CN101381389A - Chemical Synthesis of 5,7-Diene Steroids - Google Patents

Abstract

The invention discloses a method for synthesizing 5,7-diene steroids represented by formula (I). The synthesis method comprises the following steps: firstly combining hydrazone represented by formula (II) with formula (III) The base shown is reacted in an organic solvent at -20-50°C for 0-6 hours, then heated up to 25-150°C, and kept for 0.5-6 hours. Recrystallization gave the final product 5,7-diene steroids. The present invention has mild reaction conditions, high reaction yield (generally above 85%, even above 95%), low production cost and good selectivity, and is an advanced process route.

Description

The chemical synthesis method of 5,7-diene steroids

(1) Technical field

The invention relates to a chemical synthesis method of 5,7-diene steroids.

(2) Background technology

5,7-diene steroids are the precursors of vitamin D drugs, which are widely used in medicine, food, pesticide, chemical industry and other fields, and have high practical value. The main function of vitamin D drugs is to regulate the metabolism of calcium and phosphorus, promote the absorption of calcium and phosphorus in the intestine and bone calcification, and maintain the balance of blood calcium and blood phosphorus. Essential vitamins for good health.

Before the present invention was made, most of the chemical synthesis methods of prior art 5,7-diene steroids used 5-ene-7-bromo steroids as raw materials to obtain 5,7-diene steroids through debromination, For example, debromination in Bu ₄ N ⁺ F-, collidine (WO2008089093, US2571330) and other systems to obtain 5,7-diene steroids, the yield of this method is low, about 30-50%, and the pollution is serious . 5,7-diene steroids can also be obtained from 7-sulfoxide substituents through elimination reactions (J.Org.Chem., 1981, 46, 1030; Tetrahedron Lett., 1991, 32, 5171; US20080171728) The yield is medium; it can also be obtained from the 7-ester substituent by noble metal Pd catalysis or high-temperature elimination reaction by heating (Tetrahedron Lett., 1992, 33, 2549; J.Am.Chem.Soc., 1952, 74, 3318), This method uses the expensive Pd catalyst, and the cost is relatively high. In addition, the above method will also produce some impurities that cannot be removed, which will seriously affect the photochemical reaction in the synthesis of vitamin D drugs.

(3) Contents of the invention

The technical problem to be solved by the present invention is to provide a chemical synthesis method of 5,7-diene steroids with reasonable process, good selectivity, high reaction yield, low production cost and environmental friendliness.

In order to solve the problems of the technologies described above, the present invention uses hydrazone and alkali to prepare 5,7-diene steroids, and the specific technical scheme is as follows:

A kind of synthetic method of 5,7-diene steroids shown in formula (I), it is characterized in that described synthetic method is: the hydrazone shown in formula (II) and the base shown in formula (III) React in an organic solvent, and the reaction solution obtains the final product 5,7-diene steroid compound (I) through aftertreatment;

In formula (I), formula (II) or formula (III), R ¹ is selected from hydrogen or C1～C8 acyl; R ² is selected from benzenesulfonyl, p-toluenesulfonyl or methanesulfonyl; R ³ is selected from hydrogen , hydroxyl or acyloxy group (ester group); ^R4 is selected from C1～C6 alkyl, C1～C6 alkoxy, amino, diisopropylamino, tert-butylamino or hydrogen; M is sodium, potassium or lithium.

The reaction formula is as follows:

Further, the synthesis method is preferably carried out according to the following steps: first react the hydrazone represented by formula (II) and the base represented by formula (III) in an organic solvent solution at -20-50°C for 0-6 hours, and then heat up to 25-150°C, heat preservation reaction for 0.5-6 hours, the reaction solution is treated with deprotection group and the solvent is recovered to obtain the crude product, and the crude product is recrystallized to obtain the final product 5,7-diene steroid compound; the formula (II) The amount ratio of the hydrazone shown and the base shown in the formula (III) is recommended to be 1:1.0-6.0, and the total mass dosage of the organic solvent is 2 to 30 times the mass of the hydrazone shown in the formula (II) . The base represented by formula (III) can be added in solid form, or can be dissolved in an organic solvent first, and then added to the reaction system. It is preferred to first dissolve the base with an organic solvent, and then add it to the reaction system.

