Synthesis method of key intermediate of paroxysmal hemoglobinuria indication drug ipropam

Abstract

The present invention provides a paroxysmal hemoglobinuria indication drug ipropam key intermediate synthesis method, and relates to the technical field of ipropam, the method comprises: taking p-bromobenzaldehyde as an initial raw material, adopting an S-configuration catalyst to obtain an intermediate 03, carrying out protection group removal on the intermediate 03, carrying out automatic ring closing to obtain an intermediate 04, and carrying out post-treatment to obtain the paroxysmal hemoglobinuria indication drug ipropam key intermediate. Reducing the intermediate 04 with sodium borohydride to obtain a single cis-configuration intermediate 05, then carrying out a chiral flip reaction and hydrolysis to remove p-nitrobenzoic acid, then carrying out an etherification reaction with diethyl sulfate to obtain an intermediate 08, reducing amide of the intermediate 08 with sodium borohydride and boron trifluoride diethyl etherate to obtain an intermediate 09, then carrying out an acetylation reaction to protect amino, and finally carrying out a reaction to obtain the chiral cis-configuration intermediate 03. Cuprous cyanide is subjected to a cyanation reaction and a hydrolytic esterification reaction to obtain the ipropam key intermediate TM. The method is low in raw material price, high in chiral control selectivity, easy in reaction condition control and low in equipment requirement, avoids column chromatography and other operations, and is more suitable for industrial production.

Description

Technical Field

[0001] The present invention mainly relates to the technical field of iptacopan, and specifically relates to a method for synthesizing a key intermediate of iptacopan for the indication of paroxysmal nocturnal hemoglobinuria. Background Art

[0002] Iptacopan is an orally administered complement factor inhibitor developed by Novartis, which treats complement-mediated diseases by targeting the alternative complement pathway. It is mainly used to treat rare diseases related to overactivation of the complement system such as paroxysmal nocturnal hemoglobinuria (PNH). Its mechanism of action is to selectively inhibit the C5 protein of the alternative complement pathway, reduce hemolysis and inflammatory reactions by blocking the terminal complement reaction.

[0003] The synthetic route of iptacopan is as Figures 1-3 shown. It can be found that intermediate TM is the key intermediate for synthesizing iptacopan. After investigation, it has been reported in previous literature that this chiral compound is obtained by column chromatography separation using a chiral column or by salt formation and resolution using a resolving agent, with high cost and low efficiency. Therefore, this application designs a new asymmetric synthesis route method to meet the requirements of industrial production. Summary of the Invention

[0004] 1. Technical problems to be solved by the invention: The present invention provides a method for synthesizing a key intermediate of iptacopan for the indication of paroxysmal nocturnal hemoglobinuria to solve the technical problems existing in the above background art.

[0005] 2. Technical solution: To achieve the above object, the technical solution provided by the present invention is: a method for synthesizing a key intermediate of iptacopan for the indication of paroxysmal nocturnal hemoglobinuria, which is characterized by including the following steps: S1. Using p-bromobenzaldehyde as the starting material and an S-configuration catalyst to obtain intermediate 03; S2. After deprotecting intermediate 03, it automatically cyclizes to obtain intermediate 04, and intermediate 04 is reduced with sodium borohydride to obtain a single cis-configuration intermediate 05; S3. Intermediate 05 undergoes a chiral inversion reaction, hydrolyzes to remove p-nitrobenzoic acid, and then undergoes an etherification reaction with diethyl sulfate to obtain intermediate 08; S4. Intermediate 08 is reduced by sodium borohydride and boron trifluoride diethyl ether complex to obtain intermediate 09; S5. Intermediate 09 protects the amino group through an acetylation reaction, undergoes a cyanation reaction using cuprous cyanide reagent, and then undergoes hydrolysis esterification of the cyano group under the conditions of thionyl chloride and ethanol, while removing the acetyl group to obtain the key intermediate TM of iptacopan.

