Intermediate for synthesizing enoxaparin and synthesis method of enoxaparin

Abstract

The invention discloses an intermediate for synthesizing enoxaparin and a synthesis method of enoxaparin, and relates to the technical field of chemical total synthesis. The enoxaparin is prepared through a total synthesis path for the first time, dependence on natural heparin raw materials is thoroughly eliminated, the problems of limited raw material sources and batch difference are solved, and stable guarantee is provided for large-scale production. Through modular design and directional synthesis of 19 key intermediates, accurate control of a sugar ring structure, a substituent position and a sulfation site is realized. According to the method, total synthesis of enoxaparin is achieved for the first time, dependence of natural heparin is avoided, the product is verified to be accurate in structure through 1HNMR and has high purity (larger than 98%) and batch consistency, and a reliable path is provided for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical total synthesis, and in particular to an intermediate for synthesizing enoxaparin and a method for synthesizing the enoxaparin. Background Art

[0002] Enoxaparin, a low-molecular-weight heparin, is widely used in clinical practice to prevent and treat diseases such as thrombosis and has important medicinal value. However, despite growing market demand for enoxaparin, its synthesis process faces numerous challenges.

[0003] Currently, the synthesis of enoxaparin primarily relies on chemical modification and transformation of natural heparin. While this approach has achieved some success, it presents a series of challenges. Firstly, the relatively limited source of natural heparin makes it difficult to meet the demands of large-scale production. Secondly, the complex chemical modification process makes it difficult to precisely control the product's structure and properties, resulting in difficulties in ensuring consistent and stable product quality.

[0004] Furthermore, there is no mature total synthesis method that can effectively prepare enoxaparin. The advantage of total synthesis is that it can precisely design and construct the structure of the target molecule, thereby potentially obtaining products of higher purity and more stable quality, and can also break away from dependence on natural raw materials and achieve large-scale industrial production.

[0005] Based on the above background, the present invention aims to provide a new intermediate for the synthesis of enoxaparin and a synthesis method thereof, to solve the problems existing in the prior art through a total synthesis route, to fill the gap in this field, and to provide a more efficient, controllable and sustainable solution for the production of enoxaparin. Summary of the Invention

[0006] The purpose of the present invention is to provide an intermediate for synthesizing enoxaparin and a method for synthesizing enoxaparin in response to the problems existing in the prior art, so as to solve the problems existing in the existing enoxaparin synthesis process, such as reliance on chemical modification of natural heparin, difficulty in accurately controlling the structure and properties of the product, and difficulty in ensuring the consistency and stability of product quality. The present invention fills the gap in the field of total synthesis of enoxaparin, realizes efficient, controllable and scalable total synthesis production of enoxaparin, and meets the market demand for high-quality enoxaparin.

[0007] To achieve the above object, the technical solution adopted by the present invention is: an intermediate compound for synthesizing enoxaparin, the intermediate compound comprising: intermediate 1, intermediate 2, intermediate 3, intermediate 4, intermediate 5, intermediate 6, intermediate 7, intermediate 8, intermediate 9, intermediate 10, intermediate 11, intermediate 12, intermediate 13, intermediate 14, intermediate 15, intermediate 16, intermediate 17, intermediate 18, intermediate 19, corresponding to the structure shown below:

[0008] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

[0009] Further, the synthesis method of the intermediate 2 is:

[0010] ;

[0011] The first step in the synthesis of intermediate 2 is to add 3-bromo-5-(methoxycarbonyl)cyclohex-4-ene-1,2-diacetyl diacetate, sodium carbonate, and tetrahydrofuran to a reaction system under a nitrogen atmosphere at a reaction temperature of 60-80°C for 8-12 hours. After the reaction, intermediate 1 is obtained by post-treatment methods acceptable in the field of chemical synthesis.

[0012] The molar ratio of 3-bromo-5-(methoxycarbonyl)cyclohex-4-ene-1,2-diacetyl diacetate and sodium carbonate is 1:6;

[0013] The second step of the synthesis of intermediate 2: Under a nitrogen atmosphere, intermediate 1, methyl iodide, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate and dimethyl sulfoxide are added to the reaction system at a reaction temperature of 80-90° C. for 16-20 hours. After the reaction, intermediate 2 is obtained by post-treatment methods acceptable in the field of chemical synthesis;

[0014] The molar ratio of the intermediate 1, methyl iodide, pyridine-2-carboxylic acid, CuI and potassium phosphate trihydrate is 1:2.5:0.02:0.1:4.

[0015] Further, the synthesis method of the intermediate 4 is:

[0016] ;

[0017] The first step in the synthesis of intermediate 4: under a nitrogen atmosphere, 3,4,5-trihydroxycyclohexane-1-carboxylic acid, methyl iodide, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate, and dimethyl sulfoxide are added to the reaction system at a reaction temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 3 is obtained by post-treatment methods acceptable in the field of chemical synthesis.

[0018] The molar ratio of 3,4,5-trihydroxycyclohexane-1-carboxylic acid, methyl iodide, pyridine-2-carboxylic acid, CuI, and potassium phosphate trihydrate is 1:3.2:0.03:0.15:6;

[0019] The second step of the synthesis of intermediate 4: Under a nitrogen atmosphere, intermediate 3, N-bromosuccinimide and dichloromethane were added to the reaction system at a reaction temperature of 25-30°C for 16 hours, and the reaction was stopped. Intermediate 4 was obtained by post-treatment methods acceptable in the field of chemical synthesis;

[0020] The molar ratio of intermediate 3 to N-bromosuccinimide is 1:1.2.

[0021] Further, the synthesis method of the intermediate 5 is:

[0022] ;

[0023] The first step in the synthesis of intermediate 5: under a nitrogen atmosphere, 6-(hydroxymethyl)tetrahydro-2H-pyran-2,5-diol, sulfonyl chloride, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate, and dimethyl sulfoxide are added to the reaction system at a reaction temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 5 is obtained by post-treatment methods acceptable in the field of chemical synthesis.

[0024] The molar ratio of 6-(hydroxymethyl)tetrahydro-2H-pyran-2,5-diol, sulfonyl chloride, pyridine-2-carboxylic acid, CuI and potassium phosphate trihydrate is 1:1.2:0.01:0.05:2.

[0025] Furthermore, the active sites of 6-(hydroxymethyl)tetrahydro-2H-pyran-2,5-diol are numbered as follows: 1-hydroxy a , 1-hydroxy b and 1-hydroxy c The specific structural sites are shown in Figure 2 The rigid structure of the pyran ring leads to the 1-hydroxyl group in the ring a and 1-hydroxy bThe surrounding space is crowded and the sulfonyl chloride molecule is difficult to approach; while the 1-hydroxyl group of hydroxymethyl c The chain structure outside the ring is more open, and sulfonyl chloride is more accessible and reacts more easily.