In the present invention, after the feeding of the reactants is completed, it is preferred to first heat-preserve and react at -20-20°C for 0.5-3 hours, then raise the temperature to 50-120°C, heat-preserve and react for 1-3 hours, and the resulting reaction solution is then subjected to deprotection group treatment.

The recommended deprotection group treatment is: add water or alcohol and a deprotection reagent to the reaction solution, and raise the temperature to reflux temperature to fully react and remove the protection group. The preferred deprotection reagent is one of the following: sodium hydroxide, potassium hydroxide, lithium hydroxide, and the molar amount of the deprotection reagent is 0.01-2.0 times, preferably 0.1-1.5 times, the mole number of hydrazone. There is no special requirement for the amount of water or alcohol added.

Recovering solvent treatment after deprotection group treatment: When water and deprotection reagent are added in the above deprotection group treatment, it is necessary to stand and separate first, then take the organic phase and dry it with anhydrous sodium sulfate, and then evaporate the solvent to obtain the crude product . When alcohol and a deprotecting reagent are added in the deprotecting group treatment, the solvent can be distilled off directly in the solvent recovery step.

The organic solvent of the present invention can be one of the following formulas or a combination of two or more in any proportion: ① C4-C12 alkanes, ② C6-C12 aromatics, ③ C2-C18 ethers.

Specifically, the organic solvent is a combination of one or more of the following formulas in any proportion: hexane, petroleum ether, benzene, toluene, xylene, cumene, tert-butylbenzene, chlorobenzene, bromobenzene , Dichlorobenzene, dibromobenzene, nitrobenzene, ethyl ether, propyl ether, isopropyl ether, butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, anisole.

Preferred organic solvent is one of the following or any combination of any of the following in any proportion: 1. hexane, 2. petroleum ether, 3. anisole, 4. 2-methyltetrahydrofuran, 5. toluene, 6. xylene, 7. chlorobenzene , ⑧nitrobenzene, ⑨tetrahydrofuran.

The preferred recrystallization solvent is one of the following or a mixture of any of the following in any proportion: toluene, n-hexane, cyclohexane, acetone, cyclohexanone, ether, petroleum ether, methanol, ethanol. When the mixed solution is used for recrystallization, the relative volume ratio of the components of the mixed solution is not particularly required.

The molar ratio of the hydrazone to the base is recommended to be 1:1.0-6.0, preferably 1:1.0-3.0. The total mass amount of the organic solvent used is 2 to 30 times, preferably 5 to 10 times, the mass of the hydrazone represented by formula (II). If the base shown in formula (III) is dissolved with an organic solvent before adding to the reaction, the total mass of the organic solvent includes the sum of the organic solvents used to dissolve the hydrazone and the base, used to dissolve the organic solvent shown in the formula (III) The amount of the organic solvent of the base can dissolve the base shown in formula (III).

It is specifically recommended that the synthetic method be carried out in accordance with the following steps: first dissolve the hydrazone shown in formula (II) and the base shown in formula (III) with an organic solvent respectively, and then maintain the temperature at -20 to 20°C to dissolve the organic solvent of the base. The solvent solution is added to the organic solvent solution of the hydrazone shown in formula (II), the temperature is maintained for 0.5 to 3 hours, the temperature is slowly raised to 50 to 120°C, the temperature is kept for 1 to 3 hours, and water or alcohol is added to the reaction solution and deprotected Reagent, heat up to reflux temperature and react for 0.1 to 2 hours, adjust the pH to about 7 with acid, recover the solvent to obtain the crude product, and the crude product is recrystallized to obtain the final product 5,7-diene steroid compound; said formula (II) The molar ratio of the hydrazone, the base shown in formula (III) and the deprotection reagent is 1:1.0～3.0:0.1～1.5, and the total mass consumption of the organic solvent is the mass of hydrazone shown in formula (II) 5-10 times; the deprotection reagent is one of the following: sodium hydroxide, potassium hydroxide, lithium hydroxide.

