CN107011402B - Preparation method of melengestrol intermediate - Google Patents

Preparation method of melengestrol intermediate Download PDF

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CN107011402B
CN107011402B CN201710278199.8A CN201710278199A CN107011402B CN 107011402 B CN107011402 B CN 107011402B CN 201710278199 A CN201710278199 A CN 201710278199A CN 107011402 B CN107011402 B CN 107011402B
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melengestrol
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CN107011402A (en
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蒋青锋
杨坤
潘玉秋
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Guangxi Wande Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
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    • C07J71/0068—Nitrogen and oxygen at position 16(17)

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Abstract

The invention discloses a preparation method of a melengestrol intermediate, which is characterized in that a compound VII, namely the melengestrol intermediate, is prepared from a compound 4-androstene-3, 17 dione through etherification, methyleneation, cyano substitution, siloxy protection, intramolecular affinity substitution and reduction reaction. The adopted raw material 4-androstene-3, 17-dione is cheap and easy to obtain, the process route is reasonably and optimally designed, and the synthesized product has the advantages of less impurities, good quality, high yield, simple operation, mild reaction conditions, low cost, safety and suitability for industrialization.

Description

Preparation method of melengestrol intermediate
Technical Field
The invention relates to the field of pharmaceutical intermediate manufacture, in particular to a preparation method of a melengestrol intermediate.
Background
Melengestrol, also known as Melengestrol, british name 17 α -hydroxy-16-methylene-4, 6-dienogest-3, 20-dione, having the following structural formula:
Figure GDA0002342095940000011
currently, the market of society has a great demand and reports a plurality of synthetic routes, but the synthetic routes are complicated, the cost is high and the yield is low, while 17 α -hydroxy-16-methylene-4-enopregne-3, 20-diketone is an important intermediate for synthesizing melengestrol and can obtain the melengestrol by introducing a methyl reaction through the 5 th position.
Preparation of melengestrol, huntingle, Liaoqingjiang: a novel synthesis process of melengestrol acetate, disclosed in 3 rd volume 15 of Chinese medicinal chemistry journal 2005, is a preparation method of melengestrol, which is prepared by taking dehydropregnenolone acetate as a raw material through multi-step reactions, and comprises the following synthesis processes:
Figure GDA0002342095940000012
the dehydropregnenolone acetate is mainly obtained by multi-step chemical synthesis of diosgenin extracted from yellow ginger and other raw materials. In recent years, the cost of artificial planting of yellow gingers is increased, the price of diene is also increased, and in the synthesis process of diene, heavy metal oxidants such as chromic anhydride are used more, so that the increased cost in the aspect of environmental protection treatment is also higher. The step of introducing the 16 th methylene group is cumbersome. In addition, the intermediate is obtained by using progesterone as a raw material through methylenation, and the raw material progesterone in the method is expensive.
In the application publication No. US4921638A, the side reactions of the reaction after the cyanation reaction are many, the reaction conditions are very severe, the reaction after the cyanation reaction generates 17 β -hydroxy-16-methylene-4-ene pregna-3, 20-dione, which is isomerized with the target product, and the selectivity of the target product is very low, thus the industrial production is not facilitated, and the main synthesis process is:
Figure GDA0002342095940000021
the patent with application publication number US4443377A discloses a preparation method of melengestrol, which is prepared by taking 4-androstenedione as a raw material through etherification, carbonyl introduction, elimination reaction and the like, and the synthetic process route is as follows:
Figure GDA0002342095940000022
the method is characterized in that 17 β -hydroxyl is synthesized in the third step, a target product is 17 α -hydroxyl, so that spatial isomerization needs to be converted, side reaction is easy to generate due to the existence of β acetyl, and the reaction is difficult to carry out, and acetylene used in the third step is extremely easy to generate gas, has high equipment requirement and high cost, and is not beneficial to industrial production.
The above background disclosure is only for the purpose of assisting understanding of the inventive concept and technical solutions of the present invention, and does not necessarily belong to the prior art of the present patent application, and should not be used for evaluating the novelty and inventive step of the present application in the case that there is no clear evidence that the above content is disclosed at the filing date of the present patent application.
Disclosure of Invention
The invention aims to provide a preparation method of a melengestrol intermediate, which has the advantages of less impurities, good quality, high yield, simple operation, mild reaction conditions, low cost and higher safety, and solves the problems of more impurities, poor quality, low yield, complex operation, harsh reaction conditions, high cost and high risk coefficient in the prior art.
Therefore, the invention provides a preparation method of a melengestrol intermediate, which comprises the following specific technical scheme:
a preparation method of melengestrol intermediate takes compound I4-androstene-3, 17 dione as a starting raw material and comprises the following steps:
s1: and (3) etherification reaction: adding the compound I into an etherification solvent, and reacting with an etherification reagent under the action of a first catalyst to obtain a compound II;
Figure GDA0002342095940000031
s2, performing methyleneation, namely adding the compound II into a methyleneation solvent, replacing α hydrogen at the 16-position with first organic alkali and oxalate, performing methylene elimination on β hydrogen at the 16-position with an elimination reagent, and finally hydrolyzing to obtain a compound III;
Figure GDA0002342095940000032
s3: cyano substitution reaction: adding the compound III into a cyaniding solvent, and reacting with a cyaniding reagent under the action of a second catalyst in an alkaline environment to obtain a compound IV;
Figure GDA0002342095940000041
s4: and (3) carrying out a silicon alkoxide protection reaction: adding the compound IV into a protective solvent, and reacting with a siloxy reagent in the presence of a second organic base to obtain a compound V;
Figure GDA0002342095940000042
s5: intramolecular nucleophilic substitution reaction: adding the compound V into a substitution solvent, and reacting with an amino alkali metal reagent to obtain a compound VI;
Figure GDA0002342095940000043
s6: reduction reaction: and adding the compound VI into a reduction solvent to react with metal to obtain a compound VII, namely the intermediate of the melengestrol.
