A process synthesis method of a cleavable linker Gly-Gly-Phe-Gly

Abstract

This invention discloses a process for synthesizing a tetrapeptide cleavable linker of the ADC drug glycine-glycine-phenylalanine-glycine. Specifically, this invention provides a process for synthesizing a compound of formula I, which includes the following steps: compound 4 undergoes a condensation reaction with SM2 to obtain compound 5; compound 5 is deprotected to obtain compound I.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis, and more specifically to a process for synthesizing Gly-Gly-Phe-Gly linkers that can be cleaved. Background Technology

[0002] (S)-16-amino-10-benzyl-6,9,12,15-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecanoic acid (code name Gly-Gly-Phe-Gly, as shown in chemical formula I) is a cleavable linker commonly used in many ADC drugs under development. It is coupled to the payload via an aminomethoxy-methylene carbonyl (-NH-CH2-O-CH2-CO-) spacer, releasing the payload through cathepsin cleavage. Its application prospects are very broad.

[0003]

[0004] Patent WO2019195665 reports a milligram-scale synthetic method for Gly-Gly-Phe-Gly. Starting with ((9H-fluorene-9-yl)methoxy)carbonyl)glycylglycine, it reacts with lead tetraacetate to yield (2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)acetamido)methyl acetate. This intermediate undergoes a substitution reaction with benzyl glycolate to give 1-(9H-fluorene-9-yl)-3,6-dioxo-2,9-dioxo-4,7-diazaundecane-11-acid benzyl ester. This intermediate is then de-fluorenemethoxycarbonylated with piperidine to give 2-((2-aminoacetamido)methoxy)benzyl acetate. This intermediate undergoes a substitution reaction with 2,5-dioxopyrrolidine-1-yl((9H-fluorene-9-yl)methoxy)carbonyl)-L-phenylalanine glycine ester to yield (S). -5-Benzyl-1-(9H-fluorene-9-yl)-3,6,9-trioxo-2,12-dioxo-4,7,10-triazatetradecane-14-acid benzyl ester, this intermediate is de-fluorenemethoxycarbonylated with piperidine to give (S)-2-((2-(2-amino-3-phenylpropamido)acetamido)methoxy)benzyl acetate, this intermediate is reacted with ((9H-fluorene-9-yl)methoxy)carbonyl)glycyl Glycine undergoes a condensation reaction to yield the key intermediate (S)-11-benzyl-1-(9H-fluorene-9-yl)-3,6,9,12,15-pentoxy-2,18-dioxo-4,7,10,13,16-pentazaeicosanoate-20 benzyl ester. This intermediate is first debenzylated with palladium on carbon and hydrogen, and then debenzylated with piperidine to obtain the final product Gly-Gly-Phe-Gly. This route employs silica gel column purification for multiple steps, with the sixth step using Prep-HPLC for preparative purification. Scale-up production is costly, and the yields of each step are low. The patented method only yields unpurified milligram-level products and lacks a final product purification process, which is detrimental to scale-up production.

