Phosphate fatty alkanoic acid and synthesis method of intermediate of phosphate fatty alkanoic acid

Abstract

The invention discloses a synthetic method of phosphate fatty alkanoic acid and an intermediate thereof, and relates to the technical field of organic synthesis. The synthesis method of the first intermediate of phosphate fatty alkanoic acid comprises the following steps: by taking long-chain alkane diacid as an initial raw material, carrying out esterification reaction, unilateral hydrolysis reaction and reduction reaction to prepare long-chain alkanol monoester; the preparation method comprises the following steps: carrying out substitution reaction on long-chain alkanol monoester and paratoluensulfonyl chloride to obtain paratoluensulfonyl long-chain alkanoic acid monoester which is used as a first intermediate; according to the invention, Ts is added to TsCl to obtain a first intermediate, so that the first intermediate can be subsequently subjected to a halogenation reaction to obtain a second intermediate, OH is substituted by halogen through a two-step method, and the problem of residual triphenylphosphine PPH3 during substitution by using a conventional one-step method (triphenylphosphine PPH3 is utilized) is avoided; the method has the advantages of simplicity in operation, high yield, easiness in large-scale production and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a method for synthesizing phosphate fatty alkanoic acid and an intermediate thereof. Background Art

[0002] In the 1980s, scientists discovered glucagon-like peptide-1 (GLP-1). In 2005, the GLP-1 analog exenatide was approved for marketing by the US FDA, but it required two injections a day, resulting in poor patient compliance. In 2010, the FDA approved the world's second GLP-1 drug, liraglutide, for once-daily injection. In 2017, semaglutide was approved by the US FDA for once-weekly injection. In 2023, the world's first dual-target agonist telpotide was approved by the FDA for once-weekly injection. In 2019, the FDA-approved oral semaglutide formulation Rybelsus (for diabetes) became the only approved oral GLP-1 drug in the world.

[0003] GLP-1 drugs have demonstrated great clinical demand and value, and are currently being actively expanded to include dozens of indications, which is expected to address more clinical needs.

[0004] After decades of development, GLP-1 drugs have been marketed for more than a dozen drugs and hundreds of drugs are in clinical research, but most of them are injections, and only the oral formulation of semaglutide, Rybelsus, is on the market. Compared with injections, oral administration is more convenient, has better compliance, and can also avoid the so-called "needle phobia" of some patients, that is, they are very afraid of injecting themselves. However, there is only one oral GLP-1 drug.

[0005] VK2735, which is currently under clinical development, has attracted widespread attention due to its excellent effectiveness and safety, and the fact that it has two dosage forms, injection and oral, under development. Compared with previous GLP-1 drugs, the core of VK2735 is to convert the terminal carboxyl group of the side chain into a phosphate group, making it more drugable. Patent application WO2022159395A1 discloses the synthesis route of the side chain 19-benzyl phosphate nonadecanoic acid, without a detailed description of the process. The process route in this patent application has obvious shortcomings. It uses the Witting reaction and adopts a twelve-plus-seven method to grow the carbon chain; heavy metal oxidant PCC is used in this method to prepare fatty aldehydes, and the instability of fatty aldehydes leads to low utilization of atoms in the witting reaction; and the product obtained by the Witting reaction requires palladium carbon reduction, which is costly and has certain risks.

[0006] In view of this, the present invention is proposed. Summary of the invention

[0007] The purpose of the present invention is to provide a method for synthesizing phosphate fatty alkanoic acid and its intermediates, which uses long-chain alkanedioic acid as a raw material, and obtains phosphate fatty alkanoic acid through esterification reaction, unilateral hydrolysis reaction, reduction reaction, substitution reaction, halogenation reaction, re-substitution reaction and hydrolysis reaction, thereby avoiding the problem of low atom utilization rate when using witting reaction to increase carbon chain; the selective hydrolysis conversion rate is high; the product purity is high; at the same time, by first adding Ts with TsCl and then halogenating, since there is no need to use PPh3, the problem of PPh3 residue in the conventional one-step OH halogenation process is solved; there is no column chromatography separation and purification; the operation is simple, the yield is high, and it is easy to scale up production and the like.

[0008] The present invention is achieved in that: In a first aspect, the present invention provides a method for synthesizing a first intermediate of a phosphate fatty alkanoic acid, comprising: S1. Using a long-chain alkanedioic acid as a starting material, a long-chain alkanol monoester is prepared by esterification reaction, unilateral hydrolysis reaction and reduction reaction; the structural formula of the long-chain alkanedioic acid is , the structural formula of the long-chain alkanol monoester is , wherein N=10-26, R1=Me, Et, t-Bu, Bn or H; S2, subjecting the long-chain alkanol monoester and p-toluenesulfonyl chloride to a substitution reaction to obtain p-toluenesulfonyl long-chain alkanoic acid monoester as a first intermediate, wherein the p-toluenesulfonyl long-chain alkanoic acid monoester has the structural formula: .

[0009] In an optional embodiment, the esterification reaction in step S1 includes: dissolving the long-chain alkanedioic acid in a first organic solvent, adding thionyl chloride or anhydride, and reacting to obtain a long-chain diester, wherein the long-chain diester has a structural formula of ; The esterification reaction includes at least one of features (1) to (3): Feature (1): The first organic solvent is methanol, acetonitrile, tetrahydrofuran, or dichloromethane; Feature (2): The acid anhydride is trifluoroacetic anhydride, acetic anhydride, or Boc anhydride; Feature (3): The reaction temperature of the esterification reaction is 20-30°C and the reaction time is 4-12h.

[0010] In an optional embodiment, the unilateral hydrolysis reaction in step S1 includes: dissolving the long-chain diester in a second organic solvent, adding a hydrolysis base, and reacting to obtain a long-chain alkanoic acid monoester, wherein the long-chain alkanoic acid monoester has a structural formula of ; The unilateral hydrolysis reaction includes at least one of features (4) to (6): Feature (4): the second organic solvent comprises at least one of methanol, ethanol, tetrahydrofuran and N,N-dimethylformamide; Feature (5): The hydrolysis base includes at least one of barium hydroxide and sodium hydroxide; Feature (6): The reaction temperature of the unilateral hydrolysis reaction is 40-60°C and the reaction time is 1-4h.

[0011] In an optional embodiment, the reduction reaction in step S1 includes: dissolving the long-chain alkanoic acid monoester in a third organic solvent, adding sodium borohydride or borane tetrahydrofuran solution, adding a catalyst after the reaction is completed, stirring until no gas is generated, and reacting to obtain a long-chain alkanol monoester, wherein the long-chain alkanol monoester has a structural formula of ; The reduction reaction includes at least one of features (7) to (9); Feature (7): The third organic solvent comprises at least one of methanol, tetrahydrofuran, N,N-dimethylformamide and water; Feature (8): The catalyst comprises at least one of zinc chloride, methanol, boron trifluoride etherate and iodine; Feature (9): The reaction temperature of the reduction reaction is -5~5°C and the reaction time is 1-3h.

[0012] In an optional embodiment, the substitution reaction of the long-chain alkanol monoester and the p-toluenesulfonyl chloride in step S2 comprises dissolving the long-chain alkanol monoester and the p-toluenesulfonyl chloride in a fourth organic solvent, adding a substitution base, and reacting to obtain a p-toluenesulfonyl long-chain alkanoic acid monoester; the substitution reaction comprises at least one of features (10) to (12); Feature (10): The fourth organic solvent comprises at least one of dichloromethane, tetrahydrofuran, N,N-dimethylformamide and acetonitrile; Feature (11): The substitution base comprises at least one of triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate and sodium carbonate; Feature (12): The reaction temperature of the substitution reaction is 20-30°C and the reaction time is 6-16h.

