CN114957372B - Preparation method of 10 alpha-methyl-5, 7-diene steroid compound and dydrogesterone - Google Patents

Preparation method of 10 alpha-methyl-5, 7-diene steroid compound and dydrogesterone Download PDF

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CN114957372B
CN114957372B CN202111516146.8A CN202111516146A CN114957372B CN 114957372 B CN114957372 B CN 114957372B CN 202111516146 A CN202111516146 A CN 202111516146A CN 114957372 B CN114957372 B CN 114957372B
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methyl
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compound
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diene
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CN114957372A (en
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唐杰
甘杰
李凯
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Hunan Keyixin Biomedical Co ltd
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Hunan Jiukang Medical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The application discloses a preparation method of 10 alpha-methyl-5, 7-diene steroid compound and dydrogesterone. The preparation method of the 10 alpha-methyl-5, 7-diene steroid compound comprises the following steps: the 5, 7-diene steroid compound with the C-10 position being beta-methyl is subjected to photochemical conversion under the irradiation of a light source emitting broad-spectrum ultraviolet light, so that the C-10 methyl is turned from beta configuration to alpha configuration, and the 10 alpha-methyl-5, 7-diene steroid compound is obtained. The preparation method of dydrogesterone comprises the following steps: the 5, 7-diene steroid compound with beta-methyl at C-10 position as raw material or intermediate is converted into 10 alpha-methyl-5, 7-diene-steroid compound, and then dydrogesterone is prepared through chemical synthesis and/or biological fermentation. The method can conveniently synthesize dydrogesterone only by constructing AB ring double bonds and modifying side chains, has high total yield and short route, and solves the problems of low conversion rate, more byproducts, high safety risk and difficult industrialized production in the light conversion process in the prior art.

Description

Preparation method of 10 alpha-methyl-5, 7-diene steroid compound and dydrogesterone
Technical Field
The application relates to the technical field of medicine synthesis, in particular to a preparation method of a 10 alpha-methyl-5, 7-diene steroid compound and dydrogesterone.
Background
Dydrogesterone (Dydrogesterone), also known as Dydrogesterone, chemical name 9β,10α -pregna-4, 6-diene-3, 20-dione, CAS number: 152-62-5, the chemical formula is as follows:
dydrogesterone takes pregnane as a mother nucleus, the pregnane has a framework structure with four rings of ABCD (from left to right, the four rings are sequentially defined as A, B, C and D), and the carbon numbers (1-21) are as follows, and are marked as C-1 position, C-2 position and the like in the following.
Dydrogesterone is widely used for preventing miscarriage and abortion, and is also widely used for treating various diseases caused by endogenous progesterone deficiency, such as: dysmenorrhoea, endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progestogen deficiency, infertility caused by luteal insufficiency, etc.
Some synthetic routes are currently based on ergosterol, followed by photochemical synthesis of a 10 alpha configuration intermediate, followed by wobbe oxidation, double bond translocation, ozone oxidation, enamine, and finally oxidation to give dydrogesterone. However, the light conversion process has low conversion rate and difficult separation, ozone oxidation is needed in the process, safety risks exist, and byproducts are more.
The ultraviolet lamp source generally adopted in the light conversion process is an LED ultraviolet lamp. The LED ultraviolet lamp is single wavelength, the power is low (the power of a single lamp bead is about 3-5 mW), the wavelength selection range is limited (only 254nm, 265nm, 275nm and 310nm are available in the market ultraviolet light source), a large number of LED lamp beads are required to be integrated in large-scale photochemical reaction, the light source is complex to manufacture, and the cost is high.
Disclosure of Invention
Aiming at the problems, the application provides a preparation method of 10 alpha-methyl-5, 7-diene steroid compound and dydrogesterone, which solves the defects of low conversion rate, more byproducts, high safety risk and difficult industrialized production in the light conversion process in the prior art.
The application aims at realizing the following scheme:
the application provides a preparation method of a 10 alpha-methyl-5, 7-diene-steroid compound, which comprises the following steps:
carrying out photochemical conversion on a 5, 7-diene steroid compound with beta-methyl at the C-10 position under the irradiation of a light source emitting broad-spectrum ultraviolet light, so that the methyl at the C-10 position is turned from beta configuration to alpha configuration;
ultraviolet light emitted by the light source is filtered by a filter liquid and then irradiates the reaction system to carry out photochemical conversion, wherein the filter liquid contains Cu 2+ ；
The photochemical conversion is carried out in two stages, cu in the filter liquid in the first stage 2+ The concentration of Cu in the filtering liquid is less than or equal to that in the second stage 2+ Is a concentration of (3).
