WO2023035906A1 - 中间体化合物及其制备方法和应用 - Google Patents

中间体化合物及其制备方法和应用 Download PDF

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WO2023035906A1
WO2023035906A1 PCT/CN2022/113559 CN2022113559W WO2023035906A1 WO 2023035906 A1 WO2023035906 A1 WO 2023035906A1 CN 2022113559 W CN2022113559 W CN 2022113559W WO 2023035906 A1 WO2023035906 A1 WO 2023035906A1
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compound
structural formula
intermediate compound
substituted
alkyl
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PCT/CN2022/113559
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English (en)
French (fr)
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刘喜荣
唐杰
李凯
甘杰
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湖南醇康医药科技有限公司
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Priority claimed from CN202111049973.0A external-priority patent/CN114957368A/zh
Priority claimed from CN202111516146.8A external-priority patent/CN114957372B/zh
Application filed by 湖南醇康医药科技有限公司 filed Critical 湖南醇康医药科技有限公司
Publication of WO2023035906A1 publication Critical patent/WO2023035906A1/zh

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • 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
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • 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

Definitions

  • the application relates to the field of chemical pharmacy, in particular to an intermediate compound and its preparation method and application.
  • Dydrogesterone also known as dehydroprogesterone, has a chemical name of 9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione, CAS number: 152-62-5, and its chemical formula is as follows:
  • Dydrogesterone takes pregnane as the mother nucleus, and pregnane has the following skeleton structure, with four rings of ABCD (from left to right, the four rings are defined as A, B, C and D in turn), and the carbon label (1-21) are as follows, hereinafter referred to as C-1 position, C-2 position, etc.
  • Dydrogesterone is widely used not only for miscarriage protection and miscarriage prevention, but also for the treatment of various diseases caused by endogenous progesterone deficiency, such as dysmenorrhea, endometriosis, secondary amenorrhea, and irregular menstrual cycles. Regular, dysfunctional uterine bleeding, premenstrual syndrome, threatened or habitual abortion caused by progesterone deficiency, infertility caused by corpus luteum insufficiency, etc.
  • trans-progesterone As a raw material and chloranil as an oxidant to synthesize.
  • the synthetic route is short, the raw material trans-progesterone used does not exist in natural products, and it needs to be synthesized to obtain , and the current synthesis is very difficult, and there is no industrialized product, so there is no possibility of industrialized production at present.
  • One of the purposes of the present application is to provide a production process for industrially synthesizing dydrogesterone, with easy-to-obtain raw materials, high overall yield, and easy scale-up to industrial production.
  • R 1 is selected from halogen or OR 3 ;
  • R 3 is selected from H, The dotted line indicates the connection position with O;
  • R 4 is selected from substituted or unsubstituted C1 ⁇ C6 straight chain or branched chain alkyl, or substituted or unsubstituted phenyl by C1 ⁇ C6 alkyl, hydroxyl or halogen atom, or substituted by C1 ⁇ C6 alkyl, Hydroxy or halogen atom substituted or unsubstituted naphthyl, or substituted or unsubstituted C1-C6 alkyl, hydroxyl or halogen atom substituted or unsubstituted pyridyl;
  • R 5 is selected from substituted or unsubstituted C1 ⁇ C6 straight chain or branched chain alkyl, or substituted or unsubstituted phenyl by C1 ⁇ C6 alkyl, hydroxyl or halogen atom, or substituted by C1 ⁇ C6 alkyl, Hydroxy or halogen atom substituted or unsubstituted naphthyl, or substituted or unsubstituted C1-C6 alkyl, hydroxyl or halogen atom substituted or unsubstituted pyridyl;
  • R 6 is selected from H or a hydroxyl protecting group
  • R 3 is selected from H or the following groups:
  • the intermediate compound includes the following structural formula:
  • R 2 is selected from -OR 6 or a protected carbonyl group
  • R 6 ' is selected from C1-C8 alkyl groups.
  • the intermediate compound includes the following structural formula:
  • Another aspect of the present application also provides a method for preparing an intermediate compound, the intermediate compound is the intermediate compound described in any one of the above; the method includes: performing photochemical conversion of the compound of structural formula IIa to make C-10 The methyl group at the position is reversed from the ⁇ configuration to the ⁇ configuration to obtain the compound of structural formula II;
  • the compound of structural formula IIa is subjected to photochemical conversion under the irradiation of an ultraviolet high-pressure mercury lamp, so that the methyl group at the C-10 position is reversed from a ⁇ configuration to an ⁇ configuration; the ultraviolet high-pressure mercury lamp emits The ultraviolet light is filtered by the filter solution and then irradiates the reaction system for photochemical conversion.
  • the filter solution contains Cu 2+ ; the photochemical conversion is carried out in two stages, and the Cu 2+ in the filter solution of the first stage The concentration is less than or equal to the concentration of Cu 2+ in the filter solution of the second stage.
  • the filter solution of the first stage filters out part or all of the light with a wavelength of less than 270nm
  • the filter solution of the second stage filters out part or all of the light with a wavelength of less than 300nm.
  • the concentration of Cu 2+ in the filter solution of the first stage is 0.1-0.5wt%
  • the concentration of Cu 2+ in the filter solution of the second stage is 0.5-1.2wt% %
  • Cu in the filter solution of the second stage is 0.7-1wt%, such as 0.7wt%, 0.8wt%, 0.9wt%, 1wt%, etc.
  • R2 in the compound of structural formula IIa is selected from -OR 6 ; the compound of structural formula II is a compound of structural formula IIb;
  • the method further includes: the step of obtaining the compound of the structural formula III through the oxidation of the hydroxyl group at the C-3 position and the shift of the double bond at the C-5 and 6 positions of the compound of the structural formula IIb;
  • the method for converting the compound of the structural formula IIb into the compound of the structural formula III includes: oxidizing the C-3 hydroxyl group to a keto group and shifting the 5,6 double bond to the 4,5 digits; or
  • the compound of the structural formula IIb is oxidized by using an oxidizing reagent to oxidize the C-3 hydroxyl group in the compound of the structural formula IIb to a keto group.
  • the structural formula of the oxidizing reagent is as follows: Then perform basic treatment to shift the 5,6 double bond to the 4,5 position to obtain the compound of structural formula III.
  • an oxidizing agent is used for oxidation treatment, and the molar ratio of the oxidizing agent to the compound of formula IIb is (1.2-1.8):1.
  • bicarbonate and water are also added during the oxidation treatment, and the molar ratio of the bicarbonate, the water and the compound of structural formula IIb is (1.5 ⁇ 2.5):(0.8 ⁇ 1.2) :1.
  • organic amines are used for alkaline treatment.
  • the method further includes: a step of shifting the double bond of the compound of structural formula III to obtain the compound of structural formula IV;
  • the method for converting the compound of structural formula III into the compound of structural formula IV comprises: under the condition of protic acid, the 7,8 double bond of the compound of structural formula III is shifted to the 6,7 position to obtain The compound of structural formula IV; the protonic acid is added in the form of a hydrogen halide alcohol solution, and the alcohol includes at least one of ethanol, isopropanol, butanol or ethylene glycol.
  • the method for converting the compound of structural formula III into the compound of structural formula IV comprises: adding the alcoholic solution of hydrogen halide to the reaction solvent containing the compound of structural formula III, and the addition amount of the alcoholic solution of hydrogen halide is 10v ⁇ 15v (that is, the mass ratio of the volume of the hydrogen halide alcohol solution to the compound is 10mL ⁇ 15mL:1g, in other words, for 1g of the compound, the addition amount of the hydrogen halide alcohol solution is 10mL ⁇ 15mL),
  • the mass percentage of water in the hydrogen halide alcohol solution is less than 0.2%, and the weight of the hydrogen halide accounts for 25wt%-40wt% of the total weight of the hydrogen halide alcohol solution.
  • an antioxidant is also added to the reaction solvent containing the compound of structural formula III, and the mass of the antioxidant is 0.8% to 1.2% of the mass of the compound of structural formula III.
  • the intermediate compound is compound E; the method further includes: the step of obtaining compound E by hydrolyzing the compound of structural formula IV;
  • R 1 in the compound of structural formula IV is selected from halogen or OR 3
  • R 3 is selected from
  • the present application also provides an application of an intermediate compound, comprising constructing a keto group at the C-20 position of any one of the intermediate compounds described above to prepare dydrogesterone.
  • the intermediate compound has the following structural formula or the intermediate compound is converted into an intermediate compound of the following structure:
  • the method of said structure ketone group comprises:
  • the application provides a new method for the preparation of dydrogesterone that is urgently needed in the field.
  • the starting material used in the method can be obtained from the fermentation product of phytosterols, and has a wide range of sources and is environmentally friendly; the intermediate compound of the technical solution of the application Dydrogesterone can be synthesized conveniently only by constructing the double bond of AB ring and modifying the side chain, with high overall yield and short route.
  • the raw materials are difficult to obtain, the conversion rate of the photoconversion process is low, the by-products are more, the safety risk is high, and it is not easy to industrialize the production.
  • one (species) or more (species) may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (species) or more (species).
  • m-n refers to the range from m to n and the subranges and individual point values therein.
  • C1-C6 or “C1-6” covers the range of 1-6 carbon atoms, and should be understood to also cover any sub-range therein and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., and C1, C2, C3, C4, C5, C6, etc.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms attached to the rest of the molecule by a single bond.
  • Alkyl can have 1-8 carbon atoms, that is, “C1-8 alkyl”, such as C1-4 alkyl, C1-3 alkyl, C1-2 alkyl, C3 alkyl, C4 alkyl, C1 -6 alkyl, C3-6 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or their isomers body.
  • silyl group refers to an alkyl group as defined above, wherein at least one C atom is replaced by a Si atom.
  • the silyl groups are linked to the rest of the molecule through silicon atoms.
  • C1-8 silyl group refers to a silyl group containing 1-8 carbon atoms, wherein the alkyl moiety can be linear, branched or cyclic.
  • Silyl groups include, but are not limited to, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS, or TBDMS), dimethylisopropylsilyl (IPDMS), di-tert-butylmethylsilyl etc. (DTBMS).
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Purification and isolation of such materials can be achieved by standard techniques known in the art.