[0005] Summary of the Invention

[0006] This invention provides a process for synthesizing a compound of formula I, comprising the following steps: Step A: Compound 4 undergoes a condensation reaction with SM2 to give compound 5; , Wherein, R is selected from benzyloxycarbonyl, benzyl, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl or triphenylmethyl, preferably benzyloxycarbonyl; The condensation reaction is carried out in a condensing agent and a solvent. Preferably, the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-carbonyldiimidazole, 1-propylphosphoric anhydride, 1-butylphosphoric anhydride, (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1H-benzotriazole-1-yloxytripyrrolyl hexafluorophosphate, tripyrrolylphosphonium bromide hexafluorophosphate, 2-(1H-benzotriazole)-1-yloxytripyrrolyl hexafluorophosphate, and 2-(1H-benzotriazole)-1-yloxytripyrrolyl hexafluorophosphate. The reaction solvent is selected from acetonitrile, a mixture of acetonitrile and water, tetrahydrofuran, a mixture of tetrahydrofuran and water, dichloromethane, N,N-dimethylformamide, a mixture of N,N-dimethylformamide and water, N,N-dimethylacetamide, a mixture of N,N-dimethylacetamide and water, dimethyl sulfoxide, N-methylpyrrolidone, or dioxane; the reaction temperature is 0~100℃. Step B: Compound 5 is deprotected to obtain compound I; , The deprotection reaction is carried out in a metal catalyst-hydrogen gas, an acid or base and a suitable solvent; When the deprotection reaction is carried out in a metal catalyst-hydrogen gas and a suitable solvent, the metal catalyst is preferably selected from palladium on carbon, palladium hydroxide on carbon, platinum on carbon, or nickel; the hydrogen pressure is selected from 0.001~2 MPa; the solvent is selected from acetonitrile, a mixed solvent of acetonitrile and water, tetrahydrofuran, a mixed solvent of tetrahydrofuran and water, dichloromethane, ethyl acetate, methanol, a mixed solvent of methanol and water, ethanol, a mixed solvent of ethanol and water, a mixed solvent of tetrahydrofuran-methanol-water, or a mixed solvent of tetrahydrofuran-ethanol-water, etc.; the reaction temperature is 0~100℃; When the deprotection reaction is carried out in an acid and a suitable solvent, the acid is preferably selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid or p-toluenesulfonic acid; the solvent is selected from dichloromethane, tetrahydrofuran, methanol, ethanol, toluene, dioxane, ethyl acetate or not applicable; the reaction temperature is 0~100℃; When the deprotection reaction is carried out in a base and a suitable solvent, the base is preferably selected from dimethylamine, diethylamine, diisopropylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium hydroxide hydrate, sodium bicarbonate, potassium bicarbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene or 4-dimethylaminopyridine; the solvent is selected from acetonitrile, a mixture of acetonitrile and water, tetrahydrofuran, a mixture of tetrahydrofuran and water, dichloromethane, ethyl acetate, methanol, a mixture of methanol and water, ethanol, a mixture of ethanol and water, a mixture of tetrahydrofuran-methanol-water, or a mixture of tetrahydrofuran-ethanol-water, etc.; the reaction temperature is 0~120℃.

[0007] In some embodiments of the present invention, the condensing agent in step A is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; the solvent is a mixed solvent of acetonitrile and water, preferably a mixed solvent with a volume ratio of acetonitrile to water of 1-10:1, more preferably a mixed solvent with a volume ratio of acetonitrile to water of 6:1; the reaction temperature is 10~60°C, preferably 20~40°C, for example 20°C, 25°C, 30°C, 35°C, 40°C.

[0008] In some embodiments of the present invention, the deprotection reaction in step B is carried out in a hydrogen atmosphere with a metal catalyst, hydrogen, and a suitable solvent, wherein the metal catalyst is palladium on carbon; the hydrogen pressure is 0.001~2 MPa, preferably 0.01~0.5 MPa; the solvent is a mixed solvent of tetrahydrofuran and water, preferably a mixed solvent with a volume ratio of tetrahydrofuran to water of 1-5:1, more preferably a mixed solvent with a volume ratio of tetrahydrofuran to water of 1:1; the reaction temperature is 10~50°C, preferably 20~40°C, for example 20°C, 25°C, 30°C, 35°C, 40°C.

[0009] In some embodiments of the present invention, the process synthesis method of the compound of formula I further includes the following steps: Step C: Compound 3 is deprotected in a base and a suitable solvent to give compound 4;

[0010] The base is selected from dimethylamine, diethylamine, diisopropylamine, 4-dimethylaminopyridine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, diisopropylethylamine, pyridine, morpholine, N-methylmorpholine, potassium carbonate, sodium carbonate, potassium phosphate, sodium bicarbonate, or potassium bicarbonate; the solvent is selected from acetonitrile, tetrahydrofuran, dichloromethane, diethyl ether, dioxane, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, methyltetrahydrofuran, methanol, or ethanol, etc.; the reaction temperature is 0~100℃; In some embodiments of the present invention, the base in step C is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene, the solvent is selected from acetonitrile, and the reaction temperature is preferably 0~40℃.

