A method for the synthesis of apixaban

Abstract

The application provides a synthesis method of apixaban and a preparation method of an intermediate thereof. The method takes a key intermediate IX as a raw material, and obtains apixaban (formula I) through oxidation, elimination, addition, reduction and aminolysis successively. The synthesis route of the application is rationally designed, reaction conditions are mild, operation is simple, the yield is high, the process is economical, and the route is easy to be produced on an industrial scale.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for synthesizing apixaban and its intermediates. Background Technology

[0002] Apixaban is a direct, selective factor Xa inhibitor. Its chemical name is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1Hpyrazolo[3,4-c]pyridine-3-carboxamide, and it has the structure of formula I:

[0003]

[0004] Apixaban, a highly selective direct factor Xa inhibitor, is primarily used clinically to treat deep vein thrombosis, pulmonary thrombosis, and to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation. It is also the first-line drug for atrial fibrillation and cancer-related venous thromboembolism. Approved for marketing in the EU on May 20, 2011, it surpassed rivaroxaban, the first drug targeting the same target, in 2018, and in 2020, it became the top-selling small molecule chemical drug.

[0005] Patent CN 101967145B reports a route for synthesis I, as shown below:

[0006]

[0007] This route uses NaH multiple times, requiring strict operating conditions and posing potential safety hazards. It also repeatedly uses 5-chloropentanoyl chloride, which, due to its high reactivity and numerous impurities, results in a high number of dimorpholine-substituted byproducts during the synthesis of compound 4. Overall, the route has low yields, is difficult to purify, and is unsuitable for industrial application.

[0008] Patent CN 103896940B reports a route for synthesis I, as shown below:

[0009]

[0010] The ethyl 3-chloropropionate and ethyl 3-diaza-2-oxopropionate used in this route are not readily available and often need to be prepared in-house. It also uses 5-chloropentanoyl chloride, which contains many impurities, is difficult to purify, and is environmentally unfriendly. The entire synthetic route is too long, and the overall process yield is low, which is not conducive to large-scale production.

[0011] The existing synthetic methods for apixaban have many shortcomings, so there is still a need to develop a synthetic route that is inexpensive, readily available, has mild reaction conditions, simple post-processing, and high yield. Summary of the Invention

[0012] The purpose of this invention is to overcome the shortcomings of existing technologies. On one hand, this invention provides a method for synthesizing compound I, comprising:

[0013] (1) Compound IX was oxidized to give mixture VII / VIII;

[0014] (2) The mixture VII / VIII was eliminated to obtain the mixture V / VI;

[0015] (3) Mixture V / VI reacts with compound IV via an addition reaction to obtain mixture II / III / ;

[0016] (4) Mixture II / III was reduced to compound II;

[0017] (5) Compound II is given by ammonolysis as apixaban (Formula I).

[0018]

[0019] The oxidant in step (1) is selected from sodium chlorite, and the catalyst is selected from carbon dioxide.

[0020] The reaction solvent in step (1) can be selected as needed. The solvent includes, but is not limited to, nitrile solvents such as acetonitrile and propionitrile, ether solvents such as tetrahydrofuran and dimethyltetrahydrofuran, and aprotic solvents such as toluene, acetone, and dichloromethane; preferably acetonitrile and acetone.

[0021] The alkali in step (2) is selected from carbonates such as Na2CO3, K2CO3 or Li2CO3, preferably Li2CO3; the catalyst is selected from LiBr or LiCl.

[0022] The reaction solvent in step (2) can be selected as needed. The solvent includes, but is not limited to, polar aprotic solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and N,N-dimethylacetamide.

[0023] The base in step (3) is selected from organic bases such as sodium methoxide, sodium ethoxide, diisopropylethylamine, triethylamine or tripropylamine, and inorganic bases such as Na2CO3, K2CO3, KHCO3 or NaHCO3, preferably organic bases such as sodium methoxide, sodium ethoxide, diisopropylethylamine, triethylamine or tripropylamine; more preferably triethylamine or diisopropylethylamine.

[0024] The reaction solvent in step (3) can be selected as needed. The solvent is selected from one or more of ethyl acetate, dichloromethane, N,N-dimethylformamide or toluene, preferably ethyl acetate or toluene.

[0025] The reduction system in step (4) is, for example, 10% Pd / C-HCOONa or Zn-CH3COOH, preferably Zn-CH3COOH.

