WO2021093494A1 - 一种可工业化合成地屈孕酮的生产工艺 - Google Patents

一种可工业化合成地屈孕酮的生产工艺 Download PDF

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WO2021093494A1
WO2021093494A1 PCT/CN2020/120276 CN2020120276W WO2021093494A1 WO 2021093494 A1 WO2021093494 A1 WO 2021093494A1 CN 2020120276 W CN2020120276 W CN 2020120276W WO 2021093494 A1 WO2021093494 A1 WO 2021093494A1
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reaction
solvent
compound
dydrogesterone
methanol
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PCT/CN2020/120276
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English (en)
French (fr)
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潘成学
苏桂发
于成龙
覃江克
李永怡
杨倩
方淑君
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广西师范大学
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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

Definitions

  • the invention relates to the technical field of drug synthesis, in particular to a process for industrially preparing dydrogesterone bulk drugs.
  • Dydrogesterone 1 also known as dehydroprogesterone, has a chemical name of 9 ⁇ ,10 ⁇ -pregesta-4,6-diene-3,20-dione, CAS number: 152-62-5.
  • Dydrogesterone is not only widely used to prevent miscarriage and miscarriage, but also to treat various diseases caused by insufficient endogenous progesterone, such as: dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycle Rules, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progesterone deficiency, infertility caused by corpus luteum insufficiency, etc.
  • Duphaston Duphaston dydrogesterone tablets
  • Metone Fluorine estradiol tablets/estradiol dydrogesterone tablets composite packaging
  • US patent US3198792 discloses the synthesis using trans-progesterone as raw material and tetrachlorobenzoquinone as the oxidant (Scheme 2). Although the route is short, the raw material trans-progesterone used does not exist in natural products and needs to be synthesized It can only be obtained, and it is difficult to synthesize at present, and there are no industrialized products, so there is no possibility of industrialized production at present.
  • the Belgian patent BE656770 discloses that the diethylene diacetal of 9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione is used as a raw material, and saturated anhydrous ethanol and hydrogen chloride solution are added at low temperature for deprotection , Dydrogesterone 1 (Scheme 3) was obtained with a yield of about 60%.
  • the diethylene diacetal 6 of 9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione can use progesterone as a raw material, after carbonyl protection, oxidation, hydrazone, dehydrazone, and photochemical reaction. Synthesized, but its synthetic route and process are not disclosed.
  • the world patent WO2016154772 also reported the synthesis of dydrogesterone using the diethylene dicondensation 6 of 9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione as a raw material, and the synthesis of dydrogesterone through a two-step reaction of a and b. Method, deprotection with 5-10% dilute sulfuric acid, 5-10% dilute hydrochloric acid, 40-60% concentration of acetic acid, or p-toluenesulfonic acid at a reaction temperature of 0-90°C to obtain Intermediate 7.
  • the Indian patent IN 201811020593 discloses a bisketal-protected progesterone 3 as a raw material, which first undergoes a bromination reaction with dibromodimethylhydantoin in petroleum ether to obtain intermediate 4, and intermediate 4 is in tetrabutyl Ammonium fluoride as a base and methyltetrahydrofuran as a solvent for debromination reaction to obtain the intermediate 9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione diethylene diacetal 5, and then A mercury lamp is used as a light source to filter out the light whose wavelength is less than 260 nanometers and perform a photochemical reaction to obtain the important intermediate 9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione diethylene diacetal. Finally, deprotection and double bond isomerization were performed with HCl in absolute ethanol to obtain dydrogesterone (Scheme 5).
  • the world patent WO2018109622 discloses a route to synthesize dydrogesterone by taking progesterone as a raw material and undergoing a five-step reaction of dehydrogenation, oxidation, decarboxylation, cyclization and dehydrogenation (Scheme 6).
  • some patents disclose key synthesis intermediates such as the diethylene diacetal 5 of 9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione and 9 ⁇ ,10 ⁇ -pregna -Synthesis of diethylene diacetal 6 of 4,6-diene-3,20-dione.
  • the Chinese patent ZL201910484547.6 discloses the preparation of diethylene diacetal 5 that uses 7-hydroxyprogesterone as a raw material to synthesize 9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione. Method (Scheme 7).
  • the world patent WO2013078575 discloses a preparation method (Scheme 8) that takes progesterone as a raw material and undergoes a four-step reaction of ketal protection, oxidation, hydrazone and dehydrazone.
  • European patent EP0558119 Chinese patents ZL201410085871.8 and ZL201010621400.6 announced the use of medium and high pressure mercury lamps as the light source, and the diethylene diacetal of 9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione (9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene diacetal) 5 is a method for preparing 9 ⁇ ,10 ⁇ -dehydro progesterone diethylene diketal 6 (Scheme 9).
  • the object of the present invention provides a production process for industrially synthesizing dydrogesterone, which has easy-to-obtain raw materials, high total yield, and is easy to scale to industrial production.
  • a production process for industrially synthesizing dydrogesterone includes the following steps:
  • Compound 4 is catalyzed by adding an organic base. In the presence of solvent C, it is heated to reflux under the protection of nitrogen/inert gas, or under solvent-free conditions, heated to 115-125°C for debromination reaction. After the reaction is complete, Obtain compound 5 diethylene ketal of 9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione;
  • the wavelength range is 265-300 nanometers.
  • the photochemical ring-opening reaction is carried out to obtain a solution containing the ring-opening reaction intermediate.
  • the solution containing the ring-opening reaction intermediate is irradiated with a single-wavelength LED light source under the protection of nitrogen/inert gas, and the wavelength range is 305-365 nanometers.
  • the photochemical ring-closing reaction is carried out. After the ring-opening reaction intermediate is transformed, the compound is separated 6 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal;
  • the organic solvent A is one or more mixed solvents of tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, glyme or glyme;
  • the solvent B is one or more mixed solvents of dioxane, isooctane, 90-120°C boiling point petroleum ether, cyclohexane, tetrahydrofuran or methyltetrahydrofuran;
  • the solvent C is one or two mixed solvents of cyclohexane or methyltetrahydrofuran;
  • the solvent D is methanol, ethanol, isopropanol, glyme, glyme, tetrahydrofuran, methyltetrahydrofuran or cyclohexane;
  • the solvent E is a mixed solvent of one of tetrahydrofuran, acetonitrile, acetone or methanol and water;
  • the solvent F is one or two mixed solvents of tetrahydrofuran, glyme, methanol or ethanol.
  • the quenching reaction is carried out by adding triethylamine, pyridine or diisopropylethylamine; after the quenching reaction, it also includes: cooling at -15°C to 0°C, filtering, and obtaining The solid was washed with water, then washed with ethanol or acetone, and dried to obtain the crude product of compound 3;
  • the crude product of compound 3 is added with acetone and pyridine, heated to reflux and stirred for 0.5 to 1.5 hours, cooled at -15 to -5°C, filtered, and dried to obtain refined compound 3.