[0006] Preferably, step S1 specifically includes: S11. Add tert-butyl carbamate and tetrahydrofuran to a reaction vessel. After purging with nitrogen, successively add water, sodium p-toluenesulfonate, freshly distilled p-bromobenzaldehyde, and formic acid, and stir. Filter the reaction solution. After washing the filter cake with water, add a mixed solvent of hexane and dichloromethane and stir. Filter and wash again, and dry under reduced pressure to obtain intermediate 01. Then, successively add intermediate 01, tetrahydrofuran, and potassium carbonate to a dry reaction vessel, reflux and stir. After the reaction is completed, cool to room temperature, filter through diatomaceous earth, and concentrate the filtrate to obtain intermediate 02; S12. Add intermediate 02, an S-configured catalyst, and toluene to a reaction vessel. After purging with nitrogen and cooling, dropwise add methyl acetoacetate SM2. After the reaction is completed, quench with a dichloromethane solution of trifluoroacetic acid, add dichloromethane again, and wash successively with saturated sodium bicarbonate solution and sodium chloride solution. Concentrate the organic phase and slurry with n-heptane for purification to obtain intermediate 03.

[0007] Preferably, step S2 specifically includes: S21. Dissolve intermediate 03 in tetrahydrofuran, add hydrochloric acid to remove the Boc protecting group, and then add potassium carbonate to adjust to alkaline to carry out a ring-closing reaction to obtain intermediate 04; S22. Dissolve intermediate 04 in tetrahydrofuran, add sodium borohydride for reduction to obtain a cis product intermediate 05 with a single configuration.

[0008] Preferably, step S3 specifically includes: S31. Carry out the Mitsunobu reaction between intermediate 05 and p-nitrobenzoic acid to invert the chirality of the hydroxyl group, and then hydrolyze to obtain a trans product intermediate 07 with a single configuration; S32. Carry out an etherification reaction between intermediate 07 and diethyl sulfate under alkaline conditions to obtain a trans product intermediate 08 with a single configuration.

[0009] Preferably, the catalyst reagent structure selected in step S12 is (S)-3,3'-bis[3,5-bis(trifluoromethyl)phenyl]-1,1'-binaphthalene-2,2'-disulfonimide, and the catalyst dosage is 2% - 5% molar equivalent based on the amount of substance of intermediate 02.

[0010] Preferably, step S21 adopts a one-pot method for deprotection and ring closure.

[0011] 3. Beneficial effects: Adopting the technical solution provided by the present invention, compared with the prior art, it has the following beneficial effects: The present invention abandons high-cost processes such as traditional chiral column chromatography separation and salt formation separation using a resolving agent. Through an innovative asymmetric synthesis strategy, it reduces the use of expensive chiral column consumables and the consumption of the resolving agent, significantly reducing the raw material cost and the separation and purification cost, providing a cost advantage for large-scale industrial production. The new synthesis route provided by the present invention avoids the method of chiral preparative separation and purification reported in previous literature, greatly reducing the separation and purification cost and shortening the route. The route of the present invention has a total of 12 reaction steps with a total yield of 10-15%. The raw materials are simple in source and low in cost, enabling the rapid preparation of intermediate TM and meeting the high requirements for efficiency in industrial production. The operation process of the present invention is simple and stable, easy to realize continuous and automated production, effectively reducing the manual operation cost and the difficulty of production management. At the same time, this route has good scalability and repeatability, and can operate stably on production equipment of different scales, providing a reliable guarantee for industrial production. The present invention reduces the use of a large amount of organic solvents and resolving agents in the traditional method, reduces the generation amount of three wastes, simplifies the waste treatment process, conforms to the concepts of green chemistry and sustainable development, helps enterprises reduce the environmental protection pressure, and achieves a win-win situation of economic benefits and environmental benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 is a schematic diagram of the synthetic route of the background technology of the present invention; Figure 2 is a schematic diagram of the synthetic route of the background technology of the present invention; Figure 3 is a schematic diagram of the synthetic route of the background technology of the present invention; Figure 4 is a schematic diagram of the synthetic route of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0013] To facilitate the understanding of the present invention, the present invention will be described more comprehensively below with reference to the relevant drawings. Several embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thorough and comprehensive.

