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CN113387991B - Method for synthesizing dydrogesterone and compound - Google Patents

Method for synthesizing dydrogesterone and compound Download PDF

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Publication number
CN113387991B
CN113387991B CN202010175402.0A CN202010175402A CN113387991B CN 113387991 B CN113387991 B CN 113387991B CN 202010175402 A CN202010175402 A CN 202010175402A CN 113387991 B CN113387991 B CN 113387991B
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acid
dydrogesterone
methyl
photochemical reaction
reaction
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CN113387991A (en
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杨映权
袁海涛
刘常仁
王飞
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SUZHOU LANXITE BIOTECHNOLOGY CO Ltd
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SUZHOU LANXITE BIOTECHNOLOGY 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
    • C07J7/001—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 substituted in position 20 by a keto group
    • C07J7/0015—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 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—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 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • 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
    • C07J7/0065—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 substituted in position 20 by an OH group free esterified or etherified
    • C07J7/007—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 substituted in position 20 by an OH group free esterified or etherified not substituted in position 17 alfa

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a method for synthesizing dydrogesterone, which takes dehydropregnenolone as a starting material to prepare carbonyl-protected dehydropregnenolone, then obtains a methyl configuration turnover compound through a photocatalytic reaction, and further obtains dydrogesterone through deprotection, hydroxyl oxidation and double bond rearrangement reaction. The method has the advantages of easily obtained raw materials, high yield, simple and mild reaction conditions and suitability for industrial production of dydrogesterone.

Description

Method for synthesizing dydrogesterone and compound
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a novel synthesis method of dydrogesterone.
Background
Dydrogesterone is an artificially synthesized progestogen, can be used for treating diseases caused by endogenous progesterone deficiency, such as dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progestogen deficiency and infertility caused by corpus luteum deficiency, and is a relatively ideal progestogen medicine at present.
Literature Recueil des Travaux Chimiques des Pays-Bas (1961), 80:43-46 reports that 3-hydroxy-pregna-5, 7-dien-20-one is used as a raw material, a steroid B switching ring reaction is carried out in tetrahydrofuran by using a high-pressure mercury lamp to complete the inversion of a 10-position angle methyl by configuration isomerization, and dydrogesterone is obtained by Wolff oxidation and rearrangement of a product. In the illumination step, a large amount of tetrahydrofuran is used, a large amount of raw materials remain, the yield of the whole illumination is only 10.6%, and the raw material sources of subsequent reactions and the efficiency of the whole production process are severely restricted.
Literature Recueil des Travaux Chimiques des Pays-Bas (1971), 90:27-32 reports the route to dydrogesterone starting from progesterone by glycol protection, bromination, debromination, rearrangement by high-pressure mercury lamp illumination. The protection yield of the glycol in the route is low (32% -67%The Journal of Organic Chemistry,1952,vol.17,p.1369,1373), the bromination and debromination have a lot of isomerism, so that the two-step yield is low (49%), the yield is only 22% in the key illumination step, and the industrialization is very difficult.
The Chinese patent (CN 102558272B) published in 2014 reports that the total conversion rate of the illumination raw materials is 35.4-44.6% and the total photochemical yield is 35.8-41.6% based on the route of the double-ketal inward-immersion uplink bubbling double-filtering system in the department of academy of physics and chemistry.
Published chinese patent CN103848880 a in 2014 was also optimized for this route in the institute of physics and chemistry of the chinese academy of sciences on the reaction apparatus. They used a dual wavelength microfluidics technique with a highest overall photochemical yield of 46.3%
2008 Disclosed in patent CN101318982A Taizhou Wanfu pharmaceutical Co., ltd. With 3-acetoxy-pregna-5, 7-dien-20-one, the photochemical reaction yield is relatively low (30-35%), probably because Norrish I and/or Norrish II reactions (modern molecular photochemistry Wuzhu Zhenge, etc.) occur in carbonyl groups in the molecule, so that the illuminated product impurities are increased, and the yield of the target product is relatively low.
Thus, the efficient preparation of intermediates for the isomerisation of the 10-position angle methyl configuration is a core and key step in the industrial production of dydrogesterone, and the preparation of such intermediates in high yields and high purity still requires further exploration.
Disclosure of Invention
The invention provides a novel synthesis method of dydrogesterone, which can efficiently synthesize dydrogesterone and powerfully solve the defects in the route.
