A kind of synthesis process of dydrogesterone

Abstract

The present invention discloses a synthesis process of dydrogesterone, comprising the following steps: (1) compound A is oxidized and then reacted in an alcohol solvent R 1 Under the action of OH, compound B is generated by acid catalysis; (2) compound B reacts with p-methylbenzenesulfonylmethyl isocyanide under alkaline conditions to generate compound C; (3) compound C and methyl magnesium bromide undergo a Grignard reaction, and then compound D is generated under the action of acid; (4) under acid conditions, the 7,8 double bond of compound D shifts to form a 4,6 conjugated double bond to obtain compound E, which is dydrogesterone. The synthesis process of the present invention has the characteristics of high yield, safety and environmental protection, mild reaction conditions, etc., and has good application prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a synthesis process of a steroid compound. Background Art

[0002] Dydrogesterone, also known as dehydrogenated progesterone, has a chemical name of 9β,10α-pregnane-4,6-diene-3,20-dione, CAS number: 152-62-5. The chemical formula of dydrogesterone is as follows:

[0003] .

[0004] Dydrogesterone is widely used for preserving pregnancy and preventing miscarriage, and is also widely used to treat various diseases caused by endogenous progesterone deficiency, such as dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progesterone deficiency, infertility caused by corpus luteum deficiency, etc.

[0005] There are currently two main synthetic routes for dydrogesterone: one route is to start from ergosterol, photochemically synthesize the 19a configuration intermediate, and then undergo oxidation, double bond transposition, ozone oxidation, enamination, and finally oxidation to obtain dydrogesterone. The specific reaction steps are as follows:

[0006] .

[0007] This reaction process requires ozone oxidation, which poses safety risks and produces many by-products.

[0008] Another route is to start from progesterone and obtain the 5,7 double bond bisketal through ketalization, oxidation, hydrazone, and dehydrazone, and then obtain regional progesterone through photochemical reaction, hydrolysis reaction, and transposition reaction. The specific reaction steps are as follows:

[0009] .

[0010] This reaction process uses oxygen oxidation and liquid ammonia, which poses a safety risk, and in the process of hydrolysis and transposition, a large amount of 17-racemized byproducts are inevitably produced.

[0011] In general, the synthesis route of dydrogesterone in the prior art has the defects of harsh reaction conditions and many by-products. Summary of the invention

[0012] The technical problem to be solved by the present invention is to overcome the deficiencies and defects mentioned in the above background technology and provide a synthesis process of dydrogesterone with mild reaction conditions and high conversion rate. In order to solve the above technical problems, the technical solution proposed by the present invention is:

[0013] A synthesis process of dydrogesterone comprises the following steps:

[0014] (1) Compound A is oxidized and then acid-catalyzed in the presence of an alcohol solvent R1OH to generate compound B.

[0015] (2) Compound B reacts with p-toluenesulfonylmethyl isocyanide under alkaline conditions to generate compound C.

[0016] (3) Compound C and methylmagnesium bromide undergo a Grignard reaction and then generate compound D under the action of an acid.

[0017] (4) Under acidic conditions, the 7,8 double bond of compound D shifts to form a 4,6 conjugated double bond, yielding compound E, which is dydrogesterone.

[0018] The reaction equation is as follows:

[0019] .

[0020] Wherein, R1 is selected from C 1-6 Alkyl (such as methyl, ethyl or isopropyl).

[0021] In the above synthesis process, preferably, the synthesis process of compound A comprises the following steps: compound 1 is subjected to a photochemical reaction to obtain compound 2; compound 2 is first mixed with PTS (p-toluenesulfonic acid) for reaction, and then sodium hydroxide is added for reflux reaction, and compound A is obtained by extraction.

[0022] The reaction equation is as follows:

[0023] .

[0024] In the above synthesis process, preferably, the photochemical reaction of compound 1 to obtain compound 2 includes the following steps: taking compound 1 and an antioxidant, dissolving them in ethyl acetate, pouring them into a photochemical reactor, turning on the internal cooling system, irradiating the reaction with a 260-270nm LED ultraviolet light, and then irradiating the reaction with a 310-330nm LED ultraviolet light. After the reaction is completed, concentrating the reaction liquid to an oily state, adding methanol, stirring to precipitate compound 1, concentrating the mother liquor to dryness, mixing the sample with silica gel, and passing through a chromatography column to obtain compound 2.