  • the bromosuccinimide is 1.1-1.2eq; the dibromohaidan is 0.55-0.6eq, and the free radical initiator is 0.01-0.05eq;
  • the bromination reaction After the bromination reaction is completed, it also includes: washing the filter cake with solvent B, dissolving the filter cake with dichloromethane, washing the dichloromethane solution with saturated sodium bicarbonate solution, drying, removing the desiccant, and recovering the filter cake below 40°C. Chloromethane to give compound 4.
  • the organic base is triethylamine, 1,8-diazabicycloundec-7-ene, diisopropylethylamine or 2,4,6-trimethylpyridine ;
  • the debromination reaction also includes: recovering the solvent and organic base catalyst under reduced pressure, then adding a mixed solvent of acetonitrile and methanol or a mixed solvent of acetone and acetonitrile or a mixed solvent of acetone and water, cooling to below 60°C, adding dioxane or Methyl tert-butyl ether or butyl ether or isopropyl ether was cooled at -15 ⁇ -5°C to precipitate solids, filtered, and washed with water, methanol or acetonitrile or acetone successively, and dried to obtain compound 5.
  • the reaction temperature is between -35°C and 35°C, and during the entire reaction process, the range of controlling the reaction temperature does not fluctuate more than 10°C.
  • the separation includes: the solution containing 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is distilled under reduced pressure to recover the solvent, and then heated to reflux with the purification solvent, cooled, and solids are deposited and separated For solid and liquid, take the liquid and recover the solvent to obtain 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal;
  • the purification solvent includes: a mixed solvent of ethanol and acetonitrile, a mixed solvent of methanol and acetonitrile, a mixed solvent of methanol and tetrahydrofuran, a mixed solvent of acetone and tetrahydrofuran, a mixed solvent of acetonitrile and tetrahydrofuran, methanol or isopropanol.
  • step S5 after the deprotection reaction is completed, it further includes: removing the solvent, extracting with ethyl acetate or DCM, washing with sodium bicarbonate solution, drying, heating to reflux with a mixed solvent of acetone and methanol or a mixed solvent of acetone and isopropanol After cooling and crystallization, the solid was separated to obtain compound 7.
  • the reaction conditions are that the solvent F is added with concentrated hydrochloric acid and the reaction is heated, or the reaction is carried out in a saturated HCl solution of ethyl acetate, THF or methanol.
  • the reaction also includes: recovering the solvent, extracting with dichloromethane, washing with sodium bicarbonate solution, drying, and removing the solvent, adding ethyl acetate and isooctane mixed solvent or ethyl acetate and cyclohexane mixed solvent or ethyl acetate It is recrystallized with n-heptane mixed solvent, and finally refined with isopropanol to obtain the target product dydrogesterone.
  • the present invention uses readily available progesterone as a raw material to prepare dydrogesterone through the steps of carbonyl protection, bromination, debromination, photochemical ring opening reaction, photochemical ring closing reaction, deprotection, and double bond isomerization. It has starting materials It has the advantages of easy availability, easy realization of each step, high yield, simple operation, green environmental protection, and easy scale-up to industrial production.
  • the key step of the present invention is to use LED light source to prepare 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal from 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal.
  • the conversion of the ring-opening reaction The rate can exceed 90%.
  • the photochemical ring-closing reaction is further carried out, about 20-75% of the raw materials are converted into the target product.
  • the total yield is high, the operation is simple, the operation is simple, the control points are few, the scale-up production is easy, and the introduction of solvents is small.
  • the process has low energy consumption, and is a technology that is more environmentally friendly and has fewer reaction by-products than the prior art mercury lamp preparation.
  • the invention provides a method for industrially producing dydrogesterone, which enables domestic self-production of dydrogesterone and has very important economic and social value.
  • Figure 1 is a 1 H-NMR spectrum of Compound 5.
  • FIG. 2 is a 13 C-NMR spectrum chart of compound 5.
  • FIG. 3 is a 1 H-NMR spectrum chart of compound 6.
  • FIG. 4 is a 13 C-NMR spectrum chart of compound 6.
  • Figure 5 is a 1 H-NMR spectrum of the target product dydrogesterone.
  • Figure 6 is a 13 C-NMR spectrum of the target product dydrogesterone.
  • Figure 7 is the HHCOSY spectrum of the target product dydrogesterone.
  • Figure 8 is the NOE spectrum of the target product dydrogesterone.
  • Figure 9 is the HMQC spectrum of the target product dydrogesterone.
  • Figure 10 is the HMBC spectrum of the target product dydrogesterone.
  • Fig. 11 is a schematic diagram of the reaction system of the photochemical ring-opening reaction and the photochemical ring-closing reaction.
  • the yield of compound 5 is non-standard 79 % And 70%.
  • the photochemical reaction in this embodiment is the most critical technology, and the adopted reaction system includes a feed tank, a first photochemical reactor, a second photochemical reactor, and a receiving tank.
  • a flow meter is provided in the reaction device to control the flow rate of the solution during the reaction.
  • the position of the flow meter can be set appropriately. In this embodiment, it is set between the feed tank and the first photochemical reactor. Take for example.
  • the flow rate of the solution is adjusted by using the height difference or the relative angle between the feeding tank and the receiving tank, of course, it can also be adjusted by a valve.
  • the feed tank, the first photochemical reactor, the second photochemical reactor, and the receiving tank are all matched with a condensation system.
  • the light sources of the first photochemical reactor and the second photochemical reactor are both LED light sources produced by photoelectric technology.
  • the first photochemical reactor and the second photochemical reactor are directly connected.
  • the photochemical ring-opening reaction is carried out in the first photochemical reactor, and the photochemical closed-loop reaction is carried out in the second photochemical reactor.
  • the material tank is connected, and the reaction system is filled with nitrogen or inert gas to protect the photochemical switch reaction and the photochemical closed-loop reaction.
  • the reaction time is about 30 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 40%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 57%, and the content of other impurities is about 3%. .
  • the wavelength of the photochemical ring-opening reaction was changed to 280 nm
  • the wavelength of the photochemical ring-closing reaction was changed to 345 nm
  • the reaction solvent was 10L tetrahydrofuran
  • the other conditions were the same as in Example 9.
  • the reaction time is about 8 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 41%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 54%, the content of other impurities is about 5%.
  • the wavelength of the photochemical ring-opening reaction was changed to 295 nm
  • the wavelength of the photochemical ring-closing reaction was changed to 330 nm
  • the reaction solvent was 10L ethanol
  • other conditions were the same as in Example 9.
  • the reaction time is about 12 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 60%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 25%, the content of other impurities is about 15%.
  • the wavelength of the photochemical ring-opening reaction was changed to 265 nanometers
  • the wavelength of the photochemical ring-closing reaction was changed to 330 nanometers
  • the reaction solvent was 10L ethanol
  • other conditions were the same as in Example 9.
  • the reaction time is about 10 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 50%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 30%, the content of other impurities is about 20%.
  • the wavelength of the photochemical ring-opening reaction was changed to 280 nm, the wavelength of the photo-closed ring reaction was changed to 350 nm, and the reaction solvent was 10L tetrahydrofuran.
  • Other conditions were the same as in Example 9.
  • the reaction time is about 12 hours.