[0013] In a second aspect, the present invention provides a method for synthesizing a second intermediate of a phosphate fatty alkanoic acid, comprising: subjecting a first intermediate, p-toluenesulfonyl long-chain alkanoic acid monoester, prepared by the method for synthesizing a first intermediate of a phosphate fatty alkanoic acid according to any one of the aforementioned embodiments to a halogenation reaction to obtain a halogenated long-chain alkanoic acid monoester as a second intermediate, wherein the halogenated long-chain alkanoic acid monoester has a structural formula of , X is halogen.

[0014] In an optional embodiment, the halogenation reaction comprises dissolving the p-toluenesulfonyl long-chain alkanoic acid monoester in a fifth organic solvent, adding sodium halide, and obtaining a halogenated long-chain alkanoic acid monoester; the halogenation reaction comprises at least one of features (13) to (15); Feature (13): The fifth organic solvent comprises at least one of acetone, N,N-dimethylformamide and acetonitrile; Feature (14): The sodium halide includes sodium iodide, sodium bromide or sodium chloride; Feature (15): The reaction temperature of the halogenation reaction is 70-90°C and the reaction time is 2-6h.

[0015] In a third aspect, the present invention provides a method for synthesizing a phosphate fatty alkanoic acid, comprising subjecting a second intermediate prepared by the method for synthesizing a second intermediate of a phosphate fatty alkanoic acid according to any one of the aforementioned embodiments to a substitution reaction with a phosphate to generate a phosphate long-chain alkanoic acid monoester, and hydrolyzing the phosphate long-chain alkanoic acid monoester to generate a phosphate fatty alkanoic acid; Wherein, the structural formula of the phosphate ester is The structural formula of the phosphate long-chain alkanoic acid monoester is The structural formula of the phosphate fatty acid is , R2=Me, Et, t-Bu, Bn or H, R3=Me, Et, t-Bu, Bn or H.

[0016] In an optional embodiment, the re-substitution reaction comprises: reacting the halogenated long-chain alkanoic acid monoester and the phosphate ester in the presence of a sixth organic solvent, adding a re-substitution base; the re-substitution reaction comprises at least one of features (16) to (18): Feature (16): The sixth organic solvent comprises at least one of N,N-dimethylformamide and acetonitrile; Feature (17): The re-substitution base comprises cesium carbonate; Feature (18): The reaction temperature of the re-substitution reaction is 20-30°C and the reaction time is 5-20h.

[0017] In an optional embodiment, the hydrolysis of the phosphate long-chain alkanoic acid monoester comprises: dissolving the phosphate long-chain alkanoic acid monoester in a seventh organic solvent, and adding a hydrolysis base or a hydrolysis acid; the hydrolysis of the phosphate long-chain alkanoic acid monoester comprises at least one of features (19) to (21): Feature (19): The seventh organic solvent includes at least one of tetrahydrofuran, methanol, ethanol, dichloromethane and dioxane; Feature (20): The hydrolysis base includes at least one of sodium hydroxide, lithium hydroxide, and potassium hydroxide; Feature (21): The hydrolysis acid includes at least one of a hydrochloric acid solution of dioxane and a hydrochloric acid solution of ethyl acetate.

[0018] The present invention has the following beneficial effects: The synthesis method of phosphate fatty alkanoic acid provided by the present invention uses long-chain alkanedioic acid as raw material, and obtains phosphate fatty alkanoic acid through esterification reaction, unilateral hydrolysis reaction, reduction reaction, substitution reaction, halogenation reaction, re-substitution reaction and hydrolysis reaction. In the present invention, there is no need to use witting reaction to grow the carbon chain, and thus there is no problem of low atomic utilization rate; the conversion rate of selective unilateral hydrolysis in the present invention is high; the product purity is high; at the same time, by first adding Ts with TsCl and then halogenating, the present invention realizes the replacement of OH by halogen through a two-step method, avoiding the problem of residual triphenylphosphine PPH3 when using a conventional one-step method (using triphenylphosphine PPH3) for replacement; in addition, each compound of the present invention is purified by conventional pulping, acid and alkali pouring, crystallization and other methods during the purification process, and does not require column chromatography separation and purification steps, and has the advantages of simple operation, high yield, and easy scale-up production. Further, the present invention does not use high temperature, ultra-low temperature, palladium carbon hydrogenation and other reactions, which greatly reduces the danger of production. The present invention does not use highly toxic chemicals. The invention has high reaction yield in each step, high product quality and small maximum single impurity. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0020] Figure 1 This is a chromatogram of the phosphate fatty alkanoic acid prepared in Example 7-1 of the present invention; Figure 2 This is the hydrogen spectrum of the phosphate fatty alkanoic acid prepared in Example 7-1 of the present invention; Figure 3 This is a chromatogram of the phosphate fatty alkanoic acid prepared in Example 7-2 of the present invention; Figure 4 This is the hydrogen spectrum of the phosphate fatty alkanoic acid prepared in Example 7-2 of the present invention; Figure 5 This is the chromatogram of the phosphate fatty alkanoic acid prepared in Example 7-3 of the present invention. DETAILED DESCRIPTION

[0021] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0022] The present invention provides a method for synthesizing a phosphate fatty alkanoic acid, wherein the structural formula of the phosphate fatty alkanoic acid is , wherein R1=Me, Et, t-Bu, Bn or H, R2=Me, Et, t-Bu, Bn or H, R3=Me, Et, t-Bu, Bn or H.

[0023] The synthetic route is as follows (taking halogen as I as an example):

[0024] Among them, A-05 is used as the first intermediate of phosphate fatty alkanoic acid, and A-06 is used as the second intermediate of phosphate fatty alkanoic acid. Next, the present invention will explain the specific operation of each step in detail: (1) Using long-chain alkanedioic acid A-01 as the starting material, a long-chain diester A-02 is obtained by esterification reaction. The reaction equation is as follows: ; Specifically, the long-chain alkanedioic acid A-01 is dissolved in a first organic solvent, and thionyl chloride or anhydride is added to react to obtain a long-chain diester A-02; wherein the first organic solvent includes but is not limited to methanol, acetonitrile, tetrahydrofuran or dichloromethane; the anhydride includes but is not limited to trifluoroacetic anhydride, acetic anhydride or Boc anhydride; the reaction time of the esterification reaction is 4-12 hours. In the present invention, the reaction molar ratio of the long-chain alkanedioic acid A-01, the first organic solvent, and thionyl chloride or anhydride can be in accordance with conventional ratios, without special requirements.

[0025] According to the selection of R1, the first organic solvent, thionyl chloride or acid anhydride, reaction time, etc. can be adjusted accordingly. When R1 is methyl, thionyl chloride is added; the first organic solvent is methanol; the reaction time of the esterification reaction is 6-12h. When R1 is ethyl or tert-butyl, acid anhydride is added, the first organic solvent is acetonitrile, tetrahydrofuran, dichloromethane; the reaction time of the esterification reaction is 4-10h.

[0026] After the above esterification reaction is completed, conventional steps such as product alkali adjustment, extraction, washing, drying and concentration are required to obtain the long-chain diester A-02.