[0025] In the above synthesis process, preferably, compound 2 is first mixed with PTS for reaction, and then sodium hydroxide is added for reflux reaction, and the extraction to obtain compound A includes the following steps: adding compound 2 and PTS to an acetone / water solvent system, stirring the reaction at room temperature, adding sodium hydroxide for reflux and stirring the reaction after the reaction is completed, and after the reaction is completed, acetone is removed by vacuum rotary evaporation, and then extracted with dichloromethane for multiple times, the organic layers are combined, washed with water, and vacuum rotary evaporation to dryness to obtain compound A.

[0026] In the above synthesis process, preferably, the oxidation method of compound A is Wohlner oxidation, Swern oxidation or Dess-Martine oxidation, and the reagents used in the oxidation process are aluminum isopropoxide / cyclohexanone, dimethyl sulfoxide / oxalyl chloride or Dess-Martine periodic acid reagent (corresponding to the above oxidation method); the acid used in the acid-catalyzed generation of compound B is concentrated hydrochloric acid.

[0027] In the above synthesis process, preferably, the reaction temperature when compound B reacts with p-toluenesulfonylmethyl isocyanide under alkaline conditions to generate compound C is -40 to 50°C, the solvent used is one or more of tetrahydrofuran, ether, hexamethylphosphoramide, dimethyl ether or dimethyl sulfoxide, the base for adjusting the alkaline conditions is potassium tert-butoxide or sodium methoxide, and the molar ratio of compound B to p-toluenesulfonylmethyl isocyanide is 1: (2.2-3.0). More preferably, the reaction temperature is -20°C, and the solvent used is tetrahydrofuran.

[0028] In the above synthesis process, preferably, when compound C and methyl magnesium bromide undergo a Grignard reaction and then generate compound D under the action of an acid, the solvent of the reaction process is one or more of tetrahydrofuran, ether, hexamethylphosphoramide and dimethyl ether, the reaction temperature is controlled to be 0-5°C, and the molar ratio of compound C to methyl magnesium bromide is 1:(1.1-1.5).

[0029] In the above synthesis process, preferably, in the anhydrous protonic acid solution, the 7,8 double bond of compound D is displaced to form a 4,6 conjugated double bond to obtain compound E, the solvent of the anhydrous protonic acid solution is one or more of ethanol, isopropanol, methanol and tetrahydrofuran, the anhydrous protonic acid is dry HCl gas, the mass concentration of the acid in the anhydrous protonic acid solution is 20-40%, the reaction temperature is controlled to be -40~25°C during the reaction, and the ratio of the volume of the anhydrous protonic acid solution to the mass of compound D is controlled to be 6-12mL / g. More preferably, the solvent of the anhydrous protonic acid solution is anhydrous ethanol, the mass concentration of the acid in the anhydrous protonic acid solution is 35-40%, the reaction temperature is controlled to be -20~-15°C, and the ratio of the volume of the anhydrous protonic acid solution to the mass of compound D is controlled to be 6mL / g.

[0030] Compared with the prior art, the advantages of the present invention are:

[0031] The present invention discloses a novel production process for synthesizing dydrogesterone. Compared with the two mainstream synthesis methods of dydrogesterone, the synthesis process of the present invention does not require the use of reagents with greater safety risks such as ozone or liquid ammonia, and the reaction temperature is room temperature or low temperature, the side reaction is small, and the yield is high. Overall, the synthesis process of the present invention has the characteristics of high yield, safety and environmental protection, mild reaction conditions, etc., and has good application prospects. DETAILED DESCRIPTION

[0032] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively and carefully in combination with preferred embodiments below, but the protection scope of the present invention is not limited to the following specific embodiments.

[0033] Unless otherwise defined, all the professional terms used below have the same meanings as those generally understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention.

[0034] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0035] Example:

[0036] A synthesis process of dydrogesterone comprises the following steps:

[0037] (1) Compound A is oxidized and then reacted in an alcohol solvent R1OH (R1 is a methyl group, and other C 1-6 Under the action of alkyl), compound B is generated by acid catalysis.

[0038] (2) Compound B reacts with p-toluenesulfonylmethyl isocyanide under alkaline conditions to generate compound C.

