CN116574150A - Preparation method of dihydrotestosterone and intermediate thereof - Google Patents

Preparation method of dihydrotestosterone and intermediate thereof Download PDF

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Publication number
CN116574150A
CN116574150A CN202310475067.XA CN202310475067A CN116574150A CN 116574150 A CN116574150 A CN 116574150A CN 202310475067 A CN202310475067 A CN 202310475067A CN 116574150 A CN116574150 A CN 116574150A
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Prior art keywords
compound
acid
reaction
preparation
dihydrotestosterone
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CN202310475067.XA
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Chinese (zh)
Inventor
张宏峰
吴晓川
揭致壕
刘锦康
钟永健
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Guangzhou Kaishi Pharmaceutical Co ltd
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Guangzhou Kaishi Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J21/005—Ketals
    • C07J21/006—Ketals at position 3
    • 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
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention provides a preparation method of dihydrotestosterone and a key intermediate thereof, which takes epiandrosterone as a raw material, and the intermediate is obtained through two steps of oxidation and selective protection, and then the dihydrotestosterone is obtained through two steps of reduction and deprotection of the intermediate. The method has the advantages of short synthetic route, mild reaction conditions, high product yield, good reproducibility, simple and convenient operation, easy amplification of the process, economic and easily obtained raw materials, environment-friendly and pollution-free preparation process, suitability for industrial scale preparation and higher application value.