[0014] In the description of the present invention, it should be understood that the orientation or positional relationship indicated by the terms "center", "longitudinal", "transverse", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "page", "bottom", "inner", "outer", "clockwise", "counterclockwise", etc. is based on the orientation or positional relationship shown in the drawings, and is only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be construed as a limitation on the present invention.

[0015] In addition, the terms "first" and "second" are only used for descriptive purposes and should not be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include one or more of such features. In the description of the present invention, the meaning of "a plurality" is two or more, unless otherwise specifically defined.

[0016] In the present invention, unless otherwise clearly specified and limited, the terms "installed", "connected", "connected to", "fixed", "provided with", etc. should be understood in a broad sense. For example, it may be a fixed connection, a detachable connection, or an integral connection; it may be a mechanical connection or an electrical connection; it may be directly connected or indirectly connected through an intermediate medium, and it may be the communication inside two elements. For those of ordinary skill in the art, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0017] It should be noted that the structures not introduced in the present invention are the same as the prior art or can be implemented by the prior art because they do not involve the design key points and improvement directions of the present invention, and will not be elaborated herein.

[0018] Referring to the attached Figure 4 , a method for synthesizing a key intermediate of ipcopam, a drug for the indication of paroxysmal nocturnal hemoglobinuria, characterized by comprising the following steps: S1. Using p-bromobenzaldehyde as the starting material and an S-configuration catalyst to obtain intermediate 03; S2. After the intermediate 03 is deprotected, it automatically cyclizes to obtain intermediate 04, and the intermediate 04 is reduced with sodium borohydride to obtain a single cis-configuration intermediate 05; S3. The intermediate 05 undergoes a chiral inversion reaction, hydrolyzes to remove p-nitrobenzoic acid, and then undergoes an etherification reaction with diethyl sulfate to obtain intermediate 08; S4. The intermediate 08 is reduced by sodium borohydride and boron trifluoride diethyl ether complex to obtain intermediate 09; In S5, the amino group of intermediate 09 is protected through an acetylation reaction, a cyanation reaction is carried out using cuprous cyanide reagent, and then the cyano group is hydrolyzed and esterified under the conditions of thionyl chloride and ethanol, while the acetyl group is removed to obtain the key intermediate TM of iptacopan.

[0019] Preferably, the step S1 specifically includes: S11. Add tert-butyl carbamate and tetrahydrofuran to a reaction vessel. After purging with nitrogen, successively add water, sodium p-toluenesulfonate, freshly distilled p-bromobenzaldehyde, and formic acid, and stir. Filter the reaction solution. After washing the filter cake with water, add a mixed solvent of hexane and dichloromethane and stir. Filter and wash again, and conduct drying under reduced pressure to obtain intermediate 01. Then, successively add intermediate 01, tetrahydrofuran, and potassium carbonate to a dry reaction vessel, reflux and stir. After the reaction is completed, cool to room temperature, filter through diatomaceous earth, and concentrate the filtrate to obtain intermediate 02; S12. Add intermediate 02, an S-configured catalyst, and toluene to a reaction vessel. After purging with nitrogen and cooling, dropwise add methyl acetoacetate SM2. After the reaction is completed, quench with a dichloromethane solution of trifluoroacetic acid, then add dichloromethane, and wash successively with saturated sodium bicarbonate solution and sodium chloride solution. Concentrate the organic phase and then slurry with n-heptane for purification to obtain intermediate 03.

[0020] The step S2 specifically includes: S21. Dissolve intermediate 03 in tetrahydrofuran, add hydrochloric acid to remove the Boc protecting group, and then add potassium carbonate to adjust to alkaline to carry out a ring-closing reaction to obtain intermediate 04; Step S21 adopts a one-pot method for deprotection and ring closing.

