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The synthetic method of fluticasone propionate key intermediate

A technology of fluticasone propionate and a synthetic method, which is applied in the production of steroids, bulk chemicals, organic chemistry, etc., can solve the problems of reduced yield and slow reaction speed, and achieve improved purity, simplified post-processing, and low process costs. Improved effect

Inactive Publication Date: 2015-11-18
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Wherein in the second step 17-hydroxyl propionylation process, due to the influence of the 16-position methyl group, the reaction rate slows down, which will produce two unfavorable consequences. 1) The hydroxyl group at the 11-position will also be partially acylated, and the yield reduce

Method used

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  • The synthetic method of fluticasone propionate key intermediate
  • The synthetic method of fluticasone propionate key intermediate
  • The synthetic method of fluticasone propionate key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The synthesis of embodiment 1 flumetasone ethyl cyclopropionate I-1

[0022]

[0023] Suspend 4.2 g of flumetasone (SM) in 20 mL of dichloromethane, add 4.2 ml of triethyl orthopropionate, add 210 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. Most of 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 I-1 was drained to obtain 4.1g of pure product. .

[0024] 1 HNMR (400MHz, CDCl 3 )δ7.27(d, J=9.9Hz, 1H), 6.32(dd, J=10.1, 1.7Hz, 1H), 6.10(s, 1H), 4.35(dd, J=9.3, 5.0Hz, 1H), 4.00(d,J=17.2Hz,1H),3.89(d,J=16.7Hz,1H),3.47(dq,J=9.2,7.3Hz,1H),3.35(dq,J=8.8,7.1Hz,1H ),1.54(s,3H),1.11(t,J=7.0Hz,3H),0.97(s,3H),0.9...

Embodiment 2

[0025] The synthesis of embodiment 2 flumetasone methyl cypionate I-2

[0026]

[0027] Use trimethyl orthopropionate to replace triethyl orthopropionate in Example 1, the following cyclic ortho ester intermediate I-2 can be obtained in the same way:

[0028] Suspend 4.2 g of flumetasone (SM) in 20 mL of dichloromethane, add 4.2 ml of trimethyl orthopropionate, add 210 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. Suck off most of the solvent to obtain a viscous oil, add 100mL petroleum ether, stir at room temperature, the solid gradually precipitates, filter with suction, wash twice with petroleum ether (25mL), and drain the obtained solid I-2 to obtain 4.1g of pure product .

[0029] 1 HNMR (400MHz, CDCl 3 )δ7.25(d,J=9.7Hz,1H),6.32(dd,J=9.9,1.7Hz,1H),6.14(s,1H),4.38(dd,J=9.5,5.3Hz,1H),...

Embodiment 3

[0030] The oxidative hydrolysis of embodiment 3 flumetasone ethyl cyclopropionate I-1

[0031]

[0032] Dissolve 2.4 g of flumetasone ethyl cypionate I-1 in 50 mL of chloroform, add 100 mL of water and 5 mL of acetone, add 1.0 g of periodic acid in 20 mL of aqueous solution dropwise in an ice bath, add one hour, and continue stirring for 30 minutes. TLC tracking showed that the reaction was complete, separated, the oil phase was washed twice with 50 ml of water, dried over anhydrous sodium sulfate, concentrated to semi-dry, added 20 ml of petroleum ether, stirred for 10 minutes, collected the precipitated solid, and drained to obtain the pure intermediate II2. 2 grams. The crude product after washing and drying can also be directly used in the next step.

[0033] Compound II: molecular weight, 452.49; 1 HNMR (400MHz, CDCl 3 )δ7.27(t, J=5.0Hz, 1H), 6.28(dd, J=10.1, 1.4Hz, 1H), 6.03(s, 1H), 4.52(s, 1H), 4.29(dd, J=24.7 ,4.9Hz,1H),3.12(t,J=4.8Hz,1H),2.91–2.70(m,1H),2.59(td...

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Abstract

The invention provides a method for synthesizing a key intermediate of fluticasone propionate. According to the method, 17-hydroxy propionyl group protective group is efficiently introduced by using a strategy of a ring ortho-ester (I) open loop, and 20-bit carboxylic acid is constructed by using a strategy of a periodic acid in situ open loop and an oxidized open loop which are boiled in one boiler. The intermediate (I) has a structural formula shown in the specification, and the key intermediate (II) of fluticasone propionate has a structural formula shown in the specification. By adopting the process, the problem of selectively protecting 17-bit hydroxyl with crowded space is solved, the step is not increased, the operation is improved, and the cost is reduced.

Description

technical field [0001] The invention relates to a method for synthesizing a key intermediate of fluticasone propionate. The method solves the problem of selective protection of the 17-position hydroxyl group with space congestion, and provides a new synthesis route with high efficiency and low cost. 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 classic synthetic route to fluticasone propionate involves the following steps. Wherein in the second step 17-hydroxyl propionylation process, due to the influence of the 16-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J3/00
CPCY02P20/55
Inventor 丁凯宫丰杰
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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