The yield of the product 5,7-diene steroid compound prepared by the synthesis method of the invention can reach more than 85%.

Compared with the prior art, the present invention has the following advantages:

1. The reaction yield is high (generally above 85%, even can reach above 95%), and the production cost is low;

2. Advanced process route and mild reaction conditions;

3. Good selectivity, basically no rearrangement by-products.

(4) Specific implementation methods

The present invention will be further described below in conjunction with specific examples, but the protection scope of the present invention is not limited thereto.

Example 1

In a 1000ml four-neck flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (61g) of 3-acetoxycholesterol-7-p-toluenesulfonylhydrazone, dissolve it in 400mL of toluene, cool to -20°C, add A solution of methyl lithium (6.6 g, 300 mmol) in toluene (50 mL) was maintained at -20°C, reacted for 0.5 hour, then raised to 25°C and stirred for 2 hours. After the reaction is complete, add 100 mL of water and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, leave the organic phase to dry with anhydrous sodium sulfate after standing for layers, and evaporate the solvent. Recrystallization with ethanol/toluene gave 36.1 g of the target product 5,7-dienyl cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 94%.

Example 2

In a 1000ml four-neck flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (61g) of 3-acetoxycholesterol-7-p-toluenesulfonylhydrazone, dissolve it in 400mL of toluene, cool to -20°C, add A solution of methyl lithium (6.6 g, 300 mmol) in toluene (50 mL) was maintained at -20°C, reacted for 0.5 hour, then raised to 25°C and stirred for 2 hours. After the reaction is complete, add 100 mL of methanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 36.6 g of Diene Cholesterol is a light yellow solid with a melting point of 145-146° C. and a yield of 95%.

Example 3

In a 1000ml four-neck flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (61g) of 3-acetoxycholesterol-7-p-toluenesulfonylhydrazone, dissolve it in 400mL of toluene, cool to -20°C, add A solution of methyl lithium (6.6 g, 300 mmol) in toluene (50 mL) was maintained at -20°C, reacted for 0.5 hour, then raised to 25°C and stirred for 2 hours. After the reaction is complete, add 100 mL of ethanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 36.6 g of Diene Cholesterol is a light yellow solid with a melting point of 145-146° C. and a yield of 95%.

Example 4

In a 1000ml four-necked flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (59.6g) of 3-acetoxycholesterol-7-benzenesulfonylhydrazone, dissolve it in 400mL of toluene, cool down to -20°C, add A solution of methyl lithium (6.6 g, 300 mmol) in toluene (50 mL) was maintained at -20°C, reacted for 0.5 hour, then raised to 25°C and stirred for 2 hours. After the reaction is complete, add 100 mL of methanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 35.3 g of Diene Cholesterol is a light yellow solid with a melting point of 145-146° C. and a yield of 92%.

Example 5

In a 1000ml four-necked flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (53.4g) of 3-acetoxycholesterol-7-methanesulfonylhydrazone, dissolve it in 400mL of toluene, cool down to -20°C, add A solution of methyl lithium (6.6 g, 300 mmol) in toluene (50 mL) was maintained at -20°C, reacted for 0.5 hour, then raised to 25°C and stirred for 2 hours. After the reaction is complete, add 100 mL of methanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 32.3 g of Diene Cholesterol is a light yellow solid with a melting point of 145-146° C. and a yield of 84%.

Example 6

In a 1000ml four-necked flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (61.0g) of 3-acetoxycholesterol-7-p-benzenesulfonylhydrazone, dissolve it in 400mL of toluene, cool down to 0°C, and add A solution of lithium amide (6.9 g, 300 mmol) in toluene (50 mL) was maintained at 0° C. for 0.5 hours, and then heated to 110° C. for 2 hours. After the reaction is complete, add 100 mL of methanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 27.3 g of Diene Cholesterol is a light yellow solid with a melting point of 145-146° C. and a yield of 71%.