[0011] In some embodiments of the present invention, the process synthesis method of the compound of formula I further includes the following steps: Step D: Compound 2 and SM1 undergo a substitution reaction to give compound 3;

[0012] The substitution reaction is carried out in a base and a suitable solvent. The base is selected from sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, or sodium hydride. The reaction solvent is selected from ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, diethylene glycol dimethyl ether, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dichloromethane, diethyl ether, dioxane, ethyl acetate, methanol, or ethanol, etc. The reaction temperature is -40~50℃. In some embodiments of the present invention, the alkali in step D is selected from sodium hydroxide, the solvent is selected from ethylene glycol dimethyl ether, and the reaction temperature is preferably 0°C.

[0013] In some embodiments of the present invention, the process synthesis method of the compound of formula I further includes the following steps: Step E: Compound 1 reacts with lead tetraacetate to give compound 2;

[0014] The reaction solvent is selected from acetic acid, a mixed solvent of acetic acid and tetrahydrofuran, tetrahydrofuran, toluene, benzene, diethyl ether, methyltetrahydrofuran, a mixed solvent of acetic acid and toluene, a mixed solvent of acetic acid and benzene, a mixed solvent of acetic acid and diethyl ether, or a mixed solvent of acetic acid and methyltetrahydrofuran, etc.; the reaction temperature is 0~100℃; In some embodiments of the present invention, the solvent in step E is selected from a mixed solvent of acetic acid and tetrahydrofuran, preferably a mixed solvent in which the volume ratio of tetrahydrofuran to acetic acid is 1-10:1, more preferably a mixed solvent in which the volume ratio of tetrahydrofuran to acetic acid is 5:1; the reaction temperature is 40-80°C.

[0015] The present invention also provides an intermediate for synthesizing compounds of formula I, having the following structure:

[0016] Wherein, R is selected from benzyloxycarbonyl, tert-butyloxycarbonyl, fluorenyloxycarbonyl, allyloxycarbonyl or triphenylmethyl, preferably benzyloxycarbonyl.

[0017] The process synthesis route of this invention is simple and readily available, avoiding the use of solid-phase synthesis and medium-pressure C18 reverse-phase purification. It adopts a crystallization purification method that is easier to produce, reducing process costs. Not only is the overall yield high, but the purity of the obtained product is also very high, making it suitable for scale-up production. Detailed Implementation

[0018] The following specific embodiments further illustrate the content of the present invention, but it should not be construed as limiting the scope of the present invention to the following examples. All methods, steps, reagents, temperatures, and other features disclosed in this specification, except in cases of obvious contradictions or mutual exclusion, can be combined or reasonably substituted in any way, and these all fall within the scope of protection of the present invention.

[0019] In this invention, the room temperature is 20~30℃. Example

[0020]

[0021] At room temperature, compound 1 (9.0 kg, 25.4 mol), tetrahydrofuran (135 L), and acetic acid (27 L) were added to a 300 L reactor. After the addition was complete, the reaction system was heated to 45 °C. After the system was dissolved, lead tetraacetate (18.0 kg, 40.6 mol) was slowly added. The reaction system was then heated to 75 °C and reacted for 3 h. HPLC showed that compound 3 remained at less than 0.5%. The reaction system was cooled to room temperature and stirred for another 1.5 h. After filtration, the filter cake was washed with ethyl acetate (45 L). The mother liquor obtained from filtration was washed three times with an aqueous solution of 20% trisodium citrate dihydrate (45 L). The organic phase was concentrated to about 90 L. Water (27 L) was added to the organic phase and stirred for 30 min. Then, water (90 L) was added dropwise. The temperature was lowered to 0 °C and stirred for 5 h. After filtration, the solution was washed with a cold aqueous solution of 30% tetrahydrofuran (18.0 kg, 40.6 mol). L) Wash the filter cake and dry it in an oven at 40°C for 48 hours to obtain a pale yellow solid compound 2 (8.6 kg, yield: 92%, purity: 94%). LCMS: ESI-MS (m / z): [M+Na]+ = 391.1. Example