In an embodiment of the application, the broad spectrum ultraviolet light comprises light of some or all wavelengths in the range of 200 to 400 nm.
In an embodiment of the application, wherein the light source is an ultraviolet high pressure mercury lamp.
In an embodiment of the present application, the first stage filter filters out part or all of the light having a wavelength of less than 270nm, and the second stage filter filters out part or all of the light having a wavelength of less than 300 nm.
In an embodiment of the present application, wherein the first stage of the filter comprises Cu 2+ The concentration of Cu in the filtering liquid in the second stage is 0.1-0.5 wt% 2+ The concentration of (2) is 0.5-1.2 wt%.
In an embodiment of the present application, wherein the first stage of the filter comprises Cu 2+ The concentration of Cu in the second stage filter liquid is 0.3-0.5 wt%, such as 0.3wt%, 0.4wt%, 0.5wt%, etc 2+ The concentration of (C) is 0.7-1 wt%, such as 0.7wt%, 0.8wt%, 0.9wt%, 1wt%, etc.
The application provides a preparation method of dydrogesterone, which comprises the following steps: with the method according to any of the above embodiments, a 5, 7-diene steroid having a beta-methyl group in the C-10 position as starting material or intermediate is converted into a 10 alpha-methyl-5, 7-diene-steroid, which is then prepared by chemical synthesis and/or biological fermentation.
In an embodiment of the present application, wherein the 5, 7-diene steroid compound in which the C-10 position is a beta-methyl group is
The application provides a preparation method of dydrogesterone, which comprises the following steps:
(1) Performing photochemical conversion on the compound shown in the formula A to enable methyl at the C-10 position to be turned from beta configuration to alpha configuration, so as to obtain a compound shown in the formula B;
(2) Oxidizing a C-3 hydroxyl group in the compound shown in the formula B into a ketone group, and shifting a C-5,6 double bond to obtain a compound shown in the formula C;
(3) Under the condition of protonic acid, the double bonds at the 7,8 positions in the compound shown in the formula C are shifted to the 6,7 positions through reaction, so that a compound shown in the formula D is obtained;
(4) Hydrolyzing the compound shown in the formula D to obtain a compound shown in the formula E;
(5) Oxidizing the hydroxyl group at the 21-position of the compound shown in the formula E into aldehyde group to obtain a compound shown in the formula F;
(6) Subjecting aldehyde groups in the compound shown in the formula F to enamine reaction to obtain a compound shown in the formula G;
(7) Oxidizing the C-20 position of the compound shown in the formula G into carbonyl to obtain dydrogesterone shown in the formula H;
in the present application, the protonic acid is added in the form of an alcoholic solution of hydrogen halide; preferably, the alcohol includes at least one of ethanol, isopropanol, butanol or ethylene glycol, and the added amount of the alcohol solution of hydrogen halide is 10 v-15 v (i.e., the mass ratio of the volume of the alcohol solution of hydrogen halide to the compound represented by formula C is 10 mL-15 mL:1 g), such as 10v, 11v, 12v, 13v, 14v or 15v, and the like, and the weight of hydrogen halide is 25wt% to 40wt%, such as 25wt%, 28wt%, 30wt%, 32wt%, 35wt%, 37wt% or 40wt%, and the like, based on the total weight of the alcohol solution of hydrogen halide.
In the present application, a larger power (20 kw, which is a common power for industry) can be achieved by using an ultraviolet high-pressure mercury lamp, so that the cost can be reduced by using an ultraviolet high-pressure mercury lamp.
However, the spectrum of the ultraviolet high-pressure mercury lamp is wide (the ultraviolet region has a broad spectrum distribution between 250nm and 370 nm). Mechanistically, the wavelengths required for the two-step photochemical reactions of the present application are respectively: the first stage, the required wavelength range is 270-300nm; in the second stage, the desired wavelength range is 300-350nm. If the ultraviolet high-pressure mercury lamp is directly used for irradiation during the first-stage ring opening, the by-product configuration is high due to the unwanted wavelength (for example, light with a wavelength of about 254nm or the like). It is necessary to filter the ultraviolet high-pressure mercury lamp.
The device containing the filter liquid is arranged between the reaction system and the light source, so that light rays firstly penetrate through the filter liquid, filter the light rays and irradiate the light rays into the reaction system.
Regarding the filter liquid, it contains Cu 2+ May be copper salt such as copper sulfate, copper chloride, copper acetate, etc., or may contain other substances which do not affect Cu 2+ Other substances or impurities with a filtering effect which are colorless in water. The filter liquid can be aqueous solution or other solution without affecting Cu 2+ Filtering and dissolving Cu 2+ Is a colorless solvent.