[0026] The ammonolysis reagent in step (5), such as CH3ONa-HCONH2, ammonia water, ammonia gas, or a methanolic solution of ammonia, is preferably ammonia water or a methanolic solution of ammonia.

[0027] In another aspect, the present invention provides a method for synthesizing compound IX:

[0028]

[0029] Compound X is first formed into a salt, then chlorinated to obtain compound IX.

[0030] Where Y is Cl - ,Br - I - HSO4 - SO4 2- NO3 - PO4 3- ClO4 - CH3COO - CF3COO - or HCOO - Cl is preferred - ,Br - I - CH3COO - CF3COO - or HCOO - .

[0031] The acid used to form the salt is selected from inorganic acids and organic acids. The inorganic acid is selected from organic solutions including, but not limited to, aqueous solutions of sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydroiodic acid, hydrogen chloride, methanol, and ethanol, as well as aqueous solutions of hydrogen bromide, methanol, and ethanol. The organic acid includes, but is not limited to, formic acid, acetic acid, and trifluoroacetic acid.

[0032] The chlorinating agent is selected from phosphorus pentachloride.

[0033] The reaction solvent is dichloromethane, chloroform, and 1,2-dichloroethane; preferably dichloromethane.

[0034] The positive effects of this invention are:

[0035] (1) The present invention uses the NaClO2 / CO2 oxidation system to construct piperidinone, and no longer uses 5-chlorovaleryl chloride, which fundamentally solves the design defects of the relevant synthetic route. Although the oxidation also produces impurities, the impurities can be converted back into the target product in the subsequent reaction process.

[0036] (2) In the process of synthesizing compound IX, the present invention adopts a synthesis method of first salting and then chlorination. Salting can reduce the electron cloud density on compound X piperidinone, which greatly improves the reaction selectivity, and the reaction system is clean and has a high yield. This helps to improve the production efficiency of the process and facilitates the industrialization of the process.

[0037] (3) The mixture VII / VIII undergoes an elimination reaction under Li2CO3 / LiCl conditions, and then cyclizes with compound IV to obtain compound II. This reduces the number of steps and simplifies the operation.

[0038] (4) The compound VIII piperidinone carbonyl α-Cl in the mixture VII / VIII is cleverly reduced to compound II by 10% Pd / C-HCOONa or Zn / CH3COOH through dechlorination reaction, which not only improves the economic efficiency of the process, but also greatly reduces the difficulty and pressure of impurity removal. Detailed Implementation

[0039] The present invention is illustrated by the following embodiments, which are merely examples. Any technology implemented based on the present invention by those skilled in the art should be considered within the scope of protection of the present invention.

[0040] Preparation example: Synthesis of compound X

[0041] Add 1-(4-(piperidin-1-yl)phenyl)piperidin-2-one (11.1 g, 0.05 mol), FeCl3 (1.2 g, 0.0075 mol), activated carbon (4.2 g), and ethanol (110 mL) to a 250 mL reaction flask. Heat to 80 °C and add hydrazine hydrate solution (14.7 g, 0.25 mol) dropwise. After the addition is complete, reflux for 2–3 h. After the reaction is complete, cool to room temperature, filter to remove activated carbon, and distill the filtrate under reduced pressure to dryness to obtain the reduction product. Add 1,5-dibromopentane (13.8 g, 0.06 mol), K2CO3 (10.4 g, 0.075 mol), and xylene (18 mL) to the reduction product, and reflux for 10–12 h under nitrogen protection. After the reaction is complete, cool to room temperature, filter, and distill the filtrate under reduced pressure to obtain compound X, with a yield of approximately 92%.

[0042] X: 1H NMR (400MHz, CDCl3) δ: 1.57 (d, 2H, J = 5.0Hz), 1.69 (s, 4H), 1.91 (s, 4H), 2.53 (s, 2 H), 3.12~3.15 ​​(m, 4H), 3.58 (s, 2H), 6.92 (d, 2H, J=8.7Hz), 7.09 (d, 2H, J=8.7Hz).

[0043] Example 1: Synthesis of Compound IX

[0044] Preparation of hydrogen chloride methanol solution: Add 25 mL of anhydrous methanol to a 100 mL reaction flask, cool to about 0 °C, slowly add 2 g of acetyl chloride dropwise, and after the addition is complete, keep warm at 0–5 °C and stir for about 10 min, then set aside.