  • the embodiment of the present application provides an intermediate compound, which can be used to prepare dydrogesterone, and has the following structural formula:
  • R 1 may be selected from halogen or OR 3 ;
  • R 3 may be selected from H, Wherein the dotted line indicates the connection position with O;
  • R4 is selected from substituted or unsubstituted C1 ⁇ C6 straight chain or branched chain alkyl, or substituted or unsubstituted phenyl by C1 ⁇ C6 alkyl, hydroxyl or halogen atom, Or substituted or unsubstituted naphthyl by C1 ⁇ C6 alkyl, hydroxyl or halogen atom, or substituted or unsubstituted pyridyl by C1 ⁇ C6 alkyl, hydroxyl or halogen atom;
  • R5 is selected from substituted or unsubstituted Substituted C1 ⁇ C6 linear or branched alkyl, or phenyl substituted or unsubstituted by C1 ⁇ C6 alkyl,
  • R is selected from H or the following groups:
  • the intermediate compound includes the following structural formula:
  • R 2 is selected from -OR 6 or a protected carbonyl group
  • R 6 is selected from H or a hydroxyl protecting group
  • the protected carbonyl group is selected from a ketal
  • R 6 ' is selected from a C1-C8 alkyl group.
  • the partial specific structural formula of said structural formula I is as follows:
  • hydroxyl or carbonyl of some of these compounds can be protected by protecting groups.
  • protecting groups For example:
  • the embodiment of the present application also provides a method for preparing any one of the aforementioned intermediate compounds.
  • the method comprises the step of photochemically converting the compound of the structural formula IIa to invert the methyl group at the C-10 position from the ⁇ configuration to the ⁇ configuration to obtain the compound of the structural formula II;
  • R 2 is selected from -OR 6 .
  • R is H
  • the compound of the structural formula II is a compound of the structural formula IIb
  • the conversion of the compound of the structural formula IIa into the compound of the structural formula IIb is achieved by a two-step photochemical conversion reaction
  • the two-step photochemical conversion reaction may include: opening the ring of the compound of the structural formula IIa under the irradiation of ultraviolet light of the first wavelength to complete the first step of photochemical conversion reaction; making the ring-opened compound of the structural formula IIa The ring is closed under the irradiation of ultraviolet light of the second wavelength to complete the second step photochemical conversion reaction.
  • the fermentation product (see the formula below) can be obtained by using phytosterol as a raw material and fermenting with microorganisms belonging to the genus Mycobacterium, and then obtaining the compound of the structural formula IIa by chemical synthesis.
  • R 2 is selected from -OR 6
  • the compound of structural formula IIa can be obtained through shorter steps. Therefore, the raw materials of the examples of the present application are easy to obtain.
  • the reaction solvents of the first step photochemical conversion reaction and the second step photochemical conversion reaction are methanol, ethanol, n-hexane, petroleum ether, n-heptane, ethyl acetate, tetrahydrofuran, ethylene glycol 1.
  • At least one of isopropanol, the reaction temperature is -10°C to 50°C; the first wavelength is 270nm to 290nm, and the second wavelength is 300nm to 330nm.
  • high pressure mercury lamps or LED lamps are used to provide the ultraviolet light.
  • the LED ultraviolet lamp has a single wavelength, low power, and a limited range of wavelength selection. Large-scale photochemical reactions need to integrate a large number of LED lamp beads, and the production of light sources is complicated and costly.
  • an ultraviolet high-pressure mercury lamp is used, which can achieve greater power and reduce costs.
  • the ultraviolet high-pressure mercury lamp has a wide spectral range (the ultraviolet region has a broad-spectrum distribution at 250nm-370nm).
  • the required wavelengths for the two-step photochemical reaction of the present invention are: the first stage, the required wavelength range is 270-300nm; the second stage, the required wavelength range is 300-350nm.
  • the ultraviolet high-pressure mercury lamp is directly used for irradiation in the first stage of ring opening, the proportion of the by-product configuration is very high due to the unnecessary wavelength (such as light with a wavelength of about 254nm). Therefore, it is necessary to filter the ultraviolet high-pressure mercury lamp.
  • a device containing a filter liquid is arranged between the reaction system and the light source, so that the light first passes through the filter liquid, filters the light, and then irradiates the reaction system.
  • the filter solution contains Cu 2+ , which can be copper salt, such as copper sulfate, copper chloride, copper acetate, etc., and can also contain other substances that do not affect the filtering effect of Cu 2+ and are colorless in water or impurities.
  • the filter solution can be an aqueous solution, or other colorless solvents that do not affect the Cu 2+ filtering effect and can dissolve Cu 2+ .
  • the filter solution after the aqueous solution of Cu 2+ with a concentration of 0.1 to 0.5 wt%, specifically 0.3 to 0.5 wt%, after filtering, the wavelength is mostly greater than 270nm (substantially filter out the light with a wavelength below 270nm), and when the concentration is 0.5-1.2wt%, specifically 0.7-1wt% Cu 2+ aqueous solution, after filtering, most of the wavelengths are greater than 300nm, reaching the required wavelength range for photochemical reactions. That is, the intensity ratio of ultraviolet rays of different wavelengths is adjusted through the filter liquid, so that the proportion of favorable wavelengths is higher.
  • low-concentration filter solution in the first stage of ring opening is conducive to ring opening and transformation to the desired configuration, and reduces damage to raw materials, while closed-loop requires a higher concentration of filter solution to strengthen the detection of low wavelengths. Filtering shifts the reaction equilibrium towards a closed loop. Higher yields can be obtained.
  • Photochemical transformations produce multiple products.
  • R 1 is an aromatic group, such as R 1 is OTs
  • the photochemical conversion reaction of this step has better conversion rate and selectivity (selectivity reaches more than 40%), and can obtain better yield (yield can reach 25%), and the compound of structural formula IIb is easier to separate from the product, and the post-treatment is simple and convenient.
  • R 1 in the compound of structural formula IIb is -OR 3 and R 3 is selected from , the C-3 hydroxyl group can be protected first, then R1 can be converted into an ester group, and then deprotected, which can make the esterification product easier to separate.
  • the method further includes: the step of obtaining the compound of the structural formula III through the oxidation of the hydroxyl group at the C-3 position and the displacement of the double bond at the C-5 and 6 positions of the compound of the structural formula IIb;
  • the structure of the compound of formula IIb such as the conjugated double bond of the B ring makes the structure worse, the methyl group in the ⁇ configuration at the C-10 position changes the solubility of the compound, and the group at the C-21 position is different, etc.
  • the oxidation reaction of this step has higher requirements on the oxidation system. If some commonly used oxidation systems are used, either the target product cannot be obtained, or the yield is very low.
  • the compound of structural formula III can be obtained by using Sven oxidation, but the yield is very low, and the impurities are difficult to control and the conditions are harsh.
  • the C-3 hydroxyl group can be oxidized to a keto group and the 5,6 double bond can be shifted to the 4,5 position by using the Woshi oxidation reaction.
  • Wo Shi oxidation (reagent such as aluminum isopropoxide / cyclohexanone), which is a high-temperature reaction, and there must be high temperature to remove high-boiling substances, although Wo Shi oxidation can simultaneously carry out double bond displacement, but the compound of structural formula III in It is unstable under high temperature or strong alkaline conditions, resulting in low reaction yield (molar yield about 48%).
  • the method for converting the compound of the structural formula IIb into the compound of the structural formula III may include: subjecting the compound of the structural formula IIb to oxidation treatment, so that the C-3 hydroxyl group in the compound of the structural formula IIb is oxidized to a ketone base; and then carry out basic treatment to shift the 5,6 double bond to the 4,5 position to obtain the compound of structural formula III.
  • the oxidizing reagent that the embodiment of the present application adopts has following structural formula (Dess Martin's reagent):
  • the oxidation reaction can be performed at low temperature (eg -5°C to 25°C, or 5°C to 10°C).
  • the molar ratio of the oxidizing agent to the compound of structural formula IIb may be (1.2-1.8):1.
  • water and bicarbonate such as sodium bicarbonate, potassium bicarbonate
  • the molar ratio of the bicarbonate, water and the compound of structural formula IIb is (1.5-2.5): (0.8-1.2):1.
  • Adopt organic base again preferably amine, such as triethylamine, pyridine etc.
  • carry out alkaline treatment under mild condition can obtain the structural formula III compound of higher yield, this method has avoided high temperature, concentrated for a long time, strong alkali Influence.
  • the method further comprises: a step of translating the double bond of the compound of structural formula III to obtain the compound of structural formula IV;
  • the method for converting the compound of structural formula III into the compound of structural formula IV comprises: under the condition of protic acid, the 7,8 double bonds of the compound of structural formula III are shifted to the 6,7 positions to obtain the compound of structural formula IV .
  • the protonic acid used can be HCl, HBr, etc.
  • the method for converting the compound of structural formula III into the compound of structural formula IV comprises: adding the alcoholic solution of hydrogen halide to the reaction solvent containing the compound of structural formula III, adding 10 mL to 15 mL of hydrogen halide according to 1 g of compound of structural formula III
  • the alcohol solution of hydrogen halide is added in the form of alcohol solution, that is, the amount of the alcohol solution of hydrogen halide added is 10v ⁇ 15v.
  • the mass percentage of water in the hydrogen halide alcohol solution is less than 0.2%, and the weight of the hydrogen halide accounts for 25wt%-40wt% of the total weight of the hydrogen halide alcohol solution.
  • ethanol In the alcohol solution of hydrogen halide, ethanol, isopropanol, butanol, ethylene glycol and the like can be used as alcohol.
  • the conversion rate of ethanol can be as high as 89%, while the conversion rate of methanol is only about 55% under the same conditions.
  • this step can also add an antioxidant with a mass fraction of 0.8%-1.2% (based on the mass of the compound of structural formula III) to suppress peroxidized impurities and increase the yield.
  • antioxidants include sodium ascorbate, TBHQ.
  • the melting point of the compound of structural formula IV is relatively low, so it is difficult to obtain a solid, and it will deteriorate to a certain extent into oil under high concentration of acid, which will affect the properties of the solid.
  • ethanol was used as a solvent during the post-treatment to obtain a solid with gradient cooling while stirring.
  • the intermediate compound is compound E; the method further includes: the step of hydrolyzing the compound of structural formula IV to obtain compound E;
  • R 1 in the structural formula IV is -OR 3 and R 3 is
  • the method for converting the compound of the structural formula IV into the compound of the structural formula E comprises: hydrolyzing the compound of the structural formula IV under basic conditions to form a 21-position hydroxyl structure, wherein the basic substances used include NaOH, KOH, potassium acetate, at least one of sodium acetate and sodium benzoate.
  • R 1 is -OR 3 and R 3 is
  • the method for converting the compound of the structural formula IV into the compound of the structural formula E comprises: using DMF and KOAc to convert R in the compound of the structural formula IV into an ester group; then hydrolyzing under basic conditions, wherein the basic substance used At least one of NaOH, KOH, potassium acetate, sodium acetate and sodium benzoate is included.