[0022] At room temperature, compound 2 (8.6 kg, 23.4 mol) was added to a 300 L reactor to neutralize ethylene glycol dimethyl ether (130 L). Then, SM1 (4.3 kg, 25.7 mol) was added to the reaction system. The reaction system was cooled to 5 °C, and under controlled temperature, sodium hydroxide aqueous solution (11.7 L, 23.4 mol, 2 mol / L) was slowly added dropwise. The mixture was stirred for 1.5 h. HPLC analysis showed that compound 2 was less than 0.5%. Acetic acid (1.4 kg, 23.4 mol) was added to the reaction system, and stirring continued for 1 h. Water (25.8 L) was added to the reaction system, and stirring continued for 1 h. Water (86 L) was added dropwise, and stirring continued for 4 h. The precipitate was filtered, and the filter cake was washed with 50% ethylene glycol dimethyl ether aqueous solution (25.8 L). ethylene glycol dimethyl ether (130 L) was added to the filter cake. L), dissolve the filter cake, add water (112 L), cool to 0℃, stir for 4 h, filter the precipitate, wash the filter cake with 50% ethylene glycol dimethyl ether aqueous solution (25.8 L), dry the filter cake at 40℃, add toluene (172 L) to the solid, heat the system to 70℃, stir, dissolve, cool the mother liquor to 0℃, stir for 2 h, filter the precipitate, wash the filter cake with cold toluene, dry the filter cake at 40℃, to obtain compound 3 white solid (6.5 kg, yield: 58.3%, purity 97%). LCMS: ESI-MS (m / z): [M+Na]+= 497.2. Example

[0023]

[0024] At room temperature, compound 3 (5.8 kg, 12.2 mol) and acetonitrile (145 L) were added to a 200 L reactor. Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (931 g, 6.1 mol) was added to the reaction system, and the reaction was continued for 4 h. HPLC analysis showed that compound 3 was less than 0.5%. Next, 1-hydroxybenzotriazole (4.1 kg, 26.9 mol) was added to the reaction system in portions, and the mixture was stirred for 1 h. The reaction system was then cooled to 0 °C and stirred for 10 h. After filtration, the filter cake was washed with 12 L of cold acetonitrile and dried in a 40 °C oven for 12 h to obtain a pale yellow solid, which was the 1-hydroxybenzotriazole salt of compound 4 (4.5 kg, yield: 90%, purity: 98%). LCMS: ESI-MS (m / z): [M+H]+ = 253.1. Example

[0025]

[0026] At room temperature, compound 4 (4.5 kg, 11.1 mol), acetonitrile (54 L), and water (9 L) were added to a 200 L reactor. Then, SM2 (4.45 kg, 10.8 mol) was added to the reaction system. The reaction system was cooled to 5 °C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.5 kg, 13.3 mol) was added to the reaction system. The system was heated to room temperature and stirred for 2 h. After the reaction was confirmed to be complete by HPLC, ethanol (18 L) and water (68 L) were added to the reaction system and stirred overnight. Then, water (58 L) was added to the reaction system in portions and stirred for 0.5 h. The system was then cooled to 0 °C and stirred for 3 h. The precipitate was filtered, and the filter cake was washed with acetonitrile:water = 1:2 (15 L). The precipitate was then dried at 40 °C to obtain a white solid compound 5 (6.2 kg, yield: 86%, purity: 97%). LCMS: ESI-MS(m / z): [M+Na]+= 670.2. Example

[0027]