  • HPLC detection results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 51%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 40%, the content of other impurities is about 9%.
  • the wavelength of the photochemical ring-opening reaction was changed to 280 nm
  • the wavelength of the photochemical ring-closing reaction was changed to 360 nm
  • the reaction solvent was 10L tetrahydrofuran
  • the reaction temperature was controlled at -0 ⁇ 5°C
  • other conditions were the same as in Example 9.
  • the reaction time is about 15 hours, and the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 65%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 30%, the content of other impurities is about 5%.
  • the wavelength of the photochemical ring-opening reaction was changed to 280 nanometers
  • the wavelength of the photochemical ring-closing reaction was changed to 365 nanometers
  • the reaction solvent was 10L tetrahydrofuran
  • other conditions were the same as in Example 9.
  • the reaction time is about 24 hours, and the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 65%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 20%, the content of other impurities is about 15%.
  • the wavelength of the photochemical ring-opening reaction was changed to 280 nm
  • the wavelength of the photo-closed ring reaction was changed to 365 nm
  • the reaction solvent was 10L methyltetrahydrofuran
  • the other conditions were the same as in Example 9.
  • the reaction time is about 20 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 65%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 20%, the content of other impurities is about 15%.
  • the wavelength of the photochemical ring-opening reaction was changed to 270 nm
  • the wavelength of the photochemical ring-closing reaction was changed to 330 nm
  • the reaction solvent was 10L methanol
  • the reaction temperature was controlled at -15 ⁇ 5°C
  • other conditions were the same as in Example 9.
  • the reaction time is about 4 hours.
  • HPLC detection results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 30%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 62%, and the content of other impurities is about 8%.
  • the wavelength of the photochemical ring-opening reaction was changed to 270 nm
  • the wavelength of the photochemical ring-closing reaction was changed to 330 nm
  • the reaction solvent was 10L methanol
  • the reaction temperature was controlled at 30 ⁇ 5°C
  • other conditions were the same as in Example 9.
  • the reaction time is about 3.2 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 50%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 43%, the content of other impurities is about 7%.
  • the wavelength of the photochemical ring-opening reaction was changed to 270 nanometers
  • the wavelength of the photochemical ring-closing reaction was changed to 330 nanometers
  • the reaction raw material was 50g
  • the amount of solvent was 4L
  • other conditions were the same as in Example 9.
  • the reaction time is about 28 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 40%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 55%, the content of other impurities is about 5%.
  • the wavelength of the photochemical ring-opening reaction was changed to 270 nanometers
  • the wavelength of the photochemical ring-closing reaction was changed to 330 nanometers
  • the reaction solvent was 10L ethanol
  • other conditions were the same as in Example 9.
  • the reaction time is about 3.6 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 46%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 50%, the content of other impurities is about 4%.
  • the wavelength of the photochemical ring-opening reaction was changed to 270 nm
  • the wavelength of the photochemical ring-closing reaction was changed to 330 nm
  • the reaction solvent was 10 L of isopropanol
  • the other conditions were the same as in Example 9.
  • the reaction time is about 4.2 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 50%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 45%, the content of other impurities is about 5%.
  • the wavelength of the photochemical ring-opening reaction was changed to 270 nanometers
  • the wavelength of the photochemical ring-closing reaction was changed to 330 nanometers
  • the reaction solvent was 10L glyme
  • other conditions were the same as in Example 9.
  • the reaction time is about 5 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 50%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 43%, the content of other impurities is about 7%.
  • the wavelength of the photochemical ring-opening reaction was changed to 270 nanometers
  • the wavelength of the photochemical ring-closing reaction was changed to 330 nanometers
  • the reaction solvent was 10L glyme
  • other conditions were the same as in Example 9.
  • the reaction time is about 5 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 51%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 43%, the content of other impurities is about 6%.
  • the wavelength of the photochemical ring-opening reaction was changed to 270 nanometers
  • the wavelength of the photochemical ring-closing reaction was changed to 330 nanometers
  • the reaction solvent was 10L methyltetrahydrofuran
  • other conditions were the same as in Example 9.
  • the reaction time is about 5 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 50%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 44%, the content of other impurities is about 6%.
  • the wavelength of the photochemical ring-opening reaction was changed to 270 nanometers
  • the wavelength of the photochemical ring-closing reaction was changed to 330 nanometers
  • the reaction solvent was 10L cyclohexane
  • other conditions were the same as in Example 9.
  • the reaction time is about 5 hours.
  • the HPLC test results show that the content of the raw material 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal is about 48%, and the content of the target product 9 ⁇ ,10 ⁇ -dehydroprogesterone diethylene ketal About 45%, the content of other impurities is about 7%.
  • acetonitrile/water 3:1
  • acetone/water 3:1
  • the NMR structure characterization data of the target product (Compound 1): 1 H NMR (400MHz, CDCl 3 ) ⁇ 6.13 ⁇ 6.19(m,1H), 5.66(s,1H), 2.41 ⁇ 2.56(m,4H), 2.19 ⁇ 2.29(m,2H),2.12(s,3H),1.94 ⁇ 1.98(m,2H),1.62 ⁇ 1.87(m,7H),1.31 ⁇ 1.55(m,1H),1.29(s,3H),0.69 (s,3H).