  • the embodiment of the present application also provides a method for preparing dydrogesterone, comprising constructing a keto group at the C-20 position of the intermediate compound of the embodiment of the present application.
  • the intermediate compound has the following structural formula:
  • the method for constructing a keto group at the C-20 position of the intermediate compound comprises:
  • the 21-hydroxyl of the intermediate compound is oxidized to an aldehyde group to obtain compound F.
  • the oxidation system may include NaClO, NaBr and 2,2,6,6-tetramethylpiperidine-1-oxyl radical, and the pH range of the oxidation system is controlled at 8-9.
  • the aldehyde group of compound F is subjected to enamination reaction to obtain compound Ga, wherein R 8 and R 9 are selected from C1-C6 alkyl or R 8 -NR 9 to form a 5- to 7-membered azacyclic ring.
  • compound F is subjected to enamination reaction with 1-(1-piperidinyl)cyclohexene to obtain compound G;
  • Oxidation of the compound G yields dydrogesterone.
  • the compound G can be oxidized in air under the catalysis of Cu + to obtain dydrogesterone.
  • one of the synthetic routes L1 for preparing dydrogesterone H in the embodiment of the present application is as follows:
  • R 2 is selected from -OR 6 .
  • each arrow represents one or several steps.
  • IIb can be obtained directly through photoconversion, and when R2 is other groups, one or several steps (before or after photoconversion) are required to obtain IIb.
  • R 1 of different compounds in the above synthetic route L1 can be the same or different within the defined range. To formally reflect this, it can be transformed into the following route:
  • R 10 , R 11 , R 12 , and R 13 are the same as those of R 1 above, and they are independently selected within the defined range.
  • R 10 is selected from OR 3 ;
  • R 11 , R 12 , R 13 are selected from halogen or OR 3 ;
  • R 3 is selected from
  • R 10 is an OTs group, and after photoconversion, OTs is converted to OAc or Br (then OTs, OAc or Br are collectively denoted as R 11 ), and then the reactions from IIb to III are carried out.
  • R 10 , R 11 , and R 12 are OTs groups. After obtaining the compound of formula IV, OTs is converted into OAc (at this time, OTs and OAc are collectively denoted as R 13 ), and then hydrolyzed.
  • the raw material used is the compound of structural formula IIa.
  • the compound of structural formula IIa may not be used as the initial raw material for the preparation of dydrogesterone, but compound E or any compound before compound E (compound of structural formula IIb, compound of structural formula III, compound of structural formula IV) may be used as initial raw material.
  • the selected initial raw materials are different, and the corresponding synthetic route can be correspondingly deleted based on the synthetic route L1.
  • the compound of structural formula III is selected as a raw material, part of the route IIa ⁇ IIb ⁇ III can be deleted on the basis of the synthetic route L1.
  • R1 of the structural formula IIa is OTs
  • R2 is OH
  • a specific compound A in the compound of the structural formula IIa is selected as a raw material to synthesize dydrogesterone H
  • the synthetic route L2 is obtained:
  • the amount of Dess Martin reagent can be about 1.3eq, and the conversion rate does not increase significantly by increasing the amount, but increases the difficulty of post-treatment and affects the yield; the solvent is changed to chloroform, but the yield does not increase; adding bicarbonate Sodium can promote the reaction and increase the conversion and yield. Adding a small amount of water can also promote the reaction and increase the conversion and yield as well as the rate.
  • the principle may be to form a more active DMP oxidation intermediate state in advance.
  • v represents the volume mL of solvent required for each g compound, such as 12v HCl (35%)/absolute ethanol means that 1g compound uses 12mL HCl (35%)/absolute ethanol.
  • this reaction requires high water content, and the reaction conversion rate of concentrated hydrochloric acid or 95% ethanol is low, and the reaction of dry hydrogen chloride gas/dehydrated alcohol system is required to greatly increase the conversion rate.
  • This reaction has requirements on the concentration of the acid, the acid content is low (20%), and the conversion rate is relatively low, and the acid content can reach a better effect at 30-38%.
  • the reaction has requirements on the amount of acid, and 10v-15v is more suitable. Too low conversion rate will cause low conversion rate, and too high will lead to product degradation, which is manifested as post-treatment solid oily, difficult to separate out solids, and lower yield.
  • the reaction is related to the strength of the acid, and the conversion rates of concentrated sulfuric acid, trifluoroacetic acid and trifluoromethanesulfonic acid are also different.
  • the conversion rate is also lower when anhydrous methanol is used as a solution, and the conversion rate is lower than anhydrous ethanol when THF and isopropanol are used as solvents.
  • Antioxidants are added to the reaction to suppress peroxidized impurities and increase the yield.
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • B 4 was esterified by a method similar to Example 7, and then deprotected to obtain B 2 .

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Abstract