The invention takes dehydropregnenolone as a starting material (DG-7) to prepare carbonyl-protected dehydropregnenolone (DG-8), then a methyl configuration turnover compound DG-9 is obtained through a photocatalytic reaction, DG-9 is deprotected to obtain DG-10, DG-10 is subjected to hydroxyl oxidation to obtain ketene DG-11, and double bond rearrangement is carried out under the acidic condition of DG-11 to obtain dydrogesterone.
The synthesis route of dydrogesterone is as follows:
Wherein R 1、R2 are the same or different and are alkyl groups, optionally R 1、R2 may be terminally linked.
As one embodiment, R 1、R2 is the same or different and is C1-C5 alkyl, such as methyl, ethyl, etc., preferably methyl.
As one embodiment, R 1、R2 is the same or different and is C1-C5 alkyl and R 1、R2 is linked at the tail end, such as ethylene, propylene, preferably ethylene.
In the step a, the DG-7 is carbonyl protected under the catalysis of acid to obtain ketal DG-8, wherein the acid is protonic acid or Lewis acid, and comprises hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ferric trichloride, aluminum trichloride, zinc chloride and the like; preferably, the acid is p-toluene sulfonic acid or p-toluene sulfonic acid.
In the step B, DG-8 is subjected to a photochemical reaction at first to finish the opening of the bonds at the 9 and 10 positions of the steroid B ring; and then, closing the 9 and 10-position bonds of the ring of the steroid B through secondary photochemical reaction to obtain 10-position angle methyl isomerism DG-9.
Preferably, the primary photochemical reaction selects light with the wavelength of 200-300 nm for illumination, and the secondary photochemical reaction selects light with the wavelength of 310-400 nm for illumination. Illumination for the photochemical reaction is preferably provided by a high pressure mercury lamp with a power of 500-1000 watts.
In step b, the solvent is preferably ethanol, DG-8: the weight-volume ratio of the ethanol is 1:100-1000.
In step d, DG-10 is oxidized by hydroxyl groups to give ketene DG-11. The hydroxyl oxidation reaction is carried out under the conditions of dessert oxidation, aluminum alkoxide oxidation, swern oxidation and the like, and preferably, the oxidant for hydroxyl oxidation is dessert or aluminum alkoxide.
In step e, DG-11 is double bond rearranged under acidic conditions to give dydrogesterone.
In another aspect, the present invention provides a class of intermediate compounds DG-8 and DG-9, which have the following structures:
wherein R1 and R2 are defined as above.
The intermediate compounds may be used in the preparation of dydrogesterone.
In summary, the present invention provides a novel synthesis method of dydrogesterone, which uses dehydropregnenolone as a starting material (DG-7) to prepare carbonyl-protected dehydropregnenolone (DG-8), then a methyl configuration inversion compound DG-9 is obtained through a photocatalytic reaction, and dydrogesterone is obtained through deprotection, hydroxyl oxidation and double bond rearrangement reaction of DG-9. The method has the advantages of easily obtained raw materials, high yield, simple and mild reaction conditions and suitability for industrial production of dydrogesterone.
As the core and key steps of the whole route, photochemical conversion in the DG-9 preparation process determines the efficiency of the whole production process, and by adopting the method, the photochemical conversion rate and selectivity are greatly improved, the total yield is improved to more than 60%, the total yield is far higher than that reported in the current literature, the illumination yield is low, the product purity is high, the problems of more impurities, incomplete ring opening, more ring closing impurities and the like are solved, and the whole route is a very efficient and simple route and is very suitable for industrial production.
Detailed Description
In order that those skilled in the art can better understand the present invention, the following description of the technical solution of the present invention will be given by way of specific examples. It is to be understood that the following examples are given only for better illustration of the present invention and are not to be construed as limiting the present invention.
Synthesis of DG-8 series Compounds
Example 1:
500g DG-7, 500g ethylene glycol, 500g triethyl orthoformate, 5g p-toluenesulfonic acid and 5000ml methylene dichloride are added into a reaction bottle, the reaction is completed by stirring at room temperature, 1000ml water is added, the mixture is stirred, then the mixture is kept stand for liquid separation, and the organic phase is concentrated under reduced pressure to obtain solid DG-8.1, and the yield is 95.2%.
ESI-HRMS theory: c 23H34O3[M+H]+ 359.2508, found 359.2510.