Example 7

In a 1000ml four-necked flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (61.0g) of 3-acetoxycholesterol-7-p-benzenesulfonylhydrazone, dissolve it in 400mL of toluene, cool down to 0°C, and add A solution of lithium diisopropylamide (32.1 g, 300 mmol) in toluene (50 mL) was maintained at 0° C. for 0.5 hours, and then heated to 110° C. for 2 hours. After the reaction is complete, add 100 mL of methanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 30.0 g of dienyl cholesterol is a light yellow solid with a melting point of 145-146°C and a yield of 78%.

Example 8

In a 1000ml four-necked flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (61.0g) of 3-acetoxycholesterol-7-p-benzenesulfonylhydrazone, dissolve it in 400mL of toluene, cool down to 0°C, and add A solution of lithium tert-butylamide (23.7 g, 300 mmol) in toluene (50 mL) was maintained at 0° C. for 0.5 hours, and then heated to 110° C. for 2 hours. After the reaction is complete, add 100 mL of methanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 32.6 g of Diene Cholesterol is a light yellow solid with a melting point of 145-146° C. and a yield of 85%.

Example 9

In a 1000ml four-neck flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (61.0g) of 3-acetoxycholesterol-7-p-benzenesulfonylhydrazone, dissolve it in 400mL of toluene, cool down to 20°C, add A solution of sodium methoxide (16.2 g, 300 mmol) in toluene (50 mL) was maintained at 20° C. for 0.5 hour, and then heated to 110° C. for 2 hours. After the reaction is complete, add 100 mL of methanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 29.2 g of Diene Cholesterol is a light yellow solid with a melting point of 145-146° C. and a yield of 76%.

Example 10

In a 1000ml four-neck flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (61.0g) of 3-acetoxycholesterol-7-p-benzenesulfonylhydrazone, dissolve it in 400mL of toluene, cool down to 20°C, add A solution of sodium ethoxide (20.4 g, 300 mmol) in toluene (50 mL) was maintained at 20° C., reacted for 0.5 hour, and then heated to 110° C. for 2 hours. After the reaction is complete, add 100 mL of methanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 28.4 g of Diene Cholesterol is a light yellow solid with a melting point of 145-146° C. and a yield of 74%.

Example 11

In a 1000ml four-neck flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (61.0g) of 3-acetoxycholesterol-7-p-benzenesulfonylhydrazone, dissolve it in 400mL of toluene, cool down to 20°C, add A solution of potassium tert-butoxide (33.6 g, 300 mmol) in toluene (50 mL) was maintained at 20° C. for 0.5 hour, and then heated to 110° C. for 2 hours. After the reaction is complete, add 100 mL of methanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 30.7 g of Diene Cholesterol is a light yellow solid with a melting point of 145-146° C. and a yield of 80%.

Example 12

In a 1000ml four-necked flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (61.0g) of 3-acetoxycholesterol-7-p-benzenesulfonylhydrazone, dissolve it in 400mL of toluene, cool down to 0°C, and add A solution of sodium hydride (7.2 g, 300 mmol) in toluene (50 mL) was maintained at 0° C. for 0.5 hours, and then heated to 110° C. for 2 hours. After the reaction is complete, add 100 mL of methanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 34.6 g of Diene Cholesterol is a light yellow solid with a melting point of 145-146° C. and a yield of 90%.

Example 13

In a 1000ml four-necked flask equipped with a thermometer, reflux condenser and mechanical stirring, add 100mmol (61.0g) of 3-acetoxycholesterol-7-p-benzenesulfonylhydrazone, dissolve it in 400mL of toluene, cool down to 0°C, and add A solution of lithium hydride (2.4 g, 300 mmol) in toluene (50 mL) was maintained at 0° C. for 0.5 hours, and then heated to 110° C. for 2 hours. After the reaction is complete, add 100 mL of methanol and stir thoroughly, add 4 g of sodium hydroxide, heat up to reflux, react for 30 minutes, adjust the pH to 7 with hydrochloric acid or acetic acid, evaporate the solvent, and recrystallize with ethanol/toluene to obtain the target product 5,7- 33.4 g of Diene Cholesterol is a light yellow solid with a melting point of 145-146° C. and a yield of 87%.

Example 14

The reaction solvent was 2-methyltetrahydrofuran, and other operations were the same as in Example 2 to obtain 35.3 g of the target product 5,7-dienyl cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 92%.