Figure GDA0002342095940000051
Further, in the preparation method of the melengestrol intermediate, in the step S1, the etherification solvent is one or more of tetrahydrofuran, dichloromethane, chloroform and dioxane; the first catalyst is p-toluenesulfonic acid or perchloric acid; the etherification reagent is trimethyl orthoformate or triethyl orthoformate; the reaction temperature of the etherification reaction is 30-40 ℃.
Further, in the preparation method of the melengestrol intermediate, in the step S2, the methylation reagent is one or more of dichloromethane, chloroform, acetone and dioxane; the first organic base is one or more of sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the elimination reagent is one or more of formaldehyde, acetaldehyde and propionaldehyde; the oxalate is one or more of diethyl oxalate, dimethyl oxalate and dipropyl oxalate; the reaction temperature of the substitution reaction is-10-0 ℃, and the reaction temperature of the elimination reaction is 10-40 ℃.
Further, in the preparation method of the melengestrol intermediate, the cyanidation solvent in the step S3 is one or more of methanol, ethanol, n-propanol, isopropanol, acetone and water; the cyaniding reagent is one or more of acetone cyanohydrin, potassium cyanide and sodium cyanide; the alkaline environment is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; the second catalyst is hexachloroacetone or hexafluoroacetone; the reaction temperature of the cyano substitution reaction is 20-40 ℃.
Further, in the preparation method of the melengestrol intermediate, the protective solvent in the step S4 is one or more of dichloromethane, chloroform, carbon tetrachloride, benzene, lower aromatic hydrocarbon and acetone; the second organic base is one or more of 4-dimethylamino pyridine, imidazole, triethylamine and DBU; the siloxy reagent is one or more of chloromethyl dimethyl chlorosilane, chloromethyl dimethyl bromosilane and chloromethyl dimethyl iodosilane; the reaction temperature of the siloxy protection reaction is-10-30 ℃; the lower aromatic hydrocarbon is one or more of toluene, o-xylene, p-xylene and ethylbenzene.
Further, in the preparation method of the melengestrol intermediate, in the step S5, the substitution solvent is one or more of tetrahydrofuran, dimethyltetrahydrofuran, cyclohexane, diethyl ether and benzene; the amino alkali metal reagent is one or more of lithium diisopropylamide, lithium diisobutylamine and n-butyl lithium; the reaction temperature of the intramolecular nucleophilic substitution reaction is-80 to-30 ℃.
Further, in the preparation method of the melengestrol intermediate, the reducing solvent in the step S6 is glacial acetic acid; the metal is one or more of zinc and iron; the reaction temperature of the reduction reaction is 20-60 ℃.
Furthermore, in the preparation method of the melengestrol intermediate, the temperature of the elimination reaction in the step S2 is 25-30 ℃.
Furthermore, in the preparation method of the melengestrol intermediate, the reaction temperature of the siloxy protection reaction in the step S4 is-5-0 ℃.
Furthermore, in the preparation method of the melengestrol intermediate, the reaction temperature of the nucleophilic substitution reaction in the molecule in the step S5 is-70 to-65 ℃.
Compared with the prior art, the invention has the following advantages:
(1) the invention has the advantages of low cost and easy acquisition of the used starting materials, easy realization of each step of reaction, high yield and low production cost, and is more suitable for industrial production.
(2) The invention avoids the operations of multi-step protection and deprotection through the design optimization of the synthesis line.
(3) The invention directly synthesizes 17 α -hydroxyl and 17 β -acetyl by using the second catalyst, and reduces the transformation of spatial isomerism.
(4) The invention adopts a novel side chain preparation mode, and reduces the use of inflammable and explosive gases.
Detailed Description
Example 1
A preparation method of a melengestrol intermediate comprises the following specific steps:
s1: and (3) etherification reaction: adding 10g of compound I (4-androstene-3, 20-dione) into a reaction bottle, adding 40g of tetrahydrofuran, introducing nitrogen, adding 0.40g of p-toluenesulfonic acid, uniformly stirring, heating to 30 ℃, slowly adding 24.06g of trimethyl orthoformate, reacting for two hours under the controlled temperature, and completely reacting by TLC (thin layer chromatography) detection;
and (3) post-treatment process: cooling to 5-10 ℃, adding 10g of water, reacting for 6 minutes, quickly adding 20.05g of 2% sodium carbonate aqueous solution, stirring for half an hour, elutriating by 160.04g of ice water, stirring, filtering, and drying at 20-32 ℃ to obtain a compound II, namely 3-methyl ether-4-androstene-17-one, wherein the molar yield is 96.12%.
S2: and (3) performing a methylenation reaction: putting 10g of the compound II into a reaction bottle, adding 90g of dioxane, uniformly stirring, setting the substitution temperature to-10 ℃ under the protection of nitrogen, adding 5.5g of potassium methoxide into the mixed solution, and uniformly stirring; slowly dropwise adding 6g of diethyl oxalate into the mixed solution, carrying out heat preservation reaction after the addition is finished, stirring for 3-4 hours, and monitoring by TLC until the reaction is complete; adding 0.45g of glacial acetic acid, 3.05g of triethylamine and 27g of methanol, uniformly stirring, adding 3.66g of formaldehyde, eliminating the reaction temperature, setting the temperature to 10 ℃, controlling the temperature to react for 1-2 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: adding 9g of water to terminate, carrying out rotary evaporation at 45 ℃ to remove the organic solvent, 10g of water, recovering under reduced pressure, keeping the temperature of 1-7 ℃ for 2h, carrying out elutriation at 90g of water, carrying out suction filtration, and drying at 40-42 ℃ to obtain a compound III, namely 16-methenyl-4-androstene-3, 17-dione, wherein the molar yield is 97.56%.