[0026] Further, the synthesis method of the intermediate 7 is:

[0027] ;

[0028] The first step in the synthesis of intermediate 7: Under a nitrogen atmosphere, 3,4-dihydroxycyclohexane-1-carboxylic acid, methyl iodide, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate, and dimethyl sulfoxide are added to the reaction system at a temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 6 is obtained by post-treatment methods acceptable in the field of chemical synthesis.

[0029] The molar ratio of 3,4-dihydroxycyclohexane-1-carboxylic acid, methyl iodide, pyridine-2-carboxylic acid, CuI, and potassium phosphate trihydrate is 1:2.2:0.02:0.10:4;

[0030] The second step of the synthesis of intermediate 7: Under a nitrogen atmosphere, intermediate 6, N-bromosuccinimide and dichloromethane were added to the reaction system at a reaction temperature of 25-30° C. for 16 hours, and the reaction was stopped. Intermediate 7 was obtained by post-treatment methods acceptable in the field of chemical synthesis;

[0031] The molar ratio of intermediate 6 to N-bromosuccinimide is 1:2.2.

[0032] Furthermore, the active sites of the intermediate 6 are numbered as follows: 2-active site a , 2-active site group b and 2-active site c The specific structural sites are shown in Figure 3 The strong electron-withdrawing effect of the carboxyl group activates the 2-active site group b , weakening the CH bond and promoting the bromine radical (Br·) to extract hydrogen. The electron-donating conjugation effect of the methoxy group enhances the 2-active site c and 2-active site b electron density, but its adjacent position is more accessible to Br· due to its small steric hindrance, so Br· is limited to the active site c and 2-active site b A reaction occurs.

[0033] Further, the synthesis method of the intermediate 11 is:

[0034] ;

[0035] The first step in the synthesis of intermediate 11: (E)-N-(2,4,5-trimethoxy-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)acetimidate was dissolved in 10 times the mass of tetrahydrofuran, the system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 was added dropwise. The reaction was stopped at room temperature for 2 hours, and intermediate 8 was obtained by post-processing methods acceptable in the field of chemical synthesis.

[0036] The molar ratio of (E)-N-(2,4,5-trimethoxy-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)acetimidate and BBr3 is 1:1;

[0037] The dichloromethane solution of BBr3 is a dichloromethane solution containing 10% BBr3;

[0038] Step 2 of the synthesis of intermediate 11: To a Schlenk flask equipped with a stirring bar, intermediate 8, triethylamine, and 1,4-dioxane were added, and the mixture was treated with positive pressure of sulfur dioxide difluoride gas, followed by five high vacuum evacuation / backfill cycles. The mixture was vigorously stirred at room temperature for 2 h, and palladium acetate, 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl, potassium phosphate, trimethylboroxane, and 1,4-dioxane were added. The mixture was treated with positive pressure of nitrogen and five high vacuum evacuation / backfill cycles. The mixture was reacted at 120°C for 2 h. The reaction was stopped, and intermediate 9 was obtained by post-treatment methods acceptable in the field of chemical synthesis.

[0039] The molar ratio of intermediate 8, triethylamine, palladium acetate, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, potassium phosphate, and trimethylboroxane is 1:5:0.05:0.06:2:0.5;

[0040] The third step of the synthesis of intermediate 11: Intermediate 9 was dissolved in 10 times the mass of tetrahydrofuran, the system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 was added dropwise. The reaction was stopped at room temperature for 2 hours, and intermediate 10 was obtained by post-treatment methods acceptable in the field of chemical synthesis.

[0041] The molar ratio of intermediate 9 and BBr3 is 1:2;

[0042] Step 4 of the synthesis of intermediate 11: Dissolve intermediate 10 and triethylamine in 10 times the mass of dichloromethane, introduce sulfur dioxide difluoride SO2F2 gas and stir at room temperature for 4 hours, flush the SO2F2 with argon, stop the reaction, and obtain intermediate 11 by post-treatment methods acceptable in the field of chemical synthesis;

[0043] The molar ratio of intermediate 10 and triethylamine is 1:1.5.

[0044] Furthermore, the active site number of the (E)-N-(2,4,5-trimethoxy-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)acetimidate is: 3-active site a , 3-active site group b , 3-active site c , 3-active site d , 3-active site e The specific structural sites are shown in Figure 4 3-Active site d The methoxymethyl group is directly adjacent to the N on the six-membered ring. Its strong electron-withdrawing effect significantly polarizes the oxygen atom of the methoxy group, reducing the electron density of O-CH3 and making it more susceptible to attack by the boron-deficient center of BBr3. d Located in the chain structure outside the ring (rather than the rigid site inside the ring), the steric hindrance is much smaller than that of other methoxy groups inside the ring, and BBr3 can approach the oxygen atom more freely. The neighboring nitrogen atom forms a weak coordination effect with BBr3 through the lone pair of electrons, preferentially guiding the reagent to approach the 3-active site d At the same time, the chair conformation of the ring makes the methoxy group in a flat bond, and the oxygen atom is fully exposed. These factors synergistically lead to the 3-active site d The methoxymethyl group was specifically removed to generate the hydroxy-substituted intermediate 8.

[0045] Furthermore, the synthesis method of the intermediate 14 is:

[0046] ;

[0047] The first step in the synthesis of intermediate 14: 2-(benzyloxy)-3-methyl-6,8-dioxacyclo[3.2.1]octan-4-ol, sodium hydride, and dry toluene were added to the reaction system, stirred at room temperature for 1 hour, cyanuric chloride was added, and stirring was continued for 1 hour. The temperature was raised to 110°C and stirred for 10 hours. Ammonium carbonate, dichlorobis(triphenylphosphine)nickel, and potassium phosphate were added under an argon atmosphere, and the mixture was stirred at 100°C for 12 hours. The reaction was stopped, and intermediate 12 was obtained by post-processing methods acceptable in the field of chemical synthesis.