本申请提供一种中间体化合物及其制备方法和应用，其中所述中间体化合物具有如下结构式（I）；采用本申请的中间体化合物只需进行AB环双键构建和侧链改造即可方便的合成地屈孕酮，总收率高、路线短。

Description

中间体化合物及其制备方法和应用 技术领域
本申请涉及化学制药领域，尤其涉及一种中间体化合物及其制备方法和应用。
背景技术
地屈孕酮(Dydrogesterone)，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，化学式如下：
Figure PCTCN2022113559-appb-000001
地屈孕酮以孕甾烷为母核，孕甾烷具有如下的骨架结构，具有ABCD四个环(从左到右，四个环依次定义为A、B、C和D)，碳的标号(1-21)如下，在下文中记为C-1位、C-2位等。
Figure PCTCN2022113559-appb-000002
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。
目前一些合成路线是从麦角甾醇出发，经过光化学合成10α构型中间体，然后经过沃氏氧化、双键转位、臭氧氧化、烯胺化、最后氧化获得地屈孕酮。但是光转化过程转化率低、分离困难，同时此过程需要用到臭氧氧化，存在安全风险，且副产物较多。另一些合成路线是通过光甾-4,7,22-三烯-3-酮为原料经4步反应来合成，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。还有一些合成路线以反式孕酮为原料，以四氯苯 醌为氧化剂来合成，虽然该合成路线短，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。
发明内容
本申请的目的之一是提供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。
本申请的一方面提供一种中间体化合物，具有如下结构式：
Figure PCTCN2022113559-appb-000003
其中，R 1选自卤素或OR 3；
R 2选自＝O、-OR 6或被保护的羰基；
R 3选自H、
Figure PCTCN2022113559-appb-000004
其中虚线表示与O连接位置；
R 4选自取代或未被取代的C1～C6直链或支链烷基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的苯基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的萘基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的吡啶基；
R 5选自取代或未被取代的C1～C6直链或支链烷基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的苯基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的萘基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的吡啶基；
R 6选自H或羟基保护基团；
在结构式I中，
Figure PCTCN2022113559-appb-000005
表示化学键为单键或双键，且当某一
Figure PCTCN2022113559-appb-000006
为双键时，与其相邻的
Figure PCTCN2022113559-appb-000007
为单键。
在本申请的一些实施例中，R 4选自C1～C3直链或支链烷基，或者被C1～C3烷基取代或未被取代的苯基；和/或，R 5选自C1～C3直链或支链烷基，或者被C1～C3烷基取代或未被取代的苯基，或者被C1～C3烷基取代或未被取代的萘基，或者被C1～C3烷基取代或未被取代的吡啶基；和/或，所述羟基保护基团选自-C(＝O)R 7、C1～C8烷基或C1～C8硅烷基；和/或， R 7选自取代或未被取代的C1～C6直链或支链烷基；和/或，所述被保护的羰基选自缩酮；和/或，所述卤素或所述卤原子选自Cl、Br或I。
在本申请的一些实施例中，R 3选自H或如下基团：
Figure PCTCN2022113559-appb-000008
在本申请的一些实施例中，所述中间体化合物包括如下结构式：
Figure PCTCN2022113559-appb-000009
其中，R 2选自-OR 6或被保护的羰基，R 6’选自C1～C8烷基。
在本申请的一些实施例中，所述中间体化合物包括如下结构式：
Figure PCTCN2022113559-appb-000010
Figure PCTCN2022113559-appb-000011
本申请的另一方面还提供一种制备中间体化合物的方法，所述中间体化合物为上述任一项所述的中间体化合物；所述方法包括：将结构式IIa化合物进行光化学转化使C-10位的甲基由β构型翻转为α构型得到结构式Ⅱ化合物的步骤；
Figure PCTCN2022113559-appb-000012
Figure PCTCN2022113559-appb-000013
在本申请的一些实施例中，将结构式IIa化合物在紫外线高压汞灯的照射下进行光化学转化，使C-10位的甲基由β构型翻转为α构型；所述紫外线高压汞灯发射的紫外光经滤光液滤光后再照射反应体系进行光化学转化，所述滤光液含有Cu 2+；所述光化学转化分两个阶段进行，第一阶段的滤光液中Cu 2+的浓度小于或等于第二阶段的滤光液中Cu 2+的浓度。
在本申请的一些实施例中，其中所述第一阶段的滤光液滤除部分或全部波长小于270nm的光，第二阶段的滤光液滤除部分或全部波长小于300nm的光。
在本申请的一些实施例中，其中所述第一阶段的滤光液中Cu 2+的浓度为0.1～0.5wt％，第二阶段的滤光液中Cu 2+的浓度为0.5～1.2wt％。可选地，其中所述第一阶段的滤光液中Cu 2+的浓度为0.3～0.5wt％，如0.3wt％、0.4wt％、0.5wt％等，第二阶段的滤光液中Cu 2+的浓度为0.7～1wt％，如0.7wt％、0.8wt％、0.9wt％、1wt％等。
在本申请的一些实施例中，结构式IIa化合物中的R2选自-OR 6；所述结构式Ⅱ化合物为结构式Ⅱb化合物；
Figure PCTCN2022113559-appb-000014
在本申请的一些实施例中，所述方法还包括：将所述结构式Ⅱb化合物经C-3位羟基的氧化和C-5,6位双键移位得到结构式Ⅲ化合物的步骤；
Figure PCTCN2022113559-appb-000015
在本申请的一些实施例中，将所述结构式Ⅱb化合物转化成所述结构式Ⅲ化合物的方法包括：采用沃氏氧化反应使C-3位羟基氧化为酮基且5,6双键移位到4,5位；或者
采用氧化试剂将所述结构式Ⅱb化合物进行氧化处理，使所述结构式Ⅱb化合物中的C-3位羟基氧化为酮基，所述氧化试剂的结构式如下：
Figure PCTCN2022113559-appb-000016
然后进行碱性处理，使5,6双键移位到4,5位，得到结构式Ⅲ化合物。
在本申请的一些实施例中，采用氧化试剂进行氧化处理，所述氧化试剂与结构式Ⅱb化合物的摩尔比为(1.2～1.8):1。
在本申请的一些实施例中，氧化处理时还添加碳酸氢盐和水，所述碳酸氢盐、所述水及所述结构式Ⅱb化合物的摩尔比为(1.5～2.5):(0.8～1.2):1。
在本申请的一些实施例中，采用有机胺进行碱性处理。
在本申请的一些实施例中，所述方法还包括：将所述结构式Ⅲ化合物双键移位得到结构式Ⅳ化合物的步骤；
Figure PCTCN2022113559-appb-000017
在本申请的一些实施例中，将结构式Ⅲ化合物转化成结构式Ⅳ化合物的方法包括：在质子酸条件下，使所述结构式Ⅲ化合物的7,8位双键移位到6,7位，得到结构式Ⅳ化合物；所述质子酸采用卤化氢的醇溶液的形式添加，所述醇包括乙醇、异丙醇、丁醇或乙二醇中的至少一种。
在本申请的一些实施例中，将结构式Ⅲ化合物转化成结构式Ⅳ化合物的方法包括：将卤化氢的醇溶液加入含结构式Ⅲ化合物的反应溶剂中，所述卤化氢的醇溶液的添加量为10v～15v(即所述卤化氢的醇溶液的体积与所述化合物的质量比为10mL～15mL：1g，换言之，针对1g的化合物，所述卤化氢的醇溶液的添加量为10mL～15mL)，所述卤化氢的醇溶液中水的质量百分比小于0.2％，所述卤化氢的重量占所述卤化氢的醇溶液总重量的25wt％～40wt％。
在本申请的一些实施例中，还向所述含结构式Ⅲ化合物的反应溶剂中添加抗氧化剂，所述抗氧化剂的质量为所述结构式Ⅲ化合物质量的0.8％～1.2％。
在本申请的一些实施例中，所述中间体化合物为化合物E；所述方法还包括：将结构式Ⅳ化合物经水解得到化合物E的步骤；
Figure PCTCN2022113559-appb-000018
结构式Ⅳ化合物中的R 1选自卤素或OR 3，R 3选自
Figure PCTCN2022113559-appb-000019
在本申请还提供一种中间体化合物的应用，包括在上述任一项所述的中间体化合物的C-20位构造酮基以制备地屈孕酮。
在本申请的一些实施例中，所述中间体化合物具有如下结构式或将所述中间体化合物转化为如下结构的中间体化合物：
Figure PCTCN2022113559-appb-000020
所述构造酮基的方法包括：
将所述中间体化合物的21位羟基氧化为醛基，得到化合物F；
将所述化合物F的醛基进行烯胺化反应，然后将C-20位氧化为羰基，获得地屈孕酮；
Figure PCTCN2022113559-appb-000021
本申请提供了一种本领域急需的制备地屈孕酮的新方法，该方法采用的起始原料可以由植物甾醇的发酵产物制得，来源广泛、绿色环保；本申请技术方案的中间体化合物只需进行AB环双键构建和侧链改造即可方便地合成地屈孕酮，总收率高、路线短，是一种可工业化的合成地屈孕酮的新工艺，因此解决了现有技术中原料难以获得、光转化过程转化率低、副产物较多、安全风险高、不易工业化生产的问题。
具体实施方式
除非另有定义，本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。若存在矛盾，则以本申请提供的定义为准。当本文中出现商品名时，意在指代其对应的商品或其活性成分。本文引用的所有专利、已经公开的专利申请和出版物均通过引用并入到本文中。
术语“一个(种)或多个(种)”或者类似的表述“至少一个(种)”可以表示例如1、2、3、4、5、6、7、8、9、10个(种)或更多个(种)。
本文所用的表述m-n指m至n的范围以及由其中的各个点值组成的亚范围以及各个点值。例如，表述“C1-C6”或“C1-6”涵盖1-6个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C2-C5、C3-C4、C1-C2、C1-C3、C1-C4、C1-C5、C1-C6等，以及C1、C2、C3、C4、C5、C6等。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接。“烷基”可以具有1-8个碳原子，即“C1-8烷基”，例如C1-4烷基、C1-3烷基、C1-2烷基、C3烷基、C4烷基、C1-6烷基、C3-6烷基。烷基的非限制性实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基 戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基，或者它们的异构体。
术语“硅烷基”，是指如上定义的烷基，其中至少一个C原子被Si原子取代。硅烷基与分子的其他部分通过硅原子相连。“C1-8硅烷基”是指含有1-8个碳原子的硅烷基，其中的烷基部分可为直链、支链或环状结构。硅烷基包括但不仅限于，三甲基硅基(TMS)、叔丁基二甲基硅基(TBS，或称TBDMS)、二甲基异丙基硅基(IPDMS)、二叔丁基甲基硅基等(DTBMS)。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。此类物质的纯化和分离可通过本领域已知的标准技术实现。
下述发明详述旨在举例说明非限制性实施方案，使本领域其它技术人员更充分地理解本发明的技术方案、其原理及其实际应用，以便本领域其它技术人员可以以许多形式修改和实施本发明，使其可最佳地适应特定用途的要求。
中间体化合物
本申请实施例一方面提供一种中间体化合物，所述中间体化合物可以用于制备地屈孕酮，具有如下结构式：
Figure PCTCN2022113559-appb-000022
在结构式I中，R 1可以选自卤素或OR 3；R 2选自＝O、-OR 6或被保护的羰基；R 3选自H、