[0021] S22. Dissolve intermediate 04 in tetrahydrofuran, add sodium borohydride for reduction to obtain the cis product intermediate 05 with a single configuration.

[0022] The step S3 specifically includes: S31. Carry out the Mitsunobu reaction between intermediate 05 and p-nitrobenzoic acid to invert the chirality of the hydroxyl group, and then hydrolyze to obtain the trans product intermediate 07 with a single configuration; S32. Carry out an etherification reaction between intermediate 07 and diethyl sulfate under alkaline conditions to obtain the trans product intermediate 08 with a single configuration.

[0023] The catalyst reagent structure selected in step S12 is (S)-3,3'-bis[3,5-bis(trifluoromethyl)phenyl]-1,1'-binaphthalene-2,2'-disulfonimide, and the catalyst dosage is 2% - 5% molar equivalent, based on the amount of substance of intermediate 02.

[0024] The present invention is achieved through the following technical solution, a new synthesis method for the key intermediate of the drug iptacopan for the indication of paroxysmal nocturnal hemoglobinuria.

[0025] The synthetic route is as Figure 4 shown below: The present invention relates to a new synthetic method for a key intermediate of the drug Iptacopan for the indication of paroxysmal nocturnal hemoglobinuria. The present invention will be further illustrated by the following examples. It should be correctly understood that: the methods in the examples of the present invention are only given for the purpose of describing the invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention fall within the scope of protection of the present invention.

[0026] Preparation of Intermediate 01:

[0027] A 500 mL three-necked round-bottom flask equipped with a mechanical stirrer was charged with tert-butyl carbamate (13.00 g, 110.9 mmol, 1.00 eq.) and tetrahydrofuran (40 mL), and purged with nitrogen three times. Water (100 mL), sodium p-toluenesulfonate (21.78 g, 110.9 mmol, 1.00 eq.), freshly distilled p-bromobenzaldehyde (12.48 mL, 113.1 mmol, 1.02 eq.), and formic acid (99%, 24.3 mL, 643 mmol) were added in batches in sequence. The mixture was stirred under a nitrogen atmosphere at room temperature for 18 hours, and a precipitate formed during the stirring. After the reaction was complete, the reaction mixture was filtered through a Buchner funnel, and the filter cake was washed with distilled water (200 mL). The filter cake was added to a 500 mL single-necked flask, and a mixed solvent of hexane / dichloromethane (150 mL / 15 mL) was added, and the mixture was stirred at room temperature for 2 hours. After complete stirring, the mixture was filtered through a Buchner funnel, and the filter cake was washed with hexane / dichloromethane (91 / 9 mL). The filter cake was dried under reduced pressure at 25 °C to obtain Intermediate 01 (30.79 g, 98.5%), and the yield was 80%.

[0028] The spectral analysis data of Intermediate 01 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.78 (d, J = 8.1 Hz, 2 H), 7.56 (d, J = 8.5Hz, 2 H), 7.35 (d, J = 8.1 Hz, 2 H), 7.32 (d, J = 8.5 Hz, 2 H), 5.85 (d, J =10.5 Hz, 1 H), 5.66 (d, J = 10.5 Hz, 1 H), 2.44 (s, 3 H), 1.27 (s, 9 H). 13CNMR (101 MHz, CDCl3) δ 153.4, 145.3, 133.4, 131.9, 130.4, 129.8, 129.5, 129.1, 124.1, 81.3, 73.1, 27.9, 21.6. Preparation of Intermediate 02:

[0029] In a dry 500 mL round-bottom flask, Intermediate 01 (30.00 g, 68.32 mmol, 1.00 eq), tetrahydrofuran (600 mL) and potassium carbonate (56.66 g, 409.97 mmol, 6.00 eq) were successively added, and the mixture was stirred overnight under reflux. After the reaction was complete, it was cooled to room temperature and filtered through a Buchner funnel lined with diatomaceous earth. The filtrate was concentrated to obtain Intermediate 02 (17.68 g, purity 97.8%), and the yield was 91%.