[0027] (2) The long-chain diester A-02 is subjected to unilateral hydrolysis to obtain the long-chain alkanoic acid monoester A-03, and the reaction equation is as follows:

[0028] Specifically, the unilateral hydrolysis reaction includes: dissolving the long-chain diester A-02 in a second organic solvent, adding a hydrolysis base, and reacting to obtain the long-chain alkanoic acid monoester A-03.

[0029] Among them, the second organic solvent includes but is not limited to at least one of methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide and water; preferably the second organic solvent is ethanol or N,N-dimethylformamide; the base for hydrolysis includes but is not limited to at least one of barium hydroxide, potassium hydroxide and sodium hydroxide, and preferably the base for hydrolysis is barium hydroxide; the time of unilateral hydrolysis reaction is 1-4h.

[0030] After the above unilateral hydrolysis reaction is completed, conventional steps such as product filtration, pulping, freeing, drying and concentration are required to obtain long-chain alkanoic acid monoester A-03.

[0031] (3) Long-chain alkanoic acid monoester A-03 is subjected to reduction reaction to obtain long-chain alkanol monoester A-04, and the reaction equation is as follows:

[0032] The reduction reaction comprises: dissolving the long-chain alkanoic acid monoester A-03 in a third organic solvent, adding sodium borohydride or borane tetrahydrofuran solution, and after the reaction is completed, adding a catalyst, stirring sufficiently until no gas is generated, and reacting to obtain the long-chain alkanol monoester A-04.

[0033] The third organic solvent includes but is not limited to at least one of methanol, tetrahydrofuran, N,N-dimethylformamide and water, and preferably the third organic solvent is tetrahydrofuran; the catalyst includes but is not limited to at least one of zinc chloride, methanol, boron trifluoride ether and iodine, and preferably the catalyst is iodine; the reduction reaction time is 1-3h.

[0034] After the reduction reaction is completed, conventional steps such as product quenching, concentration, washing, drying and concentration are required to obtain long-chain alkanol monoester A-04.

[0035] (4) The long-chain alkanol monoester A-04 and p-toluenesulfonyl chloride are subjected to a substitution reaction to obtain p-toluenesulfonyl long-chain alkanoic acid monoester A-05 as the first intermediate. The reaction equation is as follows: .

[0036] The substitution reaction of the long-chain alkanol monoester A-04 and p-toluenesulfonyl chloride comprises dissolving the long-chain alkanol monoester A-04 and p-toluenesulfonyl chloride in a fourth organic solvent, adding a substitution base, and reacting to obtain p-toluenesulfonyl long-chain alkanoic acid monoester A-05.

[0037] Wherein, the fourth organic solvent includes but is not limited to at least one of dichloromethane, tetrahydrofuran, N,N-dimethylformamide and acetonitrile, and the fourth organic solvent is preferably dichloromethane; the substitution base includes but is not limited to at least one of triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate and sodium carbonate, and the substitution base is preferably triethylamine or N,N-diisopropylethylamine; the substitution reaction time is 6-16h.

[0038] After the above substitution reaction is completed, conventional steps such as product acid adjustment, extraction, drying and concentration are required to obtain p-toluenesulfonyl long-chain alkanoic acid monoester A-05.

[0039] (5) The p-toluenesulfonyl long-chain alkanoic acid monoester A-05 is subjected to a halogenation reaction to obtain a halogenated long-chain alkanoic acid monoester A-06 as a second intermediate. The synthetic route thereof is as follows:

[0040] X is halogen.

[0041] The halogenation reaction comprises dissolving p-toluenesulfonyl long-chain alkanoic acid monoester A-05 in a fifth organic solvent and adding sodium halide to obtain halogenated long-chain alkanoic acid monoester A-06.

[0042] Among them, the fifth organic solvent includes but is not limited to at least one of acetone, N,N-dimethylformamide and acetonitrile, and the fifth organic solvent is preferably acetonitrile; the sodium halide includes but is not limited to sodium iodide, sodium bromide or sodium chloride, and the sodium halide is preferably sodium iodide; the halogenation reaction time is 2-6h.

[0043] After the halogenation reaction is completed, conventional steps such as product concentration, extraction, drying and concentration are required to obtain halogenated long-chain alkanoic acid monoester A-06.

[0044] It can be seen from step (4) and step (5) that in the present invention, first, at the OH position of the long-chain alkanol monoester A-04, TsCl and H + The reaction of OH and H + The present invention uses a two-step method to replace OH with a halogen, thereby avoiding the problem of residual triphenylphosphine PPH3 when using a conventional one-step method (using triphenylphosphine PPH3) for replacement.

[0045] (6) The halogenated long-chain alkanoic acid monoester A-06 and the phosphate ester D undergo a substitution reaction to generate the phosphate ester long-chain alkanoic acid monoester A-07. The synthesis route is as follows:

[0046] The re-substitution reaction comprises: reacting the halogenated long-chain alkanoic acid monoester A-06 and the phosphate ester D in the presence of a sixth organic solvent, and adding a re-substitution base.

[0047] Among them, the sixth organic solvent includes but is not limited to at least one of N,N-dimethylformamide and acetonitrile, and the sixth organic solvent is preferably N,N-dimethylformamide; the base for re-substitution includes but is not limited to at least one of cesium carbonate, sodium carbonate, potassium tert-butoxide and sodium hydride, and the base for re-substitution is preferably cesium carbonate; the time for the re-substitution reaction is 5-20 hours.

[0048] (7) The phosphate long-chain alkanoic acid monoester A-07 is hydrolyzed to generate phosphate fatty alkanoic acid A, and the synthesis route is as follows:

[0049] Specifically, the phosphate long-chain alkanoic acid monoester A-07 is dissolved in the seventh organic solvent, and a base or an acid for hydrolysis is added.

[0050] Among them, the seventh organic solvent includes but is not limited to at least one of tetrahydrofuran, methanol, ethanol, dichloromethane and dioxane; the base for hydrolysis includes but is not limited to at least one of sodium hydroxide, lithium hydroxide and potassium hydroxide; the acid for hydrolysis includes but is not limited to at least one of hydrochloric acid dioxane solution and hydrochloric acid ethyl acetate solution.

[0051] In the present invention, the selection of the seventh organic solvent, the base for hydrolysis or the acid for hydrolysis may be adaptively adjusted according to the selection of R1, R2 and R3.

[0052] When R1 is methylethyl, R2 and R3 are tert-butyl and benzyl, A-07 is dissolved in the seventh organic solvent, a base for hydrolysis is added, and the reaction is performed to obtain compound A. The seventh organic solvent is tetrahydrofuran: water, methanol: water, ethanol: water, preferably tetrahydrofuran: water; the preferred ratio is 4:1 (volume ratio); the base for hydrolysis is sodium hydroxide, lithium hydroxide, potassium hydroxide, preferably lithium oxide; the preferred reaction time is 10-20 hours; the product is stripped, acidified, extracted, dried, and concentrated to obtain compound A.

[0053] When R1 is tert-butyl, R2 and R3 are methyl, ethyl, benzyl, A-07 is dissolved in the seventh organic solvent, and an acid for hydrolysis is added to react to obtain compound A. The seventh organic solvent is tetrahydrofuran, dichloromethane, dioxane, preferably dioxane; the acid for hydrolysis is 4N hydrochloric acid dioxane solution, 4N hydrochloric acid ethyl acetate solution, trifluoroacetic acid, preferably 4N hydrochloric acid dioxane solution; the preferred reaction time is 5-10h; the product is alkali-adjusted, stripped, acid-adjusted, extracted, dried, and concentrated to obtain compound A.