Example 15

The reaction solvent was tetrahydrofuran, and other operations were the same as in Example 2 to obtain 34.9 g of the target product 5,7-dienyl cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 91%.

Example 16

The reaction solvent was n-hexane, and other operations were the same as in Example 2 to obtain 31.5 g of the target product 5,7-diene cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 82%.

Example 17

The reaction solvent was petroleum ether, and other operations were the same as in Example 2 to obtain 33.4 g of the target product 5,7-diene cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 87%.

Example 18

The reaction solvent was anisole, and other operations were the same as in Example 2 to obtain 36.1 g of the target product 5,7-dienyl cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 94%.

Example 19

The reaction solvent was chlorobenzene, and other operations were the same as in Example 2 to obtain 33.8 g of the target product 5,7-dienyl cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 88%.

Example 20

The reaction solvent was xylene, and other operations were the same as in Example 2 to obtain 35.7 g of the target product 5,7-dienyl cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 93%.

Example 21

The reaction solvent was nitrobenzene, and other operations were the same as in Example 2 to obtain 34.9 g of the target product 5,7-dienyl cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 91%.

Example 22

Add alkali at -20°C, react for 1 hour, then raise the temperature to 50°C and react for 2 hours, and other operations are the same as in Example 2 to obtain 33.0 g of the target product 5,7-diene cholesterol, which is a light yellow solid with a melting point of 145-146 °C, yield 86%.

Example 23

Add alkali at -20°C, react for 1 hour, then raise the temperature to 100°C and react for 2 hours, and other operations are the same as in Example 2 to obtain 33.8 g of the target product 5,7-diene cholesterol, which is a light yellow solid with a melting point of 145-146 °C, yield 88%.

Example 24

Add alkali at 0°C, react for 1 hour, then raise the temperature to 50°C and react for 2 hours, and other operations are the same as in Example 2 to obtain 31.1 g of the target product 5,7-diene cholesterol, which is a light yellow solid with a melting point of 145-146°C , yield 81%.

Example 25

Add alkali at 0°C, react for 1 hour, then raise the temperature to 100°C and react for 2 hours, and other operations are the same as in Example 2 to obtain 32.6 g of the target product 5,7-diene cholesterol, which is a light yellow solid with a melting point of 145-146°C , yield 85%.

Example 26

Add alkali at 20°C, react for 1 hour, then raise the temperature to 100°C and react for 2 hours, and other operations are the same as in Example 2 to obtain 29.2 g of the target product 5,7-diene cholesterol, which is a light yellow solid with a melting point of 145-146°C , yield 76%.

Example 27

Add alkali at a temperature of 50°C, react for 1 hour, then raise the temperature to 100°C and react for 2 hours, and other operations are the same as in Example 2 to obtain 26.9 g of the target product 5,7-diene cholesterol, which is a light yellow solid with a melting point of 145-146°C , yield 70%.

Example 28

The solvent is anisole, the temperature of adding alkali is -20°C, react for 1 hour, then raise the temperature to 150°C and react for 6 hours, other operations are the same as in Example 2, and 37.6g of the target product 5,7-diene cholesterol is obtained, which is light yellow Solid, melting point 145-146°C, yield 98%.

Example 29

The solvent is anisole, the temperature of adding alkali is 50°C, react for 1 hour, then raise the temperature to 150°C and react for 6 hours, other operations are the same as in Example 2, and 36.5g of the target product 5,7-dienylcholesterol is obtained as a light yellow solid , melting point 145-146°C, yield 95%.

Example 30

The amount of alkali used was 200 mmol (2.0 equivalents), and other operations were the same as in Example 2 to obtain 30.7 g of the target product 5,7-dienyl cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 80%.

Example 31

The amount of alkali used was 400 mmol (4.0 equivalents), and other operations were the same as in Example 2 to obtain 36.1 g of the target product 5,7-dienyl cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 94%.

Example 32

The recrystallization solvent was petroleum ether/toluene, and other operations were the same as in Example 2 to obtain 33.1 g of the target product 5,7-diene cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 86%.