[0030] Spectral analysis data of Intermediate 02 are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 1.60 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 165.7, 162.4, 137.9, 135.1, 134.2, 130.2, 129.1, 127.1, 82.6, 27.9. Preparation of Intermediate 03:

[0031] In a 500 mL round-bottom flask, Intermediate 02 (15.00 g, 52.99 mmol, 1.00 eq.), (S)-3,3'-bis[3,5-bis(trifluoromethyl)phenyl]-1,1'-binaphthalene-2,2'-disulfonimide (1.50 g) and toluene (150 mL) were added, and the mixture was purged with nitrogen three times. The mixture was cooled to -30 °C, and methyl acetoacetate SM2 was added dropwise to the reaction solution, and the temperature was maintained while stirring for 72 hours. After the reaction was complete, the reaction solution was quenched with a dichloromethane solution of 10% trifluoroacetic acid (200 mL), and then dichloromethane (200 mL) was added. The organic phase was washed successively with a saturated sodium bicarbonate solution (200 mL) and a 10% sodium chloride solution (200 mL). After the organic phase was completely concentrated, 100 ml of n-heptane was added for slurry purification to obtain Intermediate 03 (16.9 g, purity 98.6%), and the yield was 79.71%.

[0032] The spectral analysis data of Intermediate 03 are as follows: 1 H NMR (400MHz, CDCl3) δ 0.84 (t, 3H), 1.18 - 1.38 (m, 3H), 1.42 - 1.52(m, 7H), 1.79 (dd, 1 H), 1.96 (m, 2H), 2.10 (m, 1 H), 2.38 (m, 1 H), 2.68 (m,2H), 3.60 (m, 2H), 4.44 (m, 3H), 7.58 (d, 2H), 7.75 (d, 2H). Preparation of Methyl Acetoacetate SM2:

[0033] In a 250 - mL round - bottom flask, add diisopropylamine (12.20 g, 120.63 mmol, 1.40 eq.) and tetrahydrofuran (100 mL), and displace the air with nitrogen three times. Cool the temperature to 0 °C, and dropwise add LDA (2.5 M hexane solution, 120.63 mmol, 1.40 eq.). Stir for 15 minutes, then cool the mixture temperature to - 78 °C, and add SM2 - A (10.00 g, 86.16 mmol, 1.00 eq.). Continue to stir for 1 hour, add TMSCl (13.10 g, 120.63 mmol, 1.40 eq.), keep the temperature and stir for 1 hour, then slowly raise the temperature to 25 °C and stir for 2 hours. Concentrate the reaction solution until there is no flow, add pentane (50 mL), filter through a Buchner funnel lined with diatomaceous earth, and concentrate the filtrate to obtain methyl acetoacetate SM2 (16.81 g), with a yield of 75.19%.

[0034] The spectral analysis data of Methyl Acetoacetate SM2 are as follows: 1 H NMR (400MHz, CDCl3) δ 4.47 (s, 1H), 4.14 (d, J = 1.4 Hz, 1H), 3.94(d, J = 1.4 Hz, 1H), 3.55 (s, 3H), 0.24 (s, 9H), 0.21 (s, 9H). 13 C NMR (101MHz,CDCl3) δ 158.7, 153.5, 89.4, 77.8, 55.1, 0.6, 0.4. Preparation of Intermediate 04:

[0035] In a 500 mL round-bottom flask, add intermediate 03 (10.00 g, 24.98 mmol, 1.00 eq) and tetrahydrofuran (100 mL). Cool the temperature to 0 - 5 °C, add concentrated hydrochloric acid (4 mL), and stir at a constant temperature for 2 hours. Adjust the pH of the solution to 10 with potassium carbonate and stir overnight. After the reaction is complete, extract the reaction solution twice with dichloromethane (100 mL). Combine the organic phases and concentrate. Add 50 mL of n-heptane for pulping and purification to obtain intermediate 04 (5.5 g, purity 98.3%), and the yield is 83.20%.