S3: cyano substitution reaction: adding 10g of compound III into a reaction bottle, adding 35g of methanol and 5.52g of acetone cyanohydrin, stirring uniformly, adding 10g of 5% sodium carbonate, adding 0.3g of hexafluoroacetone, controlling the temperature at 20 ℃ for reaction for 22 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: 70g of elutriation, 1.5g of hydrochloric acid for neutralization, filtration, washing of a filter cake to be neutral, and drying at 25-30 ℃ to obtain a compound IV, wherein the molar yield is 95.4%.
S4: and (3) carrying out a silicon alkoxide protection reaction: adding 10g of the compound IV into a reaction bottle, adding 40.06g of trichloromethane and 3.5g of imidazole, stirring uniformly, cooling to-10 ℃ under the protection of nitrogen, dropwise adding 5.3g of chloromethyl dimethylchlorosilane, controlling the temperature to react for 2 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: stopping the reaction by using 0.03% potassium carbonate aqueous solution, extracting 40g of organic solvent by using dichloromethane for three times, combining the organic solvents, concentrating the organic solvents at 40 ℃ under reduced pressure to a small volume, adding a proper amount of water, concentrating the organic solvents under reduced pressure, adding 80g of water, performing water precipitation, performing suction filtration, and drying the mixture at 45-60 ℃ to obtain a compound V, wherein the molar yield is 83.48%.
S5: intramolecular nucleophilic substitution reaction: adding 10g of the compound V into a reaction bottle, adding 50g of dimethyl tetrahydrofuran, stirring uniformly, cooling to-80 ℃ under the protection of nitrogen, adding 4.03g of trimethylchlorosilane, dropwise adding 50.01g of n-butyllithium, controlling the temperature to react for 1-2 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: heating to 0-10 ℃, adding 50g of hydrochloric acid for hydrolysis reaction, monitoring by TLC until the reaction is complete, adjusting the reaction to be neutral by using 40% sodium hydroxide aqueous solution, extracting by using 40g of chloroform as an organic solvent for three times, concentrating under reduced pressure at 58 ℃, adding a proper amount of water, concentrating under reduced pressure, adding 100g of water for precipitation, crystallizing, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VI with the molar yield of 97.83%.
S6: reduction reaction: adding 10.02g of the compound VI into a reaction bottle, adding 50.5g of zinc powder, adding 40.06g of glacial acetic acid, heating to 20 ℃, controlling the temperature to react for 5-6 h, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: cooling to 45 ℃, stirring 40.00g of trichloromethane, cooling to 40 ℃, adjusting the temperature to be neutral by using 40% sodium hydroxide aqueous solution, extracting 40.08g of trichloromethane by three times, concentrating to a small volume at 45 ℃ under reduced pressure, adding a proper amount of water, concentrating under reduced pressure, recovering until no organic solvent exists, adding 70g of water for precipitation, cooling to normal temperature, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VII with the molar yield of 95.45%. HPLC content 98.46%.
Example 2
A preparation method of a melengestrol intermediate comprises the following specific steps:
s1: adding 50g of compound I (4-androstene-3, 20-dione) into a reaction bottle, adding 200g of dichloromethane, introducing nitrogen, adding 1g of p-perchloric acid, stirring uniformly, heating to 32 ℃, slowly adding 112g of triethyl orthoformate, controlling the temperature to react for two hours after the addition, and detecting by TLC to completely react;
and (3) post-treatment process: cooling to 0 ℃, adding 45g of water, reacting for 6 minutes, quickly adding 100g of 2% sodium carbonate aqueous solution, stirring for half an hour, precipitating with 700g of ice water, stirring, filtering, and drying at 20-32 ℃ to obtain a compound II, namely 3-methyl ether-4-androstene-17-one, wherein the molar yield is 96.53%.
S2: and (3) performing a methylenation reaction: adding 30g of the compound II into a reaction bottle, adding 270g of trichloromethane, uniformly stirring, cooling to-8 ℃ under the protection of nitrogen, adding 15g of potassium methoxide into the mixed solution, and uniformly stirring; slowly dropwise adding 19.5g of dimethyl oxalate into the mixed solution, carrying out heat preservation reaction after the addition is finished, stirring for 3-4 hours, and monitoring by TLC until the reaction is complete; adding 1.5g of glacial acetic acid, 10.5g of triethylamine and 90g of methanol, uniformly stirring, adding 12.6g of formaldehyde, raising the temperature to 15 ℃, controlling the temperature to react for 1-2 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: adding 30g of water to terminate, carrying out rotary evaporation at 45 ℃ to remove the organic solvent, adding 60g of water, carrying out reduced pressure recovery, carrying out heat preservation at 1-7 ℃ for 2h, carrying out elutriation at 360g of water, carrying out suction filtration, and drying at 40-42 ℃ to obtain a compound III, namely 16-methenyl-4-androstene-3, 17-dione, wherein the molar yield is 97.79%.
S3: cyano substitution reaction: adding 30g of compound III into a reaction bottle, adding 120g of n-propanol and 18g of potassium cyanide, stirring uniformly, adding 3.2g of 5% sodium hydroxide aqueous solution, adding 1.1g of hexachloroacetone, reacting at 25 ℃ for 22 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: and (3) performing elutriation by 240g, neutralizing by 5g of hydrochloric acid, filtering, washing a filter cake to be neutral by using water, and drying at 25-30 ℃ to obtain a compound IV, wherein the molar yield is 95.52%.