[0048] The molar ratio of 2-(benzyloxy)-3-methyl-6,8-dioxacyclo[3.2.1]octan-4-ol, sodium hydride, cyanuric chloride, ammonium carbonate, dichlorobis(triphenylphosphine)nickel, and potassium phosphate is: 1:1.5:0.3:5:0.05:2;

[0049] Step 2 of the synthesis of intermediate 14: Under nitrogen protection, intermediate 12, sulfonyl chloride, sodium tert-butoxide, tris(dibenzylideneacetone)dipalladium, tri-tert-butylphosphine, and toluene were added to the reaction system, the temperature was raised to 120°C, the reaction was allowed to proceed for 12 hours, the reaction was stopped, and intermediate 13 was obtained by post-treatment methods acceptable in the field of chemical synthesis;

[0050] The molar ratio of intermediate 12, sulfonyl chloride, sodium tert-butoxide, tris(dibenzylideneacetone)dipalladium, and tri-tert-butylphosphine is: 1:1.2:2:0.03:2;

[0051] Step 3 of the synthesis of intermediate 14: Intermediate 13 was dissolved in 10 times the mass of tetrahydrofuran, the system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 was added dropwise. The reaction was continued at room temperature for 2 hours, and the reaction was stopped. Intermediate 14 was obtained by post-treatment methods acceptable in the field of chemical synthesis.

[0052] The molar ratio of intermediate 13 and BBr3 is 1:1.

[0053] Furthermore, the synthesis method of the intermediate 18 is:

[0054] ;

[0055] The first step in the synthesis of intermediate 18: intermediate 4, intermediate 5, intermediate 2, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate and dimethyl sulfoxide, the reaction temperature is 80-90°C, the reaction time is 16-20 hours, and after the reaction, the intermediate 17 is obtained by post-treatment methods acceptable in the field of chemical synthesis;

[0056] The molar ratio of intermediate 4, intermediate 5, intermediate 2, pyridine-2-carboxylic acid, CuI, and potassium phosphate trihydrate is 1:1:1:0.03:0.15:6;

[0057] The second step of the synthesis of intermediate 18: Intermediate 17 was dissolved in 10 times the mass of tetrahydrofuran, the system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 was added dropwise. The reaction was continued at room temperature for 2 hours, and the reaction was stopped. Intermediate 18 was obtained by post-treatment methods acceptable in the field of chemical synthesis.

[0058] The molar ratio of intermediate 17 and BBr3 is 1:5.

[0059] Furthermore, the synthesis method of the intermediate 16 is:

[0060] ;

[0061] The first step in the synthesis of intermediate 16 is to add intermediate 7, intermediate 8, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate, and dimethyl sulfoxide to the reaction system at a reaction temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 15 is obtained by post-treatment methods acceptable in the field of chemical synthesis.

[0062] The molar ratio of intermediate 7, intermediate 8, pyridine-2-carboxylic acid, CuI, and potassium phosphate trihydrate is 1:1.2:0.01:0.05:2;

[0063] The second step of the synthesis of intermediate 16: intermediate 15, intermediate 14, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate and dimethyl sulfoxide are added to the reaction system at a reaction temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 16 is obtained by post-treatment methods acceptable in the field of chemical synthesis.

[0064] The molar ratio of intermediate 15, intermediate 14, pyridine-2-carboxylic acid, CuI and potassium phosphate trihydrate is 1:1.2:0.01:0.05:2.

[0065] An intermediate compound for synthesizing enoxaparin is used to synthesize enoxaparin. The synthesis method of enoxaparin is as follows:

[0066] ;

[0067] The first step of the synthesis of enoxaparin: intermediate 18, intermediate 16, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate and dimethyl sulfoxide are added to the reaction system at a temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 19 is obtained by post-treatment methods acceptable in the field of chemical synthesis.

[0068] The molar ratio of intermediate 18, intermediate 16, pyridine-2-carboxylic acid, CuI, and potassium phosphate trihydrate is 1:1.2:0.01:0.05:2;

[0069] The second step of the synthesis of enoxaparin: Intermediate 19 is dissolved in 10 times the mass of tetrahydrofuran, the system temperature is lowered to 0°C, and a dichloromethane solution of BBr3 is added dropwise. The reaction is stopped at room temperature for 2 hours, and enoxaparin is obtained by post-processing methods acceptable in the field of chemical synthesis.

[0070] The molar ratio of intermediate 19 and BBr3 is 1:4.

[0071] Compared with existing technologies, the present invention offers the following advantages: It is the first to prepare enoxaparin via a fully synthetic route, completely eliminating dependence on natural heparin raw materials, resolving issues such as limited raw material sources and batch variability, and providing a stable guarantee for large-scale production. Through the modular design and targeted synthesis of 19 key intermediates, precise control of the sugar ring structure, substituent positions, and sulfation sites is achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 The enoxaparin synthesized by the present invention 1 HNMR spectrum;

[0073] Figure 2 is the numbering of the active sites of 6-(hydroxymethyl)tetrahydro-2H-pyran-2,5-diol;

[0074] Figure 3 The active sites of intermediate 6 are numbered;

[0075] Figure 4 The active sites of (E)-N-(2,4,5-trimethoxy-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)acetimidate are numbered. DETAILED DESCRIPTION

[0076] The following will clearly and completely describe the technical solution of the present invention in conjunction with the accompanying drawings. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0077] Example 1

[0078] Synthesis of Enoxaparin:

[0079] ;

[0080] The first step in the synthesis of intermediate 2: Under a nitrogen atmosphere, 3-bromo-5-(methoxycarbonyl)cyclohex-4-ene-1,2-diacetyl diacetate (1 mmol), sodium carbonate (6 mmol), and tetrahydrofuran (10 times the mass of 3-bromo-5-(methoxycarbonyl)cyclohex-4-ene-1,2-diacetyl diacetate) were added to the reaction system. The reaction temperature was 80°C and the reaction time was 12 hours. After the reaction, intermediate 1 was obtained by post-processing methods acceptable in the field of chemical synthesis with a yield of 64%.

[0081] The post-treatment comprises adjusting the pH of the system to neutral with 0.1 mol / L hydrochloric acid, adding 200 g of water thereto, shaking and separating the liquids, retaining the organic phase, drying the organic phase with anhydrous magnesium sulfate, filtering, and drying the organic phase by spin drying, and purifying by silica gel column chromatography with petroleum ether / ethyl acetate as eluent, and drying the solution by spin drying to obtain intermediate 1;

[0082] Step 2 of the synthesis of intermediate 2: Under a nitrogen atmosphere, intermediate 1 (1 mmol), methyl iodide (2.5 mmol), pyridine-2-carboxylic acid (0.2 mmol), CuI (0.1 mmol), potassium phosphate trihydrate (4 mmol) and dimethyl sulfoxide (10 times the mass of intermediate 1) were added to the reaction system. The reaction temperature was 90°C and the reaction time was 20 h. After the reaction, intermediate 2 was obtained by post-treatment methods acceptable in the field of chemical synthesis with a yield of 68%.