[0036] The spectral analysis data of intermediate 04 are as follows: 1 H NMR (400 MHz, CDCl3): δ: 2.75 (dd, 1H), 3.00 (dd, 1H), 3.39 (s, 2H), 4.82 (ddd, 1H), 7.20 (d, 2H), 7.45 (d, 2H). Preparation of intermediate 05:

[0037] Add intermediate 04 (20 g, 74.6 mmol) and 200 mL of tetrahydrofuran to a 500 mL three-necked flask. Replace the air with nitrogen three times. Cool the temperature to 0 - 5 °C, and add sodium borohydride (3.39 g, 89.5 mmol) to the three-necked flask in batches while controlling the temperature not to exceed 10 °C. After adding, let the temperature rise naturally to 20 - 30 °C and react for 6 - 8 hours. After detecting that the reaction is complete, cool the reaction to 0 - 10 °C, add 200 mL of water dropwise to quench the reaction, extract once with 200 mL of ethyl acetate, wash once with saturated brine, and concentrate under reduced pressure to obtain intermediate 05 (18.14 g, yield 89.8%).

[0038] The spectral analysis data of intermediate 05 are as follows: 1 H NMR (400 MHz, CDC13) δ 1.85 - 1.89 (2H, m), 2.11 - 2.17 (1H, m), 2.53 - 2.61 (1H, q), 2.92 - 3.00 (1H, dd), 4.10 (1H, s), 4.22 - 4.26 (1H, m), 6.96 - 6.99 (2H, d), 7.41 - 7.43 (2H, d), 7.91 (1H, s). Preparation of intermediate 06:

[0039] Add intermediate 05 (18 g, 66.6 mmol), p-nitrobenzoic acid (14.48 g, 86.6 mmol) and 180 mL of tetrahydrofuran into a 500 mL three-necked flask. Cool the temperature to 0 - 5 °C, add triphenylphosphine (29.7 g, 113.2 mmol) into the reaction flask, stir for 10 - 20 minutes, then slowly drop diisopropyl azodicarboxylate (22.89 g, 113.2 mmol) into the reaction flask. After dropping, react at 15 - 20 °C for 16 hours. Detect that the reaction is complete. Add 360 mL of water into the reaction flask, extract with ethyl acetate (180 mL × 2), separate the liquid, combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and slurry with a mixed solvent of 100 mL of ethyl acetate : n-heptane = 1 : 4 to obtain intermediate 06 (20.09 g, yield 72.1%).

[0040] The spectral analysis data of intermediate 06 are as follows: 1 H NMR (400 MHz, CDC13) δ 1.57 - 1.81(1H, m), 1.82 - 1.84(1H, m), 2.05 - 2.11(1H,q), 2.29 - 2.33(1H,dd), 3.37 - 3.79(2H,m), 7.02 - 7.09(2H,d), 7.41 - 7.43(2H,d), 7.91(1H,s), 8.21 - 8.34(4H,m). Preparation of intermediate 07:

[0041] Add intermediate 06 (20 g, 47.7 mmol), 60 mL of water and 100 mL of tetrahydrofuran into a 250 mL three-necked flask, stir to dissolve clearly, add sodium carbonate (15.2 g, 143.1 mmol) into the reaction flask, and react at room temperature for 16 hours. Detect that the reaction is complete, add 100 mL of water, extract with ethyl acetate (100 mL × 2), combine the organic phases, wash once with 100 mL of saturated sodium bicarbonate, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain intermediate 07 (11.21 g, yield 86.6%).