1H-NMR(δ,ppm,CDCl3):5.70-5.55(m,1H);5.39-5.38(m,1H);4.02-3.84(m,4H);3.66-3.59(m,1H);2.48-2.43(m,1H);2.30-2.24(m,1H);2.16-2.12(m,1H);1.98-1.94(m,1H);1.89-1.87(m,4H);1.83-1.66(m,4H);1.61-1.53(m,1H);1.51-1.41(m,2H);1.32-1.22(m,5H);0.94(s,3H);0.71(s,3H).
Example 2:
500g DG-7, 114g triethyl orthoformate, 1.4g p-toluenesulfonic acid and 540mL methanol are added into a reaction bottle to react for three hours at 50-60 ℃, the mixture is decompressed, 500mL ethyl acetate is added for extraction, then 500mL saturated sodium bicarbonate is used for washing, 500mL saturated saline solution is used for washing, anhydrous sodium sulfate is used for drying, filtration and concentration are carried out, and DG-8.2 is obtained, and the yield is 93.7%.
ESI-HRMS theory: c 23H36O3[M+H]+ 361.2664, found 361.2669.
1H-NMR(δ,ppm,CDCl3):5.74-5.58(m,1H);5.40-5.37(m,1H);4.05(s,3H);3.84(s,3H);3.70-2.45(m,2H);2.29-1.92(m,3H);1.90-1.86(m,4H);1.72-1.67(m,4H);1.60-1.43(m,3H);1.35-1.19(m,5H);0.89(s,3H);0.74(s,3H).
Synthesis of Compound DG-9 series
Example 3:
100g DG-8.1 and 100g triethylamine are added into 10L absolute ethyl alcohol, and after stirring and dissolving, 0.5g 2, 6-di-tert-butyl-p-cresol is added, and an internal illumination photochemical reactor with quartz cold hydrazine (the transmission wavelength is 200-300 nm) is added. Stirring, controlling the temperature to 10-15 ℃, circulating the refrigerating fluid, and starting a 500W high-pressure mercury lamp to irradiate for 8 hours. Turning off a high-pressure mercury lamp, filtering the reaction solution, collecting filtrate, adding the filtrate into an internal irradiation photochemical reactor with high borosilicate glass cold hydrazine (with the transparent wavelength of 310-400 nm), turning on stirring, turning on a 500W high-pressure mercury lamp to irradiate for 16 hours, turning off the high-pressure mercury lamp, concentrating the reaction solution at 35 ℃ under reduced pressure, and freezing and crystallizing to obtain white solid DG-9.1 with the purity of 99.3% and the yield of 70.6%.
ESI-HRMS theory: c 23H34O3[M+H]+ 359.2508, found 359.2511.
1H-NMR(δ,ppm,CDCl3):5.67-5.65(m,1H);5.45-5.44(m,1H);4.09-4.08(m,1H);4.02-3.92(m,2H);3.90-3.82(m,2H);2.56-2.45(m,2H);2.29-2.24(m,2H);2.11-1.99(m,1H);1.82-1.74(m,4H);1.68-1.61(m,3H);1.57-1.40(m,4H);1.30(s,3H);0.73(s,3H);0.71(s,3H).
Example 4:
100g DG-8.2 and 100g triethylamine are added into 15L absolute ethyl alcohol, then 0.5g 2, 6-di-tert-butyl-p-cresol is added into the mixture, and an internal illumination photochemical reactor with quartz cold hydrazine (the transmission wavelength is 200-300 nm) is added into the mixture. Stirring, controlling the temperature to 10-15 ℃, circulating the refrigerating fluid, and starting a 1000W high-pressure mercury lamp to irradiate for 12 hours. Turning off a high-pressure mercury lamp, filtering the reaction solution, collecting filtrate, adding the filtrate into an internal irradiation photochemical reactor with high borosilicate glass cold hydrazine (with the transparent wavelength of 310-400 nm), turning on stirring, turning on a 1000W high-pressure mercury lamp for irradiation for 20 hours, turning off the high-pressure mercury lamp, concentrating the reaction solution at 35 ℃ under reduced pressure, and freezing for crystallization to obtain white solid DG-9.2 with the purity of 99.2% and the yield of 67.4%.
ESI-HRMS theory: c 23H36O3[M+H]+ 361.2664, found 361.2661.
