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Preparation method of 6 beta-methylprednisolone

A technology for methylprednisolone and methylene, which is applied in the field of compound preparation, can solve the problems of long synthesis route, danger, low yield and the like, and achieves the effects of easy control, low cost and simple operation.

Active Publication Date: 2020-01-07
TIANJIN PHARMA GROUP CORP
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Problems solved by technology

[0004] Chinese patent CN107602652 discloses a method for preparing 6β-methylprednisolone, but the synthesis route is relatively long, and the route includes Grignard reaction, iodine reaction and biological dehydrogenation
In this patent, some 6β methyl products are prepared in the process of preparing 6α methyl, and the yield is low. This reaction method requires the presence of argon and hydrogen to participate in the reaction. The operation requires the use of an autoclave, which is inconvenient to operate Flammable and explosive is more dangerous, and in this invention the 6β methyl product exists in the form of impurities

Method used

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  • Preparation method of 6 beta-methylprednisolone
  • Preparation method of 6 beta-methylprednisolone
  • Preparation method of 6 beta-methylprednisolone

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Embodiment 1

[0041] The preparation of embodiment 1 methylene intermediate

Embodiment 1-1

[0043] Dissolve 100g of hydrocortisone in 1L of ethanol, add 80ml of triethyl orthoformate and 1g of p-toluenesulfonic acid, stir at room temperature for 10 minutes, add 120ml of 40% formaldehyde aqueous solution and 80ml of N-methylaniline, stir at room temperature for 3 hours, add Concentrated hydrochloric acid adjusted the pH value of the reaction solution to 1-2, and kept stirring for 2 hours; the reaction solution was diluted into 3 L of water, and solids were precipitated, filtered with suction, and the filter cake was washed with water until neutral, and dried to obtain 98.5 g of methylene intermediate, molar yield Yield 94.8%, HPLC purity 95%.

Embodiment 1-2

[0045] Dissolve 36g of hydrocortisone in 400mL of methanol, add 45ml of trimethyl orthoformate and 0.5g of p-toluenesulfonic acid, stir at room temperature for 10 minutes, add 60ml of 40% aqueous formaldehyde and 45ml of N-methylaniline, and stir at room temperature for 3 hours. Add concentrated sulfuric acid to adjust the pH value of the reaction solution to 1-2, keep stirring for 2 hours; dilute the reaction solution into 1.5L water, precipitate solids, filter with suction, wash the filter cake with water until neutral, and dry to obtain 35.1 g of methylene intermediate. The molar yield is 93.9%, and the HPLC purity is 94%.

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Abstract

The invention provides a preparation method of 6 beta-methylprednisolone. Hydrocortisone is used as a reaction initiator, and 6 beta-methylprednisolone is prepared through methylene reaction, reduction reaction, and dehydrogenation reaction. The preparation method comprises following steps: (1) methylene reaction: reacting hydrocortisone with an alkylation reagent at the temperature of 0-50 DEG Cin the presence of a catalyst, then reacting with formaldehyde and N-methylaniline, adjusting the pH value to 1-2 to achieve acidic conditions, and obtaining a methylene intermediate after the reaction is finished; (2) reduction reaction: heating the methylene intermediate and cyclohexene to react under the catalysis of palladium on carbon and a monophosphite ester ligand to prepare a reduction product; and (3) dehydrogenation reaction: carrying out heating reflux reaction on the reduction product and a dehydrogenation reagent to obtain the 6 beta methylprednisolone. The preparation method hasthe beneficial effects that the catalyst is added in the reduction reaction, so that the 6 beta-methylprednisolone can be prepared through three-step chemical reaction.

Description

technical field [0001] The invention relates to a new method for preparing a compound, in particular to a method for preparing 6β-methylprednisolone. Background technique [0002] Methylprednisolone belongs to glucocorticoid drugs and is used for emergency treatment of critical illnesses. It can also be used for endocrine disorders, rheumatic diseases, collagen venereal diseases, skin diseases, allergic reactions, eye diseases, gastrointestinal diseases, blood diseases, leukemia, Shock, cerebral edema, polyneuritis, myelitis, and prevention of vomiting caused by cancer chemotherapy. At present, it is mainly used clinically for organ transplantation. [0003] 6β-methylprednisolone is an important impurity in the finished product of methylprednisolone and has no pharmacological activity. In order to better control the quality of methylprednisolone, the impurities therein must be controlled, so it is necessary to prepare this substance as a reference substance. [0004] Chin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
CPCC07J5/0053
Inventor 陈伟李桢张成飞
Owner TIANJIN PHARMA GROUP CORP
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