Preparation method for betamethasone intermediate or its analogue

A technology of betamethasone and its analogs, which is applied in the field of preparation of steroid hormone drug intermediates, can solve the problems of high cost and long reaction route, and achieve the effects of stable yield, high yield and high yield

Active Publication Date: 2014-03-19
HUNAN NORCHEM PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The above-mentioned reaction routes ar

Method used

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  • Preparation method for betamethasone intermediate or its analogue

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Experimental program
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Effect test

Embodiment 1

[0018] Elimination reaction

[0019] At room temperature, under the protection of nitrogen, add 400ml of anhydrous tetrahydrofuran to a clean and dry 500ml four-neck round-bottomed flask equipped with a thermometer, reflux condenser, and mechanical stirring, and add 80.0g of compound Ⅰ under stirring, and cool the system to 0 to 10°C , add 80.0 g of phosphorus pentachloride in batches at 0 to 10°C under temperature control, and keep warm at 0 to 10°C after the addition is complete. TLC followed the reaction until no raw material remained. The reaction system was added dropwise to 1 L of ice water, a large amount of solids were precipitated, and the stirring was continued for 2 hours. The system was suction-filtered, the filter cake was washed with water until it was neutral, and dried at 50°C to obtain 70.8 g of compound II with a yield of 88.5%. 96.8%.

[0020] methylation reaction

[0021] At room temperature, under the protection of nitrogen, weigh 50.0g of compound II ...

Embodiment 2

[0032] Elimination reaction

[0033] At room temperature, under the protection of nitrogen, add 450ml of anhydrous tetrahydrofuran to a clean and dry 500ml four-necked round-bottomed flask equipped with a thermometer, reflux condenser, and mechanical stirring, and add 80.0g of compound Ⅰ under stirring, and cool the system to 0 to 10°C , add 80.0 g of p-toluenesulfonyl chloride in batches under temperature control at 0 to 10°C, and keep warm at 0 to 10°C after the addition is complete. TLC followed the reaction until no raw material remained. The reaction system was added dropwise to 1 L of ice water, a large amount of solids were precipitated, and the stirring was continued for 2 hours. The system was suction-filtered, the filter cake was washed with water until it was neutral, and dried at 50°C to obtain 69.2 g of compound II with a yield of 86.5%. 96.2%.

[0034] methylation reaction

[0035] At room temperature, under the protection of nitrogen, weigh 50.0g of compound...

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Abstract

The invention relates to a preparation method of a steroid hormone medicinal intermediate, in particular to a preparation method for a betamethasone intermediate or its analogue. The betamethasone intermediate or its analogue is prepared from a compound I by means of elimination reaction, methylation reaction, cyano-group substitution reaction, siloxy protective reaction, intramolecular nucleophilic substitution reaction and esterification reaction. The method provided by the invention has the characteristics of cheap raw materials, and high and stable yield. The reaction route is as the following, wherein R1 is Cl or Br, and R is H or hydrocarbonyl of C1-C10.

Description

technical field [0001] The invention relates to a preparation method of a steroid hormone drug intermediate, in particular to a preparation method of a betamethasone intermediate or an analogue thereof. Background technique [0002] Betamethasone is mainly used for collagen diseases, such as rheumatoid arthritis, lupus erythematosus, rheumatic heart disease, myocarditis, etc., and for rescuing critically ill patients, with long-lasting effect. [0003] my country's steroid drug and its intermediate industry has a certain scale. At present, the synthesis of betamethasone or its analogues is mainly a preparation method combining biological fermentation and chemical synthesis, which has the problems of low yield and high cost. [0004] The difficulty in the preparation of betamethasone intermediates or their analogues lies in the introduction of the 9 (11) double bond and the 16 β-methyl group. At present, the commonly used starting materials for domestic production of betame...

Claims

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Application Information

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IPC IPC(8): C07J5/00
Inventor 刘喜荣
Owner HUNAN NORCHEM PHARMACEUTICAL CO LTD
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