[0039] (3) Compound C and methylmagnesium bromide undergo a Grignard reaction and then generate compound D under the action of an acid.

[0040] (4) Under acidic conditions, the 7,8 double bond of compound D shifts to form a 4,6 conjugated double bond, yielding compound E, which is dydrogesterone.

[0041] The reaction equation is as follows:

[0042] .

[0043] Specifically, the following steps are included:

[0044] (1) Oxidative etherification reaction: Add 105 g (0.28 mol) of Dess-Martin reagent (DMP) into a 1 L three-necked flask, add 3.78 g (0.21 mol) of water, 35 g (0.41 mol) of sodium bicarbonate and 500 mL of dichloromethane (DCM) while stirring, stir for a while, add 100 g (0.21 mol) of compound A at 5-10°C, keep warm and stir for half an hour, cool to -20°C and freeze for 1-2 hours, filter, rinse the filter cake with an appropriate amount of cold dichloromethane until there is no product on the filter cake, and wash the organic phase with sodium sulfite solution, sodium bicarbonate solution and brine in sequence. The organic phase was concentrated below 45°C until there was no dichloromethane, 1000 mL of methanol was added, and the mixture was heated to reflux. 2 mL of concentrated hydrochloric acid was added, and the mixture was refluxed for half an hour. A large amount of solid was precipitated. TLC showed that compound A was converted into compound B. 4 mL of triethylamine was added to adjust the pH to >7, the mixture was cooled to 0-5°C and frozen for 1 hour, filtered, and washed with 1v (1 volume of the main raw material, i.e., the ratio of the volume of methanol (mL) to the mass of the main raw material (g) was 1, the same below) of methanol. The solid was dried at 40°C for 10 hours to obtain 84 g of an off-white solid with a molar yield of about 80%.

[0045] (2) Reductive cyanation: Add 500 mL of tetrahydrofuran (THF) to a 1L three-necked flask, add 100 g of toluenesulfonylmethyl isonitrile (TOSMIC) and 38.84 g of potassium tert-butoxide while stirring, cool to -20°C, add 80.00 g (0.21 mol) of compound B and 12.80 g of methanol, keep warm for 1 hour, TLC shows that compound B is converted into compound C, add 100 mL of water to quench the reaction (detect β / α in the reaction solution), concentrate the reaction solution to remove THF, extract the remaining aqueous phase with dichloromethane, and wash the organic phase with water and brine in turn. The organic phase is concentrated below 50°C, replaced with methanol, retaining about 10 v of methanol, cooled to 0-5°C and frozen for 1 hour, filtered, rinsed with 1 v of methanol, and the solid was dried at 40 degrees for 10 hours to obtain 66 g of off-white solid (the α configuration accounts for about 1%, and the α configuration is highly soluble in methanol and is refined and removed), with a molar yield of about 80%.

[0046] The comparative test in Table 1 below was carried out according to the above reaction step (2), and the other conditions were the same as those in this embodiment. β / α is the ratio of the two configurations in the reaction solution. The products of the α and β configurations were qualitatively analyzed by HPLC-MS and quantitatively analyzed by peak area normalization method.

[0047] Table 1: Experimental conditions and results

[0048]

[0049] As shown in Table 1, the cyanation reaction will generate two configurations (17β-CN and 17α-CN), which are as follows:

[0050] .

[0051] In this step, the type of solvent and temperature have a great influence. Among them, DME, DMSO, HMPA, and THF are investigated as solvents, and THF is preferred. At 25°C, β / α=80 / 20 has better selectivity. The temperature is -40~50°C. At -20~50°C, the lower the temperature, the better the selectivity. Continuing to cool down has little effect. Taking all factors into consideration, -20°C is preferred.

[0052] (3) Grignard reaction: Add 500 mL of THF to a 1 L three-necked flask, add 100 g (0.32 mol) of the product obtained in step (2) while stirring, protect with nitrogen, cool to 0°C, add 140 mL (0.35 mol) of methylmagnesium bromide reagent (2.5 M), keep warm at 0-5°C for 1 h, TLC (add dilute acid to the reaction solution, extract with dichloromethane) shows that compound C is converted to compound D, add 200 mL of dilute sulfuric acid (1 M) to quench the reaction, concentrate the reaction solution to remove THF, extract the remaining aqueous phase with dichloromethane, and wash the organic phase with water and brine in turn. Concentrate the organic phase below 50°C, replace with water, filter, rinse with water, and dry the solid at 50°C for 16 h to obtain 94 g of an off-white solid with a molar yield of about 93%.