[0054] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0055] The chemical names corresponding to some abbreviations used in the following examples and comparative examples are as follows: N,N-diisopropylethylamine: DIEA, dichloromethane: DCM, N,N-dimethylformamide: DMF, tetrahydrofuran: THF, triethylamine: TEA, dioxane: DOX, p-toluenesulfonyl chloride: TsCl, trifluoroacetic anhydride: TFAA, trifluoroacetic acid: TFA.

[0056] Example 1: Synthesis of Compound A1-02

[0057] Example 1-1 When N=15 and R1 is methyl, add 500g (1.5 mol, 1 eq) of A1-01 to 5L of methanol solution, add 381g of thionyl chloride (3.2 mol, 2eq), and react at 80°C for 2h. Cool the reaction solution, concentrate under reduced pressure at 50°C, add 10L of saturated sodium bicarbonate aqueous solution to the reaction solution, then add 3L of ethyl acetate, separate the liquids, extract once with 4L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50°C to obtain 527g of white solid A1-02, with a yield of 97%.

[0058] Example 1-2 When N=13 and R1 is methyl, add 500g (1.67 mol, 1eq) A1-01 to 5L methanol solution, add 418g thionyl chloride (3.5mol, 2.1eq), and react at 80℃ for 2h. Cool the reaction solution, concentrate under reduced pressure at 50℃, add 10L saturated sodium bicarbonate aqueous solution to the reaction solution, add 3L ethyl acetate, separate the liquids, extract once with 4L ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃ to obtain 531g white solid A1-02, with a yield of 97%.

[0059] Examples 1-3 When N=15 and R1 is methyl, add 50g (152 mmol, 1 eq) A1-01 to 1L methanol solution, add 38.1g thionyl chloride (320 mmol, 2.1 eq), and react at room temperature 25℃ for 10h. Concentrate under reduced pressure at 50℃, add 1L saturated sodium bicarbonate aqueous solution to the reaction solution, then add 1L ethyl acetate, separate the liquids, extract once with 2L ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃ to obtain 53.2g white solid A1-02, yield: 98%.

[0060] Examples 1-4 When N=13 and R1 is methyl, add 50g (167 mmol, 1eq) A1-01 to 1L methanol solution, add 47.1g thionyl chloride (396 mmol, 2.3 eq), and react at room temperature 25℃ for 10h. Concentrate under reduced pressure at 50℃, add 1L saturated sodium bicarbonate aqueous solution to the reaction solution, then add 1L ethyl acetate, separate the liquids, extract once with 2L ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃ to obtain 53.1g white solid A1-02, yield: 97%.

[0061] Examples 1-5 When N=15 and R1 is tert-butyl, add 50g (114 mmol, 1 eq) A1-01 to 1L THF solution, add 67.2 g TFAA (320 mmol, 2.8 eq), react at 0℃ for 2h, then add 100mL tert-butyl alcohol, and react at room temperature 25℃ for 5h. Add 1L saturated sodium bicarbonate aqueous solution to the reaction solution, then add 1L ethyl acetate, separate the liquids, extract once with 2L ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃ to obtain 65.1g white solid A1-02, yield: 97%.

[0062] Examples 1-6 When N=13 and R1 is tert-butyl, add 50g (121 mmol, 1 eq) A1-01 to 1L THF solution, add 73.5 g TFAA (350 mmol, 2.8 eq), react at 0℃ for 2h, then add 100mL tert-butyl alcohol, react at room temperature 25℃ for 5h. Add 1L saturated sodium bicarbonate aqueous solution to the reaction solution, then add 1L ethyl acetate, separate the liquids, extract once with 2L ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃ to obtain 66.6g white solid A1-02, yield: 97%.

[0063] Comparative Example 1-1 When N=15 and R1 is methyl, add 50g (152 mmol, 1 eq) of A1-01 to 1L of THF solution, add 40.6g (320 mmol, 2.1 eq) of oxalyl chloride, react at 0℃ for 1h, then add 100mL of methanol, and react at room temperature 25℃ for 3h. Concentrate under reduced pressure at 50℃, add 1L of saturated sodium bicarbonate aqueous solution to the reaction solution, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃ to obtain 38.5g of white solid A1-02, with a yield of 71%.

[0064] The moisture content is difficult to control and the yield is low, so it is not adopted.

[0065] Comparative Example 1-2 When N=15 and R1 is tert-butyl, add 50g (114 mmol, 1 eq) of A1-01 to 1L of THF solution, add 40.6 g (320 mmol, 2.8 eq) of oxalyl chloride, react at 0℃ for 1h, concentrate under reduced pressure at 45℃, add DCM at 0℃ and then 100mL of tert-butyl alcohol, react at room temperature 25℃ for 10h. Concentrate under reduced pressure at 50℃, add 1L of saturated sodium bicarbonate aqueous solution to the reaction solution, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃ to obtain 42.3g of white solid A1-02, with a yield of 63%.

[0066] When concentrating the acyl chloride, the moisture content is difficult to control and the yield is low, so it is not adopted.

[0067] Example 2: Synthesis of Compound A1-03

[0068] Example 2-1 When N=15, add 500g (1.4 mol, 1 eq) A1-02 to 5L DMF, heat to 50℃, dissolve 337g (1.01 mol, 0.70 eq) barium hydroxide octahydrate (add 215g (646mmol, 0.7 eq) barium hydroxide when R1 is tert-butyl) in 2.5L methanol, and pour the dissolved barium hydroxide methanol solution into the reaction. React at 50℃ for 2 hours. Cool down, filter, pulp the filter cake with THF, and concentrate the solid with 0.5N hydrochloric acid at 50℃ under reduced pressure; combine the filtered mother liquor and pulped mother liquor, add 4L of 0.5N hydrochloric acid aqueous solution, and then add 2L of ethyl acetate, separate the liquids, and extract once with 4L ethyl acetate, combine the EA phases, wash the combined EA phases with saturated brine once, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃. When R1 is methyl, 432 g of white solid A1-03 is obtained, with a yield of 90%. When R1 is tert-butyl, 379 g of white solid A1-03 is obtained, with a yield of 87%.

[0069] Example 2-2 When N=13, add 500g (1.5 mol, 1 eq) A1-02 to 5L DMF, heat to 50°C, dissolve 288g (865mmol, 0.6eq) barium hydroxide octahydrate (add 229g (646 mmol, 0.6eq) barium hydroxide when R1 is tert-butyl) in 2.5L methanol, and pour the dissolved barium hydroxide methanol solution into the reaction. React at 50°C for 2 hours. Cool down, filter, pulp the filter cake with THF, and concentrate the solid with 0.5N hydrochloric acid at 50°C under reduced pressure; combine the filtered mother liquor and pulped mother liquor, add 4L of 0.5N hydrochloric acid aqueous solution, and then add 2L of ethyl acetate, separate the liquids, and extract once with 4L ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50°C. When R1 is methyl, 435 g of white solid A1-03 is obtained, with a yield of 91%. When R1 is tert-butyl, 388 g of white solid A1-03 is obtained, with a yield of 90%.

