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Preparation method of 16 beta-methyl steroid

A technology of methyl steroids and compounds, which is applied in the field of preparation of 16-position β-methyl steroids, can solve the problems of complex steps, many side reactions, and low yields, and achieve simple steps, convenient operation, and high yields Effect

Active Publication Date: 2016-06-22
HUNAN NORCHEM PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There are also a small number of literature reports to construct the 16-position β methyl group by oxalyl diethyl ester and methylating reagent before the side chain is introduced. This method has complicated steps, many side reactions, and low yield. It is difficult to obtain high-purity intermediates, such as The reporting process of patent CN103641878 (as shown in reaction scheme 2)

Method used

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  • Preparation method of 16 beta-methyl steroid
  • Preparation method of 16 beta-methyl steroid
  • Preparation method of 16 beta-methyl steroid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] A kind of preparation method of 16β-methyl steroid compound of the present invention, take 16α-methyl steroid compound Ia1 as starting material, carry out enolization reaction under the catalysis of base, prepare 16β-methyl steroid compound Ⅱa1, the reaction scheme is as follows:

[0038]

[0039] The preparation method specifically comprises the following steps:

[0040] In a three-necked flask with a thermometer and a Teflon mechanical stirring rod, add 100g of compound Ia1, 600ml of tetrahydrofuran (THF), replace with nitrogen three times, stir well, add 40g of potassium tert-butoxide, and stir at room temperature (20-25°C) React for 1 hour, then slowly lower the temperature to 0°C, keep stirring for 30 minutes, then continue to slowly cool down to -60°C and stir for 2 hours. When TLC or HPLC detects that the main raw material is less than 3%, stop the reaction, slowly drop 50ml of water to quench the reaction, and then dropwise add glacial acetic acid to adjust ...

Embodiment 2

[0043] A kind of preparation method of 16β-methyl steroid compound of the present invention, take compound Ia2 as starting material, carry out enolization reaction under the catalysis of acid, prepare 16β-methyl steroid compound IIa2, the reaction route is as follows:

[0044]

[0045] The preparation method specifically comprises the following steps:

[0046] In a three-necked flask with a thermometer and a Teflon mechanical stirring rod, add 100g of compound Ia2, 300ml of acetone, replace with nitrogen three times, stir evenly, add 10g of concentrated hydrochloric acid (mass fraction is 30%), heat up to 65 ° C, reflux and stir 1h, slowly cool down to 25°C, the cooling rate is 5°C / h, keep stirring at 25°C for 6h, continue to cool down to 0°C and stir for 3h. Add triethylamine to adjust the system to neutral, suction filter, wash the filter cake with a small amount of acetone, then wash with 200ml of water, and dry at 60°C to obtain 98g of crude product with HPLC purity of 95...

Embodiment 3

[0049] A kind of preparation method of 16β-methyl steroid compound of the present invention, take compound Ib1 as starting material, react under the catalysis of base, prepare 16β-methyl steroid compound IIa3, the reaction scheme is as follows:

[0050]

[0051] The preparation method specifically comprises the following steps:

[0052] In a three-necked flask with a thermometer and a Teflon mechanical stirring rod, add 100g of compound Ib1, 600mlTHF, replace with nitrogen three times, stir evenly, add 40g of potassium methoxide, stir and react at room temperature (20-25°C) for 1h, then slowly cool down to 0°C, keep stirring for 30min, then continue to slowly cool down to -60°C and stir for 2h. TLC detected that the main raw material of the reaction was less than 3%, stopped the reaction, slowly added 50ml of water dropwise to quench the reaction, then added dropwise 20% hydrochloric acid to adjust the system to acidity, pH = 2-3, and stirred for 30min. The completion of h...

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Abstract

The invention discloses a preparation method of 16 beta-methyl steroid. The preparation method includes: using 16 beta-methyl steroid I as a starting raw material and acid or alkali as a catalyst for enolization reaction to convert 16-bit alpha methyl into 16-bit beta methyl to obtain the 16 beta-methyl steroid II. The preparation method has the advantages of simple step, high yield and stable reaction.

Description

technical field [0001] The invention relates to a chemical synthesis method of an important intermediate of a class of steroid hormone drugs in the betamethasone series, in particular to a preparation method of a 16-beta methyl steroid compound. Background technique [0002] Betamethasone series products include betamethasone, betamethasone sodium phosphate, betamethasone acetate, clobetasol propionate, beclomethasone dipropionate, betamethasone valerate, etc. During the synthesis of hormone drugs, the structure of the 16β methyl group is very critical. [0003] In the traditional synthetic route, the structure of the β methyl group is completed after the 17-position side chain is constructed, and then the 16-position methyl group is introduced through various more complicated means. This kind of method has many steps, poor selectivity, and low yield. low and production safety hazards and other issues. As reported in patents CN1118351A and CN101851263A (as shown in Reactio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J1/00
CPCC07J1/00C07J1/0011
Inventor 唐杰刘喜荣曾春玲
Owner HUNAN NORCHEM PHARMACEUTICAL CO LTD