Example 33

The recrystallization solvent was acetone/methanol, and other operations were the same as in Example 2 to obtain 33.8 g of the target product 5,7-dienyl cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 88%.

Example 34

The recrystallization solvent was n-hexane/ethanol, and other operations were the same as in Example 2 to obtain 30.7 g of the target product 5,7-diene cholesterol as a light yellow solid with a melting point of 145-146° C. and a yield of 80%.

Example 35

The substrate hydrazone is 3-benzoyloxycholesterol-7-p-toluenesulfonylhydrazone, and the feeding amount is 100mmol (67.2g). Other operations are the same as in Example 2 to obtain the target product 5,7-dienylcholesterol 34.6g, It is a light yellow solid with a melting point of 145-146°C and a yield of 90%.

Example 36

The substrate hydrazone is 3-p-tolyloxycholesterol-7-p-toluenesulfonylhydrazone, and the feeding amount is 100mmol (68.6g). Other operations are the same as in Example 2 to obtain the target product 5,7-dienylcholesterol 34.9 g, as light yellow solid, melting point 145-146°C, yield 91%.

Example 37

The substrate hydrazone is 3-propionyloxycholesterol-7-p-toluenesulfonylhydrazone, and the feeding amount is 100mmol (62.4g). Other operations are the same as in Example 2 to obtain the target product 5,7-dienylcholesterol 34.6g, which is Light yellow solid, melting point 145-146°C, yield 90%.

Example 38

The substrate hydrazone is 3-butyryloxycholesterol-7-p-toluenesulfonylhydrazone, and the feeding amount is 100mmol (63.8g). Other operations are the same as in Example 2 to obtain the target product 5,7-dienylcholesterol 35.3g, which is Light yellow solid, melting point 145-146°C, yield 92%.

Example 39

The substrate hydrazone is 3-trichloroacetoxycholesterol-7-p-toluenesulfonylhydrazone, and the feeding amount is 100mmol (71.4g). Other operations are the same as in Example 2 to obtain the target product 5,7-dienylcholesterol 33.8g, It is a light yellow solid with a melting point of 145-146°C and a yield of 88%.

Example 40

The substrate hydrazone is 3,25-diacetoxycholesterol-7-p-toluenesulfonyl hydrazone, the feeding amount is 100mmol (66.9g), the amount of sodium hydroxide is 8g, other operations are the same as in Example 2, and the target product 25- 38.0 g of hydroxy-5,7-diene cholesterol is a light yellow solid with a melting point of 175-176°C and a yield of 95%.

Example 41

The substrate hydrazone is 3,25-dibenzoyloxycholesterol-7-p-toluenesulfonylhydrazone, the feeding amount is 100mmol (79.2g), the amount of sodium hydroxide is 8g, other operations are the same as in Example 2, and the target product is obtained 37.2 g of 25-hydroxy-5,7-diene-cholesterol is a light yellow solid with a melting point of 175-176 °C and a yield of 93%.

Example 42

The substrate hydrazone is 3-acetoxy-25-benzoyloxycholesterol-7-p-toluenesulfonyl hydrazone, the feeding amount is 100mmol (73.0g), the sodium hydroxide consumption is 8g, and other operations are the same as in Example 2, 36.8 g of the target product 25-hydroxy-5,7-diene cholesterol was obtained as a light yellow solid with a melting point of 175-176° C. and a yield of 92%.

Claims (9)

1,5 shown in a kind of formula (I), the synthetic method of 7-diene steroids compounds, it is characterized in that described synthetic method comprises the steps: earlier the alkali shown in hydrazone shown in the formula (II) and the formula (III) to be reacted 0～6 hour at-20～50 ℃ in organic solvent, be warmed up to 25～150 ℃ then, insulation reaction 0.5～6 hour, reaction solution reclaims solvent and obtains crude product after going protecting group to handle, crude product obtains final product 5 through recrystallization, the 7-diene steroids compounds; The amount of substance ratio that feeds intake of the alkali shown in hydrazone shown in the described formula (II) and the formula (III) is 1:1.0～6.0; Described organic solvent is following one or more combinations by arbitrary proportion: the 1. alkane of C4～C12, the 2. aromatic hydrocarbons of C6～C12, the 3. ethers of C2～C18;

In formula (I), formula (II) or the formula (III), R ¹Be selected from the acyl group of hydrogen or C1～C8; R ²Be selected from benzenesulfonyl, p-toluenesulfonyl or methylsulfonyl; R ³Be selected from hydrogen, hydroxyl or acyloxy (ester group); R ⁴Be selected from the alkyl of C1～C6, alkoxyl group, amino, diisopropylaminoethyl, tertiary butyl amino or the hydrogen of C1～C6; M is sodium, potassium or lithium.