Figure PCTCN2022113559-appb-000023
其中虚线表示与O连接位置；R 4选自取代或未被取代的C1～C6直链或支链烷基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的苯基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的萘基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的吡啶基；R 5选自取代或未被取代的C1～C6直链或支链烷基，或者被C1～C6烷基、羟基或卤 原子取代或未被取代的苯基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的萘基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的吡啶基；R 6选自H或羟基保护基团。
在结构式I中，
Figure PCTCN2022113559-appb-000024
表示化学键为单键或双键，且当某一
Figure PCTCN2022113559-appb-000025
为双键时，与这个
Figure PCTCN2022113559-appb-000026
相邻的
Figure PCTCN2022113559-appb-000027
为单键。
R 4选自C1～C3直链或支链烷基，或者被C1～C3烷基取代或未被取代的苯基；和/或，R 5选自C1～C3直链或支链烷基，或者被C1～C3烷基取代或未被取代的苯基，或者被C1～C3烷基取代或未被取代的萘基，或者被C1～C3烷基取代或未被取代的吡啶基；和/或，所述羟基保护基团选自-C(＝O)R 7、C1～C8烷基或C1～C8硅烷基；和/或，R 7选自取代或未被取代的C1～C6直链或支链烷基；和/或，所述被保护的羰基选自缩酮；和/或，所述卤素或所述卤原子选自Cl、Br或I。
在一些实施例中，R 3选自H或如下基团：
Figure PCTCN2022113559-appb-000028
在一些实施例中，所述中间体化合物包括如下结构式：
Figure PCTCN2022113559-appb-000029
其中，R 2选自-OR 6或被保护的羰基，R 6选自H或羟基保护基团，所述被保护的羰基选自缩酮，R 6’选自C1～C8烷基。
作为示例，所述结构式I的部分具体结构式如下：
Figure PCTCN2022113559-appb-000030
其中的某些化合物的羟基或羰基可以被保护基团所保护。例如：
Figure PCTCN2022113559-appb-000031
被保护后的结构式为
Figure PCTCN2022113559-appb-000032
Figure PCTCN2022113559-appb-000033
被保护后的结构式为：
Figure PCTCN2022113559-appb-000034
中间体化合物的制备方法
(光化学转化的步骤)
本申请实施例还提供一种制备前述任一项中间体化合物的方法。所述方法包括将结构式IIa化合物进行光化学转化使C-10位的甲基由β构型翻转为α构型得到结构式Ⅱ化合物的步骤；
Figure PCTCN2022113559-appb-000035
在一些实施例中，R 2选自-OR 6。在一些实施例中，R 6为H，所述结构式Ⅱ化合物为结构式Ⅱb化合物，所述将结构式Ⅱa化合物转化成所述结构式Ⅱb化合物通过两步光化学转化反应实现；
Figure PCTCN2022113559-appb-000036
在一些实施例中，所述两步光化学转化反应可以包括：使所述结构式Ⅱa化合物在第一波长的紫外光照射下开环，完成第一步光化学转化反应；使开环后的结构式Ⅱa化合物在第二波长的紫外光照射下闭环，完成第二步光化学转化反应。
可以采用植物甾醇为原料经分枝杆菌(Mycobacterium)属的微生物发酵得到发酵产物(见下式)，然后通过化学合成得到所述结构式Ⅱa化合物。R 2选自-OR 6时，可以通过更短的步骤得到结构式Ⅱa化合物。因此，本申请实施例的原料容易获取。
Figure PCTCN2022113559-appb-000037
在一些实施例中，所述第一步光化学转化反应和所述第二步光化学转化反应的反应溶剂为甲醇、乙醇、正己烷、石油醚、正庚烷、乙酸乙酯、四氢呋喃、乙二醇、异丙醇中的至少一种，反应温度为-10℃至50℃；第一波长为270nm至290nm，所述第二波长为300nm至330nm。在一些实施例中，采用高压汞灯或LED灯来提供紫外光。
LED紫外灯为单一波长，功率低，波长选择范围有限，规模化光化反应需要集成大量LED灯珠，光源制作复杂，成本很高。在一个实施例中，采用紫外线高压汞灯，通过采用紫外线高压汞灯可以达到更大的功率，可以降低成本。但是，紫外线高压汞灯光谱范围较宽(紫外区在250nm-370nm有广谱分布)。从机理上来说，由于本发明的两步光化学反应所需波长分别为：第一阶段，所需波长范围为270-300nm；第二阶段，所需波长范围为300-350nm。如果在第一阶段开环时直接采用紫外线高压汞灯照射，由于含有不需要的波长(例如254nm左右等波长的光)，副产物构型占比很高。所以需要对紫外线高压汞灯进行滤光。
在反应体系和光源之间设置容纳有滤光液的装置，使光线先透过滤光液，将光线滤光，再照射到反应体系内。
关于滤光液，其含有Cu 2+，可以是铜盐，例如硫酸铜、氯化铜、醋酸铜等，也可以含有其它不影响Cu 2+滤光效果的、在水中呈无色的其它物质或杂质。滤光液可以是水溶液，或采用其它不影响Cu 2+滤光效果的且能够溶解Cu 2+的无色溶剂。
关于滤光液，在浓度为0.1～0.5wt％、具体地在0.3～0.5wt％的Cu 2+的水溶液滤光后波长大部分大于270nm(基本滤掉270nm以下波长的光)，在浓度为0.5～1.2wt％、具体地在0.7～1wt％的Cu 2+的水溶液滤光后波长大部分大于300nm，达到光化学反应所需波长范围。即通过滤光液调整了不同波长的紫外线的强度比例，使有利波长占比更高。
第一阶段开环时使用低浓度的滤光液有利于开环，有利于向所需构型转变，且减少对原料的破坏，而闭环需要更高浓度的滤光液，加强对低波长的过滤，让反应平衡向闭环偏移。可以获得更高的收率。
光化学转化会产生多个产物。R 1为芳香基团时，例如R 1为OTs，该步骤的光化学转化反应具有更好的转化率和选择性(选择性达40％以上)，可以取得更好的收率(收率可达25％)，同时结构式Ⅱb化合物更容易从产物中分离，后处理简便。
结构式Ⅱb化合物中的R 1为-OR 3且R 3选自
Figure PCTCN2022113559-appb-000038
时，可以先对C-3位羟基进行保护，再将R 1转化为酯基，再脱保护，这样可以使酯化产物更易分离。
(氧化和碱性条件双键移位的步骤)
在一些实施例中，所述方法还包括：将所述结构式Ⅱb化合物经C-3位羟基的氧化和C-5,6位双键移位得到结构式Ⅲ化合物的步骤；
Figure PCTCN2022113559-appb-000039
其中结构式Ⅱb化合物的结构存在特殊性，如B环的共轭双键使结构性变差、C-10位α构型的甲基改变化合物溶解性、C-21位的基团的不同等，导致该步氧化反应对氧化体系要求较高。若采用一些常用的氧化体系，要么得不到目标产物，要么收率很低。例如采用斯文氧化可以得到结构式Ⅲ化合物，但收率很低，杂质比较难控制且条件苛刻。
可以采用沃氏氧化反应使C-3位羟基氧化为酮基且5,6双键移位到4,5位。沃氏氧化(试剂例如采用异丙醇铝/环己酮)，其为高温反应，且存在必须高温才能除去的高沸点物质，虽然沃氏氧化可以同时进行双键移位，但结构式Ⅲ化合物在高温或者强碱性条件下都不稳定，从而导致反应收率较低(摩尔收率约48％)。
在一些实施例中，将所述结构式Ⅱb化合物转化成所述结构式Ⅲ化合物的方法可以包括：将所述结构式Ⅱb化合物进行氧化处理，使所述结构式Ⅱb化合物中的C-3位羟基氧化为酮基；然后进行碱性处理，使5,6双键移位到4,5位，得到结构式Ⅲ化合物。
本申请实施例采用的氧化试剂具有如下结构式(戴斯马丁试剂)：
Figure PCTCN2022113559-appb-000040
能够在低温下(例如-5℃至25℃、或5℃至10℃)进行氧化反应。所述氧化试剂与结构式Ⅱb化合物的摩尔比可以为(1.2～1.8):1。在一些实施例中，氧化处理时还添加水和碳酸氢盐(例如碳酸氢钠、碳酸氢钾)，可以促进反应，增加转化率和收率，转化率高达92％，摩尔收率高达70％。所述碳酸氢盐、水与结构式Ⅱb化合物的摩尔比为(1.5～2.5): (0.8～1.2):1。再采用有机碱，优选胺，例如三乙胺、吡啶等，在温和条件下进行碱性处理，可以获得较高收率的结构式Ⅲ化合物，这种方法避免了高温、长时间浓缩、强碱的影响。
(酸性条件双键移位的步骤)
在一些实施例中，所述方法还包括：将所述结构式Ⅲ化合物双键移位得到结构式Ⅳ化合物的步骤；
Figure PCTCN2022113559-appb-000041
在一些实施例中，将结构式Ⅲ化合物转化成结构式Ⅳ化合物的方法包括：在质子酸条件下，使所述结构式Ⅲ化合物的7,8位双键移位到6,7位，得到结构式Ⅳ化合物。
由于采用盐酸、硫酸、高氯酸、冰醋酸、对甲苯磺酸、三氟乙酸等转化率都较低，在一些实施例中，所用质子酸可以是HCl，HBr等。
由于化学结构的特殊性，该步反应如要获得高的转化率对水分含量、酸浓度、酸量也有比较苛刻的要求。在一些实施例中，将结构式Ⅲ化合物转化成结构式Ⅳ化合物的方法包括：将卤化氢的醇溶液加入含结构式Ⅲ化合物的反应溶剂中，按1g结构式Ⅲ化合物添加所述10mL～15mL的卤化氢的醇溶液的方式添加卤化氢的醇溶液，也即所述卤化氢的醇溶液的添加量为10v～15v。所述卤化氢的醇溶液中水的质量百分比小于0.2％，所述卤化氢的重量占所述卤化氢的醇溶液总重量的25wt％～40wt％。
在所述卤化氢的醇溶液中，醇可以采用乙醇、异丙醇，丁醇，乙二醇等。采用乙醇转化率可高达89％，而同等条件下采用甲醇转化率只有约55％。
在一些实施例中，该步骤还可以添加质量分数为0.8％～1.2％(基于结构式Ⅲ化合物的质量)的抗氧化剂来抑制过氧化的杂质，以提高收率。抗氧化剂示例性的包括抗坏血酸钠、TBHQ。
此外，结构式Ⅳ化合物的熔点较低，较难得到固体，且在高浓度酸下有一定程度变质成油，影响固体的性状。在本申请实施例中，为了避免此类现象发生，在后处理时采用乙醇作为溶剂边搅拌边梯度降温得到固体，粗品再用正庚烷打浆除油，可以获得较高的收率。
(水解的步骤)
在一些实施例中，所述中间体化合物为化合物E；所述方法还包括：将结构式Ⅳ化合物经水解得到化合物E的步骤；
Figure PCTCN2022113559-appb-000042
在一些实施例中，所述结构式Ⅳ中的R 1为-OR 3且R 3为
Figure PCTCN2022113559-appb-000043
将所述结构式Ⅳ化合物转化成所述结构式E化合物的方法包括：将所述结构式Ⅳ化合物在碱性条件下水解，形成21位羟基结构，其中采用的碱性物质包括NaOH、KOH、醋酸钾、醋酸钠和苯甲酸钠中的至少一种。
在一些实施例中，R 1为-OR 3且R 3为
Figure PCTCN2022113559-appb-000044
将所述结构式Ⅳ化合物转化成所述结构式E化合物的方法包括：采用DMF和KOAc使所述结构式Ⅳ化合物中的R 1转化为酯基；然后在碱性条件下水解，其中采用的碱性物质包括NaOH、KOH、醋酸钾、醋酸钠和苯甲酸钠中的至少一种。
由中间体制备地屈孕酮的方法
本申请实施例还提供一种制备地屈孕酮的方法，包括在本申请实施例的中间体化合物的C-20位构造酮基。
在一些实施例中，所述中间体化合物具有如下结构式：
Figure PCTCN2022113559-appb-000045
在所述中间体化合物的C-20位构造酮基的方法包括：
将所述中间体化合物的21位羟基氧化为醛基，得到化合物F。氧化体系可以包括NaClO、NaBr和2,2,6,6-四甲基哌啶-1-氧自由基，且所述氧化体系的pH范围控制在8-9。
Figure PCTCN2022113559-appb-000046
将所述化合物F的醛基进行烯胺化反应，得到化合物Ga，其中R 8、R 9选自C1～C6烷基或R 8-N-R 9构成5～7元氮杂环。例如使所述化合物F与1-(1-哌啶基)环己烯进行烯胺化反应，得到化合物G；
Figure PCTCN2022113559-appb-000047
氧化所述化合物G，获得地屈孕酮。例如可以将所述化合物G在Cu +催化下进行空气氧化，获得地屈孕酮。
作为示例，本申请实施例制备地屈孕酮H的其中一条合成路线L1如下：
Figure PCTCN2022113559-appb-000048