[0053] (4) Metathesis reaction: Add 460 mL of anhydrous ethanol to a 1L three-necked flask, and introduce dry hydrogen chloride gas at low temperature to prepare 600 mL of anhydrous ethanol / hydrogen chloride solution (the mass content of hydrogen chloride is about 40%); add 100 g (0.32 mol) of compound D and 1000 mL of dichloromethane to a 2L three-necked flask, dissolve, protect with nitrogen, add 600 mL of homemade anhydrous ethanol / hydrogen chloride solution dropwise at -20~-15℃, control the temperature and react for about 1 hour, and detect the raw material by TLC. The residue was less than 3%, and pure water was added to quench the reaction (detect β / α in the reaction solution). The organic phase was separated, and the organic phase was washed with sodium bicarbonate solution to a pH of 7-8. The organic phase was concentrated below 50°C, replaced with ethanol, and about 600 mL of ethanol was retained. The temperature was gradually lowered while stirring, and a white solid precipitated. The temperature was lowered by 0-5°C and frozen for 1 hour, filtered, and the crude product was dissolved in dichloroethanol, decolorized with activated carbon, recrystallized with ethanol, cold filtered, and dried to obtain 81 g of a white solid (the 17α configuration accounted for less than 0.1%), and the molar yield was about 81%.

[0054] The comparative test in Table 2 below was performed according to the above reaction step (4), and the other conditions were the same as those in this embodiment. β / α is the ratio of the two configurations in the reaction solution. The products of the α and β configurations were qualitatively analyzed by HPLC-MS and NMR, and quantitatively analyzed by peak area normalization method.

[0055] Table 2: Experimental conditions and results

[0056]

[0057] As can be seen from Table 2, the reaction in this step has high requirements for the water content of the acid. The reaction conversion rate of concentrated hydrochloric acid or 95% ethanol is low. A dry hydrogen chloride gas / anhydrous ethanol system is required to greatly improve the conversion rate. The reaction has requirements for the concentration of the acid. The acid content is low (30%), and the conversion rate is relatively low. The acid content of 35-40% can achieve better results. The reaction has requirements for the amount of acid. 6-12v is more suitable. Too low conversion rate is low. Considering comprehensively, 6v is preferred (6v represents the ratio of acid amount / mL to the mass / g of compound D is 6).

[0058] In addition, racemization will occur in this step. In addition to 17β-configuration dydrogesterone, 17α-configuration isomers will also be produced, as follows:

[0059] .

[0060] The 17α-configuration isomer was basically removed by ethanol recrystallization, accounting for less than 0.1%.

[0061] In this step, the reaction temperature has a great influence on the conversion rate and racemization. At -20~25°C, the lower the temperature, the higher the conversion rate and the smaller the isomer. If the temperature is further lowered, the effect is not significant. The preferred temperature is -20~-15°C. At the same time, the reaction is related to the strength of the acid. The conversion rates of concentrated sulfuric acid, trifluoroacetic acid and trifluoromethanesulfonic acid are also different. In terms of solvents, the conversion rate of tetrahydrofuran and isopropanol as solvents is also lower than that of anhydrous ethanol.

[0062] The dydrogesterone (β configuration) obtained in this example was tested: 1 H NMR (400 MHz, CDCl3) δ 9.56 (d, J = 3.1 Hz, 1H), 6.14 (dd, J = 10.8, 7.2 Hz, 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, 1.9 Hz, 1H), 2.01 – 1.70 (m, 7H), 1.70 – 1.31 (m, 6H), 1.31 – 1.20 (m, 4H), 1.12 (d, J = 6.9 Hz, 3H),0.78 (s, 3H).

[0063] 13C NMR (101 MHz, CDCl3) δ 204.51 (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).

[0064] Mass Spectrum: C 21 H 28 O2, 313.0.