[0042] The spectral analysis data of intermediate 07 are as follows: 11H NMR (400 MHz, CDC13) δ 1.57 - 1.81 (1H, m), 1.82 - 1.84 (1H, m), 2.05 - 2.11 (1H, q), 2.29 - 2.33 (1H, dd), 3.37 - 3.79 (2H, m), 4.22 - 4.26 (1H, m), 7.02 - 7.09 (2H, d), 7.41 - 7.43 (2H, d), 7.91 (1H, s). Preparation of Intermediate 08:

[0043] Add intermediate 07 (10 g, 37.0 mmol), potassium carbonate (15.3 g, 111.1 mmol) and 80 mL of N,N - dimethylformamide into a 250 - mL three - necked flask. Cool the temperature to 0 - 10 °C, and slowly add diethyl sulfate (8.6 g, 55.5 mmol) dropwise to the reaction flask. After dropping, react at room temperature for 24 hours. Detect that the reaction is complete, add 100 mL of water, extract with ethyl acetate (100 mL × 2), separate the liquid, combine the organic phases, wash twice with water (50 mL × 2), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and slurry with a mixed solvent of 50 mL ethyl acetate:n - heptane = 1:9 to obtain intermediate 08 (9.66 g, yield 87.6%).

[0044] Spectral analysis data of intermediate 08 is as follows: 1 1H NMR (400 MHz, CDC13) δ 1.08 - 1.11(3H,t) 1.57 - 1.81 (1H, m), 1.82 - 1.84 (1H, m), 2.05 - 2.11 (1H, q), 2.29 - 2.33 (1H, dd), 3.37 - 3.79 (2H, m), 3.77 - 3.82(2H,q), 7.02 - 7.09 (2H, d), 7.41 - 7.43 (2H, d), 7.91 (1H, s). Preparation of Intermediate 09:

[0045] In a 500 mL three-necked flask, add intermediate 08 (50 g, 0.168 mol) and 250 mL of tetrahydrofuran. Add sodium borohydride (20.9 g, 0.554 mol), stir and cool the reaction to 0 °C. Slowly add boron trifluoride diethyl etherate (95.2 g, 0.672 mol) to the above reaction solution. After the addition is complete, keep the temperature at 5 °C and stir for 5 to 10 hours; HPLC in-process control shows that the raw materials have completely reacted. Slowly add 100 mL of water to the reaction solution; after the addition is complete, add 37% concentrated hydrochloric acid (40.8 g, 0.336 mol) to the reaction solution. After the addition is complete, heat the reaction solution to 40 °C and stir for 3 to 5 hours. HPLC shows that the intermediate state has completely reacted. Adjust the pH of the system to between 6 and 7 with 50% NaOH. Let the reaction system stand directly for liquid separation; extract the aqueous phase twice with 150 mL of ethyl acetate, combine all the organic phases, concentrate under reduced pressure at 40 °C to remove the solvent, obtain the crude product, recrystallize with acetonitrile, and dry under vacuum to obtain 49.4 g of off-white intermediate 09, with a purity of 99.05% and a yield of 88%.

[0046] The spectral analysis data of intermediate 09 are as follows: MS(ESI)(m / z): 285.2(M+H + ) 1 H-NMR(400MHz, DMSO-d6): δ7.50 (m, 2H), 7.43(m, 2H), 3.62(d, 1H),3.51(m, 3H),3.43 (m, 1H), 2.62 (m, 4H), 2.31 (m, 2H), 1.52 (m, 3H). Preparation of intermediate 10:

[0047] In a 250 mL three-necked flask, add intermediate 09 (30 g, 0.105 mol) and 150 mL of tetrahydrofuran, stir until completely dissolved and clear, and add triethylamine (16.0 g, 0.158 mol). Cool to 0 to 5 °C, and slowly add acetyl chloride (9.9 g, 0.126 mol) to the reaction system; then react at room temperature for 3 hours; HPLC shows that the raw materials have completely reacted. Add 60 mL of 25% sodium chloride solution to the reaction solution, add 90 mL of methyl tert-butyl ether, let it stand for liquid separation, and concentrate the organic phase under reduced pressure at 40 °C until there is no flow to obtain 40 g of white solid. Pulp with n-hexane at room temperature for 2 hours; filter and dry in a blast dryer to obtain 34 g of intermediate 10, with a yield of 92.8% and a purity of 99.6%.