其中R 2选自-OR 6。
需要说明的是，上述合成路线L1中，每一个箭头代表一步或若干步。例如，R 2为OH时可以直接经光转化得到IIb，R 2为其它基团时除光转化的步骤外还需一步或若干步(可在光转化之前或之后)得到IIb。
上述合成路线L1中不同化合物的R 1在定义范围内可以相同或不同。为从形式上体现这一点，可以转换成下述路线：
Figure PCTCN2022113559-appb-000049
其中R 10、R 11、R 12、R 13的定义与上述R 1相同，在定义范围内各自独立的进行选择。在一些实施例中，R 10选自OR 3；R 11、R 12、R 13选自卤素或OR 3；R 3选自
Figure PCTCN2022113559-appb-000050
在一些实施例中，R 10为OTs基团，光转化后再将OTs转变为OAc或Br(此时OTs、OAc或Br统一记为R 11)，然后再进行IIb至III的反应。在一些实施例中，R 10、R 11、R 12为OTs基团，在得到式IV化合物后将OTs转变为OAc(此时OTs、OAc统一记为R 13)，然后再水解。
上述合成路线L1在制备地屈孕酮H时，采用的原料为结构式IIa化合物。但是，在其他实施例中，也可不以结构式IIa化合物作为制备地屈孕酮的初始原料，而以化合物E或化合物E之前的任一化合物(结构式IIb化合物、结构式III化合物、结构式IV化合物)作为初始原料。选择的初始原料不同，相应的合成路线可以基于合成路线L1进行相应的删减。作为示例，选择结构式III化合物作为原料时，可以在合成路线L1的基础上删除部分路线IIa→IIb→III。
作为示例，使合成路线L1中，结构式IIa的R 1为OTs，R 2为OH，也即选择结构式IIa化合物中的一个具体化合物A作为原料合成地屈孕酮H，得到合成路线L2：
Figure PCTCN2022113559-appb-000051
实施例
以所述合成路线L2为例，通过具体实施例来说明制备地屈孕酮的方法。
实施例1：A→B
在光化反应瓶里加40g化合物A和500mL四氢呋喃，5-10℃紫外灯光下先开环，波长范围为270nm～290nm，光照8小时，HPLC监测原料：产物＝70：20左右，再经紫外灯照射波长范围为300nm～330nm继续光照8h，HPLC监测，原料：产物＝55：35左右停止；有机相浓缩，甲醇置换至小体积，降温-20℃冷冻1～2小时，过滤，烘干得白色固体16g，主要为原料；母液浓缩，乙腈置换至小体积后出料，降温-20℃冷冻1～2小时，过滤，烘干得白色固体10g化合物B，一次收率约25％。
经检测， 1H NMR(400MHz,CDCl 3)δ7.78(d,J＝8.3Hz,2H),7.34(d,J＝8.1Hz,2H),5.66-5.64(m,1H),5.43–5.41(m,1H),4.09(s,1H),3.96(dd,J＝9.3,3.1Hz,1H),3.83(dd,J＝9.3,6.0Hz,1H),2.49-2.45(m,5H),2.29-2.24(m,2H),1.67–1.47(m,15H),0.97(d,J＝6.7Hz,3H),0.72(s,3H),0.57(s,3H)。
实施例1’：A→B
在光化反应瓶里加40g化合物A和500mL四氢呋喃，5-10℃在紫外线高压汞灯(500W)照射下先开环，开环时经滤光液(1wt％氯化铜水溶液)滤光，光照8小时，HPLC监测原料：产物＝70：20左右，再经滤光液(氯化铜浓度2wt％)滤光，继续光照8h，HPLC监测，原料：产物＝55：35左右停止；有机相浓缩，甲醇置换，降温-20℃冷冻4小时，过滤，烘干得白色 固体16g，主要为原料；母液浓缩，乙腈置换后出料，降温-20℃冷冻4小时，过滤，烘干得白色固体9.8g化合物B，一次收率约24.5％。
按上述反应步骤做表1中的对比试验，其它条件与本实施例相同。
表1 实验条件和结果
Figure PCTCN2022113559-appb-000052
实施例2：B→C
在1L的三口烧瓶里加戴斯马丁试剂(DMP)105g(0.28mol)，搅拌中加水3.78g(0.21mol)，碳酸氢钠35g(0.41mol)和500mL二氯甲烷(DCM)，搅拌片刻，5℃～10℃加100g(0.21mol)化合物B，保温搅拌半小时，TLC显示原料反应生成化合物B1，降温-20℃冷冻1～2小时，过滤，滤饼用冷二氯甲烷适量淋洗至滤饼无产物，有机相依次用亚硫酸钠溶液和碳酸氢钠溶液，食盐水洗涤。
有机相加100mL三乙胺，常温搅拌1～2小时，TLC显示化合物B1转化为化合物C，有机相依次用食盐水，1M稀盐酸，食盐水洗涤，有机相40℃浓缩，正庚烷置换至小体积，降温-20℃冷冻1～2小时，过滤，烘干得黄色固体70g，摩尔收率约70％。
经检测，1HNMR为： 1H NMR(400MHz,CDCl 3)δ7.78(d,J＝8.3Hz,2H),7.34(d,J＝8.1Hz,2H),5.80(s,1H),5.23–5.14(m,1H),3.96(dd,J＝9.3,3.1Hz,1H),3.83(dd,J＝9.3,6.0Hz,1H),3.01(ddd,J＝25.3,22.6,11.6Hz,2H),2.56–2.27(m,6H),2.21(dd,J＝6.9,2.6Hz,1H),2.00(dt,J＝13.4,4.7Hz,1H),1.93–1.11(m,13H),1.04(s,3H),0.97(d,J＝6.7Hz,3H),0.63–0.55(m,3H)。
按上述反应步骤做如下表2的对比试验，其它条件与本实施例相同。
表2 实验条件和结果
序号 条件 转化率％ 收率％
1 1.3eq DMP，DCM 86 66
2 1.0eq DMP，DCM 75 50
3 2.0eq DMP，DCM 87 63
4 1.3eq DMP，氯仿 85 62
5 1.3eq DMP，DCM，2eq碳酸氢钠 90 68
本实施例 1.3eq DMP，DCM，2eq碳酸氢钠1eq水 92 70
注：eq表示摩尔当量，下同。
由表2可知，戴斯马汀试剂用量1.3eq左右即可，增加用量转化率没有明显提升，反而增大后处理的难度，影响收率；溶剂改为氯仿，收率没有提高；添加碳酸氢钠，可以促进反应，增加转化率和收率，添加少量水，也可以促进反应，增加转化率和收率以及速率，其原理可能是预先形成更活泼的DMP氧化中间态。
实施例3：C→D
在1L的三口烧瓶里加840mL的无水乙醇，低温通入干燥的氯化氢气体，制备得无水乙醇/氯化氢溶液(水分要小于0.2％，含量约35％)；在2L的三口烧瓶里，加70g(0.145mol)化合物C和700mL二氯甲烷以及0.7g特丁基对苯二酚(TBHQ)，溶清，氮气保护，0℃～10℃下，滴加840mL自制的无水乙醇/氯化氢溶液，控温反应1小时左右，TLC检测原料剩余小于3％，加纯净水淬灭反应，分液，有机相用碳酸氢钠溶液洗至PH＝7～8，有机相50℃以下浓缩，乙醇置换，保留约500mL乙醇，边搅拌边梯℃降温，黄色固体析出，降温-20℃冷冻1～2小时，过滤，粗品再用正庚烷打浆，冷析过滤，烘干得米白色固体50g，摩尔收率约70％。
经检测： 1H NMR(400MHz,CDCl 3)δ7.76(d,J＝8.3Hz,2H),7.33(d,J＝8.1Hz,2H),6.24–6.05(m,2H),5.65(s,1H),3.94(dd,J＝9.3,3.0Hz,1H),3.80(dd,J＝9.2,6.0Hz,1H),2.60–2.48(m,1H),2.44(s,3H),2.41–2.32(m,1H),2.27–2.14(m,1H),1.91–1.55(m,10H),1.40–1.29(m,1H),1.29–1.07(m,6H),0.98(d,J＝6.7Hz,3H),0.70(s,3H)。
13C NMR(101MHz,CDCl 3)δ199.59(s),163.38(s),144.65(s),140.96(s),132.91(s),129.75(s),127.85(s),126.81(s),123.60(s),75.47(s),51.57(s),49.22(s),42.70(s),39.59(s),38.65(s),38.24(s),37.10(s),36.07(s),35.49(s),33.89(s),27.00(s),24.89(s),22.14(s),21.59(s),20.46(s),16.72(s),10.58(s)。
质谱：C 29H 38O 4S，482.9。
按上述反应步骤做表3中的对比试验，其它条件与本实施例相同。
表3 实验条件和结果
Figure PCTCN2022113559-appb-000053
Figure PCTCN2022113559-appb-000054
注：v表示每g化合物所需的溶剂的体积mL，如12v HCl(35％)/无水乙醇表示1g化合物采用12mL HCl(35％)/无水乙醇。
由表3可知，该反应对水分要求高，浓盐酸或者95％乙醇反应转化率低，需要干燥的氯化氢气体/无水乙醇体系反应才能大大提高转化率。该反应对酸的浓度有要求，酸含量较低(20％)，转化率相对较低，酸含量在30-38％能到达到较好的效果。该反应对酸量有要求，10v～15v较为合适，太低转化率低，太高会导致产物降解，表现为后处理固体油性较重，难析出固体，收率降低。此外，反应跟酸的强度有关，浓硫酸，三氟乙酸以及三氟甲磺酸转化率也有差异。有趣的是无水甲醇做溶液，转化率也较低，四氢呋喃和异丙醇做溶剂，转化率也低于无水乙醇。反应加抗氧化剂，可以抑制过氧化的杂质，提高收率。
实施例4：D→D1
在500mL的三口烧瓶里50g(0.10mol)化合物D和200mL DMF，溶清，加50g(0.51mol)醋酸钾，100℃反应2小时，TLC检测原料反应完全，缓慢倒入1L水中，析出固体，搅拌1小时，过滤，烘干得黄色固体36g，摩尔收率约95％。
经检测： 1H NMR(400MHz,CDCl 3)δ6.15(dt,J＝19.5,7.4Hz,2H),5.64(s,1H),4.07(dd,J＝10.7,3.5Hz,1H),3.76(dd,J＝10.7,7.3Hz,1H),2.59–2.44(m,1H),2.40(ddd,J＝11.5,7.4,4.9Hz,2H),2.24(ddd,J＝13.1,5.2,1.9Hz,1H),2.03(s,3H),1.95–1.67(m,7H),1.67–1.52(m, 2H),1.43–1.31(m,2H),1.29–1.13(m,5H),1.00(d,J＝6.6Hz,3H),0.75(s,3H).
13C NMR(101MHz,CDCl 3)δ199.40(s),171.22(s),163.31(s),141.05(s),126.73(s),123.59(s),69.30(s),52.66(s),49.32(s),42.80(s),39.68(s),38.73(s),38.45(s),37.13(s),35.61(d,J＝13.6Hz),33.90(s),27.21(s),25.01(s),22.14(s),20.91(s),20.53(s),16.99(s),10.66(s).
质谱：C 24H 34O 3，371.0。
实施例5：D1→E
在250mL的三口烧瓶里加36g(0.10mol)化合物D1和180mL甲醇，氮气保护，降温0℃～5℃，加7.2g(0.18mol)氢氧化钠固体，控温小于25℃，加完后自然回室温反应，反应0.5～1小时。TLC监测反应完全。加醋酸中和，再缓慢滴加水180mL，析出固体，冰浴搅拌1小时，过滤，烘干得黄色固体30g，摩尔收率约95％。
经检测： 1H NMR(400MHz,CDCl 3)δ6.17(dt,J＝23.1,7.5Hz,2H),5.65(s,1H),3.64(dd,J＝10.5,3.2Hz,1H),3.39(dd,J＝10.5,6.6Hz,1H),2.69–2.46(m,1H),2.46–2.32(m,2H),2.25(ddd,J＝13.1,5.2,1.9Hz,1H),1.82(dddd,J＝16.7,14.9,13.7,9.7Hz,6H),1.69–1.50(m,4H),1.38(ddd,J＝17.9,12.4,4.6Hz,2H),1.28–1.15(m,5H),1.05(d,J＝6.6Hz,3H),0.76(s,3H).
13C NMR(101MHz,CDCl 3)δ199.62(s),163.54(s),141.31(s),126.72(s),123.56(s),67.78(s),52.27(s),49.36(s),42.72(s),39.73(s),38.93–38.34(m),37.17(s),35.55(s),33.93(s),27.32(s),25.05(s),22.15(s),20.57(s),16.65(s),10.70(s).