The concentration of Cu in the filter liquid is 0.1-0.5 wt%, preferably 0.3-0.5 wt% 2+ Most of the aqueous solutions of (a) have a wavelength of more than 270nm (light having a wavelength of 270nm or less is substantially filtered), and a concentration of Cu of 0.5 to 1.2wt%, preferably 0.7 to 1wt% 2+ Most of the filtered aqueous solution has a wavelength greater than 300nm and reaches the wavelength range required by photochemical reaction. The ratio of the intensity of ultraviolet rays with different wavelengths is adjusted by the filter liquid, so that the ratio of the favorable wavelength is higher.
The first stage of ring opening uses low concentration filtering liquid to facilitate ring opening, facilitate conversion to required configuration, reduce damage to raw materials, and the closed loop requires higher concentration filtering liquid to enhance low wavelength filtering, so that reaction balance shifts to closed loop. Higher yields can be obtained.
The technical scheme of the application provides a novel method for preparing dydrogesterone, which is urgently needed in the field, the intermediate compound of the technical scheme of the application can conveniently synthesize dydrogesterone only by carrying out AB ring double bond construction and side chain transformation, has high total yield and short route, and is a novel process for industrially synthesizing dydrogesterone, so that the problems of low conversion rate, more byproducts, high safety risk and difficult industrial production in the light conversion process in the prior art are solved.
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. If there is a conflict, the present disclosure provides definitions. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof. All patents, published patent applications, and publications cited herein are incorporated by reference.
The term "one or more" or similar expression "at least one" may denote, for example, 1,2, 3, 4,5, 6,7, 8, 9, 10 or more.
The expression m-n as used herein refers to the range of m to n and the sub-ranges consisting of the individual point values therein as well as the individual point values. For example, the expression "C1-C6" or "C1-6" "encompasses a range of 1-6 carbon atoms and is understood to also encompass any subrange therein as well as every point value, e.g., C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc.
The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached to the remainder of the molecule by a single bond. "alkyl" may have 1-6 carbon atoms, i.e. "C1-8 alkyl", such as C1-4 alkyl, C1-3 alkyl, C1-2 alkyl, C3 alkyl, C4 alkyl, C1-6 alkyl, C3-6 alkyl. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or isomers thereof.
The compounds of the application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the application. Purification and isolation of such materials can be accomplished by standard techniques known in the art.
The following detailed description is intended to illustrate non-limiting embodiments so that others skilled in the art may more fully understand the application's solution, its principles and its practical application, to thereby modify and practice the application in many forms best suited to the requirements of a particular use.
Definition of the definition
The "5, 7-diene steroid compound having a beta-methyl group at the C-10 position" of the present application refers to a compound having a steroid skeleton in which the C-3 and C-17 positions or other positions may be substituted with substituents.
The methyl at C-10 position is turned from beta configuration to alpha configuration and then has the steroid skeleton as follows.
Intermediates or starting materials for the synthesis of dydrogesterone are numerous in the art, such as, for example, ergosterol:
they all require photochemical conversion, the mechanism of which is about the same, so the process of the application can be applied to such compounds.
The term "broad spectrum ultraviolet light" as used herein refers to ultraviolet light comprising a broad range of wavelengths, as opposed to a single wavelength or single spectral peak of an LED ultraviolet lamp. For example, light having a wavelength in a range of 200 to 400nm, and ultraviolet light having a plurality of spectral peaks in a range of 253 to 367 nm. Under the above definition, an ultraviolet high-pressure mercury lamp is a light source capable of emitting ultraviolet light in a broad spectrum. In order to solve the problems, the broad-spectrum ultraviolet light includes at least a part or all of light having a wavelength of less than 270nm (for example, light having a wavelength of about 254 nm), a part or all of light having a wavelength of 270 to 300nm, and a part or all of light having a wavelength of 300 to 350nm. The light source capable of emitting broad-spectrum ultraviolet light may also emit part of light in other wavelength bands, such as visible light.
The "two stages of photochemical conversion" of the present application generally includes two stages (the general reaction process of the steroidal ring skeleton is as follows): the first stage is open-loop under ultraviolet light irradiation of a certain wavelength range, and the second stage is closed-loop under ultraviolet light irradiation of another certain wavelength range. In terms of macroscopic operation, the first stage is to irradiate with ultraviolet light of a certain wavelength range for a period of time, and the second stage is to irradiate with ultraviolet light of another certain wavelength range for another period of time, the irradiation time being adjusted according to the specific reaction degree.