[0045] A pre-prepared hydrogen chloride methanol solution was added to compound X (5.00 g), and the mixture was stirred for about 10 min. The solvent was removed by vacuum distillation to obtain the salt-forming compound. 120 mL of DCM was added to the salt-forming compound, and the mixture was cooled to 0–5 °C. Phosphorus pentachloride (12.10 g) was added in portions. After the addition was complete, the mixture was refluxed for 5–6 h, and the starting material was observed to disappear by TLC. After the reaction was complete, sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to 9–10. The mixture was filtered to remove impurities, and the filtrate was separated into layers. The aqueous phase was extracted with DCM (30 mL × 3). The organic phases were combined, dried, and decolorized by silica gel filtration. The solvent was removed by vacuum distillation to obtain compound IX, with a yield of approximately 92%.

[0046] IX: 1 H NMR (400MHz, CDCl3) δ: 1.57~1.61 (m, 2H), 1.71 (s, 4H), 2.18~2.24 (m, 2H), 2.88~2.91 (m, 2 H), 3.15~3.18 (m, 4H), 3.70 (t, 2H, J=6.2Hz), 6.94 (d, 2H, J=8.9Hz), 7.12 (d, 2H, J=8.9Hz); 13 C NMR (100MHz, CDCl3) δ: 163.52, 151.16, 133.38, 126.29 (2C), 116.58 (2C), 83. 40, 52.03, 50.40(2C), 44.02, 25.71(2C), 24.23, 20.68; HRMS(ESI): m / z[M+H] + calcd.for C 16 H 21 Cl2N2O: 327.1031; found: 327.1030.

[0047] Example 2: Synthesis of Compound IX

[0048] Add 10 mL of chloroform to compound X (5.00 g), then add approximately 6.5 g of 40% hydrogen bromide aqueous solution, stir for about 10 min, and remove the solvent by vacuum distillation to obtain the salt-forming compound. Add 110 mL of chloroform to the salt-forming compound, cool to 0–5 °C, and add phosphorus pentachloride (12.10 g) in portions. After the addition is complete, reflux for 5–6 h, and monitor the disappearance of the starting material by TLC. After the reaction is complete, add sodium hydroxide aqueous solution dropwise to adjust the pH of the system to 9–10, filter to remove impurities, separate the filtrate into layers, extract the aqueous phase with chloroform (25 mL × 3), combine the organic phases, dry, filter through silica gel for decolorization, and remove the solvent by vacuum distillation to obtain compound IX, with a yield of approximately 90%.

[0049] Example 3: Synthesis of Compound IX

[0050] 10 mL of 1,2-dichloroethane and 2.5 g of acetic acid were added to compound X (5.00 g). The mixture was stirred for about 10 min, and the solvent was removed by vacuum distillation to obtain the salt-forming compound. 100 mL of 1,2-dichloroethane was added to the salt-forming compound, and the mixture was cooled to 0–5 °C. Phosphorus pentachloride (12.10 g) was added in portions. After the addition was complete, the mixture was refluxed for 5–6 h, and the starting material was observed to disappear by TLC. After the reaction was complete, sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to 9–10. The mixture was filtered to remove impurities, and the filtrate was separated into layers. The aqueous phase was extracted with chloroform (25 mL × 3). The organic phases were combined, dried, and decolorized by silica gel filtration. The solvent was removed by vacuum distillation to obtain compound IX, with a yield of approximately 85%.

[0051] Example 4: Synthesis of mixture VII / VIII

[0052] Add IX (16.36 g, 0.05 mol) and acetonitrile (245 mL) to a 100 mL reaction flask, heat to dissolve, and add NaClO2 solution (16.96 g, 0.15 mol) dropwise at 50–55 °C under a CO2 atmosphere. After the addition is complete, maintain the reaction temperature for 3–4 h. After the reaction is complete, cool until a solid precipitates, filter, quench the filtrate with Na2SO3, distill under reduced pressure to dryness, add water to make a slurry, filter, and dry to obtain mixture VII / VIII, with a yield of approximately 92%.