Description

Preparation method of dihydrotestosterone and intermediate thereof
Technical Field
The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of dihydrotestosterone and an intermediate thereof.
Background
Dihydrotestosterone (dihydroestterone) chemical name 17β -hydroxy-5α -androstane]Alkane-3-ketone, 5α -dihydrotestosterone, CAS number: 521-18-6, molecular formula: c (C) 19 H 30 O 2 Molecular weight: 290.45, structural formula:
dihydrotestosterone, a steroid hormone secreted by the testes, is the major androgen in the human body and is involved in the development of secondary male sex characteristics. The dihydrotestosterone has the main functions of: 1. maintaining the effect of producing sperm; 2. stimulating the development of reproductive organs, promoting the appearance of male parasexual characteristics and maintaining the normal morphology of the male parasexual characteristics; 3. promote the synthesis of proteins, in particular the synthesis of proteins of muscles and reproductive organs, and promote bone growth and calcium and phosphorus deposition and erythropoiesis.
Patent CN107098944a discloses a preparation method of dihydrotestosterone:
the method comprises the following steps: the compound I reacts with acetone cyanohydrin or sodium cyanide to obtain a compound II; the compound II is ketalized by using glycol and triethyl orthoformate in an acidic environment, and then a compound III is generated in an alkaline environment; reducing the 17-keton group in the compound III to form a hydroxyl group by sodium borohydride or potassium borohydride to generate a compound IV; hydrogenating the compound IV under the action of a palladium-carbon catalyst to obtain a compound V; and hydrolyzing ketal under an acidic environment to obtain the target product. The method can generate a large amount of cyanide-containing wastewater in the synthesis of a key intermediate cyanohydrin, and the cyanide-containing industrial wastewater formed by the method can be discharged after reaching standards because of the extremely toxic property of the cyanide-containing compound. According to the national discharge standard, the concentration of cyanide ions in the discharged wastewater must not exceed 5ppm, the treatment difficulty is great, and the huge pressure of environmental protection treatment of enterprises restricts the application of the process route in industrial production. In addition, isomer impurities are generated in the palladium catalytic hydrogenation reaction, and the impurity separation and purification cost is high.
In view of the above, it is of great importance to develop an economical and environment-friendly preparation method of dihydrotestosterone, which is suitable for industrial production.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a preparation method of dihydrotestosterone and an intermediate thereof, which has the advantages of mild reaction conditions, high product yield, good repeatability, simple operation, economic and easily obtained raw materials, environment-friendly and pollution-free preparation process and suitability for industrial production.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides a preparation method of a dihydrotestosterone intermediate 4, which comprises the following reaction routes:
the invention also provides a preparation method of the dihydrotestosterone, and the reaction route is as follows:
compared with the prior art, the invention has the following beneficial effects:
the method has the advantages of mild reaction conditions, high product yield, good reproducibility, simple and convenient operation, easy amplification of the process, economic and easily obtained raw materials, environment-friendly and pollution-free preparation process, suitability for industrial scale preparation and higher application value.
Detailed Description
The technical scheme of the invention is described in detail below.
The invention provides a preparation method of a dihydrotestosterone intermediate 4, which comprises the following reaction routes:
the method comprises the following steps:
(I) The compound 2 is subjected to oxidation reaction under the action of an oxidizing reagent to obtain a compound 3;
and (II) performing carbonyl protection reaction on the compound 3 under the action of a glycol compound and a catalyst to obtain a compound 4.
In some embodiments of the invention, the oxidizing agent is any one of PCC, PDC, DMSO, IBX, dess-Martin agents;
further, the oxidizing agent is IBX.
In some embodiments of the invention, the oxidation reaction is performed in the presence of a solvent, which is any one of dichloromethane, ethyl acetate, acetonitrile, acetone, tetrahydrofuran;
further, the solvent is ethyl acetate.
In some embodiments of the invention, the temperature of the oxidation reaction is from 0 to 100 ℃; further, the temperature of the oxidation reaction is 80-100 ℃.
In some embodiments of the invention, the molar ratio of oxidizing agent to compound 2 is 1-5:1.
The oxidation method is convenient to post-treat, and can be put into subsequent reaction through simple filtration and concentration. Extraction is not needed, and the process operation and the solvent use are greatly simplified.
In some embodiments of the invention, the glycol compound is at least one of ethylene-alcohol, bis-trimethylsilyl ethylene glycol, dithioethylene glycol, 1, 3-propanediol, ding Tongyi glycol ketal;
further, the diol compound is bis (trimethylsilyl) glycol.
In some embodiments of the invention, the catalyst is at least one of p-toluenesulfonic acid, camphorsulfonic acid, oxalic acid, succinic acid, adipic acid and hydrates thereof, trimethylsilyl triflate.