[0083] The post-treatment is as follows: after the reaction is completed, the mixture is filtered with silica gel while hot, the filtrate is dried by spin drying, and the mixture is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent, and the solution is dried by spin drying to obtain intermediate 2.

[0084] The intermediate 2 1 HNMR (deuterated chloroform) δ 6.88 (m, 1H), 4.51 (m, 1H), 4.18 (m, 1H), 4.02 (m, 1H), 3.35 (t, 6H), 2.86 (m, 1H), 2.60 (m, 1H).

[0085] ;

[0086] The first step in the synthesis of intermediate 4: Under a nitrogen atmosphere, 3,4,5-trihydroxycyclohexane-1-carboxylic acid (1 mmol), methyl iodide (3.2 mmol), pyridine-2-carboxylic acid (0.03 mmol), CuI (0.15 mmol), potassium phosphate trihydrate (6 mmol), and dimethyl sulfoxide (10 times the mass of 3,4,5-trihydroxycyclohexane-1-carboxylic acid) were added to the reaction system. The reaction temperature was 90°C and the reaction time was 20 h. After the reaction, intermediate 3 was obtained by post-treatment methods acceptable in the field of chemical synthesis in a yield of 62%.

[0087] The post-treatment is as follows: after the reaction is completed, the mixture is filtered with silica gel while hot, the filtrate is dried, and the mixture is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent, and the solution is dried to obtain intermediate 3;

[0088] Step 2 of the synthesis of intermediate 4: Under a nitrogen atmosphere, intermediate 3 (1 mmol), N-bromosuccinimide (1.2 mmol), and dichloromethane (10 times the mass of intermediate 3) were added to the reaction system at a temperature of 25-30°C for 16 h. The reaction was then stopped and post-processed using a method acceptable in the field of chemical synthesis to obtain intermediate 4 in a yield of 73%.

[0089] The post-treatment is as follows: after the reaction is completed, the reaction mixture is cooled and extracted with an ammonia solution and methyl tert-butyl ether, the organic phase is washed five times with water, and then washed twice with a saturated NaCl solution; finally, the combined organic phase is dried over anhydrous magnesium sulfate, the organic phase is spin-dried, and the organic phase is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent, and the solution is spin-dried to obtain intermediate 4.

[0090] The intermediate 4 1 HNMR (deuterated chloroform) δ 4.53 (dd, 1H), 4.09 (ddq, 1H), 4.01-3.90 (m, 2H), 3.48-3.37 (m, 9H), 3.11 (q, 1H), 2.38 (dt, 1H), 2.14-2.04 (m, 1H).

[0091] ;

[0092] The first step in the synthesis of intermediate 5: Under a nitrogen atmosphere, 6-(hydroxymethyl)tetrahydro-2H-pyran-2,5-diol (1 mmol), sulfonyl chloride (1.2 mmol), pyridine-2-carboxylic acid (0.01 mmol), CuI (0.05 mmol), potassium phosphate trihydrate (2 mmol), and dimethyl sulfoxide (10 times the mass of 6-(hydroxymethyl)tetrahydro-2H-pyran-2,5-diol) were added to the reaction system. The reaction temperature was 90°C and the reaction time was 20 h. After the reaction, intermediate 5 was obtained by post-treatment methods acceptable in the field of chemical synthesis with a yield of 75%.

[0093] The post-treatment is as follows: after the reaction is completed, the reaction mixture is cooled and extracted with an aqueous ammonia solution and methyl tert-butyl ether, the organic phase is washed five times with water, and then washed twice with a saturated NaCl solution; finally, the combined organic phase is dried over anhydrous magnesium sulfate, the organic phase is spin-dried, and the organic phase is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent, and the solution is spin-dried to obtain intermediate 5.

[0094] The intermediate 5 1HNMR (deuterated chloroform) δ8.83 (s, 1H), 5.22 (d, 1H), 5.02 (td, 1H), 4.41 (dd, 1H), 4.19 (dd, 1H), 3.94 (qd, 1H), 3.77 (dt, 1H), 3.02 (d, 1H), 2.06-1.82 (m, 2H), 1.81-1.58 (m, 2H).

[0095] ;

[0096] The first step in the synthesis of intermediate 7: Under a nitrogen atmosphere, 3,4-dihydroxycyclohexane-1-carboxylic acid (1 mmol), methyl iodide (2.2 mmol), pyridine-2-carboxylic acid (0.02 mmol), CuI (0.10 mmol), potassium phosphate trihydrate (4 mmol), and dimethyl sulfoxide (10 times the mass of 3,4-dihydroxycyclohexane-1-carboxylic acid) were added to the reaction system. The reaction temperature was 90°C and the reaction time was 20 h. After the reaction, intermediate 6 was obtained by post-treatment methods acceptable in the field of chemical synthesis in a yield of 69%.

[0097] The post-treatment is as follows: after the reaction is completed, the reaction mixture is cooled and extracted with an aqueous ammonia solution and methyl tert-butyl ether, the organic phase is washed five times with water, and then washed twice with a saturated NaCl solution; finally, the combined organic phase is dried over anhydrous magnesium sulfate, the organic phase is spin-dried, and the organic phase is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent, and the solution is spin-dried to obtain intermediate 6;

[0098] Step 2 of the synthesis of intermediate 7: Under a nitrogen atmosphere, intermediate 6 (1 mmol), N-bromosuccinimide (2.2 mmol), and dichloromethane (10 times the mass of intermediate 6) were added to the reaction system. The reaction temperature was set at 30°C for 16 h. The reaction was then stopped and post-processed using a method acceptable in the field of chemical synthesis to obtain intermediate 7 in a yield of 58%.

[0099] The post-treatment is as follows: after the reaction is completed, the reaction mixture is cooled and extracted with an ammonia solution and methyl tert-butyl ether, the organic phase is washed five times with water, and then washed twice with a saturated NaCl solution; finally, the combined organic phase is dried over anhydrous magnesium sulfate, the organic phase is spin-dried, and the organic phase is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent, and the solution is spin-dried to obtain intermediate 7.

[0100] Intermediate 7 1HNMR (deuterated chloroform) δ 4.58 (dd, 1H), 4.45 (td, 1H), 4.22 (m, 1H), 4.07 (ddq, 1H), 3.39 (dd, 6H), 3.11 (q, 1H), 2.57 (dt, 1H), 2.31 (dt, 1H).

[0101] ;

[0102] The first step in the synthesis of intermediate 11: (E)-N-(2,4,5-trimethoxy-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)acetimidate (1 mmol) was dissolved in 10 times the mass of tetrahydrofuran. The system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 (1 mmol) was added dropwise. The reaction was incubated at room temperature for 2 hours, and the reaction was stopped. After post-treatment using methods acceptable in the field of chemical synthesis, intermediate 8 was obtained in a yield of 54%.