S4: and (3) carrying out a silicon alkoxide protection reaction: adding 20g of the compound IV into a reaction bottle, adding 80g of 4-dimethylaminopyridine and 7g of imidazole, stirring uniformly, cooling to-8 ℃ under the protection of nitrogen, dropwise adding 16g of chloromethyl dimethyl bromosilane, reacting for 2 hours at a controlled temperature, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: stopping the reaction by using 0.03% sodium carbonate aqueous solution, extracting the organic solvent 80g dichloromethane for three times, combining the organic solvents, concentrating the organic solvents at 40 ℃ under reduced pressure to a small volume, adding a proper amount of water, concentrating the organic solvents under reduced pressure, adding 100g of water, performing suction filtration, and drying the organic solvents at 45-60 ℃ to obtain a compound V, wherein the molar yield is 87.63%.
S5: intramolecular nucleophilic substitution reaction: adding 20g of the compound V into a reaction bottle, adding 100g of tetrahydrofuran, stirring uniformly, cooling to-70 ℃ under the protection of nitrogen, adding 8g of trimethylchlorosilane, dropwise adding 105g of diisobutylamine lithium, controlling the temperature to react for 1-2 h, and monitoring by TLC (thin layer chromatography) until the reaction is complete;
and (3) post-treatment process: heating to 10 ℃, adding 100g of hydrochloric acid for hydrolysis reaction, monitoring by TLC (thin layer chromatography) until the reaction is complete, adjusting the reaction to be neutral by using 40% sodium hydroxide aqueous solution, extracting by using 80g of chloroform as an organic solvent for three times, concentrating under reduced pressure at 58 ℃, adding a proper amount of water, concentrating under reduced pressure, adding 100g of water for elutriation, crystallizing, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VI, wherein the molar yield is 98.92%.
S6: reduction reaction: adding 15.0g of the compound VI into a reaction bottle, adding 7.5g of iron powder, adding 60g of glacial acetic acid, heating to 30 ℃, controlling the temperature to react for 5-6 h, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: cooling to 45 ℃, adding 60g of trichloromethane, stirring, cooling to 40 ℃, adjusting the temperature to be neutral by using 40% sodium hydroxide aqueous solution, extracting 80g of trichloromethane serving as an organic solvent for three times, concentrating at 45 ℃ under reduced pressure to a small volume, adding a proper amount of water, concentrating under reduced pressure, adding 80g of water for elutriation, cooling to normal temperature, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VII with the molar yield of 96.23%. HPLC content 98.75%.
Example 3
A preparation method of a melengestrol intermediate comprises the following specific steps:
s1: and (3) etherification reaction: and (3) etherification reaction: adding 100g of compound I (4-androstene-3, 20-dione) into a reaction bottle, adding 400g of trichloromethane, introducing nitrogen, adding 4.02g of p-toluenesulfonic acid, stirring uniformly, heating to 34 ℃, slowly adding 240.60g of trimethyl orthoformate, reacting for two hours under the controlled temperature, and detecting by TLC (thin layer chromatography) to completely react;
and (3) post-treatment process: cooling to 0-5 ℃, adding 100g of water, reacting for 6 minutes, rapidly adding 200.50g of 2% sodium carbonate aqueous solution, stirring for half an hour, carrying out elutriation by 1600.40g of ice water, stirring, carrying out suction filtration, and drying at 34 ℃ to obtain a compound II, namely 3-methyl ether-4-androstene-17-one, wherein the molar yield is 95.86%.
S2: and (3) performing a methylenation reaction: adding 100g of the compound II into a reaction bottle, adding 900g of acetone, uniformly stirring, cooling to-6 ℃ under the protection of nitrogen, adding 55g of sodium ethoxide into the mixed solution, and uniformly stirring; slowly dropwise adding 60g of dipropyl oxalate into the mixed solution, carrying out heat preservation reaction after the addition is finished, stirring for 3-4 hours, monitoring by TLC (thin layer chromatography) until the reaction is finished completely, adding 4.5g of glacial acetic acid, 30.5g of triethylamine and 270g of methanol, uniformly stirring, adding 36.6g of propionaldehyde, raising the temperature to 20 ℃, controlling the temperature to react for 1-2 hours, and monitoring by TLC until the reaction is finished completely;
and (3) post-treatment process: adding 90g of water to terminate, carrying out rotary evaporation at 45 ℃ to remove the organic solvent, adding 100g of water, carrying out vacuum recovery, carrying out heat preservation at 1-7 ℃ for 2h, carrying out elutriation at 900g of water, carrying out suction filtration, and drying at 40-42 ℃ to obtain a compound III, namely 16-methenyl-4-androstene-3, 17-dione, wherein the molar yield is 97.43%.
S3: cyano substitution reaction: adding 100g of compound III into a reaction bottle, adding 350g of ethanol and 55.18g of sodium cyanide, stirring uniformly, adding 100g of 5% sodium hydroxide solution, adding 3g of hexachloroacetone, reacting for 22h at 30 ℃, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: and (3) performing elutriation by 700g, neutralizing by 15g of hydrochloric acid, filtering, washing a filter cake to be neutral by water, and drying at 25-30 ℃ to obtain a compound IV with the molar yield of 95.49%.
S4: and (3) carrying out a silicon alkoxide protection reaction: adding 100g of the compound IV into a reaction bottle, adding 400.80g of carbon tetrachloride and 35g of triethylamine, stirring uniformly, cooling to-5 ℃ under the protection of nitrogen, dropwise adding 92.6g of chloromethyl dimethyl iodosilane, reacting for 2 hours at a controlled temperature, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: stopping the reaction by using 0.03% sodium carbonate aqueous solution, extracting the organic solvent 400g dichloromethane for three times, combining the organic solvents, concentrating the organic solvents at 40 ℃ under reduced pressure to a small volume, adding a proper amount of water, concentrating the organic solvents under reduced pressure, adding 800g of water for water separation, performing suction filtration, and drying the mixture at 45-60 ℃ to obtain a compound V, wherein the molar yield is 88.15%.