[0070] Comparative Example 2-1 When N=15, add 50g (140 mmol, 1 eq) A1-02 to 500mL methanol, dissolve 33.6g (101 mmol, 0.7 eq) barium hydroxide octahydrate (add 21.5g (65 mmol, 0.7 eq) barium hydroxide when R1 is tert-butyl) in 100mL water, and pour the dissolved barium hydroxide aqueous solution into the reaction. React at 40℃ for 10 hours. Cool down, filter, pulp the filter cake with THF, and concentrate the solid with 0.5N hydrochloric acid at 50℃ under reduced pressure after filtration; combine the filtered mother liquor and pulped mother liquor, add 2L of 0.5N hydrochloric acid aqueous solution, and then add 1L of ethyl acetate, separate the liquids, extract once with 2L ethyl acetate, combine the EA phases, wash the combined EA phases with saturated brine once, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃. When R1 is methyl, 32.1g of white solid A1-03 is obtained, with a yield of 67%. When R1 is tert-butyl, 26.6 g of white solid A1-03 is obtained, with a yield of 61%.

[0071] Comparative Example 2-2 When N=15, add 50g (140 mmol, 1 eq) A1-02 to 500mL methanol, dissolve 7.9g (140 mmol, 1eq) potassium hydroxide (add 6.4g (114 mmol, 1 eq) potassium hydroxide when R1 is tert-butyl) in 100mL water, and pour the dissolved potassium hydroxide aqueous solution into the reaction. React at 40℃ for 10 hours. Cool down, filter, pulp the filter cake with THF, and concentrate the solids with 0.5N hydrochloric acid at 50℃ under reduced pressure; combine the filtered mother liquor and pulped mother liquor, add 2L of 0.5N hydrochloric acid aqueous solution, and then add 1L of ethyl acetate, separate the liquids, and extract once with 2L ethyl acetate, combine the EA phases, wash the combined EA phases with saturated brine once, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃. When R1 is methyl, 31.7g of white solid A1-03 is obtained, with a yield of 66%. When R1 is tert-butyl, 29.8 g of white solid A1-03 is obtained, with a yield of 62%.

[0072] Example 3: Synthesis of Compound A1-04

[0073] Example 3-1 When N=15, add 50g (146 mmol, 1 eq) of A1-03 to 500mL of THF, add 6.1g (160mmol, 1.1 eq) of sodium borohydride (add 5.5g (145 mmol, 1.1 eq) of sodium borohydride when R1 is tert-butyl) at 0°C, dissolve 22.3g (88mmol, 0.55 eq) of iodine (add 19.9g (78.3 mmol, 0.55 eq) of iodine when R1 is tert-butyl) in 100mL of THF, add the dissolved iodine dropwise to the reaction, and react at 0°C for 2 hours. After the reaction is complete, add 200mL of methanol, stir thoroughly until no gas is generated, concentrate under reduced pressure at 50°C, add 2L of water, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50°C. When R1 is methyl, 45.6 g of white solid A1-04 is obtained, with a yield of 95%. When R1 is tert-butyl, 45.3 g of white solid A1-04 is obtained, with a yield of 94%.

[0074] Example 3-2 When N=13, add 50g (159 mmol, 1 eq) of A1-03 to 500mL of THF, add 6.6g (173mmol, 1.1 eq) of sodium borohydride (add 5.9g (155mmol, 1.1 eq) of sodium borohydride when R1 is tert-butyl) at 0°C, dissolve 24.0g (94mmol, 0.55 eq) of iodine (add 21.4g (84 mmol, 0.55 eq) of iodine when R1 is tert-butyl) in 100mL of THF, add the dissolved iodine dropwise to the reaction, and react at 0°C for 2 hours. After the reaction is complete, add 200mL of methanol, stir thoroughly until no gas is generated, concentrate under reduced pressure at 50°C, add 2L of water, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50°C. When R1 is methyl, 44.9 g of white solid A1-04 is obtained, with a yield of 94%. When R1 is tert-butyl, 45.6 g of white solid A1-04 is obtained, with a yield of 95%.

[0075] Example 3-3 When N=15, add 50g (146 mmol, 1 eq) A1-03 to 500mL THF, add 146mL 1N borane tetrahydrofuran solution (146 mmol, 1 eq) at 0°C (add 131mL 1N borane tetrahydrofuran solution (131mmol, 1 eq) when R1 is tert-butyl), and react at 0°C for 2 hours. After the reaction is completed, add 200mL methanol, stir thoroughly until no gas is generated, concentrate under reduced pressure at 50°C, add 2L water, then add 1L ethyl acetate, separate the liquids, extract once with 2L ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50°C. When R1 is methyl, 45.5g white solid A1-04 is obtained, with a yield of 95%. When R1 is tert-butyl, 45.4g white solid A1-04 is obtained, with a yield of 94%.

[0076] Embodiment 3-4 When N=13, add 50g (159 mmol, 1 eq) A1-03 to 500mL THF, add 159mL 1N borane tetrahydrofuran solution (159 mmol, 1 eq) at 0°C (add 140mL 1N borane tetrahydrofuran solution (140mmol, 1 eq) when R1 is tert-butyl), and react at 0°C for 2 hours. After the reaction is completed, add 200mL methanol, stir thoroughly until no gas is generated, concentrate under reduced pressure at 50°C, add 2L water, then add 1L ethyl acetate, separate the liquids, extract once with 2L ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50°C. When R1 is methyl, 44.3g white solid A1-04 is obtained, with a yield of 94%. When R1 is tert-butyl, 45.6g white solid A1-04 is obtained, with a yield of 95%.

[0077] Comparative Example 3-1 When N=15, add 50g (146 mmol, 1 eq) A1-03 to 500mL THF, add 6.1g (160mmol, 1.1 eq) sodium borohydride (add 5.5g (144 mmol, 1.1eq) sodium borohydride when R1 is tert-butyl) at 0℃, add 19.9g (146 mmol, 1 eq) zinc chloride (add 17.8g (131 mmol, 1 eq) zinc chloride when R1 is tert-butyl) and react at 0℃ for 2 hours. After the reaction is completed, add 0.5N dilute hydrochloric acid, stir thoroughly until no gas is generated, add 2L water, then add 1L ethyl acetate, separate the liquids, extract once with 2L ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃. The obtained products all have by-product diols and unreacted substrates, which are not used.

[0078] Example 4: Synthesis of Compound A1-05

[0079] Example 4-1 When N=15, add 50g (152 mmol, 1eq) A1-04 to 500mL DCM, add 46.2g (457mmol, 3 eq) TEA (add 40.9g (405 mmol, 3 eq) TEA when R1 is tert-butyl) at 0°C, then add 32g (168 mmol, 1.1 eq) TsCl (add 28.4g (149mmol, 1.1 eq) TsCl when R1 is tert-butyl), and react at 25°C for 10 hours. After the reaction is completed, concentrate under reduced pressure at 50°C, add 2L of water, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50°C. When R1 is methyl, 66.9g white solid A1-05 is obtained, with a yield of 91%. When R1 is tert-butyl, 65.1 g of white solid A1-05 is obtained, with a yield of 92%.

[0080] Example 4-2 When N=13, add 50g (167 mmol, 1 eq) of A1-04 to 500mL of DCM, add 50.5g (500mmol, 3 eq) of TEA (add 44.2g (438mmol, 3 eq) of TEA when R1 is tert-butyl) at 0°C, then add 35g (183mmol, 1.1 eq) of TsCl (add 38.9g (205 mmol, 1.1 eq) of TsCl when R1 is tert-butyl), and react at 25°C for 10 hours. After the reaction is completed, concentrate under reduced pressure at 50°C, add 2L of water, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at 50°C. When R1 is methyl, 68.9g of white solid A1-05 is obtained, with a yield of 91%. When R1 is tert-butyl, 66.0 g of white solid A1-05 is obtained, with a yield of 91%.