[0103] The post-treatment is as follows: quenching with water, then quenching with potassium carbonate, recovering the resulting solid by vacuum filtration and drying to obtain intermediate 8; wherein the dichloromethane solution of BBr3 is a dichloromethane solution containing 10% BBr3;

[0104] Step 2 of the synthesis of intermediate 11: To a Schlenk flask with a stirring bar, intermediate 8 (1 mmol), triethylamine (5 mmol), and 1,4-dioxane (10 times the mass of intermediate 8) were added, and the mixture was treated with positive pressure of sulfur dioxide difluoride gas, and five high vacuum evacuation / backfill cycles were performed. The mixture was vigorously stirred at room temperature for 2 h, and palladium acetate (0.05 mmol), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (0.06 mmol), potassium phosphate (2 mmol), trimethylboroxane (0.5 mmol), and 1,4-dioxane (5 times the mass of intermediate 8) were added. The mixture was treated with positive pressure of nitrogen and five high vacuum evacuation / backfill cycles. The reaction was continued at 120°C for 2 h. The reaction was stopped, and intermediate 9 was obtained by post-treatment methods acceptable in the field of chemical synthesis in a yield of 65%.

[0105] The post-treatment is as follows: quenching with water, extracting three times with ethyl acetate, combining the organic layers, washing with brine, drying over anhydrous sodium sulfate, and drying the solvent under reduced pressure. Purification by silica gel column chromatography using petroleum ether and ethyl acetate as eluents gives intermediate 9;

[0106] Step 3 of the synthesis of intermediate 11: Intermediate 9 (1 mmol) was dissolved in 10 times the mass of tetrahydrofuran. The system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 (2 mmol) was added dropwise. The reaction was allowed to stand at room temperature for 2 h, and the reaction was stopped. Intermediate 10 was obtained by post-treatment methods acceptable in the field of chemical synthesis with a yield of 52%.

[0107] The post-treatment is as follows: quenching with 200 ml of water, then quenching with 10 g of potassium carbonate, recovering the resulting solid by vacuum filtration and drying to obtain intermediate 10; wherein the dichloromethane solution of BBr3 is a dichloromethane solution containing 10% BBr3;

[0108] Step 4 of the synthesis of intermediate 11: Intermediate 10 (1 mmol) and triethylamine (1.5 mmol) were dissolved in 10 times the mass of dichloromethane, and sulfur dioxide difluoride (SO2F2) gas was introduced with stirring at room temperature for 4 h. The SO2F2 was flushed out with argon gas to stop the reaction. Intermediate 11 was obtained by post-treatment methods acceptable in the field of chemical synthesis with a yield of 60%.

[0109] The post-treatment was as follows: adding water and acidifying the reaction mixture with 10 ml of concentrated hydrochloric acid, then extracting the aqueous phase twice with 100 ml of DCM, combining the organic phases and drying over magnesium sulfate, filtering and concentrating the reaction mixture under reduced pressure, and finally purifying the crude product by silica gel column chromatography (eluent: cyclohexane / ethyl acetate, volume ratio changed from 1:0 to 9:1) to obtain intermediate 11.

[0110] Intermediate 11 1 HNMR (deuterated chloroform) δ 4.99 (dd, 1H), 4.36 (ddq, 1H), 4.24 (dt, 1H), 4.11 (d, 1H), 3.75 (s, 3H), 3.74 (dd, 1H), 3.65-3.49 (m, 1H), 3.26 (s, 3H), 2.43 (ddq, 1H), 1.96 (s, 3H), 1.13 (dt, 3H).

[0111] ;

[0112] The first step in the synthesis of intermediate 14: 2-(benzyloxy)-3-methyl-6,8-dioxacyclo[3.2.1]octan-4-ol (1 mmol), sodium hydride (1.5 mmol), and dry toluene (10 times the mass of 2-(benzyloxy)-3-methyl-6,8-dioxacyclo[3.2.1]octan-4-ol) were added to the reaction system and stirred at room temperature for 1 hour. Cyanuric chloride (0.3 mmol) was added and stirring continued for 1 hour. The temperature was raised to 110°C and stirred for 10 hours. Ammonium carbonate (5 mmol), dichlorobis(triphenylphosphine)nickel (0.05 mmol), and potassium phosphate (2 mmol) were added under an argon atmosphere. The mixture was stirred at 100°C for 12 hours. The reaction was stopped and post-processed using a method acceptable in the field of chemical synthesis to obtain intermediate 12 in a yield of 72%.

[0113] The post-treatment is as follows: cooling to room temperature, adding 100 g of dichloromethane and 100 g of water, separating the dichloromethane layer, and extracting the aqueous phase twice with dichloromethane, combining the organic layers and drying over anhydrous sodium sulfate, and drying the solvent under reduced pressure, and purifying by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain intermediate 12;

[0114] Step 2 of the synthesis of intermediate 14: Under nitrogen protection, intermediate 12 (1 mmol), sulfonyl chloride (1.2 mmol), sodium tert-butoxide (2 mmol), tris(dibenzylideneacetone)dipalladium (0.03 mmol), tri-tert-butylphosphine (2 mmol), and toluene (10 times the mass of intermediate 12) were added to the reaction system. The temperature was raised to 120°C and the reaction was allowed to proceed for 12 h. The reaction was then stopped and post-processed using an acceptable post-treatment method in the field of chemical synthesis to obtain intermediate 13 in a yield of 66%.

[0115] The post-treatment is as follows: after the reaction is completed, the temperature is slightly lowered, and the mixture is filtered using diatomaceous earth to remove salts and catalysts. After the filtrate is cooled to room temperature, it is washed with water three times, and the organic phase is retained. The aqueous phase is then extracted with ethyl acetate; after the organic phases are combined, they are dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain intermediate 13;

[0116] Step 3 of the synthesis of intermediate 14: Intermediate 13 (1 mmol) was dissolved in 10 times the mass of tetrahydrofuran. The system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 (1 mmol) was added dropwise. The reaction was allowed to stand at room temperature for 2 h, and the reaction was stopped. Intermediate 14 was obtained by post-treatment methods acceptable in the field of chemical synthesis with a yield of 63%.

[0117] The post-treatment was as follows: quenching with 200 ml of water, followed by quenching with 10 g of potassium carbonate, and recovering the resulting solid by vacuum filtration and drying to afford Intermediate 14.