S5: intramolecular nucleophilic substitution reaction: adding 100g of the compound V into a reaction bottle, adding 500g of cyclohexane, stirring uniformly, cooling to-65 ℃ under the protection of nitrogen, adding 40.28g of trimethylchlorosilane, dropwise adding 500.10g of lithium diisopropylamide, controlling the temperature to react for 1-2 hours, and monitoring by TLC (thin layer chromatography) until the reaction is complete;
and (3) post-treatment process: heating to 0-10 ℃, adding 500g of hydrochloric acid for hydrolysis reaction, monitoring by TLC until the reaction is complete, adjusting the reaction to be neutral by using 40% sodium hydroxide aqueous solution, extracting by using 400g of trichloromethane as an organic solvent for three times, concentrating under reduced pressure at 58 ℃, adding a proper amount of water, concentrating under reduced pressure, adding 1200g of water for elutriation, crystallizing, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VI with the molar yield of 98.56%.
S6: reduction reaction: 100.15g of compound VI is added into a reaction bottle, 30.5g of iron powder and 20g of zinc powder are added, 400.60g of glacial acetic acid is added, the temperature is raised to 40 ℃, the temperature is controlled to react for 5-6 h, and TLC (thin layer chromatography) is used for monitoring until the reaction is complete;
and (3) post-treatment process: cooling to 45 ℃, stirring 400g of trichloromethane, cooling to 40 ℃, adjusting the temperature to be neutral by using 40% sodium hydroxide aqueous solution, extracting 400.80g of trichloromethane by three times by using an organic solvent, concentrating to a small volume at 45 ℃ under reduced pressure, adding a proper amount of water, concentrating under reduced pressure, adding 900g of water for elutriation, cooling to normal temperature, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VII with the molar yield of 97.46%. HPLC content 99.16%.
Example 4
A preparation method of a melengestrol intermediate comprises the following specific steps:
s1: and (3) etherification reaction: adding 10g of compound I (4-androstene-3, 20-dione) into a reaction bottle, adding 200g of dioxane, introducing nitrogen, adding 1g of perchloric acid, stirring uniformly, heating to 36 ℃, slowly adding 60g of triethyl orthoformate, reacting for two hours under controlled temperature, and detecting by TLC (thin layer chromatography) to completely react;
and (3) post-treatment process: cooling to 0-5 ℃, adding 25g of water, reacting for 6 minutes, rapidly adding 50g of 2% sodium carbonate aqueous solution, stirring for half an hour, carrying out water precipitation on 400g of ice water, stirring, carrying out suction filtration, and drying at 20-32 ℃ to obtain a compound II, namely 3-methyl ether-4-androstene-17-one, wherein the molar yield is 95.32%.
S2: and (3) performing a methylenation reaction: adding 30g of the compound II into a reaction bottle, adding 270g of dichloromethane, stirring uniformly, cooling to-4 ℃ under the protection of nitrogen, adding 15g of sodium tert-butoxide into the mixed solution, and stirring uniformly; slowly dropwise adding 10.5g of diethyl oxalate and 9g of dimethyl oxalate into the mixed solution, carrying out heat preservation reaction after the addition is finished, stirring for 3-4 hours, and monitoring by TLC (thin layer chromatography) until the reaction is complete;
and (3) post-treatment process: adding 1.5g of glacial acetic acid, 10.5g of triethylamine and 90g of methanol, uniformly stirring, adding 9.6g of formaldehyde and 3g of acetaldehyde, raising the temperature to 25 ℃, controlling the temperature to react for 1-2 hours, monitoring by TLC until the reaction is complete, adding 30g of water to stop the reaction, rotationally evaporating the organic solvent at 45 ℃, adding 60g of water, recovering under reduced pressure, keeping the temperature at 1-7 ℃ for 2 hours, performing 360g of water precipitation, performing suction filtration, and drying at 40-42 ℃ to obtain a compound III, namely 16-methenyl-4-androstene-3, 17-dione, wherein the molar yield is 98.66%.
S3: cyano substitution reaction: adding 30g of compound III into a reaction bottle, adding 120g of isopropanol, 10g of acetone cyanohydrin and 8g of potassium cyanide, stirring uniformly, adding 32g of 5% potassium carbonate aqueous solution, adding 3.5g of hexafluoroacetone, controlling the temperature at 32 ℃ for reaction for 22 hours, and monitoring by TLC (thin layer chromatography) until the reaction is complete;
and (3) post-treatment process: and (3) performing elutriation by 240g, neutralizing by 5g of hydrochloric acid, filtering, washing a filter cake to be neutral by using water, and drying at 25-30 ℃ to obtain a compound IV with the molar yield of 95.72%.
S4: and (3) carrying out a silicon alkoxide protection reaction: adding 20g of the compound IV into a reaction bottle, adding 80g of benzene and 7g of DBU, uniformly stirring, cooling to-3 ℃ under the protection of nitrogen, dropwise adding 10g of chloromethyl dimethylchlorosilane and 4g of chloromethyl dimethylbromosilane, reacting for 2 hours under controlled temperature, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: stopping the reaction by using 0.03% sodium carbonate aqueous solution, extracting the organic solvent 80g dichloromethane for three times, combining the organic solvents, concentrating the organic solvents at 40 ℃ under reduced pressure to a small volume, adding a proper amount of water, concentrating the organic solvents under reduced pressure, adding 160g of water, performing water precipitation, performing suction filtration, and drying the mixture at 45-60 ℃ to obtain a compound V, wherein the molar yield is 88.47%.