(step of photochemical conversion)
Embodiments of the present application provide a method of preparing a 10α -methyl-5, 7-diene-steroid. The method comprises the steps of carrying out photochemical reaction on a 5, 7-diene steroid compound with beta-methyl at the C-10 position under the irradiation of a light source emitting broad-spectrum ultraviolet lightChemically converting to turn the methyl group at the C-10 position from beta configuration to alpha configuration; ultraviolet light emitted by the light source is subjected to optical filtering by a filtering liquid and then irradiates a reaction system to perform photochemical conversion, wherein the filtering liquid contains Cu 2+ The method comprises the steps of carrying out a first treatment on the surface of the The photochemical conversion is carried out in two stages, cu in the filter liquid in the first stage 2+ The concentration of Cu in the filtering liquid is less than or equal to that in the second stage 2+ Is a concentration of (3).
In a specific embodiment of the application, the step of photochemically transforming is:
when the side chain is OTs, the OTs group has certain absorption in the deep ultraviolet region, the photochemical conversion reaction in the step has better conversion rate and selectivity (the selectivity is more than 40 percent), better yield (the yield can be up to 24.5 percent), and meanwhile, the target compound after being turned into the alpha configuration is easier to separate from the product, and the post-treatment is simple and convenient.
The reaction solvent for the photochemical conversion reaction is at least one of methanol, ethanol, n-hexane, petroleum ether, n-heptane, ethyl acetate, tetrahydrofuran, ethylene glycol and isopropanol, and the reaction temperature is-10 ℃ to 50 ℃.
(preparation method of dydrogesterone)
The application provides a preparation method of dydrogesterone, which comprises the following steps:
(1) Performing photochemical conversion on the compound shown in the formula A to enable methyl at the C-10 position to be turned from beta configuration to alpha configuration, so as to obtain a compound shown in the formula B;
(2) Oxidizing a C-3 hydroxyl group in the compound shown in the formula B into a ketone group, and shifting a C-5,6 double bond to obtain a compound shown in the formula C;
(3) Under the condition of protonic acid, the double bonds at the 7,8 positions in the compound shown in the formula C are shifted to the 6,7 positions through reaction, so that a compound shown in the formula D is obtained;
(4) Hydrolyzing the compound shown in the formula D to obtain a compound shown in the formula E;
(5) Oxidizing the hydroxyl group at the 21-position of the compound shown in the formula E into aldehyde group to obtain a compound shown in the formula F;
(6) Subjecting aldehyde groups in the compound shown in the formula F to enamine reaction to obtain a compound shown in the formula G;
(7) Oxidizing the C-20 position of the compound shown in the formula G into carbonyl to obtain dydrogesterone shown in the formula H.
With respect to the above step (2), the applicant has pointed out by research that:
the structure of the compound B has specificity, such as the conjugated double bond of the B ring worsens the structure, the methyl of the C-10 alpha configuration changes the solubility of the compound, the difference of the C-21 groups and the like, so that the oxidation reaction has higher requirements on an oxidation system. If some common oxidation systems are adopted, the target product is not obtained or the yield is low. For example, the compound of formula III can be obtained by Style oxidation, but the yield is very low, the impurities are difficult to control and the conditions are severe.
Wolff oxidation can be used to oxidize the hydroxyl group at the C-3 position to a ketone group and shift the 5,6 double bond to the 4,5 position. The Wolff oxidation (reagent such as aluminum isopropoxide/cyclohexanone) is a high temperature reaction and there are high boiling point materials which must be removed at high temperature, and although the Wolff oxidation can simultaneously carry out double bond shift, the compound C is unstable under high temperature or strong alkaline condition, resulting in lower reaction yield (about 48 mol yield).
In some embodiments, a method of converting the compound B to the compound C may comprise: oxidizing the compound B to oxidize the hydroxyl group at the C-3 position in the compound B into a ketone group; then, an alkaline treatment is performed to shift the 5,6 double bond to the 4,5 position, thereby obtaining compound C.
The oxidizing agent used in the examples of the present application has the following structural formula (dessmartin reagent):
the oxidation reaction can be carried out at a low temperature (e.g., -5 ℃ to 25 ℃, or 5 ℃ to 10 ℃). The molar ratio of the oxidizing agent to the compound B1 is (1.2-1.8). In some embodiments, the addition of water and bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate) during the oxidation process may promote the reaction, increasing the conversion and yield, up to 92% conversion, and up to 70% molar yield. The mole ratio of the bicarbonate, water and the compound B is (1.5-2.5): (0.8-1.2): 1. Then, an organic base, preferably an amine such as triethylamine, pyridine, etc., is used to conduct alkaline treatment under mild conditions, so that a compound C with a higher yield can be obtained.