1H-NMR(δ,ppm,CDCl3):5.72-5.69(m,1H);5.49-5.46(m,1H);4.11-4.09(m,1H);3.98(s,3H);3.88(s,3H);2.60-2.44(m,2H);2.27-1.96(m,3H);1.85-1.77(m,4H);1.70-1.65(m,3H);1.59-1.51(m,4H);1.37(s,3H);0.79(s,3H);0.69(s,3H).
Comparative example 1:
Referring to the reaction conditions of example 3, DG-10 as a white solid was obtained in a purity of 68.4% and a yield of 12.6%.
ESI-HRMS theory: c 21H30O2[M+H]+ 315.2246, found 315.2247.
Synthesis of Compound DG-10
Example 5:
143g DG-9.1 was added to the reaction flask, and 1000mL THF was dissolved with stirring. The reaction temperature is controlled to be 0 ℃ by using a low-temperature bath, 1N HCl aqueous solution is added, the reaction is continued for 16 hours under the condition that the temperature is unchanged, the point plate raw materials are completely reacted, ethyl acetate is added for dilution, water washing, saturated sodium bicarbonate aqueous solution water washing, saturated salt water washing, anhydrous sodium sulfate drying and concentration are carried out, and the ethyl acetate is used for obtaining the compound DG-10, and the yield is 85.6%.
ESI-HRMS theory: c 21H30O2[M+H]+ 315.2246, found 315.2249.
1H-NMR(δ,ppm,CDCl3):5.68-5.66(m,1H);5.49-5.48(m,1H);4.11-4.10(m,1H);2.75-2.63(m,2H);2.50-2.46(m,1H);2.31-2.23(m,4H);2.14(s,3H);1.81-1.49(m,10H);0.76(s,3H);0.57(s,3H).
Example 6:
20g DG-9.2 was added to the reaction flask, and 100mL of acetone was added thereto, followed by stirring and dissolution. Adding 2.1g of p-toluenesulfonic acid, reacting for 1 hour at room temperature, completely reacting the plate raw material, adding ethyl acetate for dilution, washing with water, washing with saturated sodium bicarbonate water solution, washing with saturated saline water, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain the compound DG-10 with a yield of 86.4%.
ESI-HRMS theory: c 21H30O2[M+H]+ 315.2246, found 315.2246.
Synthesis of Compound DG-11
Example 7:
59g DG-10, 500mL toluene, 168g cyclohexanone and 23g aluminum triisopropoxide were added to the reaction flask. The reaction was heated to reflux for 1 hour and then returned to ambient temperature. Adding ethyl acetate for dilution, quenching with concentrated hydrochloric acid for reaction, washing with water, saturated saline water, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain the product DG-11 with a yield of 75.4%.
ESI-HRMS theory: C21H28O2[ M+H ] +313.2089, found 313.2093.
1H-NMR(δ,ppm,CDCl3):5.82-5.81(m,1H);5.29-5.27(m,1H);3.02-2.93(m,2H);2.67-2.63(m,1H);2.46-2.32(m,3H);2.18-2.16(m,3H);2.14(s,3H);1.99-1.96(m,1H);1.55-1.80(m,6H);1.43-1.39(m,1H);1.07(s,3H);0.61(s,3H).
Example 8:
To the reaction flask was added 20g DG-10, 300mL toluene, 90g cyclohexanone and 15g aluminum tri-tert-butoxide. The reaction was heated to reflux for 2.5 hours and then returned to ambient temperature. Adding ethyl acetate for dilution, quenching with concentrated hydrochloric acid for reaction, washing with water, saturated saline water, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain the product DG-11 with a yield of 78.2%.
ESI-HRMS theory: C21H28O2[ M+H ] +313.2089, found 313.2096.
Example 9:
To the reaction flask were added 40g DG-10, 420mL toluene, 120g cyclohexanone and 20g aluminum tri-tert-butoxide. The reaction was heated to reflux for 3 hours and then returned to ambient temperature. Adding ethyl acetate for dilution, quenching with concentrated hydrochloric acid for reaction, washing with water, saturated saline water, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain the product DG-11 with a yield of 73.6%.
ESI-HRMS theory: C21H28O2[ M+H ] +313.2089, found 313.2086.
