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Preparation of metacortandralone and derivatives thereof

A compound and reactant technology, applied in the field of preparation of steroid compounds, can solve the problems of high cost and low yield

Active Publication Date: 2009-04-01
TIANJIN PHARMA GROUP CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Method 2 has a lower yield in the hydrolysis process, and the single-step yield is only 80%, so the cost is also higher

Method used

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  • Preparation of metacortandralone and derivatives thereof
  • Preparation of metacortandralone and derivatives thereof
  • Preparation of metacortandralone and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] The preparation of embodiment one prednisolone and prednisolone ester

[0082] Bromination reaction: 9α-bromo-11β, 17α-dihydroxy-1,4-diene-pregna-3,20-dione;

[0083] Add 10g of 17α-hydroxy-1,4,9-triene-pregna-3,20-dione (CN1896090), 100ml of acetone into the reaction flask, stir, cool down to 0°C, and add NBS within 30 minutes 9g, kept at 5-10°C for 2.5 hours, added 10% sodium carbonate aqueous solution to neutralize to PH=6.5, diluted in water, filtered and dried to obtain 12.1g of bromide (1).

[0084] Debromination reaction: 11β, 17α-dihydroxy-1,4-diene-pregna-3,20-dione;

[0085] Prepare the reducing agent: take 10g of chromium particles in the reaction bottle, pass nitrogen gas, add 10ml of concentrated hydrochloric acid, react at room temperature for 20 minutes, and set aside.

[0086] Add 12.1g of bromide (1) and 60ml of dimethylformamide into another reaction flask, blow nitrogen, cool down to 10°C, slowly add the prepared chromium reducing agent, react for 3...

Embodiment 2

[0093] The preparation of embodiment two prednisolone and prednisolone ester

[0094] Bromination reaction: 9α-bromo-11β, 17α-dihydroxy-1,4-diene-pregna-3,20-dione;

[0095] Add 10g of 17α-hydroxy-1,4,9-triene-pregna-3,20-dione (CN1896090) and 50ml of tetrahydrofuran into the reaction flask, stir, cool down to 0°C, and divide into two parts within 30 minutes. Bromocyanoacetamide 7g, kept at 5-10°C for 1.5 hours, added 10% sodium bicarbonate aqueous solution to neutralize to pH=6.5, diluted in water, filtered, dried to obtain 12.2g of bromide (1).

[0096] Debromination reaction: 11β, 17α-dihydroxy-1,4-diene-pregna-3,20-dione;

[0097] Add 12.2g of bromide (1) and DMF110ml into the reaction flask, pass nitrogen, heat and control the temperature at 80-90°C, quickly drop 20ml of tributyltin hydride as a reducing agent, react for 1 hour, cool down to 30°C, pour 700ml of saturated Dilute in sodium chloride solution, stir for 1 hour, let stand for 1 hour, filter, wash with water u...

Embodiment 3

[0104] The preparation of embodiment three prednisolone and prednisolone ester

[0105] Iodine reaction: 21-diiodo-17α-hydroxy-1,4,9-triene-pregna-3,20-dione;

[0106] Add 160ml of methanol and 6g of calcium oxide into the reaction flask, add 90ml of methanol solution and 8.2g of anhydrous calcium chloride into another volumetric flask, take out 1 / 4 after dissolving, add to the reaction flask, and dissolve the rest 15.0g of iodine particles, Add 10 g of 17α-hydroxy-1,4,9-triene-pregna-3,20-dione (CN1896090) into the reaction flask, fill with nitrogen, control the temperature at 0±5°C, add iodine solution dropwise, about 3 After 1 hour of dripping, after another 1 hour of reaction, the reaction solution was diluted in 600ml of 2% ammonium chloride aqueous solution, stirred for 1 hour, left to stand for 1 hour, filtered, washed with water until neutral, and obtained the wet product iodide (6) , This product is unstable, no drying is required, and the storage time should not be ...

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Abstract

The invention relates to a preparation method of a steroid compound, in particular to the preparation for prednisolone and the derivative thereof, which takes 17-hydroxyl-1, 4, 9-triene- pregna-3, 20-diketone as the initiator and is improved by 9, 11th and 21st to obtain the prednisolone and the derivative thereof, such as prednisolone acetic ester, isoflupredone, and the like. The invention further provides the application of a compound (I) in the preparation of a compound (II). As the production process adopts the existing intermediate of the company as the initiator, the line is concise, the material is easy to obtain, expensive auxiliary materials are saved, and the yield and the cost are obviously superior to the historical synthetic method of the prednisolone and the derivative thereof; in addition, the adoption of the existing intermediate realizes the doubling production of the triamcinolone products and the prednisolone products, thus greatly reducing the production cost and industrial conditions. R1 is equal to H, F, Cl and Br; R2 is equal to H, OH and OCOR3, wherein, R3 is equal to the alkyl with less than 11carbon atoms.

Description

technical field [0001] The present invention relates to a kind of preparation method of steroid compound, especially relate to the preparation of prednisolone and its derivative. Background technique [0002] Prednisolone and its derivatives are intermediate-acting adrenocortical hormone drugs, which are widely used clinically. Their products include: prednisolone and prednisolone acetate. Prednisolone Sodium Phosphate etc. Its curative effect is equivalent to that of prednisone, and its anti-inflammatory effect is stronger, which is 3 to 5 times that of hydrocortisone. However, its water-salt metabolism effect is very weak, and it is generally not easy to cause side effects such as water and electrolyte disorders. At present, the products are oral and injection, and can also be applied externally to the skin. [0003] The synthesis process of prednisolone and its derivatives is earlier, see Schering patents US2837464A1 and US3134718A1. The synthesis method is to use hydr...

Claims

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Application Information

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IPC IPC(8): C07J7/00C07J5/00
Inventor 李金禄李桢赵友惠
Owner TIANJIN PHARMA GROUP CORP
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