With respect to the above step (3), the applicant has pointed out by study:
in some embodiments, the method of converting structural formula C to compound D comprises: under the condition of protonic acid, the double bonds at the 7,8 positions of the compound C are shifted to the 6,7 positions, so that the compound D is obtained.
Because of the low conversion of hydrochloric acid, sulfuric acid, perchloric acid, glacial acetic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc., in some embodiments, the protonic acid used may be HCl, HBr, etc.
Because of the specificity of the chemical structure, the reaction step has more severe requirements on moisture content, acid concentration and acid amount if high conversion is to be obtained. In some embodiments, the method of converting compound C to compound D comprises: adding an alcohol solution of hydrogen halide to a reaction solvent containing a compound C, wherein the addition amount of the alcohol solution of hydrogen halide is 10 v-15 v, and the alcohol solution of hydrogen halide is added in a manner that 1g of the compound C is added with 10-15 mL of the alcohol solution of hydrogen halide. The mass percentage of water in the hydrogen halide alcoholic solution is less than 0.2%, and the weight of the hydrogen halide accounts for 25-40% of the total weight of the hydrogen halide alcoholic solution.
In the alcohol solution of hydrogen halide, alcohol may be ethanol, isopropanol, butanol, ethylene glycol, or the like. The ethanol conversion rate can reach 89%, and the methanol conversion rate is only about 55% under the same condition.
In some embodiments, this step may further add an antioxidant in an amount of 0.8% to 1.2% by mass (based on the mass of compound C) to inhibit peroxidized impurities to increase yield. Antioxidants include illustratively sodium ascorbate, TBHQ.
In addition, compound D has a low melting point, is difficult to obtain a solid, and is deteriorated to some extent to an oil under high concentration of acid, affecting the properties of the solid. In the embodiment of the application, in order to avoid the occurrence of the phenomenon, ethanol is adopted as a solvent during post-treatment, the temperature is reduced in a gradient way while stirring, so as to obtain a solid, and the crude product is pulped by n-heptane for degreasing, so that higher yield can be obtained.
With respect to the above step (4), the applicant has pointed out by study:
in some embodiments, the OTs in compound D is first converted to an ester group using DMF and KOAc; and then hydrolyzing under alkaline conditions, wherein the alkaline substances comprise at least one of NaOH, KOH, potassium acetate, sodium acetate and sodium benzoate.
With respect to the above step (5), the applicant has pointed out by research that:
oxidizing the hydroxyl group at the 21-position of the compound E to an aldehyde group to obtain a compound F. The oxidation system may include NaClO, naBr, and 2, 6-tetramethylpiperidine-1-oxyl, and the pH of the oxidation system is controlled to be in the range of 8-9.
With respect to the above step (6), the applicant has pointed out by study:
subjecting the aldehyde group of compound F to enamine reaction to obtain compound G, for example subjecting compound F to enamine reaction with 1- (1-piperidinyl) cyclohexene to obtain compound G.
With respect to the above step (7), the applicant has pointed out by study:
in some embodiments, the compound G may be present in Cu + Air oxidation is carried out under catalysis to obtain dydrogesterone.
The synthetic route for the following examples is as follows:
examples
Example 1: A-B
40g of compound A and 500mL of tetrahydrofuran are added into an photochemical reaction bottle, the ring is firstly opened under the irradiation of an ultraviolet high-pressure mercury lamp (500W) at the temperature of 5-10 ℃, the ring is filtered by a filter liquid (1 wt% copper chloride aqueous solution) when the ring is opened, the light is irradiated for 8 hours, and the HPLC monitoring of the raw materials is carried out: product=70: about 20, filtering with a filter liquid (copper chloride concentration is 2 wt%) and continuing to irradiate for 8 hours, monitoring by HPLC, wherein the raw materials are as follows: product=55: stopping about 35; concentrating the organic phase, replacing methanol to small volume (viscous state), cooling to-20deg.C, freezing for 4 hr, filtering, and oven drying to obtain white solid 16g as main raw material; concentrating the mother liquor, replacing acetonitrile to a small volume (viscous state), discharging, cooling to-20 ℃ for 4 hours, filtering, and drying to obtain 9.8g of compound B as a white solid, wherein the primary yield is about 24.5%.
The comparative test in Table 1 was carried out in accordance with the above reaction procedure, and the other conditions were the same as in this example.