质谱：C 22H 32O 2，329.0。
实施例6：E→F→G→H
(1)E→F
在250mL的三口烧瓶里加30g(91.3mmol)化合物E和150mL二氯甲烷，搅拌下加1.5g(9.6mmol)tempo和溶解好的1.08g溴化钠(10.5mmol)和30mL 5％的碳酸氢钠水溶液，氮气保护，降温0℃～5℃，滴加次氯酸钠，控温小于15℃，反应0.5～1小时。TLC监测反应完全。硫代硫酸钠溶液淬灭，搅拌10分钟，分液，有机相用食盐水洗涤一次，有机相50℃以下浓缩，石油醚置换，保留3v～5v石油醚。降温到0℃冷析2小时，过滤，滤饼用冰石油醚淋洗，烘干得28g固体化合物F，摩尔收率约92％。
1H NMR(400MHz,CDCl 3)δ9.58(d,J＝3.1Hz,1H),6.30–6.04(m,2H),5.67(s,1H),2.53(dd,J＝14.2,5.4Hz,1H),2.50–2.32(m,3H),2.26(ddd,J＝13.2,5.3,2.1Hz,1H),1.98–1.78(m,5H),1.73–1.37(m,6H),1.36–1.22(m,4H),1.13(t,J＝6.1Hz,3H),0.80(s,3H).
13C NMR(101MHz,CDCl 3)δ208.83(s),199.28(s),162.87(s),140.34(s),126.99(s), 123.80(s),63.29(s),49.78(s),44.15(s),39.59(s),38.50(s),37.64(s),37.10(s),35.50(s),33.87(s),31.40(s),25.07(s),22.49(s),22.21(s),20.47(s),11.98(s).
质谱：C 22H 30O 2，327.0。
(2)F→G→H(地屈孕酮)
在100mL的三口烧瓶里加28g(85.8mmol)化合物F和42mL无水乙腈，搅拌下加22g(122mmol)环己烯哌啶(含量约90％)，氮气保护，40℃搅拌溶清，加冰醋酸，继续反应3-6小时，降温到-20℃，冷析2小时，过滤，滤饼用冰乙腈淋洗，抽干，固体35℃真空干燥箱烘，得28g化合物G。
在100mL的三口烧瓶里加0.42g(4.2mmol)氯化亚铜和42mL DMF，氮气置换三次，加热至65℃，氮气保护保温搅拌1小时，降温至室温备用。在500mL的三口烧瓶里加28g(71.2mmol)化合物G和280mL二氯甲烷，降温至0-5℃，加入氯化亚铜溶液，通入已干燥的空气，保持气体流量1L/min，反应4～8小时，TLC检测原料剩余小于2％，延长时间无变化则可停止。加入10％硫酸溶液淬灭，分液，加1％硫酸溶液洗涤有机相，有机相加0.43g醋酸，搅拌5分钟，再加6％亚氯酸钠溶液，室温搅拌30min，TLC原料几乎消失。加硫代硫酸钠淬灭，分液，有机相依次用0.5％氢氧化钠，食盐水洗涤，有机相50℃以下浓缩，水置换出料得粗品。粗品加280mL丙酮加热溶清，浓缩到小体积，降温到-20℃，冷析2小时，过滤，滤饼用冰丙酮淋洗，抽干，45℃烘箱烘干。得20g固体化合物F，摩尔收率约74.6％。
经检测： 1H NMR(400MHz,CDCl 3)δ9.56(d,J＝3.1Hz,1H),6.14(dd,J＝10.8,7.2Hz,2H),5.65(s,1H),2.59–2.44(m,1H),2.44–2.29(m,3H),2.25(ddd,J＝13.1,5.3,1.9Hz,1H),2.01–1.70(m,7H),1.70–1.31(m,6H),1.31–1.20(m,4H),1.12(d,J＝6.9Hz,3H),0.78(s,3H).
13C NMR(101MHz,CDCl 3)δ204.51(s),199.36(s),163.08(s),140.68(s),126.90(s),123.70(s),50.79(s),49.34(s),48.93(s),43.21(s),39.72(s),38.58(s),38.32(s),37.10(s),35.51(s),33.88(s),26.66(s),25.27(s),22.13(s),20.47(s),13.28(s),11.00(s).
质谱：C 21H 28O 2，313.0。
以下实施例提供地屈孕酮的合成路线中部分环节的其他合成方法。实施例7-9的路线如下：
Figure PCTCN2022113559-appb-000055
实施例7
Figure PCTCN2022113559-appb-000056
在500mL的三口烧瓶里50g(0.10mol)化合物B和200mL DMF，溶清，加50g(0.51mol)醋酸钾，100℃反应2小时，TLC检测原料反应完全，缓慢倒入1L水中，析出固体，搅拌1小时，过滤，烘干得黄色固体35g，摩尔收率约92％。
经检测： 1H NMR(400MHz,CDCl 3)δ5.64(dd,J＝5.3,2.5Hz,1H),5.52–5.39(m,1H),4.06(dd,J＝10.8,3.4Hz,2H),3.78(dd,J＝10.7,7.4Hz,1H),2.59–2.39(m,2H),2.25(dt,J＝15.7,2.6Hz,2H),2.03(s,3H),1.94(dd,J＝8.6,3.8Hz,2H),1.75–1.59(m,7H),1.42(ddd,J＝29.8,15.4,6.9Hz,6H),0.98(d,J＝6.6Hz,3H),0.71(s,3H),0.61(s,3H).
实施例8
Figure PCTCN2022113559-appb-000057
在1L的三口烧瓶里加78g(0.21mol)化合物B 2，水3.78g(0.21mol)，碳酸氢钠35g(0.41mol)和500mL二氯甲烷，5℃～10℃加戴斯马丁试剂105g(0.28mol)，保温搅拌半小时，TLC显示原料反应生成中间态异构体，降温-20℃冷冻1～2小时，过滤，滤饼用冷二氯甲烷适量淋洗至滤饼无产物，有机相依次用亚硫酸钠溶液和碳酸氢钠溶液，食盐水洗涤。
有机相加100mL三乙胺，常温搅拌1-2小时，TLC显示中间态异构体转化为化合物C 1，有机相依次用食盐水，1M稀盐酸，食盐水洗涤，有机相40℃浓缩，正庚烷置换至小体积，降温-20℃冷冻1-2小时，过滤，烘干得黄色固体51g，摩尔收率约65％。
经检测： 1H NMR(400MHz,CDCl 3)δ5.79(s,1H),5.25–5.16(m,1H),4.05(dd,J＝10.7, 3.4Hz,1H),3.77(dd,J＝10.7,7.3Hz,1H),3.62–3.54(m,1H),3.15–2.86(m,2H),2.44–2.36(m,1H),2.25–2.17(m,1H),2.03(s,3H),1.87–1.67(m,7H),1.54–1.49(m,2H),1.38(d,J＝11.2Hz,2H),1.26–1.23(m,2H),1.03(s,3H),0.98(d,J＝6.6Hz,3H),0.65(s,3H).
实施例9：
Figure PCTCN2022113559-appb-000058
在1L的三口烧瓶里加840mL的无水乙醇，低温通入干燥的氯化氢气体，制备得无水乙醇/氯化氢溶液(水分要小于0.2％，含量约35％)；在2L的三口烧瓶里，加54g(0.146mol)化合物C 1，0.54g TBHQ和700mL二氯甲烷，溶清，氮气保护，0℃～10℃下，滴加840mL自制的无水乙醇/氯化氢溶液，控温反应1小时左右，TLC检测原料剩余小于3％，加纯净水淬灭反应，分液，有机相用碳酸氢钠溶液洗至pH＝7-8，有机相50℃以下浓缩，乙醇置换，保留约500mL乙醇，边搅拌边梯度降温，黄色固体析出，降温-20℃冷冻1-2小时，过滤，粗品再用正庚烷打浆，冷析过滤，烘干得米白色固体36g，摩尔收率约66.7％。
经检测： 1H NMR(400MHz,CDCl 3)δ6.15(dt,J＝19.5,7.4Hz,2H),5.64(s,1H),4.07(dd,J＝10.7,3.5Hz,1H),3.76(dd,J＝10.7,7.3Hz,1H),2.59–2.44(m,1H),2.40(ddd,J＝11.5,7.4,4.9Hz,2H),2.24(ddd,J＝13.1,5.2,1.9Hz,1H),2.03(s,3H),1.95–1.67(m,7H),1.67–1.52(m,2H),1.43–1.31(m,2H),1.29–1.13(m,5H),1.00(d,J＝6.6Hz,3H),0.75(s,3H)。
13C NMR(101MHz,CDCl 3)δ199.40(s),171.22(s),163.31(s),141.05(s),126.73(s),123.59(s),69.30(s),52.66(s),49.32(s),42.80(s),39.68(s),38.73(s),38.45(s),37.13(s),35.61(d,J＝13.6Hz),33.90(s),27.21(s),25.01(s),22.14(s),20.91(s),20.53(s),16.99(s),10.66(s)。
质谱：C 24H 34O 3，371.0。
实施例10-13的路线如下：
Figure PCTCN2022113559-appb-000059
实施例10：
Figure PCTCN2022113559-appb-000060
在500mL的三口烧瓶里50g(0.10mol)化合物B和200mL DMF，溶清，加17.4g(0.21mol)溴化锂，100℃反应2小时，TLC检测原料反应完全，缓慢倒入1L水中，析出固体，搅拌1小时，过滤，烘干得黄色固体37.7g，摩尔收率约93％。
实施例11：
Figure PCTCN2022113559-appb-000061
在1L的三口烧瓶里加82g(0.21mol)化合物B 3，3.78g水(0.21mol)，碳酸氢钠35g(0.41mol)和500mL二氯甲烷，5℃～10℃加戴斯马丁试剂105g(0.28mol)，保温搅拌半小时，TLC显示原料反应生成中间态异构体，降温-20℃冷冻1-2小时，过滤，滤饼用冷二氯甲烷适量淋洗至滤饼无产物，有机相依次用亚硫酸钠溶液和碳酸氢钠溶液，食盐水洗涤。
有机相加100mL三乙胺，常温搅拌1-2小时，TLC显示中间态异构体转化为化合物BBr，有机相依次用食盐水，1M稀盐酸，食盐水洗涤，有机相40℃浓缩，正庚烷置换至小体积，降温-20℃冷冻1-2小时，过滤，烘干得黄色固体55.8g，摩尔收率约68％。
实施例12：
Figure PCTCN2022113559-appb-000062
在1L的三口烧瓶里加840mL的无水乙醇，低温通入干燥的氯化氢气体，制备得无水乙醇/氯化氢溶液(水分要小于0.2％，含量约35％)；在2L的三口烧瓶里，加57g(0.146mol)化合物C 2，0.57g TBHQ和700mL二氯甲烷，溶清，氮气保护，0℃～10℃下，滴加840mL自制的无水乙醇/氯化氢溶液，控温反应1小时左右，TLC检测原料剩余小于3％，加纯净水淬灭反应，分液，有机相用碳酸氢钠溶液洗至PH＝7-8，有机相50℃以下浓缩，乙醇置换，保留约500mL乙醇，边搅拌边梯℃降温，黄色固体析出，降温-20℃冷冻1-2小时，过滤，粗品再用正庚烷打浆，冷析过滤，烘干得固体38g，摩尔收率约66.7％。
经检测： 1H NMR(400MHz,CDCl 3)δ6.30–6.04(m,2H),5.66(s,1H),3.50(dd,J＝9.8,2.5Hz,1H),3.36(dd,J＝9.8,5.7Hz,1H),2.64–2.48(m,1H),2.47–2.34(m,2H),2.32–2.21(m,1H),1.95–1.55(m,9H),1.47–1.17(m,7H),1.09(d,J＝6.5Hz,3H),0.77(s,3H).