[0118] Intermediate 14 1 HNMR (deuterated chloroform) δ7.84 (d, 1H), 5.98 (s, 1H), 5.21 (d, 1H), 4.13 (dt, 1H), 4.02 (dd, 1H), 3.86-3.73 (m, 2H), 3.70 (dm, 1H), 3.43 (d, 1H), 2.14 (ddq, J1H), 0.99 (dt, 3H).

[0119] ;

[0120] The first step in the synthesis of intermediate 18: intermediate 4 (1 mmol), intermediate 5 (1 mmol), intermediate 2 (1 mmol), pyridine-2-carboxylic acid (0.03 mmol), CuI (0.15 mmol), potassium phosphate trihydrate (6 mmol) and dimethyl sulfoxide (10 times the mass of intermediate 5) were reacted at 90°C for 20 h. After the reaction, intermediate 17 was obtained by post-treatment methods acceptable in the field of chemical synthesis with a yield of 41%.

[0121] The post-treatment is as follows: after the reaction is completed, the reaction mixture is cooled and extracted with an aqueous ammonia solution and methyl tert-butyl ether, and the organic phase is washed five times with water and then washed twice with a saturated NaCl solution; finally, the combined organic phase is dried over anhydrous magnesium sulfate, the organic phase is spin-dried, and purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent, and the solution is spin-dried to obtain intermediate 17;

[0122] Step 2 of the synthesis of intermediate 18: Intermediate 17 (1 mmol) was dissolved in 10 times the mass of tetrahydrofuran. The system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 (5 mmol) was added dropwise. The reaction was allowed to stand at room temperature for 2 h, and the reaction was stopped. Intermediate 18 was obtained by post-treatment methods acceptable in the field of chemical synthesis with a yield of 57%.

[0123] The post-treatment is as follows: quenching with 200 ml of water, then quenching with 10 g of potassium carbonate, recovering the resulting solid by vacuum filtration and drying, and purifying by silica gel column chromatography using petroleum ether / ethyl acetate as eluent, and spin-drying the solution to obtain intermediate 18; wherein the dichloromethane solution of BBr3 is a dichloromethane solution containing 10% BBr3.

[0124] Intermediate 18 1 HNMR (deuterated chloroform) δ8.83 (s, 1H), 6.73 (m, 1H), 4.95 (t, 1H), 4.83 (d, 1H), 4.53-4.40 (m, 2H), 4.33-4.18 (m, 5H), 4.02-3.62 (m, 8H), 2.89-2.76 (m, 2H), 2.56 (m, 1H), 2.33 (ddd, 1H), 2.09 (dddd, 1H), 2.07-1.93 (m, 3H), 1.91-1.69 (m, 2H).

[0125] ;

[0126] The first step in the synthesis of intermediate 16: intermediate 7 (1 mmol), intermediate 8 (1.2 mmol), pyridine-2-carboxylic acid (0.01 mmol), CuI (0.05 mmol), potassium phosphate trihydrate (2 mmol), and dimethyl sulfoxide (10 times the mass of intermediate 7) were added to the reaction system. The reaction temperature was 90°C and the reaction time was 20 h. After the reaction, intermediate 15 was obtained by post-treatment methods acceptable in the field of chemical synthesis with a yield of 46%.

[0127] The post-treatment comprises the following steps: after the reaction is completed, cooling the reaction mixture, extracting the obtained reaction mixture with aqueous ammonia solution and methyl tert-butyl ether, washing the organic phase with water five times, and then washing it twice with a saturated NaCl solution; finally, drying the combined organic phases with anhydrous magnesium sulfate, drying the organic phase by spin drying, and purifying the organic phase by silica gel column chromatography using petroleum ether / ethyl acetate as eluent, and drying the solution by spin drying to obtain intermediate 15;

[0128] Step 2 of the synthesis of intermediate 16: Intermediate 15 (1 mmol), intermediate 14 (1.2 mmol), pyridine-2-carboxylic acid (0.01 mmol), CuI (0.05 mmol), potassium phosphate trihydrate (2 mmol), and dimethyl sulfoxide (10 times the mass of intermediate 15) were added to the reaction system. The reaction temperature was 90°C and the reaction time was 20 h. After the reaction, intermediate 16 was obtained by post-treatment methods acceptable in the field of chemical synthesis with a yield of 42%.

[0129] The post-treatment is as follows: after the reaction is completed, the reaction mixture is cooled and extracted with an aqueous ammonia solution and methyl tert-butyl ether, the organic phase is washed five times with water, and then washed twice with a saturated NaCl solution; finally, the combined organic phase is dried over anhydrous magnesium sulfate, the organic phase is spin-dried, and the organic phase is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent, and the solution is spin-dried to obtain intermediate 16.

[0130] Intermediate 16 1HNMR (deuterated chloroform) δ7.85 (d, 1H), 5.98 (s, 1H), 5.21 (d, 1H), 5.03 (d, 1H), 4.61 (dd, 1H), 4.36 (ddq, 1H), 4.23 (dt, 1H), 4.17 (dt, 1H), 4.10 (dt, 1H), 4.00 (dd, 1H), 3.91 (ddq, 1H), 3.75 (s,4H),3.85-3.63(m,6H),3.55(dd,1H),3.50(d,3H),3.47(d,H),3.26(s,3H),2.78(d t,1H),2.43-2.28(m,2H),2.15b1.97(m,2H),1.96(m,3H),1.12(dt,3H),0.99(dt,3H).

[0131] ;

[0132] The first step of the synthesis of enoxaparin: intermediate 18 (1 mmol), intermediate 16 (1.2 mmol), pyridine-2-carboxylic acid (0.01 mmol), CuI (0.05 mmol), potassium phosphate trihydrate (2 mmol) and dimethyl sulfoxide (10 times the mass of intermediate 18) were added to the reaction system. The reaction temperature was 90°C and the reaction time was 20 h. After the reaction, intermediate 19 was obtained by post-treatment methods acceptable in the field of chemical synthesis with a yield of 29%.

[0133] The post-treatment is as follows: after the reaction is completed, the reaction mixture is cooled and extracted with an aqueous ammonia solution and methyl tert-butyl ether, the organic phase is washed five times with water, and then washed twice with a saturated NaCl solution; finally, the combined organic phase is dried over anhydrous magnesium sulfate, the organic phase is spin-dried, and the organic phase is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent, and the solution is spin-dried to obtain intermediate 19;

[0134] The second step of the synthesis of enoxaparin: Intermediate 19 (1 mmol) was dissolved in 10 times the mass of tetrahydrofuran, the system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 (4 mmol) was added dropwise. The reaction was stopped at room temperature for 2 hours, and enoxaparin was obtained by post-treatment methods acceptable in the field of chemical synthesis with a yield of 43%.