TABLE 1 Experimental conditions and results
Through the detection, the detection results show that, 1 H 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)。
example 2: B-C
105g (0.28 mol) of dessmartin reagent (DMP) is added into a 1L three-neck flask, 3.78g (0.21 mol) of water, 35g (0.41 mol) of sodium bicarbonate and 500mL of Dichloromethane (DCM) are added into the three-neck flask, the three-neck flask is stirred for a moment, 100g (0.21 mol) of compound B is added into the three-neck flask at 5-10 ℃, the three-neck flask is kept warm and stirred for half an hour, TLC shows that the raw materials react to generate the compound B1, the three-neck flask is frozen at the temperature of minus 20 ℃ for 1-2 hours, the three-neck flask is filtered, a filter cake is leached by a proper amount of cold dichloromethane until the filter cake is free of products, and an organic phase is washed by sodium sulfite solution, sodium bicarbonate solution and saline.
100mL of triethylamine is added to the organic phase, the mixture is stirred for 1 to 2 hours at normal temperature, TLC shows that the compound B1 is converted into a compound C, the organic phase is washed by saline water, 1M of dilute hydrochloric acid and saline water, the organic phase is concentrated at 40 ℃, the n-heptane is replaced to a small volume, the temperature is reduced to minus 20 ℃ and the mixture is frozen for 1 to 2 hours, the mixture is filtered and dried to obtain yellow solid 70g, and the molar yield is about 70%.
1HNMR was detected as: 1 H 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)。
the comparative test of Table 2 below was carried out in accordance with the above reaction procedure, except that the conditions were the same as in this example.
TABLE 2 Experimental conditions and results
Sequence number Conditions (conditions) Conversion% Yield%
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, chloroform 85 62
5 1.3eq DMP,DCM,2eq sodium bicarbonate 90 68
This embodiment 1.3eq DMP,DCM,2eq sodium bicarbonate 1eq water 92 70
Note that: eq represents molar equivalent, and is the same as below.
As shown in table 2, the dosage of Dai Sima is about 1.3eq, and the dosage conversion rate is not obviously improved, but the difficulty of post-treatment is increased to influence the yield; the solvent is changed into chloroform, and the yield is not improved; sodium bicarbonate is added to promote the reaction, increase the conversion and yield, and also to promote the reaction, increase the conversion and yield and rate, possibly by pre-forming a more reactive intermediate oxidation state of the DMP.
Example 3: C-D
840mL of absolute ethyl alcohol is added into a 1L three-neck flask, and dry hydrogen chloride gas is introduced at low temperature to prepare absolute ethyl alcohol/hydrogen chloride solution (the water content is less than 0.2 percent and the content is about 35 percent); in a 2L three-neck flask, 70g (0.145 mol) of compound C, 700mL of dichloromethane and 0.7g of tert-butylhydroquinone (TBHQ) are added, dissolved, protected by nitrogen, at the temperature of 0-10 ℃, 840mL of self-made absolute ethyl alcohol/hydrogen chloride solution is dropwise added, the temperature is controlled to react for about 1 hour, TLC detection raw materials remain less than 3%, pure water quenching reaction is added, liquid separation is carried out, an organic phase is washed to PH=7-8 by sodium bicarbonate solution, the organic phase is concentrated below 50 ℃, ethanol replacement is carried out, about 500mL of ethanol is reserved, the temperature is reduced while stirring, yellow solid is separated out, the temperature is reduced to-20 ℃ and is frozen for 1-2 hours, filtration is carried out, and the crude product is pulped by n-heptane, cold analysis filtration and drying to obtain 50g of off-white solid, and the molar yield is about 70%.
And (3) detecting: 1 H 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)。
13 C 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)。
mass spectrometry: c (C) 29 H 38 O 4 S，482.9。
The comparative test in Table 3 was carried out in accordance with the above reaction procedure, and the other conditions were the same as in this example.
TABLE 3 Experimental conditions and results
Note that: v represents the volume mL of solvent required per g of Compound C, e.g., 12v HCl (35%)/absolute represents 1g of Compound C using 12mL HCl (35%)/absolute.
As can be seen from Table 3, the reaction has high requirement on moisture, low conversion rate of concentrated hydrochloric acid or 95% ethanol, and can greatly improve the conversion rate by adopting a dry hydrogen chloride gas/absolute ethanol system reaction. The reaction has the requirements on the concentration of acid, the acid content is low (20%), the conversion rate is relatively low, and the acid content can reach a good effect at 30-38%. The reaction has the requirement on the acid amount, the acid amount is proper, the conversion rate is low when the reaction is too low, the degradation of the product can be caused when the reaction is too high, the oil content of the post-treatment solid is heavy, the solid is difficult to separate out, and the yield is reduced. In addition, the reaction is related to the strength of the acid and the conversion of concentrated sulfuric acid, trifluoroacetic acid and trifluoromethanesulfonic acid is also different. Interestingly, anhydrous methanol was used as a solution, the conversion was also lower, tetrahydrofuran and isopropanol were used as solvents, and the conversion was also lower than that of absolute ethanol. The antioxidant is added in the reaction, so that the peroxidized impurities can be inhibited, and the yield is improved.