S5: intramolecular nucleophilic substitution reaction: adding 20g of the compound V into a reaction bottle, adding 100g of diethyl ether, stirring uniformly, cooling to-60 ℃ under the protection of nitrogen, adding 8g of trimethylchlorosilane, dropwise adding 70g of lithium diisopropylamide and 30g of lithium diisobutylamine, controlling the temperature to react for 1-2 h, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: heating to 0-10 ℃, adding 100g of hydrochloric acid for hydrolysis reaction, monitoring by TLC until the reaction is complete, adjusting the reaction to be neutral by using 40% sodium hydroxide aqueous solution, extracting by using 80g of chloroform as an organic solvent for three times, concentrating under reduced pressure at 58 ℃, adding a proper amount of water, concentrating under reduced pressure, adding 90g of water for elutriation, crystallizing, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VI with the molar yield of 97.64%.
S6: reduction reaction: adding 15.0g of the compound VI into a reaction bottle, adding 7.5g of zinc powder, adding 60g of glacial acetic acid, heating to 50 ℃, controlling the temperature to react for 5-6 h, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: cooling to 45 ℃, adding 60g of trichloromethane, stirring, cooling to 40 ℃, adjusting the temperature to be neutral by using 40% sodium hydroxide aqueous solution, extracting 80g of trichloromethane by using an organic solvent for three times, concentrating to a small volume at 45 ℃ under reduced pressure, adding a proper amount of water, concentrating under reduced pressure, adding 150g of water for elutriation, cooling to normal temperature, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VII with the molar yield of 97.55%. HPLC content 98.94%.
Example 5
A preparation method of a melengestrol intermediate comprises the following specific steps:
s1: and (3) etherification reaction: adding 50g of compound I (4-androstene-3, 20-dione) into a reaction bottle, adding 100g of tetrahydrofuran and 100g of trichloromethane, introducing nitrogen, adding 1g of p-toluenesulfonic acid, stirring uniformly, heating to 38 ℃, slowly adding 60g of trimethyl orthoformate, reacting for two hours under controlled temperature, and detecting by TLC (thin layer chromatography) to completely react;
and (3) post-treatment process: cooling to 0-5 ℃, adding 25g of water, reacting for 6 minutes, rapidly adding 50g of 2% sodium carbonate aqueous solution, stirring for half an hour, carrying out water precipitation on 400g of ice water, stirring, carrying out suction filtration, and drying at 20-32 ℃ to obtain a compound II, namely 3-methyl ether-4-androstene-17-one, wherein the molar yield is 94.27%.
S2: and (3) performing a methylenation reaction: putting 30g of the compound II into a reaction bottle, adding 200g of dichloromethane and 70g of dioxane, uniformly stirring, cooling to-2 ℃ under the protection of nitrogen, adding 15g of potassium tert-butoxide into the mixed solution, and uniformly stirring; slowly dropwise adding 10.5g of diethyl oxalate and 9g of dipropyl oxalate into the mixed solution, carrying out heat preservation reaction after the addition is finished, stirring for 3-4 hours, and monitoring by TLC (thin layer chromatography) until the reaction is complete;
and (3) post-treatment process: adding 1.5g of glacial acetic acid, 10.5g of triethylamine and 90g of methanol, uniformly stirring, adding 9.6g of propionaldehyde and 3g of acetaldehyde, raising the temperature to 30 ℃, controlling the temperature to react for 1-2 hours, monitoring by TLC until the reaction is complete, adding 30g of water to stop the reaction, rotationally evaporating the organic solvent at 45 ℃, adding 60g of water, recovering under reduced pressure, keeping the temperature at 1-7 ℃ for 2 hours, performing 360g of water precipitation, performing suction filtration, and drying at 40-42 ℃ to obtain a compound III, namely 16-methenyl-4-androstene-3, 17-dione, wherein the molar yield is 98.59%.
S3: cyano substitution reaction: adding 30g of compound III into a reaction bottle, adding 120g of acetone, 10g of sodium cyanide and 8g of potassium cyanide, uniformly stirring, adding 17g of 5% potassium carbonate aqueous solution and 15g of 5% sodium hydroxide aqueous solution, adding 3.5g of hexachloroacetone, controlling the temperature at 36 ℃ for reaction for 22 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: and (3) performing elutriation by 240g, neutralizing by 5g of hydrochloric acid, filtering, washing a filter cake to be neutral by using water, and drying at 25-30 ℃ to obtain a compound IV, wherein the molar yield is 96.05%.
S4: and (3) carrying out a silicon alkoxide protection reaction: adding 20g of the compound IV into a reaction bottle, adding 80g of toluene, 4g of 4-dimethylaminopyridine and 3g of imidazole, stirring uniformly, cooling to 0 ℃ under the protection of nitrogen, dropwise adding 15g of chloromethyl dimethyl iodosilane and 6g of chloromethyl dimethyl bromosilane, controlling the temperature to react for 2 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: stopping the reaction by using 0.03% sodium carbonate aqueous solution, extracting the organic solvent 80g dichloromethane for three times, combining the organic solvents, concentrating the organic solvents at 40 ℃ under reduced pressure to a small volume, adding a proper amount of water, concentrating the organic solvents under reduced pressure, adding 180g of water, performing leaching, and drying the mixture at 45-60 ℃ to obtain a compound V with the molar yield of 87.24%.
S5: intramolecular nucleophilic substitution reaction: adding 20g of the compound V into a reaction bottle, adding 100g of benzene, stirring uniformly, cooling to-50 ℃ under the protection of nitrogen, adding 8g of trimethylchlorosilane, dropwise adding 70g of diisobutylamine lithium and 30g of n-butyllithium, controlling the temperature to react for 1-2 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: heating to 0-10 ℃, adding 100g of hydrochloric acid for hydrolysis reaction, monitoring by TLC until the reaction is complete, adjusting the reaction to be neutral by using 40% sodium hydroxide aqueous solution, extracting by using 80g of chloroform as an organic solvent for three times, concentrating under reduced pressure at 58 ℃, adding a proper amount of water, concentrating under reduced pressure, adding 140g of water for elutriation, crystallizing, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VI with the molar yield of 96.35%.