实施例13：
Figure PCTCN2022113559-appb-000063
在250mL的三口烧瓶里加90mL甲醇和40mL二氯甲烷以及30g(76.6mmol)化合物D 2，0℃～10℃下滴加61mL氢氧化钠水溶液(10％，153.2mmol)，控温反应1小时左右，TLC检测原料反应完，加10mL醋酸淬灭反应，有机相50℃以下浓缩除去二氯甲烷，甲醇水出料，冷析过滤，烘干得固体22.7g，摩尔收率约90％。
经检测： 1H NMR(400MHz,CDCl 3)δ6.17(dt,J＝23.1,7.5Hz,2H),5.65(s,1H),3.64(dd,J＝10.5,3.2Hz,1H),3.39(dd,J＝10.5,6.6Hz,1H),2.69–2.46(m,1H),2.46–2.32(m,2H),2.25(ddd,J＝13.1,5.2,1.9Hz,1H),1.82(dddd,J＝16.7,14.9,13.7,9.7Hz,6H),1.69–1.50(m,4H),1.38(ddd,J＝17.9,12.4,4.6Hz,2H),1.28–1.15(m,5H),1.05(d,J＝6.6Hz,3H),0.76(s,3H)。
13C NMR(101MHz,CDCl 3)δ199.62(s),163.54(s),141.31(s),126.72(s),123.56(s),67.78(s),52.27(s),49.36(s),42.72(s),39.73(s),38.93–38.34(m),37.17(s),35.55(s),33.93(s),27.32(s),25.05(s),22.15(s),20.57(s),16.65(s),10.70(s)。
质谱：C 22H 32O 2，329.0。
实施例14：
Figure PCTCN2022113559-appb-000064
在500mL的三口烧瓶里加200mL二氯甲烷50g(0.10mol)化合物B和13.6g(0.20mol)咪唑，-5℃～5℃下滴加16.3g三甲基氯硅烷(0.15mol)，控温反应1小时左右，TLC检测原料反应完，加10mL水淬灭反应，有机相依次用水，稀盐酸水溶液，碳酸氢钠溶液洗涤，有机相50℃以下浓缩除去二氯甲烷，乙醇置换出料，冷析过滤，烘干得固体51.7g，摩尔收率约90％。
B 4采用类似实施例7的方法酯化后，脱保护得到B 2。

Claims (20)

  1. 一种中间体化合物，其特征在于，具有如下结构式：
    Figure PCTCN2022113559-appb-100001
    其中，R 1选自卤素或OR 3；
    R 2选自＝O、-OR 6或被保护的羰基；
    R 3选自H、
    Figure PCTCN2022113559-appb-100002
    其中虚线表示与O连接位置；
    R 4选自取代或未被取代的C1～C6直链或支链烷基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的苯基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的萘基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的吡啶基；
    R 5选自取代或未被取代的C1～C6直链或支链烷基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的苯基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的萘基，或者被C1～C6烷基、羟基或卤原子取代或未被取代的吡啶基；
    R 6选自H或羟基保护基团；
    在结构式I中，
    Figure PCTCN2022113559-appb-100003
    表示化学键为单键或双键，且当某一
    Figure PCTCN2022113559-appb-100004
    为双键时，与其相邻的
    Figure PCTCN2022113559-appb-100005
    为单键。
  2. 根据权利要求1所述的中间体化合物，其特征在于，R 4选自C1～C3直链或支链烷基，或者被C1～C3烷基取代或未被取代的苯基；和/或，
    R 5选自C1～C3直链或支链烷基，或者被C1～C3烷基取代或未被取代的苯基，或者被C1～C3烷基取代或未被取代的萘基，或者被C1～C3烷基取代或未被取代的吡啶基；和/或，
    所述羟基保护基团选自-C(＝O)R 7、C1～C8烷基或C1～C8硅烷基；和/或，
    R 7选自取代或未被取代的C1～C6直链或支链烷基；和/或，
    所述被保护的羰基选自缩酮；和/或，
    所述卤素或所述卤原子选自Cl、Br或I。
  3. 根据权利要求1所述的中间体化合物，其特征在于，R 3选自H或如下基团：
    Figure PCTCN2022113559-appb-100006
  4. 根据权利要求1至3任一项所述的中间体化合物，其特征在于，所述中间体化合物包括如下结构式：
    Figure PCTCN2022113559-appb-100007
    其中，R 2选自-OR 6或被保护的羰基，R 6’选自C1～C8烷基。
  5. 根据权利要求4所述的中间体化合物，其特征在于，所述中间体化合物包括如下结构式：
    Figure PCTCN2022113559-appb-100008
    Figure PCTCN2022113559-appb-100009
  6. 一种制备中间体化合物的方法，其特征在于，所述中间体化合物为权利要求1至5任一项所述的中间体化合物；所述方法包括：将结构式IIa化合物进行光化学转化使C-10位的甲基由β构型翻转为α构型得到结构式Ⅱ化合物的步骤；
    Figure PCTCN2022113559-appb-100010
  7. 根据权利要求6所述的制备中间体化合物的方法，其特征在于，所述方法包括：
    将结构式IIa化合物在紫外线高压汞灯的照射下进行光化学转化，使C-10位的甲基由β构型翻转为α构型；
    所述紫外线高压汞灯发射的紫外光经滤光液滤光后再照射反应体系进行光化学转化，所述滤光液含有Cu 2+；
    所述光化学转化分两个阶段进行，第一阶段的滤光液中Cu 2+的浓度小于或等于第二阶段的滤光液中Cu 2+的浓度。
  8. 根据权利要求7所述的制备中间体化合物的方法，其特征在于，其中所述第一阶段的滤光液中Cu 2+的浓度为0.1～0.5wt％，第二阶段的滤光液中Cu 2+的浓度为0.5～1.2wt％。
  9. 根据权利要求6所述的制备中间体化合物的方法，其特征在于，结构式IIa化合物中的R 2选自-OR 6；所述结构式Ⅱ化合物为结构式Ⅱb化合物；
    Figure PCTCN2022113559-appb-100011
  10. 根据权利要求9所述的制备中间体化合物的方法，其特征在于，所述方法还包括：将所述结构式Ⅱb化合物经C-3位羟基的氧化和C-5,6位双键移位得到结构式Ⅲ化合物的步骤；
    Figure PCTCN2022113559-appb-100012
  11. 根据权利要求10所述的制备中间体化合物的方法，其特征在于，将所述结构式Ⅱb化合物转化成所述结构式Ⅲ化合物的方法包括：
    采用沃氏氧化反应使C-3位羟基氧化为酮基且5,6双键移位到4,5位；或者
    采用氧化试剂将所述结构式Ⅱb化合物进行氧化处理，使所述结构式Ⅱb化合物中的C-3位羟基氧化为酮基，所述氧化试剂的结构式如下：
    Figure PCTCN2022113559-appb-100013
    然后进行碱性处理，使5,6双键移位到4,5位，得到结构式Ⅲ化合物。
  12. 根据权利要求11所述的制备中间体化合物的方法，其特征在于，所述氧化处理时还添加碳酸氢盐和水，所述碳酸氢盐、所述水及所述结构式Ⅱb化合物的摩尔比为(1.5～2.5):(0.8～1.2):1。
  13. 根据权利要求11所述的制备中间体化合物的方法，其特征在于，采用有机胺进行所述碱性处理。
  14. 根据权利要求10至13任一项所述的制备中间体化合物的方法，其特征在于，所述方法还包括：将所述结构式Ⅲ化合物双键移位得到结构式Ⅳ化合物的步骤；
    Figure PCTCN2022113559-appb-100014
  15. 根据权利要求14所述的制备中间体化合物的方法，其特征在于，将结构式Ⅲ化合物转化成结构式Ⅳ化合物的方法包括：在质子酸条件下，使所述结构式Ⅲ化合物的7,8位双键移位到6,7位，得到结构式Ⅳ化合物；所述质子酸采用卤化氢的醇溶液的形式添加，所述醇包括乙醇、异丙醇、丁醇或乙二醇中的至少一种。
  16. 根据权利要求15所述的制备中间体化合物的方法，其特征在于，将结构式Ⅲ化合物转化成结构式Ⅳ化合物的方法包括：将卤化氢的醇溶液加入含结构式Ⅲ化合物的反应溶剂中，所述卤化氢的醇溶液的添加量为10v～15v，所述卤化氢的醇溶液中水的质量百分比小于0.2％，所述卤化氢的重量占所述卤化氢的醇溶液总重量的25wt％～40wt％。
  17. 根据权利要求16所述的制备中间体化合物的方法，其特征在于，还向所述含结构式Ⅲ化合物的反应溶剂中添加抗氧化剂，所述抗氧化剂的质量为所述结构式Ⅲ化合物质量的0.8％～1.2％。
  18. 根据权利要求14所述的制备中间体化合物的方法，其特征在于，所述中间体化合物为化合物E；所述方法还包括：将结构式Ⅳ化合物经水解得到化合物E的步骤；
    Figure PCTCN2022113559-appb-100015
    结构式Ⅳ化合物中的R 1选自卤素或OR 3，R 3选自
    Figure PCTCN2022113559-appb-100016
  19. 一种中间体化合物的应用，其特征在于，包括在权利要求1至5任一项所述的中间体化合物的C-20位构造酮基以制备地屈孕酮。
  20. 根据权利要求19所述的应用，其特征在于，所述中间体化合物具有如下结构式或将所述中间体化合物转化为如下结构的中间体化合物：
    Figure PCTCN2022113559-appb-100017
    所述构造酮基的方法包括：
    将所述中间体化合物的21位羟基氧化为醛基，得到化合物F；
    将所述化合物F的醛基进行烯胺化反应，然后将C-20位氧化为羰基，获得地屈孕酮；
    Figure PCTCN2022113559-appb-100018
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