[0065] The α-configuration product was detected: 1 H NMR (400 MHz, DMSO) δ 6.32 – 6.13 (m, 2H), 5.59(s, 1H), 2.89 (t, J = 5.3 Hz, 1H), 2.46 (d, J = 5.7 Hz, 1H), 2.35 (dd, J =11.1, 5.3 Hz, 1H), 2.21 (ddd, J = 13.4, 12.1, 3.7 Hz, 2H), 2.08 (d, J = 7.2Hz, 3H), 1.93 (d, J = 13.8 Hz, 1H), 1.85 – 1.70 (m, 6H), 1.69 – 1.61 (m, 1H),1.54 (td, J = 13.9, 5.0 Hz, 1H), 1.27 (ddd, J = 15.5, 14.2, 7.8 Hz, 2H), 1.09(s, 3H), 0.95 (s, 3H).

[0066] In the above embodiment, compound A can be prepared by the following method, comprising the following steps:

[0067] (1) Weigh 50g of compound 1 and 0.5g of BHT (antioxidant), add 1.5L of ethyl acetate to dissolve, pour into a photochemical reactor, turn on the internal cooling system, illuminate with a 260-270nm LED ultraviolet lamp (100W) for 3 hours, then illuminate with a 310-330nm LED ultraviolet lamp (100W) for 3 hours, take samples and monitor the reaction by HPLC, after the reaction is completed, concentrate the reaction liquid to an oily state, add 150ml of methanol, stir to precipitate compound 1, filter, recover compound 1 (20g), concentrate the mother liquor to dryness, mix with silica gel, and pass through a chromatography column to obtain 10.5g of compound 2. Compound 1 can be an existing conventional product.

[0068] After testing, compound 2 1 H NMR is: 1H NMR (400 MHz, CDCl3) δ 5.57 (dd, J = 5.5, 2.1 Hz, 1H), 5.41 (dt, J = 5.3, 2.5 Hz, 1H), 4.71 (tt, J = 11.4, 4.5 Hz, 1H), 4.03 – 3.80 (m, 4H), 2.51 (ddd, J = 14.2, 4.8, 2.2 Hz, 1H), 2.42 – 2.25 (m,2H), 2.08 – 1.98 (m, 5H), 1.97 – 1.86 (m, 3H), 1.87 – 1.76 (m, 1H), 1.76 –1.63 (m, 3H), 1.61 – 1.47 (m, 4H), 1.44 – 1.31 (m, 1H), 0.96 (s, 3H), 0.79 (s, 3H).

[0069] HRMS mass spectrum (EI) m / z: theoretical calculated value 373.5: tested value: 372.9.

[0070] The reaction equation of the above step (1) is as follows:

[0071] .

[0072] (2) In a 250 mL three-necked flask, add 4.2 g of compound 2, 42 g of acetone, 0.84 g of PTS, and 21 g of water, and stir at room temperature for 12 h. After the reaction of the raw materials was completed by TLC monitoring, 1.26 g of sodium hydroxide was added, and the mixture was stirred for 1 hour under reflux. After the reaction of the raw materials was completed by TLC monitoring, acetone was removed by vacuum rotary evaporation at 40 °C in a water bath. Extract with 20 mL of dichloromethane × 3, combine the organic layers, wash with water once, and vacuum rotary evaporation to dryness at 45 °C in a water bath to obtain compound A, which was 2.9 g of a light yellow oil with a mass yield of 69.0%.

[0073] The reaction equation of the above step (2) is as follows:

[0074] .

[0075] Compound A was characterized. 1 H NMR is: 1 H NMR (400 MHz, CDCl3) δ 5.72-5.70 (m, 1H), 5.61-5.60 (m, 1H), 4.13 (s, 1H), 2.77-2.72 (m, 1H), 2.57-2.47(m, 2H), 2.34-2.06 (m, 6H), 1.82-1.64 (m, 5H), 1.52-1.45 (m, 3H), 0.84 (s, 3H), 0.77 (s, 3H).

Claims

1. A synthesis process of dydrogesterone, characterized in that: The following steps are involved: (1) Compound A is oxidized and then acid-catalyzed in the presence of an alcohol solvent R1OH to generate compound B; (2) Compound B reacts with p-toluenesulfonylmethyl isocyanide under alkaline conditions to generate compound C; (3) Compound C and methylmagnesium bromide undergo a Grignard reaction, and then compound D is generated under the action of an acid; (4) Under acidic conditions, the 7,8 double bond of compound D shifts to form a 4,6 conjugated double bond, thereby obtaining compound E, which is dydrogesterone; The reaction equation is as follows: ； Wherein, R1 is selected from C 1-6 alkyl.