[0135] The post-treatment is as follows: quenching with water, then quenching with potassium carbonate, recovering the obtained solid by vacuum filtration and drying, purifying by silica gel column chromatography, using petroleum ether / ethyl acetate as eluent, and spin-drying the solution to obtain the intermediate enoxaparin; wherein the dichloromethane solution of BBr3 is a dichloromethane solution containing 10% BBr3.

[0136] Enoxaparin 1HNMR (deuterated chloroform) δ8.83 (s, 1H), 7.85 (d, 1H), 7.74 (s, 1H), 6.73 (m, 1H), 5.98 (s, 1H), 5.21 (d, 1H), 5.04 (d, 1H), 4.95 (t, 1H), 4.70-4.62 (m, 2H), 4.53-4.40 (m, 3H), 4.33-4 .13(m,6H),4.06-3.62(m,20H),2.89-2.73(m,3H),2.56(m,2H),2.36(ddd,2H),2 .33-2.20(m,1H),2.16-1.93(m,5H),1.96(s,4H),1.91-1.69(m,2H),1.01(m,6H).

[0137] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. An intermediate compound for synthesizing enoxaparin, characterized in that: The intermediate compounds include: intermediate 1, intermediate 2, intermediate 3, intermediate 4, intermediate 5, intermediate 6, intermediate 7, intermediate 8, intermediate 9, intermediate 10, intermediate 11, intermediate 12, intermediate 13, intermediate 14, intermediate 15, intermediate 16, intermediate 17, intermediate 18, and intermediate 19, corresponding to the structures shown below: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. The intermediate compound for synthesizing enoxaparin according to claim 1, characterized in that: The synthesis method of the intermediate 2 is: ； The first step in the synthesis of intermediate 2 is to add 3-bromo-5-(methoxycarbonyl)cyclohex-4-ene-1,2-diacetyl diacetate, sodium carbonate, and tetrahydrofuran to a reaction system under a nitrogen atmosphere at a reaction temperature of 60-80°C for 8-12 hours. After the reaction, intermediate 1 is obtained by post-treatment methods acceptable in the field of chemical synthesis. The molar ratio of 3-bromo-5-(methoxycarbonyl)cyclohex-4-ene-1,2-diacetyl diacetate and sodium carbonate is 1:6; The second step of the synthesis of intermediate 2: Under a nitrogen atmosphere, intermediate 1, methyl iodide, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate and dimethyl sulfoxide are added to the reaction system at a reaction temperature of 80-90° C. for 16-20 hours. After the reaction, intermediate 2 is obtained by post-treatment methods acceptable in the field of chemical synthesis; The molar ratio of the intermediate 1, methyl iodide, pyridine-2-carboxylic acid, CuI and potassium phosphate trihydrate is 1:2.5:0.02:0.1:

4.

3. The intermediate compound for synthesizing enoxaparin according to claim 1, characterized in that: The synthesis method of the intermediate 4 is: ； The first step in the synthesis of intermediate 4: under a nitrogen atmosphere, 3,4,5-trihydroxycyclohexane-1-carboxylic acid, methyl iodide, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate, and dimethyl sulfoxide are added to the reaction system at a reaction temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 3 is obtained by post-treatment methods acceptable in the field of chemical synthesis. The molar ratio of 3,4,5-trihydroxycyclohexane-1-carboxylic acid, methyl iodide, pyridine-2-carboxylic acid, CuI, and potassium phosphate trihydrate is 1:3.2:0.03:0.15:6; The second step of the synthesis of intermediate 4: Under a nitrogen atmosphere, intermediate 3, N-bromosuccinimide and dichloromethane were added to the reaction system at a reaction temperature of 25-30°C for 16 hours, and the reaction was stopped. Intermediate 4 was obtained by post-treatment methods acceptable in the field of chemical synthesis; The molar ratio of intermediate 3 to N-bromosuccinimide is 1:1.

2.

4. The intermediate compound for synthesizing enoxaparin according to claim 1, characterized in that: The synthesis method of the intermediate 5 is: ； The first step in the synthesis of intermediate 5: under a nitrogen atmosphere, 6-(hydroxymethyl)tetrahydro-2H-pyran-2,5-diol, sulfonyl chloride, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate, and dimethyl sulfoxide are added to the reaction system at a reaction temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 5 is obtained by post-treatment methods acceptable in the field of chemical synthesis. The molar ratio of 6-(hydroxymethyl)tetrahydro-2H-pyran-2,5-diol, sulfonyl chloride, pyridine-2-carboxylic acid, CuI and potassium phosphate trihydrate is 1:1.2:0.01:0.05:

2.

5. The intermediate compound for synthesizing enoxaparin according to claim 1, characterized in that: The synthesis method of the intermediate 7 is: ； The first step in the synthesis of intermediate 7: Under a nitrogen atmosphere, 3,4-dihydroxycyclohexane-1-carboxylic acid, methyl iodide, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate, and dimethyl sulfoxide are added to the reaction system at a temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 6 is obtained by post-treatment methods acceptable in the field of chemical synthesis. The molar ratio of 3,4-dihydroxycyclohexane-1-carboxylic acid, methyl iodide, pyridine-2-carboxylic acid, CuI, and potassium phosphate trihydrate is 1:2.2:0.02:0.10:4; The second step of the synthesis of intermediate 7: Under a nitrogen atmosphere, intermediate 6, N-bromosuccinimide and dichloromethane were added to the reaction system at a reaction temperature of 25-30° C. for 16 hours, and the reaction was stopped. Intermediate 7 was obtained by post-treatment methods acceptable in the field of chemical synthesis; The molar ratio of intermediate 6 to N-bromosuccinimide is 1:2.

2.

