Preparation method for prednisone acetate and intermediate of same

A prednisone acetate and intermediate technology, applied in the field of prednisone acetate intermediate oxidation process, can solve the problems of high cost, unreachable, high reagent cost, etc., and achieve the effects of easy operation, low pollution and low cost

Inactive Publication Date: 2015-05-13
JIANGSU YUANDA XIANLE PHARMA
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Problems solved by technology

First, 4AD can be synthesized through three-step reactions to obtain 17α-hydroxyprogesterone, an important intermediate of steroid drugs. Because of the 17-position hydroxyl group, it is easy to obtain 11α, 17α-dihydroxy progesterone by biological fermentation; after introducing the 11-position hydroxyl group, the 1, 2-position double bond can also be introduced by biological fermentation to obtain 11α, 17α-dihydroxy progesterone Pregna-1,4-diene-3,20-dione intermediate; the last thing to be solved is the introduction of the 11-position carbonyl, which can be realized by oxidation methods. The inventor has tested some common oxidation methods, such as The Platts oxidation method reported in the document CN201210070704.7, this oxidation method is used to oxidize this intermediate, one is the low yield, which can only reach about 80%, and the other is the low purity, the HPLC purity is only 85%, which is obviously not very applicable ; Another example is document CN201110101279.9, which uses a positive halide (hypohalous acid and its salt) as an oxidizing agent to oxidize the 11-position hydroxyl group to the 11-position carbonyl group. This oxidation method also has the problems of low yield and high cost; In addition, the present inventors have also tested the Austenitic oxidation method, the Swern oxidation (Swern oxidation) method, the Dess-Martin reagent oxidation method, the PCC reagent oxidation method, the Collins reagent oxidation method, the pyridine-sulfur trioxide oxidation method, etc., and these oxidation methods The cost of some reagents in the method is very high, the oxidation effect of some reagents is not ideal, and the expected result cannot be achieved. After a large number of scientific research experiments by the inventor, a new oxidation method was finally found. This method not only has high yield, but also Moreover, the process is simple and stable, suitable for large-scale industrial production, and the 17α-hydroxypregna-1,4-diene-3,11,20-trione obtained by oxidation can be obtained through a simple iodine replacement reaction to obtain diethyl acetate Nissun, the whole route is low in cost and easy to operate, which greatly reduces the pressure on environmental pollution

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  • Preparation method for prednisone acetate and intermediate of same
  • Preparation method for prednisone acetate and intermediate of same
  • Preparation method for prednisone acetate and intermediate of same

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Embodiment 1

[0045] A kind of preparation method of prednisone acetate intermediate, described prednisone acetate intermediate refers to 17α-hydroxy pregna-1,4-diene-3,11,20-trione, described preparation method include:

[0046] In the preparation tank, add 10Kg of water, then slowly add 5Kg of concentrated nitric acid, and stir for ten minutes. Then add 5 Kg of manganese oxide, stir to dissolve, cool down to 10-15°C to obtain oxidant A, and set aside.

[0047] In the reaction tank, add 50Kg acetone, 10Kg glacial acetic acid, 1.2Kg manganese chloride and 10 kg raw material (11α, 17α-dihydroxypregna-1,4-diene-3,20-dione), stir to dissolve . Control the temperature at 0~5°C. Add the prepared oxidant A dropwise, control the temperature at 0-5°C, and complete the dropwise addition in about 1.5 hours. Stirring, thin-layer chromatography analysis, until the reaction of raw materials is complete. Add dropwise a mixed solution of 5Kg sodium bisulfite and 50Kg water, control the temperature be...

Embodiment 2

[0049] A kind of preparation method of prednisone acetate intermediate, described prednisone acetate intermediate refers to 17α-hydroxy pregna-1,4-diene-3,11,20-trione, described preparation method include:

[0050] In the preparation tank, add 20Kg of water, then slowly add 10Kg of concentrated sulfuric acid, and stir for ten minutes. Add 10 Kg of chromium trioxide, stir to dissolve. Cool down to 0~10°C to obtain oxidizing agent A and set aside.

[0051] In the reaction tank, add 250 Kg of dioxane, 5Kg of glacial acetic acid, 1.5Kg of manganese chloride and 10 kg of raw material (11α,17α-dihydroxypregna-1,4-diene-3,20-dione) , stir to dissolve. Control the temperature at 20~30°C. Add the prepared oxidant A dropwise, control the temperature at 20-30°C, and complete the dropwise addition in about 0.5 hours. Stirring, thin-layer chromatography analysis, until the reaction of raw materials is complete. Add dropwise a mixed solution of 12 Kg sodium dithionite and 50Kg water,...

Embodiment 3

[0053] A kind of preparation method of prednisone acetate intermediate, described prednisone acetate intermediate refers to 17α-hydroxy pregna-1,4-diene-3,11,20-trione, described preparation method include:

[0054] In the preparation tank, add 20Kg of water, then slowly add 5.5Kg of concentrated sulfuric acid, and stir for ten minutes. Add 6.8Kg of chromium trioxide and stir to dissolve. Lower the temperature to 20~30°C to obtain oxidant A, which is set aside.

[0055] In the reaction tank, add 330 Kg of dichloromethane, 10Kg of glacial acetic acid, 1.5Kg of manganese chloride and 10 kg of raw material (11α, 17α-dihydroxypregna-1,4-diene-3,20-dione), Stir to dissolve. Control the temperature at -20~10°C. Add the prepared oxidant A dropwise, control the temperature at -20~10°C, and complete the dropwise addition in about 0.5 hours. Stirring, thin-layer chromatography analysis, until the reaction of raw materials is complete. Add dropwise a mixed solution of 8 Kg sodium d...

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Abstract

The invention relates to the field of preparation of steroid drugs and an intermediate of the same, and in particular relates to a preparation method for prednisone acetate. The method comprises the steps of taking 11 alpha, 17 alpha-dyhydroxy Pregnene-1,4-diene-3,20-dione as an initial material, oxidizing to obtain 17 alpha-hydroxy Pregnene-1,4-diene-3,11,20-trione, and carrying out iodization reacting to obtain the prednisone acetate. The invention provides a novel oxidation technology more suitable for production of the intermediate of the prednisone acetate, the synthesis path has the characteristics of low cost and simple operation, environment pollution pressure can be greatly reduce, and the yield and quality of the prednisone acetate can reach a satisfactory level.

Description

technical field [0001] The present invention relates to a preparation method of steroid medicine and its intermediate, in particular to a preparation method of prednisone acetate and its intermediate (17α-hydroxypregna-1,4-diene-3,11,20-trione) The preparation method has invented a brand-new oxidation process of prednisone acetate intermediate which is more suitable for production. Background technique [0002] Steroid hormones have strong anti-infection, anti-allergic, anti-viral and anti-shock pharmacological effects, and are important drugs for treating rheumatism, cardiovascular, lymphoid leukemia, cellular encephalitis, skin diseases, anti-tumor and rescuing critically ill patients. Prednisone acetate is an important steroidal drug, mainly used for various acute severe bacterial infections, severe allergic diseases, collagen diseases (lupus erythematosus, nodular periarteritis, etc.), rheumatism, rheumatoid Arthritis, nephrotic syndrome, severe bronchial asthma, acute ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
CPCC07J5/0053C07J7/0045
Inventor 冯永华姚庆旦杜艳
Owner JIANGSU YUANDA XIANLE PHARMA
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