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Abstract

公开了一种可工业化合成地屈孕酮的生产工艺，以易得的黄体酮为原料，通过羰基保护、溴代、脱溴、光化学开环反应、光化学闭环反应、脱保护、双键异构的步骤制得地屈孕酮，具有起始原料易得、各步骤均易实现、收率较高的优点，且操作简便、绿色环保，易于放大至工业生产。

Description

一种可工业化合成地屈孕酮的生产工艺 技术领域
本发明涉及药物合成技术领域，具体涉及工业化制备地屈孕酮原料药的工艺。
背景技术
地屈孕酮(Dydrogesterone)1，又名去氢孕酮，化学名为9β,10α-孕甾-4,6-二烯-3,20-二酮，CAS号：152-62-5。地屈孕酮既广泛用于保胎及预防流产，还广泛用于治疗内源性孕酮不足引起的各种疾病，如:痛经、子宫内膜异位症、继发性闭经、月经周期不规则、功能失调性子宫出血、经前期综合征、孕激素缺乏所致先兆性流产或习惯性流产、黄体不足所致不孕症等，目前有达芙通(Duphaston地屈孕酮片)和芬吗通(Femoston雌二醇片/雌二醇地屈孕酮片复合包装)两种剂型，最初由荷兰苏威制药公司(Solvay Pharmaceuticals)研发，1961年全球上市，目前在全球60多个国家注册，150多个国家有销售。仅中国该药物近几年的年均销售额超过8亿元人民币。地屈孕酮化学式见下式：
Figure PCTCN2020120276-appb-000001
苏威制药公司2009年被美国Abbott(雅培)收购，因此目前全球实际上只有雅培一家企业生产，国内尚未有地屈孕酮仿制品种，全部依赖进口。实现地屈孕酮原料药的工业化生产将可以满足国际国内对地屈孕酮单方生产的原料需求，同时为开发其有更好的新型复方药提供条件，进一步提升国产激素类药物的国内、国际市场份额，促进我国医药药工业的发展，打破国际垄断，促进技术进步。
地屈孕酮目前公开的主要合成方法有英国专利GB929271以光甾-4,7,22-三烯-3-酮为原料经4步反应来合成(Scheme 1)。由于每步收率低、起始原料难得到等缺点，基本上不具备工业化生产的可能性。
Figure PCTCN2020120276-appb-000002
Scheme 1
美国专利US3198792公开了以反式孕酮为原料，以四氯苯醌为氧化剂来合成(Scheme 2).虽然路线短，但所用的原料反式孕酮在天然产物中并不存在，需要通过合成才能得到，且目前合成很困难，并无工业化产品，因此目前也不具备工业化生产的可能。
Figure PCTCN2020120276-appb-000003
Scheme 2
比利时专利BE656770公开了以9β,10α-孕甾-4,6-二烯-3,20-二酮的二乙二缩醛为原料，在低温下加入饱和的无水乙醇的氯化氢溶液进行脱保护，以60％左右的产率得到地屈孕酮1(Scheme 3)。其中9β,10α-孕甾-4,6-二烯-3,20-二酮的二乙二缩醛6可以以黄体酮为原料，经羰基保护、氧化、腙化、脱腙、光化学反应后合成得到，但其合成路线及工艺均没有公开。
Figure PCTCN2020120276-appb-000004
Scheme 3
世界专利WO2016154772也报道了以9β,10α-孕甾-4,6-二烯-3,20-二酮的二乙二缩6为原料，经a、b两步反应来合成地屈孕酮的方法，以5-10％稀硫酸、5-10％稀盐酸、40-60％浓度的乙酸、或对甲苯磺酸在反应温度在为0-90℃下脱保护得到中间体7，然后中间体再在碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、乙醇钾、叔丁醇钾等碱条件下完成双键的异构化得到1(Scheme 4)。其中原料9β,10α-孕甾-4,6-二烯-3,20-二酮的二乙二缩醛的合成也没有报道。
Figure PCTCN2020120276-appb-000005
Scheme 4
印度专利IN 201811020593则公开了一种以双缩酮保护的黄体酮3为原料，先与二溴二甲基 海因在石油醚中发生溴代反应得到中间体4,中间体4在四丁基氟化铵为碱以甲基四氢呋喃为溶剂条件下发生脱溴反应，得到中间体9α,10β-孕甾-4,6-二烯-3,20-二酮的二乙二缩醛5，然后以汞灯为光源，滤掉其中波长小于260纳米的光后进行光化学反应得到重要中间体9β,10α-孕甾-4,6-二烯-3,20-二酮的二乙二缩醛。最后用HCl在无水乙醇中进行脱保护及双键异构得到地屈孕酮(Scheme 5)。
Figure PCTCN2020120276-appb-000006
Scheme 5
世界专利WO2018109622公开了一种以黄体酮为原料，经脱氢、氧化、脱羧、成环及脱氢共五步反应来合成地屈孕酮的路线(Scheme 6)。
Figure PCTCN2020120276-appb-000007
Scheme 6
除此之外，一些专利则公开了其合成关键中间体如9α,10β-孕甾-4,6-二烯-3,20-二酮的二乙二缩醛5和9β,10α-孕甾-4,6-二烯-3,20-二酮的二乙二缩醛6的合成。如中国专利ZL201910484547.6则公布了一种以7-羟基黄体酮为原料来合成9α,10β-孕甾-4,6-二烯-3,20-二酮的二乙二缩醛5的制备方法(Scheme 7)。
Figure PCTCN2020120276-appb-000008
Scheme 8
世界专利WO2013078575公布了一种以黄体酮为原料经缩酮保护、氧化、腙化及脱腙共四步反应来合成5的制备方法(Scheme 8)。
Figure PCTCN2020120276-appb-000009
Scheme 8
欧洲专利EP0558119，中国专利ZL201410085871.8和ZL201010621400.6公布以中、高压汞灯为光源，以9α,10β-孕甾-4,6-二烯-3,20-二酮的二乙二缩醛(9α,10β-去氢黄体酮二乙二缩醛)5为原料来制备9β,10α-去氢黄体酮二乙二缩酮6的方法(Scheme 9)。
Figure PCTCN2020120276-appb-000010
Scheme 9
由于地屈孕酮全球市场很大，仅国内每年的销售额就超过8亿人民币，而目前仅有美国的雅培公司生产销售，且其技术一直保密。而现已公开的一些合成工艺均存在产率不高、污染较大、特别是不容易放大等缺陷，导致除了美国的雅培公司一直能够垄断该药品的生产，而国内因技术原因一直无法实现地区孕酮的仿制，因此研发易于放大的制备地屈孕酮的新工艺，具有重要的经济及社会价值。
发明内容
本发明目提供了一种可工业化合成地屈孕酮的生产工艺，原料易得、总产率高，容易放大至工业化生产。
为实现上述目的，本发明的技术方案为：
一种可工业化合成地屈孕酮的生产工艺，包括以下步骤：
S1.黄体酮与乙二醇、乙酰氯和原甲酸三甲酯在有机溶剂A中于25～45℃下反应1～2.5小时，然后淬灭反应，得化合物3
Figure PCTCN2020120276-appb-000011
S2.化合物3溶解在溶剂B中，再加入溴代丁二酰亚胺或二溴海因，然后加入自由基引发剂过氧化苯甲酰或偶氮二异丁腈，加热至65～75℃，进行溴代反应，反应完成后得化合物4
Figure PCTCN2020120276-appb-000012