Synthesis of dydrogesterone
Example 10:
To a 1L reaction flask was added 50gDG-11, 500ml of 31.5% HCl/iPrOH solution and the reaction was completed at room temperature. Adding saturated sodium bicarbonate water solution for quenching, extracting with ethyl acetate, washing with water, saturated saline water washing, drying with anhydrous sodium sulfate, concentrating, recrystallizing the crude product with acetone and n-hexane to obtain dydrogesterone with yield of 85.3% and HPLC purity of 99.1%.
ESI-HRMS theory: c 21H28O2[M+H]+ 313.2089, found 313.2087.
1H-NMR(δ,ppm,CDCl3):6.20-6.14(m,2H);5.68(s,1H);2.60-2.52(m,2H);2.60-2.52(m,2H);2.48-2.40(m,2H);2.31-2.17(m,2H);2.13(s,3H);2.03-1.95(m,2H);1.88-1.80(m,2H);1.79-1.62(m,3H);1.40-1.18(m,6H);0.71(s,3H).
Example 11:
To a 1L reaction flask was added 20gDG-11, 300ml 33% HCl/MeOH solution and the reaction was completed at room temperature. Adding saturated sodium bicarbonate water solution for quenching, extracting with ethyl acetate, washing with water, saturated saline water washing, drying with anhydrous sodium sulfate, concentrating, and recrystallizing the crude product with acetone and n-hexane to obtain dydrogesterone with a yield of 84.6% and an HPLC purity of 99.2%.
ESI-HRMS theory: c 21H28O2[M+H]+ 313.2089, found 313.2094.
Example 12:
10gDG-11, 100ml of 33% HBr/HOAc solution were added to a 1L reaction flask and reacted to completion at 0 ℃. Pouring the system into ice water to separate out a large amount of solids, filtering, washing a filter cake with water, washing with saturated sodium bicarbonate water solution, pumping, recrystallizing a crude product with acetone and n-hexane to obtain dydrogesterone, wherein the yield is 86.3%, and the HPLC purity is 99.2%.
ESI-HRMS theory: c 21H28O2[M+H]+ 313.2089, found 313.2092.

Claims (9)

1. A method for preparing dydrogesterone, which comprises the following steps:
Wherein R 1、R2 is methyl or ethyl, optionally the tail end of R 1、R2 is attached;
In the step B, DG-8 is first photochemistry reacted to complete the opening of 9 and 10 position bonds of steroid B ring, and then secondary photochemistry reacted to close the 9 and 10 position bonds of steroid B ring to obtain 10 position angle methyl isomerism DG-9.
2. The method of manufacturing according to claim 1, characterized in that: and R 1、R2 is methyl.
3. The method of manufacturing according to claim 1, characterized in that: in step a, DG-7 is carbonyl-protected under the catalysis of an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ferric trichloride, aluminum trichloride, and zinc chloride to give ketal DG-8.
4. The method of manufacturing according to claim 1, characterized in that: the first photochemical reaction selects light with the wavelength of 200-300 nm for illumination, and the second photochemical reaction selects light with the wavelength of 310-400 nm for illumination.
5. The method of manufacturing according to claim 1, characterized in that: in the step d, DG-10 is subjected to hydroxyl oxidation to obtain ketene DG-11, and the oxidant for the hydroxyl oxidation reaction is aluminum triisopropoxide or aluminum tri-tert-butoxide.
6. The method of manufacturing according to claim 1, characterized in that: in step e, DG-11 is double bond rearranged under acidic conditions to give dydrogesterone.
7. A compound having the structure:
Wherein R 1、R2 is methyl or ethyl, optionally the tail end of R 1、R2 is attached.
8. The process for preparing compound DG-9 according to claim 7, wherein the process comprises the steps of carrying out a photochemical reaction on DG-8 to open bonds at positions 9 and 10 of steroid B ring, and then carrying out a secondary photochemical reaction to close bonds at positions 9 and 10 of steroid B ring to obtain 10-bit angle methyl isomerised DG-9.
9. The method of manufacturing according to claim 8, wherein: the primary photochemical reaction selects light with the wavelength of 200-300 nm for illumination, and the secondary photochemical reaction selects light with the wavelength of 310-400 nm for illumination.
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Investigations on sterols XIX: 6-Dehydro-9β, 10α-progesterone from pregnenolone;M. P. RAPPOLDT，等;《Recueil des Travaux Chimiques des Pays-Bas》;第80卷(第01期);第44页，第46页第1段，1第45页第2段、倒数第1段，第46页第2段 *

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