[0053] VII: 1 H NMR (400MHz, CDCl3) δ: 1.91~1.99 (m, 4H), 2.21~2.27 (m, 2H), 2.56 (t, 2H, J=6.1H z), 2.90~2.93 (m, 2H), 3.65 (t, 2H, J=5.8Hz), 3.75 (t, 2H, J=6.2Hz), 7.30 (s, 4H);

[0054] VIII: 1H NMR (400MHz, CDCl3) δ: 1.91~2.02 (m, 1H), 2.22~2.28 (m, 2H), 2.30~2.46 (m, 3H), 2.90~2.9 3 (m, 2H), 3.71 (t, 2H, J=5.4Hz), 3.76 (t, 2H, J=6.3Hz), 4.58 (t, 1H, J=4.5Hz), 7.31 (s, 4H).

[0055] Example 5: Synthesis of mixture V / VI

[0056] To mixture VII / VIII (7.17 g, 0.02 mol), Li₂CO₃ (1.78 g, 0.024 mol), LiCl (0.42 g, 0.01 mol), and N,N-dimethylformamide (15 mL) were added. The mixture was heated to 105 °C under nitrogen protection and reacted for 1.5–2 h. After the reaction was complete, the mixture was cooled to room temperature, water was added and stirred, and the aqueous phase was extracted with DCM (30 mL × 3). The organic phases were combined and dried under reduced pressure to obtain a crude product. The crude product was purified by solvent (EA:PE = 10:1), dried, and the mixture V / VI was obtained, with a yield of approximately 89%.

[0057] V: 1 H NMR (400MHz, CDCl3) δ: 1.91~1.98 (m, 4H), 2.54~2.64 (m, 4H), 3.63~3.66 (m, 2H), 3.90 (t, 2H, J=6.9Hz), 6.85 (t, 1H, J=4.6Hz), 7.27 (d, 2H, J=8.7Hz), 7.33 (d, 2H, J=8.7Hz);

[0058] VI: 1 H NMR (400MHz, CDCl3) δ: 1.91~1.99(m, 1H), 2.30~2.46(m, 3H), 2.59~2.64(m, 2H), 3.70~3.74(m, 2H), 3.90(t , 2H, J=6.9Hz), 4.58 (t, 1H, J=4.3Hz), 6.86 (t, 1H, J=4.6Hz), 7.28 (d, 2H, J=8.9Hz), 7.35 (d, 2H, J=8.8Hz).

[0059] Example 6: Synthesis of mixture V / VI

[0060] To mixture VII / VIII (7.17 g, 0.02 mol), Na₂CO₃ (2.76 g, 0.026 mol), LiBr (0.52 g, 0.006 mol), and dimethyl sulfoxide (15 mL) were added. Under nitrogen protection, the mixture was heated to 110 °C and reacted for 1–1.5 h. After the reaction was complete, the mixture was cooled to room temperature, water was added and stirred, and the aqueous phase was extracted with DCM (30 mL × 3). The organic phases were combined and dried under reduced pressure to obtain a crude product. The crude product was purified by solvent (EA:PE = 10:1), dried, and mixed to obtain mixture V / VI in approximately 91% yield.

[0061] Example 7: Preparation of Mixture II / III

[0062] In a 100 mL reaction flask, mixtures V / VI (6.08 g, 0.02 mol), IV (6.16 g, 0.024 mol), and 20 mL of toluene were added. Under nitrogen protection, triethylamine (6.07 g, 0.06 mol) was added at 100 °C, and the reaction was maintained for 2–3 h. The reaction was monitored by TLC until spots V and VI disappeared. After the reaction was complete, a small amount of water was added to the reaction system and stirred. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was dissolved in ethyl acetate:petroleum ether = 1:1, decolorized, and the filtrate was collected. The solid was obtained by vacuum distillation and recrystallized from ethanol solution to obtain mixture II / III, with a yield of approximately 85%. The mixture was separated by column chromatography to obtain a single component. The 1H NMR spectrum of the obtained sample is shown below.