[0081] Comparative Example 4-1 When N=15, add 50g (152 mmol, 1 eq) of A1-04 to 500mL of DCM, add 59g (457mmol, 3 eq) of DIEA (add 52.3g (405 mmol, 3 eq) of DIEA when R1 is tert-butyl) at 0℃, then add 32g (168mmol, 1.1 eq) of TsCl (add 28.4g (149mmol, 1.1 eq) of TsCl when R1 is tert-butyl), and react at 25℃ for 10 hours. After the reaction is completed, concentrate under reduced pressure at 50℃, add 2L of water, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure at 50℃. There is always 20% of the substrate remaining after the treatment, so it is not used.

[0082] Example 5: Synthesis of Compound A1-06

[0083] Example 5-1 When N=15, add 50g (103 mmol, 1 eq) A1-05 to 500mL acetonitrile, add 31.1g (207mmol, 2 eq) sodium iodide (add 28.6g (191 mmol, 2 eq) sodium iodide when R1 is tert-butyl), and react at 80℃ for 3 hours. After the reaction is completed, concentrate under reduced pressure at 50℃, add 2L of water, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure at 50℃, and crystallize the solid with n-heptane. When R1 is methyl, 40.9g white solid A1-06 is obtained, with a yield of 91%. When R1 is tert-butyl, 41.2g white solid A1-06 is obtained, with a yield of 90%.

[0084] Example 5-2 When N=13, add 50g (110 mmol, 1eq) A1-05 to 500mL acetonitrile, add 33g (220 mmol, 2 eq) sodium iodide (add 30g (201 mmol, 2 eq) sodium iodide when R1 is tert-butyl), and react at 80℃ for 3 hours. After the reaction is completed, concentrate under reduced pressure at 50℃, add 2L of water, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure at 50℃, and crystallize the solid with n-heptane. When R1 is methyl, 41.9g white solid A1-06 is obtained, with a yield of 93%. When R1 is tert-butyl, 41.9g white solid A1-06 is obtained, with a yield of 92%.

[0085] Example 5-3 When N=15, add 50g (103 mmol, 1 eq) A1-05 to 500mL acetone, add 31.1g (207mmol, 2 eq) sodium iodide (add 28.6g (191 mmol, 2 eq) sodium iodide when R1 is tert-butyl), and react at 60℃ for 3 hours. After the reaction is completed, concentrate under reduced pressure at 50℃, add 2L of water, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure at 50℃, and crystallize the solid with n-heptane. When R1 is methyl, 41.1g white solid A1-06 is obtained, with a yield of 91%. When R1 is tert-butyl, 41.4g white solid A1-06 is obtained, with a yield of 90%.

[0086] Example 5-4 When N=13, add 50g (110 mmol, 1eq) A1-05 to 500mL acetone, add 33g (220 mmol, 2 eq) sodium iodide (add 30g (201 mmol, 2 eq) sodium iodide when R1 is tert-butyl), and react at 60℃ for 3 hours. After the reaction is completed, concentrate under reduced pressure at 50℃, add 2L of water, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure at 50℃, and crystallize the solid with n-heptane. When R1 is methyl, 41.9g of white solid A1-06 is obtained, with a yield of 93%. When R1 is tert-butyl, 41.9g of white solid A1-06 is obtained, with a yield of 92%.

[0087] Comparative Example 5-1 When N=15, add 50g (152 mmol, 1 eq) A1-04 to 500mL dichloromethane, add 43.9g (168 mmol, 1.1 eq) triphenylphosphine (add 38.9g (149 mmol, 1.1 eq) triphenylphosphine when R1 is tert-butyl), add 39.4g (175mmol, 1.15 eq) NIS (add 34.9g (135 mmol, 1.15 eq) NIS when R1 is tert-butyl), and react at room temperature for 3 hours. After the reaction is completed, concentrate under reduced pressure at 45℃, purify by column chromatography, collect the eluent when PE:EA=90:1, which is the product, and concentrate under reduced pressure at 45℃. When R1 is methyl, 42.1g white solid A1-06 is obtained, with a yield of 63%. When R1 is tert-butyl, 38.3 g of white solid A1-06 is obtained, with a yield of 59%. In this comparative example, the residual triphenylphosphine and triphenylphosphine oxide generated by the reaction are difficult to remove, and the column chromatography method is not economical and not suitable for large-scale factory production; secondly, the iodide is too active and may react with unreacted triphenylphosphine to generate by-products. Therefore, it is not adopted.

[0088] Example 6: Synthesis of Compound A1-07

[0089] Example 6-1 When N=15, add 50g (114 mmol, 1 eq) of A1-06 to 500mL of DMF, add 38.9g (148mmol, 1.3 eq) of dibenzyl phosphite (add 35.5g (135 mmol, 1.3 eq) of dibenzyl phosphite when R1 is tert-butyl), then add 111.6g (342 mmol, 3 eq) of cesium carbonate (add 101.9g (312 mmol, 3 eq) of cesium carbonate when R1 is tert-butyl), and react at 25°C for 16 hours. After the reaction is completed, add 2L of saturated ammonium chloride aqueous solution, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure at 50°C, and crystallize the solid with n-heptane:ethyl acetate (3:1). When R1 is methyl, 55.5 g of white solid A1-07 is obtained, with a yield of 85%. When R1 is tert-butyl, 55.0 g of white solid A1-07 is obtained, with a yield of 86%.

[0090] Example 6-2 When N=13, add 50g (122 mmol, 1 eq) of A1-06 to 500mL of DMF, add 41.5g (158mmol, 1.3 eq) of dibenzyl phosphite (add 37.7g (143 mmol, 1.3 eq) of dibenzyl phosphite when R1 is tert-butyl), then add 119.3g (366 mmol, 3 eq) of cesium carbonate (add 108.2g (331 mmol, 3 eq) of cesium carbonate when R1 is tert-butyl), and react at 25°C for 16 hours. After the reaction is completed, add 2L of saturated ammonium chloride aqueous solution, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure at 50°C, and crystallize the solid with n-heptane:ethyl acetate (3:1). When R1 is methyl, 57.1 g of white solid A1-07 is obtained, with a yield of 86%. When R1 is tert-butyl, 54.5 g of white solid A1-07 is obtained, with a yield of 84%.

[0091] Comparative Example 6-1 When N=15, add 50g (114 mmol, 1 eq) of A1-06 to 500mL of THF, add 38.9g (148mmol, 1.3 eq) of dibenzyl phosphite (add 35.5g (135 mmol, 1.3 eq) of dibenzyl phosphite when R1 is tert-butyl), then add 111.6g (342 mmol, 3 eq) of cesium carbonate (add 101.9g (312 mmol, 3 eq) of cesium carbonate when R1 is tert-butyl), and react at 25℃ for 16 hours. When tetrahydrofuran is used as a solvent, its solubility for salt is poor, resulting in unsatisfactory reaction results, with only a small amount of product and most of the substrate, so it is not used.

