone cypionate 2-1-1

[0034]

[0035] Use trimethyl orthopropionate to replace triethyl orthopropionate in embodiment 1, can obtain following cyclic ortho ester intermediate 2-1-1 in the same way:

[0036] Suspend 8.0 g of methylprednisolone 1-1 in 120 mL of dichloromethane, add 8 ml of trimethyl orthopropionate, add 200 mg of p-toluenesulfonic acid at room temperature, stir for 5 minutes and the system is completely clear, and TLC shows that the reaction is basically complete. To ensure complete reaction, the reaction was continued for 30 minutes. Remove the solvent to obtain a viscous oil, add 100mL of petroleum ether, stir at room temperature, the solid gradually precipitates, filter with suction, wash twice with petroleum ether (25mL), and drain the obtained solid 2-1-1 to obtain 7.9g of pure product .

[0037] Compound 2-1-1: molecular weight, 444.56; 1 H NMR (400MHz, CDCl 3 )δ7.30(d,J=10.1Hz,1H),6.24(dd,J=10.1,1....

Embodiment 3

[0038] The synthesis of embodiment 3 prednisolone ethyl cypropropionate 2-2

[0039]

[0040] Use prednisolone 1-2 to replace methylprednisolone 1-1 in embodiment 1, can obtain following cyclic ortho ester intermediate 2-2 in the same way:

[0041] Suspend 8.0 g of prednisolone 1-2 in 120 mL of dichloromethane, add 8 ml of triethyl orthopropionate, add 200 mg of p-toluenesulfonic acid at room temperature, stir for 5 minutes and the system is completely clear, and TLC shows that the reaction is basically complete. To ensure complete reaction, the reaction was continued for 30 minutes. The solvent was removed to obtain a viscous oil. Add 100mL of petroleum ether and stir at room temperature. The solid gradually precipitated, filtered with suction, washed twice with petroleum ether (25mL), and the obtained solid 2-2 was drained to obtain 8.2g of pure product.

[0042] Compound 2-2: molecular weight, 444.56; 1 H NMR (300MHz, CDCl 3 )δ7.28(d,J=10.2Hz,1H),6.39–6.09(m,1H),6.00(s,...

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Abstract

The invention provides a method for synthesizing an intermediate of a 17-bit hydroxyl acylated cortical hormone steroid medicament. The intermediate compound has a structural formula shown in the specification; 17-steroid carboxylic ester has a structural formula shown in the specification; and according to the method, a 17-bit ester group protected product is obtained by reducing an acid ester open loop under the catalysis of a gluconic acid aqueous solution. By adopting the method, a hydrolysis reaction is carried out by using the recyclable gluconic acid aqueous solution for catalysis, so that the use of organic solvent and reagents is effectively reduced, the cost is reduced, pollution is reduced, and the synthesis process is simplified.

Description

technical field [0001] The invention relates to the synthesis of an important 17-hydroxy acylated corticosteroid steroid drug intermediate. The method avoids the 21-position by-product of esterification, and is also a new green process for corticosteroids protected by the 17-hydroxy ester group. Background technique [0002] Glucocorticoid (Glucocorticoid) is an important class of steroid drugs, it has good anti-inflammatory and antipyretic effects, can improve the symptoms of poisoning, and can resist shock. This makes it useful in a wide range of therapeutic processes ranging from allergic inflammation to wound healing after surgery. Take fluticasone propionate, which treats allergic rhinitis and asthma, as an example, and its current annual sales are close to 10 billion US dollars. [0003] The research on the in vivo metabolic process of the first-generation corticosteroid hydrocortisone found that the side effects of some drugs can be suppressed while improving the act...

Claims

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Application Information

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IPC IPC(8): C07J5/00
Inventor 丁凯
Owner SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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