[0063] II: 1 H NMR (400MHz, CDCl3) δ: 1.43 (t, 3H, J=7.1Hz), 1.90~1.97 (m, 4H), 2.54~2.57 (m, 2H), 3.31 (t, 2H, J=6.7Hz), 3.58~3.62 (m, 2H), 3.81 (s, 3H) , 4.12 (t, 2H, J = 6.7Hz), 4.46 (q, 2H, J = 7.1Hz), 6.91 (d, 2H, J = 9.0Hz), 7.25 (d, 2H, J = 9.1Hz), 7.34 (d, 2H, J = 8.7Hz), 7.47 (d, 2H, J = 9.0Hz);

[0064] III: 1H NMR (400MHz, CDCl3) δ: 1.43 (t, 3H, J=7.1Hz), 1.89~1.96 (m, 1H), 2.28~2.4 1(m, 3H), 3.32(t, 2H, J=6.7Hz), 3.62~3.70(m, 2H), 3.81(s, 3H), 4.13(t, 2 H, J=6.6Hz), 4.46 (q, 2H, J=7.1Hz), 4.57 (t, 1H, J=4.3Hz), 6.91 (d, 2H, J=9 .0Hz), 7.26 (d, 2H, J=8.6Hz), 7.35 (d, 2H, J=8.7Hz), 7.47 (d, 2H, J=8.9Hz).

[0065] Example 8: Preparation of Mixture II / III

[0066] In a 100 mL reaction flask, mixtures V / VI (6.08 g, 0.02 mol), IV (6.16 g, 0.024 mol), and 20 mL of ethyl acetate were added. Under nitrogen protection, diisopropylethylamine (6.46 g, 0.05 mol) was added at 70 °C, and the reaction was maintained at this temperature for 4–5 h. The reaction was monitored by TLC until spots V and VI disappeared. After the reaction was complete, a small amount of water was added to the reaction system and stirred. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was dissolved in ethyl acetate:petroleum ether = 1:1, decolorized, and the filtrate was collected. The solid was obtained by vacuum distillation and recrystallized from ethanol solution to obtain mixture II / III, with a yield of approximately 87%.

[0067] Example 9: Preparation of Mixture II / III

[0068] In a 100 mL reaction flask, mixtures V / VI (6.08 g, 0.02 mol), IV (6.16 g, 0.024 mol), and 20 mL of N,N-dimethylformamide were added. Under nitrogen protection, potassium carbonate (6.91 g, 0.05 mol) was added at 110 °C, and the reaction was maintained for 1–2 h. The reaction was monitored by TLC until spots V and VI disappeared. After the reaction was complete, 40 mL of water was added to the reaction system and stirred. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was dissolved in ethyl acetate:petroleum ether = 1:1, decolorized, and the filtrate was collected. The solid was obtained by vacuum distillation and recrystallized from ethanol solution to obtain mixture II / III, with a yield of approximately 88%.

[0069] Example 10: Synthesis of Compound II

[0070] In a 50 mL reaction flask, mixture II / III (4.88 g, 0.01 mol), Zn powder (1.31 g, 0.02 mol), and acetic acid (10 mL) were added. The reaction was carried out under nitrogen protection at 100 °C. TLC was used to monitor the reaction until the spot of compound III disappeared. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to neutral by adding saturated NaHCO3 solution. The mixture was filtered, and the filtrate was extracted multiple times with DCM. The organic phases were combined, dried, filtered, and the filtrate was distilled under reduced pressure to dryness to give compound II in 98% yield.

[0071] II: 1 H NMR (400MHz, CDCl3) δ: 1.43 (t, 3H, J=7.1Hz), 1.90~1.97 (m, 4H), 2.54~2.57 (m, 2H), 3.31 (t, 2H, J=6.7Hz), 3.58~3.62 (m, 2H), 3.81 (s, 3H) , 4.12 (t, 2H, J = 6.7Hz), 4.46 (q, 2H, J = 7.1Hz), 6.91 (d, 2H, J = 9.0Hz), 7.25 (d, 2H, J = 9.1Hz), 7.34 (d, 2H, J = 8.7Hz), 7.47 (d, 2H, J = 9.0Hz).

[0072] Example 11: Synthesis of Compound II

[0073] Add mixture II / III (4.88 g, 0.01 mol), 10% Pd / C-HCOONa, and 30 mL of ethanol to a 50 mL reaction flask. Under nitrogen protection, maintain the reaction temperature at 70-75 °C. Monitor the reaction by TLC until the spot of compound III disappears. After the reaction is complete, cool to room temperature and adjust the pH to neutral by adding dilute hydrochloric acid aqueous solution. Filter, concentrate, and extract the filtrate multiple times with DCM. Combine the organic phases, dry, filter, and distill the filtrate under reduced pressure to dryness to give compound II, with a yield of 99%.