Example 4: D.fwdarw.D1
In a 500mL three-necked flask, 50g (0.10 mol) of compound D and 200mL of DMF were dissolved, 50g (0.51 mol) of potassium acetate was added for reaction at 100℃for 2 hours, TLC was used to detect complete reaction of the starting materials, the materials were slowly poured into 1L of water, solids were precipitated, stirred for 1 hour, filtered and dried to give 36g of yellow solid with a molar yield of about 95%.
And (3) detecting: 1 H 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).
13 C 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).
mass spectrometry: c (C) 24 H 34 O 3 ，371.0。
Example 5: d1→E
36g (0.10 mol) of compound D1 and 180mL of methanol are added into a 250mL three-neck flask, the temperature is reduced by 0 to 5 ℃ under the protection of nitrogen, 7.2g (0.18 mol) of sodium hydroxide solid is added, the temperature is controlled to be less than 25 ℃, and the reaction is naturally carried out at room temperature after the addition is finished, and the reaction time is 0.5 to 1 hour. TLC monitored reaction was complete. Adding acetic acid for neutralization, slowly dripping 180mL of water, precipitating solid, stirring for 1 hour in an ice bath, filtering, and drying to obtain 30g of yellow solid with the molar yield of about 95%.
And (3) detecting: 1 H 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).
13 C 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).
mass spectrometry: c (C) 22 H 32 O 2 ，329.0。
Example 6: e, F, G, H
(1)E→F
To a 250mL three-necked flask, 30g (91.3 mmol) of Compound E and 150mL of methylene chloride were added, and 1.5g (9.6 mmol) of tempo and dissolved 1.08g of sodium bromide (10.5 mmol) and 30mL of 5% aqueous sodium bicarbonate solution were added under stirring, and the mixture was cooled to 0℃to 5℃under nitrogen protection, sodium hypochlorite was added dropwise, and the temperature was controlled to less than 15℃to react for 0.5 to 1 hour. TLC monitored reaction was complete. Quenching sodium thiosulfate solution, stirring for 10 min, separating, washing the organic phase once with saline, concentrating the organic phase below 50 ℃, replacing the organic phase with petroleum ether, and retaining petroleum ether of 3-5 v. Cooling to 0 ℃ for cold separation for 2 hours, filtering, leaching the filter cake with ice petroleum ether, and drying to obtain 28g of solid compound F, wherein the molar yield is about 92%.
1 H 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).
13 C 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).
Mass spectrometry: c (C) 22 H 30 O 2 ，327.0。
(2) F, G and H (dydrogesterone)
28G (85.8 mmol) of compound F and 42mL of anhydrous acetonitrile are added into a 100mL three-neck flask, 22G (122 mmol) of cyclohexene piperidine (the content is about 90%) is added under stirring, nitrogen protection is adopted, stirring solution is adopted at 40 ℃ and glacial acetic acid is added, the reaction is continued for 3-6 hours, the temperature is reduced to-20 ℃, cold separation is carried out for 2 hours, filtration is carried out, the filter cake is rinsed by glacial acetonitrile, the filter cake is pumped out, and the solid is dried in a vacuum drying oven at 35 ℃ to obtain 28G of compound G.
To a 100mL three-necked flask, 0.42g (4.2 mmol) of cuprous chloride and 42mL of DMF were added, the mixture was replaced with nitrogen three times, heated to 65℃and stirred for 1 hour under nitrogen protection, and cooled to room temperature for use. 28G (71.2 mmol) of compound G and 280mL of methylene dichloride are added into a 500mL three-neck flask, the temperature is reduced to 0-5 ℃, cuprous chloride solution is added, the dried air is introduced, the gas flow is kept at 1L/min, the reaction is carried out for 4-8 hours, the residual amount of the raw materials detected by TLC is less than 2%, and the reaction can be stopped when the prolonged time is unchanged. Quenching by adding 10% sulfuric acid solution, separating, adding 1% sulfuric acid solution to wash the organic phase, adding 0.43g acetic acid to the organic phase, stirring for 5 min, adding 6% sodium chlorite solution, stirring at room temperature for 30min, and almost eliminating TLC material. Quenching with sodium thiosulfate, separating, washing the organic phase with 0.5% sodium hydroxide and saline solution, concentrating the organic phase below 50deg.C, and discharging with water to obtain crude product. Adding 280mL of acetone into the crude product, heating to dissolve, concentrating to a small volume, cooling to-20 ℃, cold-separating for 2 hours, filtering, leaching the filter cake with glacial acetone, pumping, and drying in a 45 ℃ oven. 20g of solid compound F was obtained in a molar yield of about 74.6%.