S3.化合物4加入有机碱催化，在有溶剂C的条件下，氮气/惰性气体保护加热至回流，或在无溶剂的条件下，加热至115～125℃，进行脱溴反应，反应完成后，得化合物5 9α,10β-孕甾-4,6-二烯-3,20-二酮的二乙二缩酮；
S4.将化合物5溶解于溶剂D中，在氮气/惰性气体保护下接受单一波长的LED光源照射，波长范围为265～300纳米，进行光化学开环反应，得含有开环反应中间体的溶液，然后将含有开环反应中间体的溶液在氮气/惰性气体保护下接受单一波长的LED光源照射，波长范围为305～365纳米，进行光化学闭环反应，待开环反应中间体转化后，分离得化合物6 9β,10α-去氢黄体酮二乙二缩酮；
S5.化合物6溶解到溶剂E中，加入无机酸进行脱保护反应，反应完成后得化合物7
Figure PCTCN2020120276-appb-000013
S6.化合物7溶解到溶剂F中，加入浓盐酸加热反应，或将化合物7溶解于乙酸乙酯/甲醇的饱HCl的溶液中进行反应，反应完成后得目标产物地屈孕酮。
优选的，所述有机溶剂A为四氢呋喃、甲基叔丁基醚、异丙醚、甘醇二甲醚或甘醇二乙醚中的一种或一种以上混合溶剂；
所述溶剂B为二氧六烷、异辛烷、90-120℃沸点的石油醚、环己烷、四氢呋喃或甲基四氢呋喃中的一种或一种以上混合溶剂；
所述溶剂C为环己烷或甲基四氢呋喃中的一种或两种混合溶剂；
所述溶剂D为甲醇、乙醇、异丙醇、甘醇二甲醚、甘醇二乙醚、四氢呋喃、甲基四氢呋喃或环己烷；
所述溶剂E为四氢呋喃、乙腈、丙酮或甲醇中的一种与水的混合溶剂；
所述溶剂F为四氢呋喃、甘醇二甲醚、甲醇或乙醇中的一种或两种混合溶剂。
其中，溶剂E的更好方案为；四氢呋喃/水＝3/1、乙腈/水＝3/1，丙酮/水＝3/1，甲醇/水＝3/1或乙醇/水＝3/1，上述均为体积比。
优选的，步骤S1中，所述淬灭反应是加入三乙胺、吡啶或二异丙基乙胺进行的；淬灭反应后，还包括：在-15℃～0℃下冷却，过滤，所得固体用水洗涤，再用乙醇或丙酮洗涤，干燥得化合物3的粗产物；
优选的，化合物3的粗产物加入丙酮和吡啶，加热至回流并搅拌0.5～1.5小时后，-15～-5℃冷却，过滤，干燥得精制的化合物3。
优选的，步骤S2中，所述溴代丁二酰亚胺为1.1-1.2eq；所述二溴海因为0.55-0.6eq，所述自由基引发剂为0.01-0.05eq；
溴代反应完成后，还包括：用溶剂B洗滤饼，滤饼再用二氯甲烷溶解，饱和碳酸氢钠溶液洗涤二氯甲烷溶液，干燥，除去干燥剂，在低于40℃下回收二氯甲烷，得化合物4。
优选的，步骤S3中，所述有机碱为三乙胺、1,8-二氮杂二环十一碳-7-烯、二异丙基乙胺或2,4,6-三甲基吡啶；
脱溴反应完成后还包括：减压回收溶剂及有机碱催化剂，然后加入乙腈和甲醇混合溶剂或的丙酮和乙腈混合溶剂或丙酮和水混合溶剂，冷却至60℃以下，加二氧六烷或甲基叔丁基醚或丁醚或异丙醚，-15～-5℃冷却，析出固体，过滤，并依次用水、甲醇或乙腈或丙酮洗涤固体，干燥得化合物5。其中，更优选的，本发明提供了一种溶剂的更优体积配比，乙腈/甲醇＝1/1、丙酮/乙腈＝4/1或丙酮/水＝4/1。
优选的，步骤S4中，反应温度为-35～35℃，整个反应过程中，控制反应温度的范围上下浮动不超过10℃。
优选的，步骤S4中，所述分离包括：将含有9β,10α-去氢黄体酮二乙二缩酮的溶液，减压蒸馏回收溶剂，再与纯化溶剂加热回流，冷却，有固体析出，分离固体和液体，取液体回收溶剂，即得9β,10α-去氢黄体酮二乙二缩酮；
所述纯化溶剂包括：乙醇和乙腈混合溶剂、甲醇和乙腈混合溶剂、甲醇和四氢呋喃混合溶剂、丙酮和四氢呋喃混合溶剂、乙腈和四氢呋喃混合溶剂、甲醇或异丙醇。其中，更优选的，本发明提供了一种溶剂的更优体积配比，乙醇/乙腈＝3/1、甲醇/乙腈＝4/1、甲醇/四氢呋喃＝4/1、丙酮/四氢呋喃＝3/1或乙腈/四氢呋喃＝4/1。
优选的，步骤S5中，脱保护反应完成后还包括：除去溶剂，用乙酸乙酯或DCM萃取，碳酸氢钠液洗涤，干燥，与丙酮和甲醇混合溶剂或丙酮和异丙醇混合溶剂加热回流后冷却结晶，分离固体即得化合物7。本发明提供了一种加热回流溶剂的更优体积配比，丙酮/甲醇＝1/3或丙酮/异丙醇＝1/3。
优选的，步骤S6中，所述反应条件为溶剂F中加入浓盐酸加热反应，或在乙酸乙酯、THF或甲醇的饱HCl的溶液中进行反应。反应完成后还包括：回收溶剂，二氯甲烷萃取，碳酸氢钠液洗涤，干燥，除去溶剂后，加入乙酸乙酯和异辛烷混合溶剂或乙酸乙酯和环己烷混合溶剂或乙酸乙酯和正庚烷混合溶剂重结晶，最后用异丙醇精制，得目标产物地屈孕酮。其中，重结晶溶剂的更优体积配比为，乙酸乙酯/异辛烷＝1/5、乙酸乙酯/环己烷＝1/5或乙酸乙酯/正庚烷＝1/5。
本发明以易得的黄体酮为原料，通过羰基保护、溴代、脱溴、光化学开环反应、光化学闭环反应、脱保护、双键异构的步骤制得地屈孕酮，具有起始原料易得、各步骤均易实现、收率较高的优点，且操作简便、绿色环保，易于放大至工业生产。
本发明的关键步骤将9α,10β-去氢黄体酮二乙二缩酮利用LED光源制备出9β,10α-去氢黄体酮二乙二缩酮，在光化学开环反应中，开环反应的转化率可超过90％，进一步进行光化学闭环反应时，有20-75％左右的原料转化成目标产物，总产率高，操作简便，控制点少，容易进行放大生产，且引入的溶剂少，制备过程能耗低，是相较于现有技术汞灯制备更绿色环保、反应副产物更少的技术。
本发明提供了能工业化生产地屈孕酮的方法，使国内自行生产地屈孕酮具备了可能性，具有非常重要经济及社会价值。
附图说明
图1是化合物5的 1H-NMR谱图。
图2是化合物5的 13C-NMR谱图。
图3是化合物6的 1H-NMR谱图。
图4是化合物6的 13C-NMR谱图。
图5是目标产物地屈孕酮的 1H-NMR谱图。
图6是目标产物地屈孕酮的 13C-NMR谱图。
图7是目标产物地屈孕酮的HHCOSY谱图。
图8是目标产物地屈孕酮的NOE谱图。
图9是目标产物地屈孕酮的HMQC谱图。
图10是目标产物地屈孕酮的HMBC谱图。
图11是光化学开环反应和光化学闭环反应的反应系统示意图。
具体实施方式
以下结合具体实施例对本发明作进一步说明，但本发明的保护范围不限于以下实施例。
本实施例的制备方法如Scheme 10所示；
Figure PCTCN2020120276-appb-000014
Scheme 10
实施例1
称取2kg黄体酮(化合物2)加入到20L反应罐中，再依次加入4L乙二醇、5.5L四氢呋喃、0.1L乙酰氯，慢慢滴加2L原甲酸三甲酯，温度控制在35±5℃，反应2小时±10分钟后，加0.2L吡啶淬灭反应，-10℃±5℃冷却0.5小时，过滤，并依次用6L水洗、3L丙酮洗，抽干，40℃以下真空干燥得化合物3
Figure PCTCN2020120276-appb-000015
的粗产物。
将化合物3粗产物投入20L反应罐中，加入6L丙酮、4毫升吡啶，水浴加热至回流，搅拌1小时，-10℃±5℃冷却0.5小时，抽滤，40℃真空干燥过夜得化合物3的纯品，产率91％。
实施例2
分别用甲基叔丁基醚、异丙醚、甘醇二甲醚或甘醇二乙醚代替四氢呋喃，其它与实施例1相同，化合物3的产率分别为80％、83％、89％和85％。
实施例3
称取1kg缩酮保护的黄体酮(化合物3)加入到50L反应罐中，加入二氧六烷20L，再加150毫升DBU，氮气(或氩气)保护下加热至55～65℃是的原料溶解完全，加入1.15当量溴代 丁二酰亚胺(NBS)、偶氮二异丁腈(AIBN)5g，65～75℃下反应1h。抽滤，固体用DCM溶解，饱和碳酸氢钠溶液洗涤，干燥，减压蒸干滤液，得类白色至淡黄色固体化合物4。