[0074] Example 12: Synthesis of Compound I

[0075] Compound II was dissolved in methanol (20 mL) and placed in a 50 mL autoclave. Ammonia (1.5 mL, 0.01 mol) was added, and the mixture was heated to approximately 65 °C and maintained at this temperature for 5–6 h. After the reaction was complete, the mixture was cooled to room temperature, and suspended impurities were removed by filtration. The solvent was removed by vacuum distillation to obtain the crude product. Compound I was purified by recrystallization from ethanol / water (V / V = 2 / 1), with an overall yield of approximately 89% for both steps.

[0076] I: 1H NMR (400MHz, CDCl3) δ: 1.94 (s, 4H), 2.55 (s, 2H), 3.36 (t, J=6.6Hz, 2H), 3.59 (s, 2H), 3.81 (s, 3H), 4.10 (t, J=6.6Hz, 2H) , 5.81 (s, 1H,), 6.89 (s, 1H), 6.92 (d, J = 8.8Hz, 2H), 7.24 (d, J = 9.5Hz, 2H), 7.33 (d, J = 8.5Hz, 2H), 7.46 (d, J = 8.8Hz, 2H).

[0077] Example 13: Synthesis of Compound I

[0078] 20 mL of ammonia-containing methanol solution of compound II was added and placed in a 50 mL autoclave. The temperature was raised to approximately 65 °C, and the reaction was maintained at this temperature for 5–6 h. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed by vacuum distillation to obtain the crude product. Compound I was purified by recrystallization from ethanol / water (V / V = 2 / 1), with an overall yield of approximately 85% for both steps.

Claims

1. A process for the synthesis of Apixaban comprising the steps of: (1) oxidation of compound IX to give mixture VII / VIII, wherein, the oxidizing agent is sodium chlorite and the catalyst is carbon dioxide; (2) mixture VII / VIII is subjected to an elimination reaction to obtain mixture V / VI; (3) mixture V / VI is subjected to an addition reaction with compound IV to obtain mixture II / III; (4) mixture II / III is converted to compound II by reduction, wherein the reduction system is selected from zinc powder-acetic acid reduction system or 10% Pd / C-HCOONa system; (5) compound II is subjected to an aminolysis to obtain Apixaban (I), 2. The method of synthesis of claim 1, wherein, the base in the elimination reaction of step (2) is selected from Na2CO3, K2CO3 or Li2CO3; the catalyst is selected from LiBr or LiCl.

3. The method of synthesis of claim 2, wherein, the base in the elimination reaction of step (2) is Li2CO3.

4. The method of synthesis of claim 1, wherein, the base in the addition reaction of step (3) is selected from an organic base or an inorganic base, wherein the organic base is selected from sodium methoxide, sodium ethoxide, diisopropylethylamine, triethylamine or tripropylamine, and the inorganic base is selected from Na2CO3, K2CO3, KHCO3 or NaHCO3.

5. The method of synthesis according to claim 4, wherein, the base in the addition reaction of step (3) is an organic base, wherein the organic base is selected from sodium methoxide, sodium ethoxide, diisopropylethylamine, triethylamine or tripropylamine.

6. The method of synthesis of claim 5, wherein, the base in the addition reaction of step (3) is triethylamine or diisopropylethylamine.

7. The method of synthesis of claim 1, wherein, the reduction system of step (4) is zinc powder-acetic acid reduction system.

8. The method of synthesis of claim 1, wherein, the reagent in the aminolysis of step (5) is selected from CH3ONa-HCONH2, aqueous ammonia, ammonia gas or ammonia in methanol.

9. The method of synthesis of claim 8, wherein, the reagent in the aminolysis of step (5) is aqueous ammonia or ammonia in methanol.

10. A synthetic route of compound IX: compound X is first salified and then chlorinated to obtain compound IX, wherein Y is Cl - , Br - , I - , HSO4 - , SO4 2- , NO3 - , PO4 3- , ClO4 - , CH3COO - , CF3COO - or HCOO - .

11. The synthetic route of claim 10, wherein, Y is Cl - , Br - , I - , CH3COO - , CF3COO - or HCOO - .

12. The synthetic route of claim 10, wherein, the reaction solvent is dichloromethane, chloroform or 1,2-dichloroethane; the chlorinating agent is selected from phosphorus pentachloride.

13. The synthetic route of claim 12, wherein, the reaction solvent is dichloromethane.

14. Compound IX having the following structural formula:

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