[0028] Compound 5 (6.2 kg, 9.6 mol), tetrahydrofuran (130 L), and water (130 L) were added to a 300 L reactor at room temperature and stirred. 10% palladium on carbon (600 g) was added to the reaction system, and hydrogen was purged three times. The reaction was carried out for 12 h under a 0.04 MPa hydrogen atmosphere. HPLC showed that compound 5 was less than 0.5%. The palladium on carbon was filtered, and the filter cake was washed with water (50 L). The filtrates were combined and rotary evaporated to 25 L. Ethanol (96 L) was added to the remaining aqueous phase, and the mixture was stirred overnight. The precipitate was filtered, and the filter cake was washed with ethanol (10 L). The filter cake was dried in an oven at 40 °C for 48 h to obtain compound Gly-Gly-Phe-Gly, a white solid (3.6 kg, yield: 90%, purity: 99.0%). ESI-MS (m / z): [M+H]+ = 424.1.

[0029] 1H NMR (400 MHz, D2O) δ 7.45 – 7.24 (m, 5H), 4.76 – 4.60 (m, 3H), 4.00 – 3.90 (m, 5H), 3.89 – 3.78 (m, 3H), 3.18 (dd, J = 13.8, 6.9 Hz, 1H),3.06 (dd, J = 13.7, 8.4 Hz, 1H). The above detailed embodiments provide a further description of the present invention. However, it should not be construed as limiting the scope of the present invention to the listed embodiments; all technical solutions implemented based on the content of the present invention fall within the scope of the present invention.

Claims

1. A process for synthesizing a cuttable connector Gly-Gly-Phe-Gly, characterized in that, Includes the following steps: Step A: Compound 4 undergoes a condensation reaction with SM2 to give compound 5; ， Wherein, R is selected from benzyloxycarbonyl, benzyl, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl or triphenylmethyl, preferably benzyloxycarbonyl; The condensation reaction is carried out in a condensing agent and a solvent. Preferably, the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-carbonyldiimidazole, 1-propylphosphoric anhydride, 1-butylphosphoric anhydride, (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1H-benzotriazole-1-yloxytripyrrolyl hexafluorophosphate, tripyrrolylphosphonium bromide hexafluorophosphate, 2-(1H-benzotriazole)-1-yloxytripyrrolyl hexafluorophosphate, and 2-(1H-benzotriazole)-1-yloxytripyrrolyl hexafluorophosphate. The reaction solvent is selected from acetonitrile, a mixture of acetonitrile and water, tetrahydrofuran, a mixture of tetrahydrofuran and water, dichloromethane, N,N-dimethylformamide, a mixture of N,N-dimethylformamide and water, N,N-dimethylacetamide, a mixture of N,N-dimethylacetamide and water, dimethyl sulfoxide, N-methylpyrrolidone, or dioxane; the reaction temperature is 0~100℃. Step B: Compound 5 is deprotected to obtain compound I; ， The deprotection reaction is carried out in a metal catalyst-hydrogen gas, an acid or base and a suitable solvent; When the deprotection reaction is carried out in a metal catalyst-hydrogen gas and a suitable solvent, the metal catalyst is preferably selected from palladium on carbon, palladium hydroxide on carbon, platinum on carbon, or nickel; the hydrogen pressure is selected from 0.001~2 MPa; the solvent is selected from acetonitrile, a mixed solvent of acetonitrile and water, tetrahydrofuran, a mixed solvent of tetrahydrofuran and water, dichloromethane, ethyl acetate, methanol, a mixed solvent of methanol and water, ethanol, a mixed solvent of ethanol and water, a mixed solvent of tetrahydrofuran-methanol-water, or a mixed solvent of tetrahydrofuran-ethanol-water, etc.; the reaction temperature is 0~100℃; When the deprotection reaction is carried out in an acid and a suitable solvent, the acid is preferably selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid or p-toluenesulfonic acid; the solvent is selected from dichloromethane, tetrahydrofuran, methanol, ethanol, toluene, dioxane, ethyl acetate or not applicable; the reaction temperature is 0~100℃; When the deprotection reaction is carried out in a base and a suitable solvent, the base is preferably selected from dimethylamine, diethylamine, diisopropylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium hydroxide hydrate, sodium bicarbonate, potassium bicarbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene or 4-dimethylaminopyridine; the solvent is selected from acetonitrile, a mixture of acetonitrile and water, tetrahydrofuran, a mixture of tetrahydrofuran and water, dichloromethane, ethyl acetate, methanol, a mixture of methanol and water, ethanol, a mixture of ethanol and water, a mixture of tetrahydrofuran-methanol-water, or a mixture of tetrahydrofuran-ethanol-water, etc.; the reaction temperature is 0~120℃.