S6: reduction reaction: adding 15.0g of the compound VI into a reaction bottle, adding 7.5g of iron powder, adding 60g of glacial acetic acid, heating to 55 ℃, controlling the temperature to react for 5-6 h, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: cooling to 45 ℃, adding 60g of trichloromethane, stirring, cooling to 40 ℃, adjusting the temperature to be neutral by using 40% sodium hydroxide aqueous solution, extracting 80g of trichloromethane by using an organic solvent for three times, concentrating to a small volume at 45 ℃ under reduced pressure, adding a proper amount of water, concentrating under reduced pressure, adding 90g of water for elutriation, cooling to normal temperature, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VII with the molar yield of 98.62%. HPLC content 99.07%.
Example 6
A preparation method of a melengestrol intermediate comprises the following specific steps:
s1: and (3) etherification reaction: adding 100g of compound I (4-androstene-3, 20-dione) into a reaction bottle, adding 200g of dichloromethane and 200g of dioxane, introducing nitrogen, adding 4.02g of perchloric acid, uniformly stirring, heating to 40 ℃, slowly adding 240.60g of triethyl orthoformate, reacting for two hours under the controlled temperature, and detecting by TLC (thin layer chromatography) to completely react;
and (3) post-treatment process: cooling to 5-10 ℃, adding 100g of water, reacting for 6 minutes, rapidly adding 200.50g of 2% sodium carbonate aqueous solution, stirring for half an hour, carrying out water precipitation by 1600.40g of ice water, stirring, carrying out suction filtration, and drying at 20-32 ℃ to obtain a compound II, namely 3-methyl ether-4-androstene-17-one, wherein the molar yield is 94.33%.
S2: and (3) performing a methylenation reaction: adding 100g of the compound II into a reaction bottle, adding 500g of acetone and 400g of trichloromethane, uniformly stirring, cooling to 0 ℃ under the protection of nitrogen, adding 40g of sodium methoxide and 15g of sodium ethoxide into the mixed solution, and uniformly stirring; slowly dropwise adding 40g of dimethyl oxalate and 20g of dipropyl oxalate into the mixed solution, carrying out heat preservation reaction after the addition is finished, stirring for 3-4 hours, and monitoring by TLC (thin layer chromatography) until the reaction is complete;
and (3) post-treatment process: adding 4.5g of glacial acetic acid, 30.5g of triethylamine and 270g of methanol, uniformly stirring, adding 16.6g of formaldehyde and 20g of propionaldehyde, raising the temperature to 40 ℃, controlling the temperature to react for 1-2 hours, monitoring by TLC until the reaction is complete, adding 90g of water to terminate, rotationally evaporating the organic solvent at 45 ℃, adding 100g of water, recovering under reduced pressure, preserving the temperature at 1-7 ℃ for 2 hours, precipitating by 900g of water, performing suction filtration, and drying at 40-42 ℃ to obtain a compound III, namely 16-methine-4-androstene-3, 17-dione, wherein the molar yield is 97.43%.
S3: cyano substitution reaction: adding 100g of compound III into a reaction bottle, adding 340g of ethanol, 10g of water, 45.18g of acetone cyanohydrin and 10g of sodium cyanide, stirring uniformly, adding 90g of 5% sodium carbonate solution and 10g of 5% sodium hydroxide solution, adding 3g of hexafluoroacetone, controlling the temperature at 40 ℃ for reaction for 22 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: 700g of water is separated out, 15g of hydrochloric acid is used for neutralization and filtration, a filter cake is washed to be neutral by water and is dried at 25-30 ℃ to obtain a compound IV, and the molar yield is 95.77%.
S4: and (3) carrying out a silicon alkoxide protection reaction: adding 100g of the compound IV into a reaction bottle, adding 300.60g of dichloromethane, 100g of benzene, 30g of imidazole and 5g of triethylamine, stirring uniformly, setting the temperature at 30 ℃ under the protection of nitrogen, dropwise adding 51g of chloromethyl dimethylchlorosilane and 10g of chloromethyl dimethyl iodosilane, controlling the temperature to react for 2 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: stopping the reaction by using 0.03% potassium carbonate aqueous solution, extracting 400g of dichloromethane serving as an organic solvent for three times, combining the organic solvents, concentrating the organic solvents at 40 ℃ under reduced pressure to a small volume, adding a proper amount of water, concentrating the organic solvents under reduced pressure, adding 1200g of water, performing suction filtration, and drying the organic solvents at 45-60 ℃ to obtain a compound V, wherein the molar yield is 82.56%.
S5: intramolecular nucleophilic substitution reaction: adding 100g of the compound V into a reaction bottle, adding 400g of dimethyltetrahydrofuran and 100g of cyclohexane, stirring uniformly, cooling to-30 ℃ under the protection of nitrogen, adding 40.28g of trimethylchlorosilane, dropwise adding 450.10g of diisopropylaminolithium and 50g of n-butyllithium, controlling the temperature to react for 1-2 hours, and monitoring by TLC until the reaction is complete;
and (3) post-treatment process: heating to 0-10 ℃, adding 500g of hydrochloric acid for hydrolysis reaction, monitoring by TLC (thin layer chromatography) until the reaction is complete, adjusting the reaction to be neutral by using 40% sodium hydroxide aqueous solution, extracting by using 400g of trichloromethane as an organic solvent for three times, concentrating under reduced pressure at 58 ℃, adding a proper amount of water, concentrating under reduced pressure, adding 1400g of water for elutriation, crystallizing, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VI with the molar yield of 93.59%.