将化合物4投入反应罐中，加3.5L有机碱TEA，氮气保护下加热至120℃±5℃，温度反应2h，减压回收2/3左右的TEA，然后加入3L乙腈/甲醇＝1/1，冷却至60℃以下，加500毫升二氧六烷，-10℃±5℃冷却，析晶0.5小时，过滤，并依次用1.5L水、1.5L丙酮洗，抽干，40℃干燥过夜，得淡黄色产物化合物5，产率80％。
实施例4
分别用异辛烷、90-120℃沸点的石油醚、环己烷、四氢呋喃或甲基四氢呋喃代替二氧六烷，其它与实施例3相同，化合物5的产率81％、71％、80％、83％和85％。
实施例5
分别用二异丙基乙胺或三甲基吡啶代替TEA，其它与实施例3相同，化合物5的产率分别为86％和75％。
实施例6
用二溴海因代替NBS，其它与实施例3相同，化合物5的产率79％。
实施例7
分别用3L丙酮/乙腈＝4/1或3L丙酮/水＝4/1代替实施例3中的3L乙腈/甲醇＝1/1，其它与实施例3相同，化合物5的产率非标为79％和70％。
实施例8
分别用500毫升甲基叔丁基醚、500毫升丁醚或500毫升异丙醚代替实施例3中的500毫升二氧六烷，其它与实施例3相同，化合物5的产率非标为78％、73％和74％。
化合物5的核磁共振结构表征数据： 1H NMR(400MHz,CDCl 3)5.55～5.57(m,1H),5.37～5.39(m,1H),3.86～4.00(m,8H),2.58(dd,J＝15.0,1.5Hz,1H),2.27(dd,J＝15.0,2.8Hz,1H),2.05～2.17(m,2H),1.71～1.89(m,9H),1.59～1.62(m,2H),1.42～1.48(m,1H),1.30(s,3H),1.25(dd,J＝12.8,4.4Hz,1H),0.96(s,3H),0.72(s,3H). 13C NMR(101MHz,CDCl 3)δ140.72,139.19,120.15,116.76,112.10,108.90,65.15,64.58,64.45,63.47,57.88,54.52,46.10,42.46,40.35,38.98,37.55,37.03,31.48,24.64,23.18,22.75,21.10,16.30,13.09.
谱图如图1和2所示。
实施例9
本实施例的光化学反应，是最关键的技术，所采用的反应系统包括进料罐、第一光化学反应器、第二光化学反应器和接收罐。结合图11所示，反应装置中设置有流量计以在反应过程中对溶液流速进行控制，流量计的位置可以适当设置，本实施例是以设置在进料罐和第一光化 学反应器之间为例。溶液流速通过利用进料罐与接收罐的高度差或相对角度大小来调整，当然也可以通过阀门来调整。进料罐、第一光化学反应器、第二光化学反应器、接收罐中均匹配有冷凝系统。第一光化学反应器和第二光化学反应器的光源均为通过光电技术产生的的LED光源。第一光化学反应器和第二光化学反应器直接相连，在第一光化学反应器进行光化学开环反应，在第二光化学反应器中进行光化学闭环反应，气体钢瓶中有氮气或是惰性气体，与进料罐连接，使反应系统充入氮气或惰性气体保护光化学开关反应和光化学闭环反应。
将100克化合物5溶解于8L反应溶剂甲醇，氩气保护，光化学开环反应波长为275纳米，光化学闭环反应的波长为335纳米，然后打开流量计，反应温度控制在0±5℃。
反应时间约30小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约40％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约57％，其它杂质含量约3％。。
实施例10
光化学开环反应波长改为280纳米，光化学闭环反应的波长改为345纳米，反应溶剂为10L四氢呋喃，其它条件同实施例9。
反应时间约8小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约41％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约54％，其它杂质含量约5％。
实施例11
光化学开环反应的波长改为295纳米，光化学闭环反应的波长改为330纳米，反应溶剂为10L乙醇，其它条件同实施例9。
反应时间约12小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约60％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约25％，其它杂质含量约15％。
实施例12
光化学开环反应波长改为265纳米，光化学闭环反应的波长改为330纳米，反应溶剂为10L乙醇，其它条件同实施例9。
反应时间约10小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约50％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约30％，其它杂质含量约20％。
实施例13
光化学开环反应波长改为280纳米，光闭环反应的波长改为350纳米，反应溶剂为10L四氢 呋喃，其它条件同实施例9。
反应时间约12小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约51％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约40％，其它杂质含量约9％。
实施例14
光化学开环反应波长改为280纳米，光化学闭环反应的波长改为360纳米，反应溶剂为10L四氢呋喃，反应温度控制在-0±5℃，其它条件同实施例9。
反应时间约15小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约65％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约30％，其它杂质含量约5％。
实施例15
光化学开环反应波长改为280纳米，光化学闭环反应的波长改为365纳米，反应溶剂为10L四氢呋喃，其它条件同实施例9。
反应时间约24小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约65％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约20％，其它杂质含量约15％。
实施例16
光化学开环反应波长改为280纳米，光闭环反应的波长改为365纳米，反应溶剂为10L甲基四氢呋喃，其它条件同实施例9。
反应时间约20小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约65％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约20％，其它杂质含量约15％。
实施例17
光化学开环反应波长改为270纳米，光化学闭环反应的波长改为330纳米，反应溶剂为10L甲醇，将反应温度控制在-15±5℃，其它条件同实施例9。
反应时间约4小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约30％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约62％，其它杂质含量约8％。
实施例18