2. The synthesis process according to claim 1, characterized in that The synthesis process of compound A comprises the following steps: compound 1 is subjected to a photochemical reaction to obtain compound 2; compound 2 is first mixed with PTS for reaction, then sodium hydroxide is added for reflux reaction, and compound A is obtained by extraction; The reaction equation is as follows: 。 3. The synthesis process according to claim 2, characterized in that: The photochemical reaction of compound 1 to obtain compound 2 includes the following steps: dissolving compound 1 and an antioxidant in ethyl acetate, pouring the mixture into a photochemical reactor, turning on the internal cooling system, irradiating the reaction with a 260-270nm LED ultraviolet light, and then irradiating the reaction with a 310-330nm LED ultraviolet light. After the reaction is completed, concentrating the reaction solution to an oily state, adding methanol, stirring to precipitate compound 1, concentrating the mother liquor to dryness, mixing the sample with silica gel, and passing the sample through a chromatography column to obtain compound 2.

4. The synthesis process according to claim 2, characterized in that: Compound 2 is first mixed with PTS for reaction, and then sodium hydroxide is added for reflux reaction. Extraction to obtain compound A includes the following steps: Compound 2 and PTS were added to an acetone / water solvent system, and the mixture was stirred at room temperature for reaction. After the reaction was completed, sodium hydroxide was added and the mixture was refluxed and stirred for reaction. After the reaction was completed, acetone was removed by rotary evaporation under reduced pressure, and the mixture was extracted with dichloromethane for multiple times. The organic layers were combined, washed with water, and rotary evaporation under reduced pressure to dryness to obtain compound A.

5. The synthesis process according to any one of claims 1 to 4, characterized in that: The oxidation method of compound A is Wohlner oxidation, Swern oxidation or Dess-Martine oxidation, and the reagents used in the oxidation process are aluminum isopropoxide / cyclohexanone, dimethyl sulfoxide / oxalyl chloride or Dess-Martine periodic reagent; the acid used in the acid-catalyzed generation of compound B is concentrated hydrochloric acid.

6. The synthesis process according to any one of claims 1 to 4, characterized in that: The reaction temperature when compound B reacts with p-toluenesulfonylmethyl isocyanide under alkaline conditions to generate compound C is -40~50°C, the solvent used is one or more of tetrahydrofuran, ether, hexamethylphosphoramide, dimethyl ether and dimethyl sulfoxide, the base for adjusting the alkaline conditions is potassium tert-butoxide or sodium methoxide, and the molar ratio of compound B to p-toluenesulfonylmethyl isocyanide is 1:(2.2-3.0).

7. The synthesis process according to claim 6, characterized in that: The reaction temperature was -20°C and the solvent used was tetrahydrofuran.

8. The synthesis process according to any one of claims 1 to 4, characterized in that: When compound C and methylmagnesium bromide undergo a Grignard reaction and then generate compound D under the action of an acid, the solvent of the reaction process is one or more of tetrahydrofuran, ether, hexamethylphosphoramide and dimethyl ether, the reaction temperature is controlled at 0-5°C, and the molar ratio of compound C to methylmagnesium bromide is 1:(1.1-1.5).

9. The synthesis process according to any one of claims 1 to 4, characterized in that: In the presence of an anhydrous protonic acid solution, the 7,8 double bond of compound D shifts to form a 4,6 conjugated double bond to obtain compound E. The solvent of the anhydrous protonic acid solution is one or more of ethanol, isopropanol, methanol and tetrahydrofuran. The anhydrous protonic acid is dry HCl gas. The mass concentration of the acid in the anhydrous protonic acid solution is 20-40%. During the reaction, the reaction temperature is controlled to be -40-25°C, and the ratio of the volume of the anhydrous protonic acid solution to the mass of compound D is controlled to be 6-12 mL / g.

10. The synthesis process according to claim 9, characterized in that: The solvent of the anhydrous protonic acid solution is anhydrous ethanol, the mass concentration of the acid in the anhydrous protonic acid solution is 35-40%, the reaction temperature is controlled to be -20~-15°C, and the ratio of the volume of the anhydrous protonic acid solution to the mass of compound D is controlled to be 6mL / g.

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