S6: reduction reaction: 100.15g of compound VI is added into a reaction bottle, 40.5g of iron powder and 10g of zinc powder are added, 400.60g of glacial acetic acid is added, the temperature is raised to 60 ℃, the temperature is controlled to react for 5-6 h, and TLC (thin layer chromatography) is used for monitoring until the reaction is complete;
and (3) post-treatment process: cooling to 45 ℃, stirring 400g of trichloromethane, cooling to 40 ℃, adjusting the temperature to be neutral by using 40% sodium hydroxide aqueous solution, extracting 400.80g of trichloromethane by three times by using an organic solvent, concentrating to a small volume at 45 ℃ under reduced pressure, adding a proper amount of water, concentrating under reduced pressure, adding 1400g of water for elutriation, cooling to normal temperature, performing suction filtration, and drying at 45-60 ℃ to obtain a compound VII with the molar yield of 97.87%. HPLC content 98.62%.
The foregoing is a more detailed description of the invention in connection with specific/preferred embodiments and is not intended to limit the practice of the invention to those descriptions. It will be apparent to those skilled in the art that various substitutions and modifications can be made to the described embodiments without departing from the spirit of the invention, and such substitutions and modifications are to be considered as within the scope of the invention.

Claims (10)

1. A preparation method of melengestrol intermediate is characterized in that: the method takes compound I4-androstene-3, 17 diketone as an initial raw material and comprises the following steps:
s1: and (3) etherification reaction: adding the compound I into an etherification solvent, and reacting with an etherification reagent under the action of a first catalyst to obtain a compound II;
Figure FDA0002342095930000011
s2, performing methyleneation, namely adding the compound II into a methyleneation solvent, replacing α hydrogen at the 16-position with first organic alkali and oxalate, performing methylene elimination on β hydrogen at the 16-position with an elimination reagent, and finally hydrolyzing to obtain a compound III;
Figure FDA0002342095930000012
s3: cyano substitution reaction: adding the compound III into a cyaniding solvent, and reacting with a cyaniding reagent under the action of a second catalyst in an alkaline environment to obtain a compound IV;
Figure FDA0002342095930000013
s4: and (3) carrying out a silicon alkoxide protection reaction: adding the compound IV into a protective solvent, and reacting with a siloxy reagent in the presence of a second organic base to obtain a compound V;
Figure FDA0002342095930000021
s5: intramolecular nucleophilic substitution reaction: adding the compound V into a substitution solvent, and reacting with an amino alkali metal reagent to obtain a compound VI;
Figure FDA0002342095930000022
s6: reduction reaction: adding the compound VI into a reduction solvent, and reacting with metal to obtain a compound VII, namely an intermediate of melengestrol;
Figure FDA0002342095930000023
the second catalyst is hexachloroacetone or hexafluoroacetone;
in the step S1, the etherification solvent is one or more of tetrahydrofuran, dichloromethane, trichloromethane and dioxane; the first catalyst is p-toluenesulfonic acid or perchloric acid; the etherification reagent is trimethyl orthoformate or triethyl orthoformate;
in the step S2, the methylation solvent is one or more of dichloromethane, trichloromethane, acetone and dioxane; the first organic base is one or more of sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the elimination reagent is one or more of formaldehyde, acetaldehyde and propionaldehyde; the oxalate is one or more of diethyl oxalate, dimethyl oxalate and dipropyl oxalate;
in the step S3, the cyaniding solvent is one or more of methanol, ethanol, n-propanol, isopropanol, acetone and water; the cyaniding reagent is one or more of acetone cyanohydrin, potassium cyanide and sodium cyanide; the alkaline environment is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate;
in the step S4, the protective solvent is one or more of dichloromethane, trichloromethane, carbon tetrachloride, benzene, lower aromatic hydrocarbon and acetone; the second organic base is one or more of 4-dimethylamino pyridine, imidazole, triethylamine and DBU; the siloxy reagent is one or more of chloromethyl dimethyl chlorosilane, chloromethyl dimethyl bromosilane and chloromethyl dimethyl iodosilane; the lower aromatic hydrocarbon is one or more of toluene, o-xylene, p-xylene and ethylbenzene;
in step S5, the substitute solvent is one or more of tetrahydrofuran, dimethyltetrahydrofuran, cyclohexane, diethyl ether and benzene; the amino alkali metal reagent is one or more of lithium diisopropylamide, lithium diisobutylamine and n-butyl lithium;
in step S6, the reducing solvent is glacial acetic acid; the metal is one or more of zinc and iron.
2. The method for preparing melengestrol intermediate according to claim 1, wherein: the reaction temperature of the etherification reaction in the step S1 is 30-40 ℃.
3. The method for preparing melengestrol intermediate according to claim 1, wherein: in the step S2, the reaction temperature of the substitution reaction is-10 to 0 ℃, and the reaction temperature of the elimination reaction is 10 to 40 ℃.
4. The method for preparing melengestrol intermediate according to claim 1, wherein: the reaction temperature of the cyano substitution reaction in the step S3 is 20-40 ℃.
5. The method for preparing melengestrol intermediate according to claim 1, wherein: the reaction temperature of the silicon alkoxy protection reaction in the step S4 is-10 to 30 ℃.
6. The method for preparing melengestrol intermediate according to claim 1, wherein: the reaction temperature of the nucleophilic substitution reaction in the molecule in the step S5 is-80 to-30 ℃.
7. The method for preparing melengestrol intermediate according to claim 1, wherein: the reaction temperature of the reduction reaction in the step S6 is 20-60 ℃.
8. The method of claim 1, wherein the preparation method comprises the following steps: the temperature of the elimination reaction in the step S2 is 25-30 ℃.
9. A process for the preparation of a melengestrol intermediate as claimed in claim 1, wherein: the reaction temperature of the siloxy protection reaction in the step S4 is-5-0 ℃.
10. A process for the preparation of a melengestrol intermediate as claimed in claim 1, wherein: the reaction temperature of the nucleophilic substitution reaction in the molecule in the step S5 is-70 to-65 ℃.
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