[0092] Comparative Example 6-2 When N=15, add 50g (114 mmol, 1 eq) of A1-06 to 500mL of DMF, add 38.9g (148mmol, 1.3 eq) of dibenzyl phosphite (add 35.5g (135 mmol, 1.3 eq) of dibenzyl phosphite when R1 is tert-butyl), then add 25.5g (209 mmol, 1.8eq) of potassium tert-butoxide (add 23.3g (191 mmol, 1.8eq) of potassium tert-butoxide when R1 is tert-butyl), and react at 25°C for 16 hours. After the reaction is complete, add 2L of saturated ammonium chloride aqueous solution, then add 1L of ethyl acetate, separate the liquids, extract once with 2L of ethyl acetate, combine the EA phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure at 50°C, and crystallize the solid with n-heptane:ethyl acetate (3:1). When R1 is methyl, 35.3 g of white solid A1-07 is obtained, with a yield of 54%. When R1 is tert-butyl, 38.4 g of white solid A1-07 is obtained, with a yield of 60%. The yield is low and there are impurities, so it is not used.

[0093] In addition, this example also screened the conditions of the solvent and base in the re-substitution reaction, which can be specifically referred to Example 6-1. Please refer to Table 1 for specific screening results.

[0094] Table 1. Screening results of solvent and base conditions in the substitution reaction

[0095] It can be seen from the above table that the selection of solvent and base in the re-substitution reaction has a great influence on the yield of A1-07. By selecting the sixth organic solvent and the re-substitution base in the present invention, a good yield can be obtained.

[0096] Example 7: Synthesis of Compound A1

[0097] Example 7-1 When N=15 and R1 is methyl, add 50g (87.4 mmol, 1 eq) A1-07 to 500mL THF and 100mL water, add 7.3g (174 mmol, 2 eq) lithium hydroxide, and react at 25°C for 16 hours. After the reaction is completed, add 2L of water, then add 1L of ethyl acetate, separate the liquids, add 500mL of 1N dilute hydrochloric acid, and extract twice with 2L of ethyl acetate, one liter each time; combine the organic phases extracted after acid adjustment, wash the combined EA phase once with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure at 50°C, and crystallize the solid with ethyl acetate. 40.9g of white solid A1 is obtained, with a yield of 90%, a purity of 99.50%, and a maximum single impurity of 0.13%. 1HNMR (400MHz, DMSO-d6) δ 11.98 (br, 1H), 7.41-7.32 (m, 10H), 5.06-4.94 (m, 4H), 2.21-2.17 (m, 2H), 1.83-1.74 (m, 2H), 1.53-1.40 (m, 4H), 1.25-1.20 (m, 28H). (HPLC see Figure 1 , HNMR see Figure 2 ).

[0098] Example 7-2 When N=13 and R1 is methyl, add 50g (92 mmol, 1 eq) A1-07 to 500mL THF and 100mL water, add 11.6g (276 mmol, 3 eq) lithium hydroxide, and react at 25°C for 16 hours. After the reaction is completed, add 2L of water, then add 1L of ethyl acetate, separate the liquids, add 500mL of 1N dilute hydrochloric acid, and extract twice with 2L of ethyl acetate, one liter each time; combine the organic phases extracted after acid adjustment, wash the combined EA phase once with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure at 50°C, and crystallize the solid with ethyl acetate. 44.3g of white solid A1 is obtained, with a yield of 91%, a purity of 99.45%, and a maximum single impurity of 0.12%. 1 HNMR (400MHz, DMSO-d6) δ 11.98 (br, 1H), 7.36-7.30 (m, 10H), 5.04-4.92 (m, 4H), 2.18-2.15 (m, 2H), 1.80-1.72 (m, 2H), 1.49-1.42 (m, 4H), 1.22-1.17 (m, 28H). (HPLC see Figure 3 , HNMR see Figure 4 ).

[0099] Example 7-3 When N=15 and R1 is tert-butyl, add 50g (81 mmol, 1 eq) of A1-07 to 500mL of DOX, add 81mL (324 mmol, 4eq) of 4M hydrochloric acid dioxane solution, and react at 25°C for 16 hours. After the reaction is completed, add 2L of water, add 1L of ethyl acetate, and extract once with 2L of ethyl acetate. Combine the organic phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure at 50°C, and crystallize the solid with ethyl acetate. 41.8g of white solid A1 is obtained, with a yield of 92%, a purity of 99.57%, and a maximum single impurity of 0.10% (HPLC see Figure 5 ).

[0100] Example 7-4 When N=13 and R1 is tert-butyl, add 50g (85 mmol, 1 eq) of A1-07 to 500mL of DOX, add 85mL (340 mmol, 4 eq) of 4M hydrochloric acid dioxane solution, and react at 25°C for 16 hours. After the reaction is completed, add 2L of water, add 1L of ethyl acetate, and extract once with 2L of ethyl acetate. Combine the organic phases, wash the combined EA phases once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure at 50°C, and crystallize the solid with ethyl acetate. 41.2g of white solid A1 is obtained, with a yield of 91%.

[0101] Comparative Example 7-1 When N=15 and R1 is methyl, add 50g (87.4 mmol, 1 eq) of A1-07 to 500mL of methanol and 100mL of water, add 7.0g (174 mmol, 2 eq) of sodium hydroxide, and react at 25°C for 16 hours. After the reaction is completed, add 2L of water, then add 1L of ethyl acetate, separate the liquids, add 500mL of 1N dilute hydrochloric acid, extract twice with 2L of ethyl acetate, one liter each time; combine the organic phases extracted after acid adjustment, wash the combined EA phase once with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure at 50°C, and crystallize the solid with ethyl acetate. 19.5g of white solid A1 is obtained, with a yield of 41%.

[0102] Comparative Example 7-2 When N=15 and R1 is tert-butyl, add 50g (81 mmol, 1 eq) of A1-07 to 500mL of DOX, add 27.8g (244 mmol, 3 eq) of TFA, and react at 25°C for 16 hours. After the reaction is completed, add 2L of water, add 1L of ethyl acetate, and extract once with 2L of ethyl acetate. Combine the organic phases, wash the combined EA phases once with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure at 50°C, and crystallize the solid with ethyl acetate. 31.8g of white solid A1 is obtained, with a yield of 70%. There are impurities that remove benzyl groups, so it is not used.

[0103] In addition, in this embodiment, the hydrolysis conditions were screened as follows when N=15 and R1 was tert-butyl. During the screening, the amount of acid added was 4 eq, the reaction temperature was 25°C and the reaction was carried out for 16 h. Please refer to Table 2 for the screening results.

[0104] Table 2. Statistical table of screening results of hydrolysis conditions when N=15 and R1 is tert-butyl

[0105] It can be seen from the above table that the selection of different solvents and acids has a great influence on the yield of the product.

[0106] In summary, the synthesis method of phosphate fatty alkanoic acid provided by the present invention uses long-chain alkane dioic acid as raw material, and obtains phosphate fatty alkanoic acid through esterification reaction, unilateral hydrolysis reaction, reduction reaction, substitution reaction, halogenation reaction, re-substitution reaction and hydrolysis reaction. In the present invention, there is no need to use witting reaction to grow the carbon chain, and thus there is no problem of low atomic utilization; the conversion rate of selective unilateral hydrolysis in the present invention is high; the product purity is high; at the same time, by first adding Ts with TsCl and then halogenating, the present invention realizes the replacement of OH by halogen through a two-step method, avoiding the problem of residual triphenylphosphine PPH3 when using a conventional one-step method (using triphenylphosphine PPH3) for substitution; in addition, each compound of the present invention is purified by conventional pulping, acid and alkali pouring, crystallization and other methods during the purification process, and does not require column chromatography separation and purification steps, and has the advantages of simple operation, high yield, and easy to scale up production. Further, the present invention does not use high temperature, ultra-low temperature, palladium carbon hydrogenation and other reactions, which greatly reduces the danger of production. The present invention does not use highly toxic chemicals. The invention has high reaction yield in each step, high product quality and small maximum single impurity.