光化学开环反应波长改为270纳米，光化学闭环反应的波长改为330纳米，反应溶剂为10L甲醇，将反应温度控制在30±5℃，其它条件同实施例9。
反应时间约3.2小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约50％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约43％，其它杂质含量约7％。
实施例19
光化学开环反应波长改为270纳米，光化学闭环反应的波长改为330纳米，反应原料为50g，溶剂用量为4L，其它条件同实施例9。
反应时间约28小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约40％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约55％，其它杂质含量约5％。
实施例20
光化学开环反应波长改为270纳米，光化学闭环反应的波长改为330纳米，反应溶剂为10L乙醇，其它条件同实施例9。
反应时间约3.6小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约46％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约50％，其它杂质含量约4％。
实施例21
光化学开环反应波长改为270纳米，光化学闭环反应的波长改为330纳米，反应溶剂为10L异丙醇，其它条件同实施例9。
反应时间约4.2小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约50％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约45％，其它杂质含量约5％。
实施例22
光化学开环反应波长改为270纳米，光化学闭环反应的波长改为330纳米，反应溶剂为10L甘醇二甲醚，其它条件同实施例9。
反应时间约5小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约50％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约43％，其它杂质含量约7％。
实施例22
光化学开环反应波长改为270纳米，光化学闭环反应的波长改为330纳米，反应溶剂为10L甘醇二甲乙醚，其它条件同实施例9。
反应时间约5小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二 缩酮的含量约51％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约43％，其它杂质含量约6％。
实施例23
光化学开环反应波长改为270纳米，光化学闭环反应的波长改为330纳米，反应溶剂为10L甲基四氢呋喃，其它条件同实施例9。
反应时间约5小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约50％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约44％，其它杂质含量约6％。
实施例24
光化学开环反应波长改为270纳米，光化学闭环反应的波长改为330纳米，反应溶剂为10L环己烷，其它条件同实施例9。
反应时间约5小时，HPLC检测结果显示粗产物中原料9α,10β-去氢黄体酮二乙二缩酮的含量约48％，目标产物9β,10α-去氢黄体酮二乙二缩酮的含量约45％，其它杂质含量约7％。
实施例25
将实施例9的反应液出料，减压蒸馏回收溶剂，然后加入150毫升乙醇/乙腈＝3/1(体积比)的混合溶剂，加热回流10分钟，-5℃下冷却20分钟，大部分9α,10β-去氢黄体酮二乙二缩酮直接从混合物中析出，抽滤回收得38克化合物5。滤液减压回收溶剂，然后0℃下冷却20分钟，抽滤回收得61克9β,10α-去氢黄体酮二乙二缩酮的粗产品，粗品收率61％。可用异丙醇进一步重结晶纯化。
化合物6的核磁共振结构表征数据： 1H NMR(400MHz,CDCl3)5.61(dd,J＝5.2,2.4Hz,1H),5.43～5.44(m,1H),3.84～4.01(m,8H),2.48～2.56(m,2H),2.26～2.29(m,2H),2.02～2.10(m,2H),1.71～1.84(m,6H),1.40～1.60(m,5H),1.30(s,3H),0.76(s,3H),0.70(s,3H). 13C NMR(101MHz,CDCl3)δ140.55,140.31,120.64,115.90,111.83,109.31,65.51,64.68,64.44,63.37,59.46,49.83,45.70,41.35,40.46,37.30,36.76,36.60,31.41,24.54,23.30,22.17,19.72,19.22,13.63.
谱图如图3和4所示。
实施例26
分别用甲醇/乙腈＝4/1、甲醇/四氢呋喃＝4/1、丙酮/四氢呋喃＝3/1、乙腈/四氢呋喃＝4/1、甲醇、异丙醇代替实施例25中的乙醇/乙腈＝3/1，粗品收率分别为：60％、56％、54％、51％、56％、63％。
实施例27
将5克化合物6的粗产物溶解到30毫升四氢呋喃/水＝3:1的混合溶剂中，加入10毫升醋酸，回流反应，反应完成后，减压除去溶剂，用DCM萃取，碳酸氢钠液洗涤，干燥，减压蒸馏回收溶剂，再用丙酮/甲醇＝1:3回流5～10分钟后冷却结晶，抽滤即可得到中间体7，可直接用于下一步反应。
这一步脱缩酮保护反应可以用乙腈/水＝3:1、丙酮/水＝3:1、甲醇/水＝3:1或乙醇/水＝3:1的混合溶剂代替四氢呋喃/水＝3:1的混合溶剂；或用三氟乙酸、2N盐酸等代替醋酸，其它实验操作相同。
实施例28
将5克化合物7的溶解于50毫升四氢呋喃，再加入10毫升浓盐酸，-5℃下搅拌，反应完成后，减压除去溶剂，粗产品溶解于DCM，碳酸氢钠液洗涤，干燥，用乙酸乙酯/正己烷＝1:5重结晶，然后再用异丙醇精制，即可得到地屈孕酮，产率85％。
实施例29
用甘醇二甲醚、甲醇代替四氢呋喃，其它条件与实施例28相同，产率分别为82％，80％。
实施例30
用乙酸乙酯、四氢呋喃或甲醇的饱HCl的溶液代替四氢呋喃加浓盐酸，-20±5℃下搅拌反应，其它条件与实施例28相同，产率分别为86％、88％、85％。
实施例31
改用乙酸乙酯/异辛烷＝1/5或乙酸乙酯/环己烷＝1/5或乙酸乙酯/正庚烷＝1/5重结晶，其它条件与实施例28相同，产率分别为83％、85％和81％。
目标产物(化合物1)的核磁共振结构表征数据： 1H NMR(400MHz,CDCl 3)δ6.13～6.19(m,1H),5.66(s,1H),2.41～2.56(m,4H),2.19～2.29(m,2H),2.12(s,3H),1.94～1.98(m,2H),1.62～1.87(m,7H),1.31～1.55(m,1H),1.29(s,3H),0.69(s,3H). 13C NMR(101MHz,CDCl 3)δ209.03,199.48,163.06,140.52,127.18,123.99,63.48,49.96,44.33,39.77,38.68,37.82,37.28,35.68,34.05,31.60,25.25,22.66,22.39,20.65,12.17.