6. The intermediate compound for synthesizing enoxaparin according to claim 1, characterized in that: The synthesis method of the intermediate 11 is: ； The first step in the synthesis of intermediate 11: (E)-N-(2,4,5-trimethoxy-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)acetimidate was dissolved in 10 times the mass of tetrahydrofuran, the system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 was added dropwise. The reaction was stopped at room temperature for 2 hours, and intermediate 8 was obtained by post-processing methods acceptable in the field of chemical synthesis. The molar ratio of (E)-N-(2,4,5-trimethoxy-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)acetimidate and BBr3 is 1:1; The dichloromethane solution of BBr3 is a dichloromethane solution containing 10% BBr3; Step 2 of the synthesis of intermediate 11: Add intermediate 8, triethylamine, and 1,4-dioxane to a Schlenk flask with a stirring bar, treat with positive pressure of sulfur dioxide difluoride gas, perform five high vacuum evacuation / backfill cycles, and vigorously stir at room temperature for 2 hours. Then, add palladium acetate, 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl, potassium phosphate, trimethylboroxane, and 1,4-dioxane, treat with positive pressure of nitrogen and five high vacuum evacuation / backfill cycles, react at 120°C for 2 hours, stop the reaction, and obtain intermediate 9 by post-treatment methods acceptable in the field of chemical synthesis; The molar ratio of intermediate 8, triethylamine, palladium acetate, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, potassium phosphate, and trimethylboroxane is 1:5:0.05:0.06:2:0.5; The third step of the synthesis of intermediate 11: Intermediate 9 was dissolved in 10 times the mass of tetrahydrofuran, the system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 was added dropwise. The reaction was stopped at room temperature for 2 hours, and intermediate 10 was obtained by post-treatment methods acceptable in the field of chemical synthesis. The molar ratio of intermediate 9 and BBr3 is 1:2; Step 4 of the synthesis of intermediate 11: Dissolve intermediate 10 and triethylamine in 10 times the mass of dichloromethane, introduce sulfur dioxide difluoride SO2F2 gas and stir at room temperature for 4 hours, flush the SO2F2 with argon, stop the reaction, and obtain intermediate 11 by post-treatment methods acceptable in the field of chemical synthesis; The molar ratio of intermediate 10 and triethylamine is 1:1.

5.

7. The intermediate compound for synthesizing enoxaparin according to claim 1, characterized in that: The synthesis method of the intermediate 14 is: ； The first step in the synthesis of intermediate 14: 2-(benzyloxy)-3-methyl-6,8-dioxacyclo[3.2.1]octan-4-ol, sodium hydride, and dry toluene were added to the reaction system, stirred at room temperature for 1 hour, cyanuric chloride was added, and stirring was continued for 1 hour. The temperature was raised to 110°C and stirred for 10 hours. Ammonium carbonate, dichlorobis(triphenylphosphine)nickel, and potassium phosphate were added under an argon atmosphere, and the mixture was stirred at 100°C for 12 hours. The reaction was stopped, and intermediate 12 was obtained by post-processing methods acceptable in the field of chemical synthesis. The molar ratio of 2-(benzyloxy)-3-methyl-6,8-dioxacyclo[3.2.1]octan-4-ol, sodium hydride, cyanuric chloride, ammonium carbonate, dichlorobis(triphenylphosphine)nickel, and potassium phosphate is: 1:1.5:0.3:5:0.05:2; Step 2 of the synthesis of intermediate 14: Under nitrogen protection, intermediate 12, sulfonyl chloride, sodium tert-butoxide, tris(dibenzylideneacetone)dipalladium, tri-tert-butylphosphine, and toluene were added to the reaction system, the temperature was raised to 120°C, the reaction was allowed to proceed for 12 hours, the reaction was stopped, and intermediate 13 was obtained by post-treatment methods acceptable in the field of chemical synthesis; The molar ratio of intermediate 12, sulfonyl chloride, sodium tert-butoxide, tris(dibenzylideneacetone)dipalladium, and tri-tert-butylphosphine is: 1:1.2:2:0.03:2; Step 3 of the synthesis of intermediate 14: Intermediate 13 was dissolved in 10 times the mass of tetrahydrofuran, the system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 was added dropwise. The reaction was continued at room temperature for 2 hours, and the reaction was stopped. Intermediate 14 was obtained by post-treatment methods acceptable in the field of chemical synthesis. The molar ratio of intermediate 13 and BBr3 is 1:

1.

8. The intermediate compound for synthesizing enoxaparin according to claim 1, characterized in that: The synthesis method of the intermediate 18 is: ； The first step in the synthesis of intermediate 18: intermediate 4, intermediate 5, intermediate 2, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate and dimethyl sulfoxide, the reaction temperature is 80-90°C, the reaction time is 16-20 hours, and after the reaction, the intermediate 17 is obtained by post-treatment methods acceptable in the field of chemical synthesis; The molar ratio of intermediate 4, intermediate 5, intermediate 2, pyridine-2-carboxylic acid, CuI, and potassium phosphate trihydrate is 1:1:1:0.03:0.15:6; The second step of the synthesis of intermediate 18: Intermediate 17 was dissolved in 10 times the mass of tetrahydrofuran, the system temperature was lowered to 0°C, and a dichloromethane solution of BBr3 was added dropwise. The reaction was continued at room temperature for 2 hours, and the reaction was stopped. Intermediate 18 was obtained by post-treatment methods acceptable in the field of chemical synthesis. The molar ratio of intermediate 17 and BBr3 is 1:

5.

9. The intermediate compound for synthesizing enoxaparin according to claim 1, characterized in that: The synthesis method of the intermediate 16 is: ； The first step in the synthesis of intermediate 16 is to add intermediate 7, intermediate 8, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate, and dimethyl sulfoxide to the reaction system at a reaction temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 15 is obtained by post-treatment methods acceptable in the field of chemical synthesis. The molar ratio of intermediate 7, intermediate 8, pyridine-2-carboxylic acid, CuI, and potassium phosphate trihydrate is 1:1.2:0.01:0.05:2; The second step of the synthesis of intermediate 16: intermediate 15, intermediate 14, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate and dimethyl sulfoxide are added to the reaction system at a reaction temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 16 is obtained by post-treatment methods acceptable in the field of chemical synthesis. The molar ratio of intermediate 15, intermediate 14, pyridine-2-carboxylic acid, CuI and potassium phosphate trihydrate is 1:1.2:0.01:0.05:

2.

10. A method for synthesizing enoxaparin using an intermediate compound for synthesizing enoxaparin according to any one of claims 8 to 9, characterized in that: The synthetic method of described enoxaparin is: ； The first step of the synthesis of enoxaparin: intermediate 18, intermediate 16, pyridine-2-carboxylic acid, CuI, potassium phosphate trihydrate and dimethyl sulfoxide are added to the reaction system at a temperature of 80-90°C for 16-20 hours. After the reaction, intermediate 19 is obtained by post-treatment methods acceptable in the field of chemical synthesis. The molar ratio of intermediate 18, intermediate 16, pyridine-2-carboxylic acid, CuI, and potassium phosphate trihydrate is 1:1.2:0.01:0.05:2; The second step of the synthesis of enoxaparin: Intermediate 19 is dissolved in 10 times the mass of tetrahydrofuran, the system temperature is lowered to 0°C, and a dichloromethane solution of BBr3 is added dropwise. The reaction is stopped at room temperature for 2 hours, and enoxaparin is obtained by post-processing methods acceptable in the field of chemical synthesis. The molar ratio of intermediate 19 and BBr3 is 1:4.

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