[0107] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a first intermediate of a phosphate fatty alkanoic acid, characterized in that: It includes: S1. Using a long-chain alkanedioic acid as a starting material, a long-chain alkanol monoester is prepared by esterification reaction, unilateral hydrolysis reaction and reduction reaction; The structural formula of the long-chain alkanedioic acid is , the structural formula of the long-chain alkanol monoester is , wherein N=10-26, R1=Me, Et, t-Bu, Bn or H; S2, subjecting the long-chain alkanol monoester and p-toluenesulfonyl chloride to a substitution reaction to obtain p-toluenesulfonyl long-chain alkanoic acid monoester as a first intermediate, wherein the p-toluenesulfonyl long-chain alkanoic acid monoester has the structural formula: .

2. The method for synthesizing the first intermediate of phosphate fatty alkanoic acid according to claim 1, characterized in that: The esterification reaction in step S1 includes: dissolving the long-chain alkanedioic acid in a first organic solvent, adding thionyl chloride or anhydride, and reacting to obtain a long-chain diester, wherein the long-chain diester has a structural formula of ; The esterification reaction includes at least one of features (1) to (3): Feature (1): The first organic solvent is methanol, acetonitrile, tetrahydrofuran, or dichloromethane; Feature (2): The acid anhydride is trifluoroacetic anhydride, acetic anhydride, or Boc anhydride; Feature (3): The reaction temperature of the esterification reaction is 20-30°C and the reaction time is 4-12h.

3. The method for synthesizing the first intermediate of phosphate fatty alkanoic acid according to claim 2, characterized in that: The unilateral hydrolysis reaction in step S1 comprises: dissolving the long-chain diester in a second organic solvent, adding a hydrolysis base, and reacting to obtain a long-chain alkanoic acid monoester, wherein the long-chain alkanoic acid monoester has the structural formula ; The unilateral hydrolysis reaction includes at least one of features (4) to (6): Feature (4): the second organic solvent comprises at least one of methanol, ethanol, tetrahydrofuran and N,N-dimethylformamide; Feature (5): The hydrolysis base includes at least one of barium hydroxide and sodium hydroxide; Feature (6): The reaction temperature of the unilateral hydrolysis reaction is 40-60°C and the reaction time is 1-4h.

4. The method for synthesizing the first intermediate of phosphate fatty alkanoic acid according to claim 3, characterized in that: The reduction reaction in step S1 comprises: dissolving the long-chain alkanoic acid monoester in a third organic solvent, adding sodium borohydride or borane tetrahydrofuran solution, adding a catalyst after the reaction is completed, stirring sufficiently until no gas is generated, and reacting to obtain a long-chain alkanol monoester, wherein the long-chain alkanol monoester has a structural formula of ; The reduction reaction includes at least one of features (7) to (9); Feature (7): The third organic solvent comprises at least one of methanol, tetrahydrofuran, N,N-dimethylformamide and water; Feature (8): The catalyst comprises at least one of zinc chloride, methanol, boron trifluoride etherate and iodine; Feature (9): The reaction temperature of the reduction reaction is -5~5°C and the reaction time is 1-3h.

5. The method for synthesizing the first intermediate of phosphate fatty alkanoic acid according to claim 1, characterized in that: The substitution reaction of the long-chain alkanol monoester and the p-toluenesulfonyl chloride in step S2 comprises dissolving the long-chain alkanol monoester and the p-toluenesulfonyl chloride in a fourth organic solvent, adding a substitution base, and reacting to obtain a p-toluenesulfonyl long-chain alkanoic acid monoester; the substitution reaction comprises at least one of features (10) to (12); Feature (10): The fourth organic solvent comprises at least one of dichloromethane, tetrahydrofuran, N,N-dimethylformamide and acetonitrile; Feature (11): The substitution base comprises at least one of triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate and sodium carbonate; Feature (12): The reaction temperature of the substitution reaction is 20-30°C and the reaction time is 6-16h.

6. A method for synthesizing a second intermediate of a phosphate fatty alkanoic acid, characterized in that: It includes: The first intermediate prepared by the synthesis method of the first intermediate of the phosphate fatty alkanoic acid according to any one of claims 1 to 5, p-toluenesulfonyl long-chain alkanoic acid monoester, is subjected to a halogenation reaction to obtain a halogenated long-chain alkanoic acid monoester as a second intermediate, wherein the halogenated long-chain alkanoic acid monoester has the structural formula , X is a halogen.

7. The method for synthesizing the second intermediate of phosphate fatty alkanoic acid according to claim 6, characterized in that: The halogenation reaction comprises dissolving the p-toluenesulfonyl long-chain alkanoic acid monoester in a fifth organic solvent and adding sodium halide to obtain a halogenated long-chain alkanoic acid monoester; the halogenation reaction comprises at least one of features (13) to (15); Feature (13): The fifth organic solvent comprises at least one of acetone, N,N-dimethylformamide and acetonitrile; Feature (14): The sodium halide includes sodium iodide, sodium bromide or sodium chloride; Feature (15): The reaction temperature of the halogenation reaction is 70-90°C and the reaction time is 2-6h.

8. A method for synthesizing phosphate fatty alkanoic acid, characterized in that: The method comprises subjecting the second intermediate prepared by the synthesis method of the second intermediate of the phosphate fatty alkanoic acid according to any one of claims 6 to 7 to a substitution reaction with a phosphate to generate a phosphate long-chain alkanoic acid monoester, and hydrolyzing the phosphate long-chain alkanoic acid monoester to generate a phosphate fatty alkanoic acid; Wherein, the structural formula of the phosphate ester is The structural formula of the phosphate long-chain alkanoic acid monoester is The structural formula of the phosphate fatty acid is , R2=Me, Et, t-Bu, Bn or H, R3=Me, Et, t-Bu, Bn or H.

9. The method for synthesizing phosphate fatty alkanoic acid according to claim 8, characterized in that: The re-substitution reaction comprises: reacting the halogenated long-chain alkanoic acid monoester and the phosphate ester in the presence of a sixth organic solvent, adding a re-substitution base; the re-substitution reaction comprises at least one of the following features (16) to (18): Feature (16): The sixth organic solvent comprises at least one of N,N-dimethylformamide and acetonitrile; Feature (17): The re-substitution base comprises cesium carbonate; Feature (18): The reaction temperature of the re-substitution reaction is 20-30°C and the reaction time is 5-20h.

10. The method for synthesizing phosphate fatty alkanoic acid according to claim 8, characterized in that: The hydrolysis of the phosphate long-chain alkanoic acid monoester comprises: dissolving the phosphate long-chain alkanoic acid monoester in a seventh organic solvent, and adding a hydrolysis base or a hydrolysis acid; the hydrolysis of the phosphate long-chain alkanoic acid monoester comprises at least one of the features (19) to (21): Feature (19): The seventh organic solvent includes at least one of tetrahydrofuran, methanol, ethanol, dichloromethane and dioxane; Feature (20): The hydrolysis base includes at least one of sodium hydroxide, lithium hydroxide, and potassium hydroxide; Feature (21): The hydrolysis acid includes at least one of a hydrochloric acid solution of dioxane and a hydrochloric acid solution of ethyl acetate.

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