In some embodiments of the invention, the carbonyl protection reaction is carried out in the presence of a solvent that is a benzene solvent, an ether solvent, or a halogenated solvent;
further, the solvent is dichloromethane.
In some embodiments of the invention, the temperature of the carbonyl protection reaction is from-80 to 120 ℃; further, the temperature of the carbonyl protection reaction is-80 to-60 ℃.
The invention also provides a preparation method of the dihydrotestosterone, and the reaction route is as follows:
the method comprises the following steps:
(III) reacting the compound 4 under the action of a reducing agent to obtain a compound 5;
hydrolysis of compound 5 gives compound 1.
In some embodiments of the invention, the reducing agent is selected from at least one of sodium borohydride, lithium aluminum tetrahydroide, lithium tri-t-butyl aluminum hydride, diisobutyl aluminum hydride, lithium triethylborohydride, borane;
further, the reducing agent is sodium borohydride.
In some embodiments of the invention, the reaction temperature of step (III) is from-78 to 20 ℃; further, the reaction temperature in the step (III) is-20-0 ℃.
In some embodiments of the invention, the molar ratio of compound 4 to reducing agent is 1:1 to 5; further, the molar ratio of the compound 4 to the reducing agent is 1:1-3.
In some embodiments of the invention, the reaction of step (III) is carried out in the presence of a solvent, which is an alcoholic solvent and/or an ethereal solvent; further, the solvent is methanol.
In some embodiments of the invention, the hydrolysis reaction of step (IV) is performed under acidic conditions, the acidic compound being at least one of para-toluenesulfonic acid pyridinium salt (PPTS), hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, para-toluenesulfonic acid, camphorsulfonic acid;
further, the acidic compound is a pyridinium p-toluenesulfonate.
In some embodiments of the invention, the reaction temperature of step (IV) is from 20 to 120 ℃; further, the reaction temperature is 20 to 100 ℃.
In some embodiments of the invention, the molar ratio of compound 5 to acidic compound is 1:0.05-2; further, the molar ratio of the compound 5 to the acidic compound is 1:0.05-1.5.
In some embodiments of the invention, the reaction of step (IV) is carried out in the presence of a solvent which is an ether solvent or a mixture of an alcohol solvent and water; further, the solvent is tetrahydrofuran-water mixed solvent.
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. In addition, the raw materials related to the invention are common commercial products unless otherwise specified.
EXAMPLE 1 Synthesis of Compound 3
To a 250mL reaction flask was added compound 2 (2.9 g,10.0 mmol) and 35mL ethyl acetate to dissolve, followed by 2-iodoxybenzoic acid (IBX) (30 mmol), and the resulting mixture was stirred at reflux temperature until reaction was complete (TLC monitoring), cooled to room temperature, insoluble matter was filtered through celite, and the resulting filtrate was concentrated under reduced pressure to give compound 3 (2.9 g, 100%) and used directly in the next step.
1 H NMR(400MHz，Chloroform-d)δ2.53-2.31(m，6H)，1.77-1.38(m，15H)，1.31(ddd，J＝8.0，6.1，3.8Hz，1H)，1.08(s，3H)，0.84(s，3H).ESI-MS m/z：289.2[M+H]+.
EXAMPLE 2 Synthesis of Compound 4
To compound 3 (2.9 g,10 mmol) was added 80mL of methylene chloride under nitrogen to dissolve, then bis (trimethylsilyl) glycol (10 mmol) was added and cooled to-78 ℃. Trimethylsilyl triflate (0.3 mmol) was then added dropwise and stirred at this temperature until the reaction was complete (TLC monitoring). After the completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution, extracted 1 time with 100mL of dichloromethane, and the organic phase was collected, concentrated under reduced pressure to give Compound 4 (3.2 g, 96%) and used directly in the next step.
1 H NMR(400MHz，Chloroform-d)δ3.90(d，J＝1.4Hz，4H)，2.54-2.40(m，4H)，2.07(dd，J＝14.1，5.0Hz，2H)，2.01-1.95(m，2H)，1.95-1.92(m，3H)，1.92-1.85(m，1H)，1.82-1.55(m，5H)，1.56-1.36(m，6H)，1.33(ddd，J＝8.0，6.1，3.7Hz，2H)，0.84(d，J＝19.4Hz，3H).ESI-MS m/z：333.2[M+H]+.
EXAMPLE 3 Synthesis of Compound 5
Compound 4 (1.6 g,4.8 mmol) was taken in a 250mL eggplant bottle and dissolved in 50mL of methanol, sodium borohydride (375 mg,10.0 mmol) was added slowly in portions at-20℃and reacted for 2 hours at this temperature before being transferred to room temperature with stirring. The reaction was quenched with 60mL of saturated aqueous ammonium chloride, the solvent was removed by rotary evaporation, then extracted twice with 50mL of ethyl acetate, the organic phase was washed once with saturated aqueous sodium chloride, and the solvent was dried by column chromatography (petroleum ether: ethyl acetate=4:1 to 2:1) to give compound 5 (1.5 g, 93%).
1 H NMR(400MHz，Chloroform-d)δ3.95-3.85(m，5H)，3.63(dddt，J＝5.4，4.6，3.6，1.0Hz，1H)，2.09(ddd，J＝14.3，3.8，1.4Hz，1H)，2.01-1.85(m，3H)，1.76-1.31(m，18H)，0.86(s，3H)，0.80(s，3H).ESI-MS m/z：335.2[M+H]+.
EXAMPLE 4 Synthesis of Compound 1
Compound 5 (1.5 g,4.5 mmol) was dissolved in a 100mL eggplant-shaped bottle, tetrahydrofuran/water (8:1, 45 mL) was added, and then PPTS (1 mmol) was added, and the mixture was heated to reflux and stirred for 3 hours. Cooling, adjusting pH to 7-8 with sodium bicarbonate solid, removing the organic solvent under reduced pressure, adding 50mL of ethyl acetate, separating the organic phase, washing once with 2N hydrochloric acid solution (15 mL) and saturated sodium bicarbonate solution (15 mL), respectively, and subjecting the spin-dried solvent to column chromatography (petroleum ether: ethyl acetate=2:1) to give compound 1 (1.27 g, 98%).
1 H NMR(400MHz，Chloroform-d)δ3.92(d，J＝5.2Hz，1H)，3.63(dddt，J＝5.4，4.6，3.5，0.9Hz，1H)，2.52-2.28(m，4H)，1.79-1.35(m，18H)，1.09(s，3H)，0.81(s，3H).ESI-MS m/z：291.2[M+H]+。
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.