And (3) detecting: 1 H 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).
13 C 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).
mass spectrometry: c (C) 21 H 28 O 2 ，313.0。
Finally, it should be noted that: the embodiments described above are only for illustrating the technical solution of the present application, and are not limiting; although the application has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced with equivalents; such modifications and substitutions do not depart from the spirit of the application.

Claims (9)

1. A process for the preparation of a 10 α -methyl-5, 7-diene-steroid compound, characterized by the steps of:
carrying out photochemical conversion on a 5, 7-diene steroid compound with beta-methyl at the C-10 position under the irradiation of a light source emitting broad-spectrum ultraviolet light, so that the methyl at the C-10 position is turned from beta configuration to alpha configuration;
ultraviolet light emitted by the light source is filtered by a filter liquid and then irradiates the reaction system to carry out photochemical conversion, wherein the filter liquid contains Cu 2+ ；
The photochemical conversion is carried out in two stages, the first stage is subjected to ring opening under the irradiation of ultraviolet light in a certain wavelength range, the second stage is subjected to ring closing under the irradiation of ultraviolet light in another certain wavelength range, the concentration of Cu < 2+ > in the filtering liquid in the first stage is 0.1-0.5 wt%, the concentration of Cu < 2+ > in the filtering liquid in the second stage is 0.5-1.2 wt%,
wherein the 5, 7-diene steroid compound with beta-methyl at C-10 position is a compound with the following steroid skeleton:
the methyl at C-10 position is inverted from beta configuration to alpha configuration and then has the following steroid skeleton:
wherein the first stage filter liquid filters out part or all of light with wavelength less than 270nm, and the second stage filter liquid filters out part or all of light with wavelength less than 300 nm.
2. The method of claim 1, wherein the broad-spectrum ultraviolet light comprises light of some or all wavelengths in the range of 200-400 nm.
3. The method of claim 1, wherein the light source is an ultraviolet high pressure mercury lamp.
4. The method according to claim 1, wherein the first-stage filter contains Cu 2+ The concentration of Cu in the filtering liquid in the second stage is 0.3 to 0.5 weight percent 2+ The concentration of (C) is 0.7-1 wt%.
5. A method for preparing dydrogesterone, which is characterized by comprising the following steps: the process according to any one of claims 1 to 4, wherein the 5, 7-diene steroid having a beta-methyl group in the C-10 position as starting material or intermediate is converted into a 10 alpha-methyl-5, 7-diene-steroid, and the dydrogesterone is prepared by chemical synthesis and/or biological fermentation.
6. The process according to claim 5, wherein the 5, 7-diene steroid compound having a beta-methyl group at C-10 position is
7. The preparation method according to claim 5, characterized in that it comprises the steps of:
(1) Performing photochemical conversion on the compound shown in the formula A to enable methyl at the C-10 position to be turned from beta configuration to alpha configuration, so as to obtain a compound shown in the formula B;
(2) Oxidizing a C-3 hydroxyl group in the compound shown in the formula B into a ketone group, and shifting a C-5,6 double bond to obtain a compound shown in the formula C;
(3) Under the condition of protonic acid, the double bonds at the 7,8 positions in the compound shown in the formula C are shifted to the 6,7 positions through reaction, so that a compound shown in the formula D is obtained;
(4) Hydrolyzing the compound shown in the formula D to obtain a compound shown in the formula E;
(5) Oxidizing the hydroxyl group at the 21-position of the compound shown in the formula E into aldehyde group to obtain a compound shown in the formula F;
(6) Subjecting aldehyde groups in the compound shown in the formula F to enamine reaction to obtain a compound shown in the formula G;
(7) Oxidizing the C-20 position of the compound shown in the formula G into carbonyl to obtain dydrogesterone shown in the formula H;
8. the method of claim 7, wherein the protic acid is added as an alcoholic solution of hydrogen halide.
9. The process according to claim 8, wherein the alcohol solution of hydrogen halide is added in an amount of 10v to 15v,
the weight of the hydrogen halide accounts for 25-40 wt% of the total weight of the hydrogen halide alcohol solution.
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