High-yield simple preparation method of 17alpha-hydroxy progesterone
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A simple and simple technology for hydroxyprogesterone, which is applied in the field of medicine and chemical industry to achieve the effects of simplified process, high yield and mild reaction conditions
Inactive Publication Date: 2014-10-01
山东众诚生物医药股份有限公司
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[0004] In summary, the existing 17α-hydroxyprogesterone preparation process has many technical shortcomings and is also limited by many factors, so the preparation method of 17α-hydroxyprogesterone needs to be improved urgently
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Embodiment 1、17
[0031] The preparation of embodiment 1,17α-hydroxyprogesterone
[0032] 1. Add 50kg of methanol, 50kg of 4‐androstenedione, 100kg of acetone hydroalcohol into the reaction kettle, add 100kg of potassium hydroxide solution with a mass fraction of 0.1%, stir, control the temperature in the kettle to 50°C, and keep it warm at 50°C After the reaction was completed, the temperature was lowered to 0°C, filtered, washed with water, and dried to obtain 52.5kg of yellow solid 17-αhydroxyl-17-βcyanoandrost-4-en-3-one (II). 95.9%, HPLC content 98.5%.
[0033] Get the obtained 17-alpha hydroxy-17-beta cyanoandrost-4-en-3-one (II) 50kg and add in the reactor, then add ethylene glycol 150kg, triethyl orthoformate 100kg, p-toluenesulfonic acid Monohydrate 1.0kg, react at a temperature of 10-15°C for 24 hours, and the reaction is complete. Add sodium hydroxide solution, adjust pH=7-8, press filter, wash with water, and dry to obtain 55 kg of off-white solid ketal product (Ⅲ), the yield is 9...
Embodiment 2
[0036] As described in Example 1, the difference is that the initiator in step 2 is zinc chloride to obtain 45kg of 17α-hydroxyprogesterone, with a yield of 90.9%, the product appearance is white or off-white crystalline powder, the HPLC purity is 99.5%, and the melting point is: 219~220℃.
Embodiment 3
[0038] As described in Example 1, the difference is that the reflux time of step 2 is 11 hours, 45 kg of 17α-hydroxyprogesterone is obtained, the yield is 97.4%, the product appearance is white or off-white crystalline powder, the HPLC purity is 99.6%, and the melting point: 219.1-219.5 ℃.
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Abstract
The invention relates to a high-yield simple preparation method of 17alpha-hydroxy progesterone. With 4-androstenedione as an initial raw material, the method comprises the following steps: performing a cyanogen alcoholization addition reaction between the 17-site carbonyl of 4-androstenedione and acetone hydrogen alcohol to obtain 17-alpha hydroxyl-17-beta cyanoandrostane-4-ene-3-one; performing a ketal protection reaction of the C3-site carbonyl to obtain a ketal product; and performing a direct methylation reaction between the ketal product and zinc chloride methane, and hydrolyzing to obtain 17alpha-hydroxy progesterone. The method provided by the invention has the advantages of short process, high yield, high product purity, mild reaction conditions, low cost and low energy consumption and is particularly suitable for industrial production.
Description
technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of 17α-hydroxyprogesterone, an intermediate of steroid medicine. Background technique [0002] 17α-hydroxyprogesterone is a key intermediate in the synthesis of methadone, prednisolone, dexamethasone and many other steroidal drugs. The synthesis of 17α-hydroxyprogesterone from androstenedione has a short route, few steps and mild reaction , Low cost and other advantages. In the synthesis methods reported in the prior art, the 17-position hydroxyl protecting group is introduced to protect the 17-position hydroxyl group, and then the ketal is subjected to a methylation reaction. This reaction introduces a new group, which is not conducive to the recovery of the solvent in the later stage, increases the reaction steps, and increases the cost. [0003] CN103524588A discloses a method for preparing progesterone. The method uses 4-androst...
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