2, as claimed in claim 15, the synthetic method of 7-diene steroids compounds is characterized in that the described protecting group of going is treated to: add entry or alcohol in the reaction solution and remove to protect reagent, be warming up to reflux temperature and fully react and remove protecting group; Described to remove to protect reagent be one of following: sodium hydroxide, potassium hydroxide, lithium hydroxide, described mole dosage of removing to protect reagent are 0.01～2.0 times of the hydrazone mole number shown in the formula (II).

3, as claimed in claim 15, the chemical synthesis process of 7-diene steroids compounds is characterized in that described organic solvent is the mixing of following one or more arbitrary proportions: hexane, sherwood oil, benzene,toluene,xylene, isopropyl benzene, trimethylphenylmethane, chlorobenzene, bromobenzene, dichlorobenzene, dibromobenzene, oil of mirbane, ether, propyl ether, isopropyl ether, butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl-phenoxide.

4, as claimed in claim 35, the chemical synthesis process of 7-diene steroids compounds is characterized in that described organic solvent is the mixing of following one or more arbitrary proportions: hexane, sherwood oil, methyl-phenoxide, 2-methyltetrahydrofuran, toluene, dimethylbenzene, chlorobenzene, oil of mirbane, tetrahydrofuran (THF).

5, as claimed in claim 15, the synthetic method of 7-diene steroids compounds is characterized in that recrystallization reagent is selected from the mixing of following one or more arbitrary proportions: toluene, normal hexane, hexanaphthene, acetone, pimelinketone, ether, sherwood oil, methyl alcohol, ethanol.

6, described 5 as one of claim 1～5, the synthetic method of 7-diene steroids compounds, it is characterized in that feeding intake finish after, hydrazone and alkali-20～20 ℃ of insulation reaction 0.5～3 hour, are warmed up to 50～120 ℃, insulation reaction 1～3 hour earlier then.

7, described 5 as one of claim 1～5, the chemical synthesis process of 7-diene steroids compounds, what it is characterized in that the alkali shown in hydrazone shown in the described formula (II) and the formula (III) feeds intake amount of substance than being 1:1.0～3.0.

8, described 5 as one of claim 1～5, the chemical synthesis process of 7-diene steroids compounds, the quality consumption that it is characterized in that employed organic solvent are 5～10 times of the hydrazone quality shown in the formula (II).

9, as claimed in claim 45, the chemical synthesis process of 7-diene steroids compounds, it is characterized in that described synthetic method carries out according to following steps: earlier the alkali shown in hydrazone shown in the formula (II) and the formula (III) is used organic solvent dissolution respectively, holding temperature joins in the organic solvent solution of the hydrazone shown in the formula (II) at-20～20 ℃ of organic solvent solutions with the alkali shown in the formula (III) then, insulation reaction 0.5～3 hour, slowly be warmed up to 50～120 ℃, insulation reaction 1～3 hour, reaction solution adds entry or alcohol and removes to protect reagent, be warming up to reflux temperature reaction 0.1～2 hour, with about acid for adjusting pH to 7, reclaim solvent and obtain crude product, crude product obtains final product 5 through recrystallization, the 7-diene steroids compounds; Alkali shown in hydrazone shown in the described formula (II), the formula (III) protects the amount of substance ratio that feeds intake of reagent to be 1:1.0～3.0:0.1～1.5 with going, and the total mass consumption of described organic solvent is 5～10 times of the hydrazone quality shown in the formula (II); Described to remove to protect reagent be one of following: sodium hydroxide, potassium hydroxide, lithium hydroxide.