Claims (10)

1. A process for the preparation of dihydrotestosterone intermediate 4 comprising the steps of:
(I) The compound 2 is subjected to oxidation reaction under the action of an oxidizing reagent to obtain a compound 3;
and (II) performing carbonyl protection reaction on the compound 3 under the action of a glycol compound and a catalyst to obtain a compound 4.
2. The preparation method according to claim 1, wherein the oxidizing reagent is any one of PCC, PDC, DMSO, IBX, dess-Martin reagent; IBX is preferred.
3. The method according to claim 1, wherein the temperature of the oxidation reaction is 0 to 100 ℃; preferably 80 to 100 ℃.
4. The method of claim 1, wherein the molar ratio of oxidizing agent to compound 2 is 1-5:1.
5. The method according to claim 1, wherein the diol compound is at least one of ethylene glycol, bis (trimethylsilyl) ethylene glycol, dithioethylene glycol, 1, 3-propanediol, ding Tongyi glycol ketal; preferably bis trimethylsilyl glycol.
6. The preparation method according to claim 1, wherein the catalyst is at least one of p-toluenesulfonic acid, camphorsulfonic acid, oxalic acid, succinic acid, adipic acid and hydrates thereof, trimethylsilyl triflate; trimethylsilyl triflate is preferred.
7. The method according to claim 1, wherein the temperature of the carbonyl-protecting reaction is-80 to 120 ℃; preferably-80 to-60 ℃.
8. A method for preparing dihydrotestosterone, comprising the following steps:
(III) reacting the compound 4 under the action of a reducing agent to obtain a compound 5;
hydrolysis of compound 5 gives compound 1.
9. The method according to claim 8, wherein the reducing agent is at least one selected from the group consisting of sodium borohydride, lithium tetrahydroaluminate, lithium tri-t-butyl aluminum hydride, diisobutyl aluminum hydride, lithium triethylborohydride, and borane; sodium borohydride is preferred;
the reaction temperature of the step (III) is-78-20 ℃; preferably-20 to 0 ℃;
the mol ratio of the compound 4 to the reducing agent is 1:1-5; preferably 1:1 to 3.
10. The method according to claim 8, wherein the hydrolysis reaction in step (IV) is carried out under acidic conditions, and the acidic compound is at least one of pyridinium p-toluenesulfonate, hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid; preferably, pyridinium p-toluenesulfonate;
the reaction temperature of the step (IV) is 20-120 ℃; preferably 20 to 100 ℃.
The mol ratio of the compound 5 to the acid compound is 1:0.05-2; preferably 1:0.05 to 1.5.
CN202310475067.XA 2023-04-27 2023-04-27 Preparation method of dihydrotestosterone and intermediate thereof Pending CN116574150A (en)

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