2. The process synthesis method according to claim 1, characterized in that, The condensing agent in step A is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; the solvent is a mixed solvent of acetonitrile and water, preferably a mixed solvent with a volume ratio of acetonitrile to water of 1-10:1, more preferably a mixed solvent with a volume ratio of acetonitrile to water of 6:1; the reaction temperature is 10~60℃, preferably 20~40℃.

3. The process synthesis method according to claim 1 or 2, characterized in that, The deprotection reaction in step B is carried out in a hydrogen atmosphere with a metal catalyst, hydrogen, and a suitable solvent. The metal catalyst is palladium on carbon. The hydrogen pressure is 0.001~2 MPa, preferably 0.01~0.5 MPa. The solvent is a mixed solvent of tetrahydrofuran and water, preferably a mixed solvent with a volume ratio of tetrahydrofuran to water of 1-5:1, more preferably a mixed solvent with a volume ratio of tetrahydrofuran to water of 1:

1. The reaction temperature is 10~50℃, preferably 20~40℃.

4. The process synthesis method according to any one of claims 1 to 3, characterized in that, It also includes the following steps: Step C: Compound 3 is deprotected in a base and solvent to give compound 4; 5. The base is selected from dimethylamine, diethylamine, diisopropylamine, 4-dimethylaminopyridine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium phosphate, sodium bicarbonate, or potassium bicarbonate; the solvent is selected from acetonitrile, tetrahydrofuran, dichloromethane, diethyl ether, dioxane, ethyl acetate, methanol, or ethanol, etc.; the reaction temperature is 0~100℃; Preferably, the base in step C is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene, the solvent is selected from acetonitrile, and the reaction temperature is preferably 0~40℃.

6. The process synthesis method according to any one of claims 4, characterized in that, It also includes the following steps: Step D: Compound 2 and SM1 undergo a substitution reaction to give compound 3; 7. The substitution reaction is carried out in a base and a suitable solvent, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, or sodium hydride; the reaction solvent is selected from ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, diethylene glycol dimethyl ether, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dichloromethane, diethyl ether, dioxane, ethyl acetate, methanol, or ethanol, etc.; the reaction temperature is -40~50℃; Preferably, in step D, the alkali is selected from sodium hydroxide, the solvent is selected from ethylene glycol dimethyl ether, and the reaction temperature is preferably 0°C.

8. The process synthesis method according to claim 5, characterized in that, It also includes the following steps: Step E: Compound 1 reacts with lead tetraacetate in a solvent to give compound 2. ， The solvent is selected from acetic acid, a mixed solvent of acetic acid and tetrahydrofuran, tetrahydrofuran, toluene, benzene, diethyl ether, methyltetrahydrofuran, a mixed solvent of acetic acid and toluene, a mixed solvent of acetic acid and benzene, a mixed solvent of acetic acid and diethyl ether, or a mixed solvent of acetic acid and methyltetrahydrofuran, etc.; the reaction temperature is 0~100℃.

9. The process synthesis method according to claim 5, characterized in that, In step E, the solvent is a mixed solvent of acetic acid and tetrahydrofuran, preferably a mixed solvent with a volume ratio of tetrahydrofuran to acetic acid of 1-10:1, more preferably a mixed solvent with a volume ratio of tetrahydrofuran to acetic acid of 5:1; the reaction temperature is 40~80℃.

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