谱图如图7-10所示。

Claims (10)

  1. 一种可工业化合成地屈孕酮的生产工艺，其特征在于包括以下步骤：
    S1.黄体酮与乙二醇、乙酰氯和原甲酸三甲酯在有机溶剂A中于25～45℃下反应1～2.5小时，然后淬灭反应，得化合物3
    Figure PCTCN2020120276-appb-100001
    S2.化合物3溶解在溶剂B中，再加入溴代丁二酰亚胺或二溴海因，然后加入自由基引发剂过氧化苯甲酰或偶氮二异丁腈，加热至65～75℃，进行溴代反应，反应完成后得化合物4
    Figure PCTCN2020120276-appb-100002
    S3.化合物4加入有机碱催化，在有溶剂C的条件下，氮气/惰性气体保护加热至回流，或在无溶剂的条件下，加热至115～125℃，进行脱溴反应，反应完成后，得化合物5 9α,10β-孕甾-4,6-二烯-3,20-二酮的二乙二缩酮；
    S4.将化合物5溶解于溶剂D中，在氮气/惰性气体保护下接受波长范围为265～300纳米的LED光源照射，进行光化学开环反应，得含有开环反应中间体的溶液，然后将含有开环反应中间体的溶液在氮气/惰性气体保护下接受波长范围为305～365纳米的LED光源照射，进行光化学闭环反应，待开环反应中间体转化后，分离得化合物6 9β,10α-去氢黄体酮二乙二缩酮；
    S5.化合物6溶解到溶剂E中，加入无机酸进行脱保护反应，反应完成后得化合物7
    Figure PCTCN2020120276-appb-100003
    S6.化合物7溶解到溶剂F中，加入浓盐酸加热反应，或将化合物7溶解于乙酸乙酯、THF或甲醇的饱HCl的溶液中进行反应，反应完成后得目标产物地屈孕酮。
  2. 根据权利要求1所述的可工业化合成地屈孕酮的生产工艺，其特征在于：
    所述有机溶剂A为四氢呋喃、甲基叔丁基醚、异丙醚、甘醇二甲醚或甘醇二乙醚中的一种或一种以上混合溶剂；
    所述溶剂B为二氧六烷、异辛烷、90-120℃沸点的石油醚、环己烷、四氢呋喃或甲基四氢呋喃中的一种或一种以上混合溶剂；
    所述溶剂C为环己烷或甲基四氢呋喃或无溶剂反应；
    所述溶剂D为甲醇、乙醇、异丙醇、甘醇二甲醚、甘醇二乙醚、四氢呋喃、甲基四氢呋喃或环己烷；
    所述溶剂E为四氢呋喃、乙腈、丙酮或甲醇中的一种或两者的混合溶剂；
    所述溶剂F为四氢呋喃、甘醇二甲醚、甲醇或乙醇中的一种或两种混合溶剂。
  3. 根据权利要求1所述的可工业化合成地屈孕酮的生产工艺，其特征在于：
    步骤S1中，所述淬灭反应是加入三乙胺、吡啶或二异丙基乙胺进行的；
    淬灭反应后，还包括：在-15℃～0℃下冷却，过滤，所得固体用水洗涤，再用乙醇或丙酮洗涤，干燥得化合物3的粗产物。
  4. 根据权利要求3所述的可工业化合成地屈孕酮的生产工艺，其特征在于：
    化合物3的粗产物加入丙酮和吡啶，加热至回流并搅拌0.5～1.5小时后，-15～-5℃冷却，过滤，干燥得精制的化合物3。
  5. 根据权利要求1所述的可工业化合成地屈孕酮的生产工艺，其特征在于：
    步骤S2中，所述溴代丁二酰亚胺为1.1-1.2eq；所述二溴海因为0.55-0.6eq，所述自由基引发剂为0.01-0.05eq；
    溴代反应完成后，还包括：用反应溶剂B洗滤饼，滤饼再用二氯甲烷溶解，饱和碳酸氢钠溶液洗涤二氯甲烷溶液，干燥，在低于40℃下回收二氯甲烷，得化合物4。
  6. 根据权利要求1所述的可工业化合成地屈孕酮的生产工艺，其特征在于：
    步骤S3中，所述有机碱为三乙胺、1,8-二氮杂二环十一碳-7-烯、二异丙基乙胺或2,4,6-三甲基吡啶；
    脱溴反应完成后还包括：减压回收溶剂及有机碱催化剂，然后加入乙腈和甲醇混合溶剂或的丙酮和乙腈混合溶剂或丙酮和水混合溶剂，冷却至60℃以下，加二氧六烷或甲基叔丁基醚或 丁醚或异丙醚，-15～-5℃冷却，析出固体，过滤，并依次用水、甲醇或乙腈或丙酮洗涤固体，干燥得化合物5。
  7. 根据权利要求1所述的可工业化合成地屈孕酮的生产工艺，其特征在于：
    步骤S4中，反应温度为-35～35℃，整个反应过程中，控制反应温度的范围上下浮动不超过10℃。
  8. 根据权利要求1所述的可工业化合成地屈孕酮的生产工艺，其特征在于：
    步骤S4中，所述分离包括：将含有9β,10α-去氢黄体酮二乙二缩酮的溶液，减压蒸馏回收溶剂，再与纯化溶剂加热回流，冷却，有固体析出，分离固体和液体，取液体回收溶剂，即得9β,10α-去氢黄体酮二乙二缩酮；
    所述纯化溶剂包括：乙醇和乙腈混合溶剂、甲醇和乙腈混合溶剂、甲醇和四氢呋喃混合溶剂、丙酮和四氢呋喃混合溶剂、乙腈和四氢呋喃混合溶剂、甲醇或异丙醇。
  9. 根据权利要求1所述的可工业化合成地屈孕酮的生产工艺，其特征在于：
    步骤S5中，所述无机酸为醋酸、三氟乙酸或2N盐酸；
    脱保护反应完成后还包括：除去溶剂，用乙酸乙酯或DCM萃取，碳酸氢钠液洗涤，干燥，与丙酮和甲醇混合溶剂或丙酮和异丙醇混合溶剂加热回流后冷却结晶，分离固体即得化合物7。
  10. 根据权利要求1所述的可工业化合成地屈孕酮的生产工艺，其特征在于：
    步骤S6中，所述双键移位反应条件为F中加入浓盐酸加热反应，或用乙酸乙酯、THF或甲醇的饱HCl的溶液中进行反应；
    应完成后还包括：回收溶剂，二氯甲烷萃取，碳酸氢钠液洗涤，干燥，除去溶剂后，加入乙酸乙酯和异辛烷混合溶剂或乙酸乙酯和环己烷混合溶剂或乙酸乙酯和正庚烷混合溶剂重结晶，最后用异丙醇精制，得目标产物地屈孕酮。
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Publication number Priority date Publication date Assignee Title
CN110818760B (zh) * 2019-11-12 2021-06-25 广西师范大学 一种可工业化合成地屈孕酮的生产工艺
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CN112409434B (zh) * 2020-11-27 2021-10-26 厦门欧瑞捷生物科技有限公司 一种去氢孕酮的合成方法
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CN115894593B (zh) * 2022-11-12 2024-03-08 药康众拓(江苏)医药科技有限公司 一种地屈孕酮及其中间体的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101668739A (zh) * 2007-04-24 2010-03-10 帝斯曼知识产权资产管理有限公司 用于制造前维生素d的光化学方法
WO2011138460A1 (en) * 2010-05-07 2011-11-10 Institut National De La Sante Et De La Recherche Medicale (Inserm) Progesterone receptor antagonists and uses thereof
IN201811020593A (zh) * 2018-06-01 2018-06-22
CN110818760A (zh) * 2019-11-12 2020-02-21 广西师范大学 一种可工业化合成地屈孕酮的生产工艺

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101318982A (zh) * 2007-08-03 2008-12-10 台州市万福制药有限公司 3-乙酰氧基-9β,10α-孕甾-5,7-二烯-20-酮的合成方法
CN102558272B (zh) * 2010-12-24 2014-04-23 中国科学院理化技术研究所 光化学异构化反应合成9-β，10-α-去氢黄体酮缩酮的方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101668739A (zh) * 2007-04-24 2010-03-10 帝斯曼知识产权资产管理有限公司 用于制造前维生素d的光化学方法
WO2011138460A1 (en) * 2010-05-07 2011-11-10 Institut National De La Sante Et De La Recherche Medicale (Inserm) Progesterone receptor antagonists and uses thereof
IN201811020593A (zh) * 2018-06-01 2018-06-22
CN110818760A (zh) * 2019-11-12 2020-02-21 广西师范大学 一种可工业化合成地屈孕酮的生产工艺

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