[0048] The spectral analysis data of intermediate 10 are as follows: 1H-NMR(400MHz, DMSO-d6): δ 7.46 (m, 2H), 7.43 (m, 2H), 3.63 (m, 3H), 3.43 (m, 1H), 2.62 (m, 4H), 2.31 (m, 2H), 1.52 (m, 3H). Preparation of Intermediate 11:

[0049] Add Intermediate 10 (250 g, 0.766 mol) and 150 mL of N,N-dimethylformamide to a 500 mL three-necked flask, then add cuprous cyanide (25.8 g, 1.532 mol), and heat up to 130 °C for reaction for 16 hours; detect by HPLC and there is no raw material residue, cool the reaction to 20 °C; filter, drop the mother liquor into 300 mL of ice water, stir for 2 hours; filter, and dry by blowing air to obtain 35.3 g of light yellow solid Intermediate 11, with a yield of 83.1% and a purity of 98.7%.

[0050] The spectral analysis data of Intermediate 11 are as follows: 1 H-NMR(400MHz, DMSO-d6): δ 7.75 (m, 2H), 7.52 (m, 2H), 3.63 (m, 3H), 3.43 (m, 1H), 2.62 (m, 4H), 2.31 (m, 2H), 1.52 (m, 3H). Preparation of Key Intermediate TM:

[0051] Add Intermediate 11 (30 g, 0.11 mol) and 150 mL of ethanol to a 500 mL three-necked flask, slowly dropwise add 60 mL of thionyl chloride, react and stir at 75 °C for 2 days, detect by HPLC and the raw materials have completely reacted, slowly drop the reaction solution into 500 mL of ice water, add 200 mL of ethyl acetate for extraction twice, and concentrate the organic phase under reduced pressure at 40 °C to obtain 36 g of light brown crude product. Recrystallize with acetonitrile to obtain 27.1 g of off-white solid target product Key Intermediate TM, with a purity of 98.5% and a yield of 78%.

[0052] The spectral analysis data of Intermediate TM are as follows: 11H-NMR (400 MHz, DMSO-d6): δ 7.80 (d, 2H), 7.36 (d, 2H), 4.50 (m, 1H), 4.26 (m, 1H), 3.76 - 3.59 (m, 3H), 3.30 - 3.20 (m, 2H), 2.85 (m, 1H), 2.02 - 1.49 (m, 4H), 1.39 - 1.31 (m, 4H), 1.17 (t, 3H). The above embodiments only represent certain implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent for the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several variations and improvements can be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention shall be subject to the appended claims.

Claims

1. A synthetic method of a key intermediate of ipocopan, a drug for paroxysmal nocturnal hemoglobinuria indication, characterized in that, The following steps are involved: S1, using p-bromobenzaldehyde as the starting material and an S-configured catalyst to obtain intermediate 03; After deprotection of S2 and intermediate 03, the ring is closed automatically to obtain intermediate 04, and intermediate 04 is reduced with sodium borohydride to obtain intermediate 05 with a single cis configuration; S3 and intermediate 05 undergo chiral inversion reaction, hydrolysis to remove p-nitrobenzoic acid, and then etherification reaction with diethyl sulfate to obtain intermediate 08; S4, intermediate 08 is reduced to intermediate 09 by amide reduction with sodium borohydride and boron trifluoride etherate; S5 and intermediate 09 are subjected to acetylation reaction to protect the amino group, and then cyanidation reaction is carried out using cuprous cyanide reagent. Then, thionyl chloride and ethanol are used to hydrolyze and esterify the cyano group, and the acetyl group is removed to obtain the key intermediate TM of iprocopan.

2. The synthesis method of the key intermediate of ipocopan for the indication of paroxysmal nocturnal hemoglobinuria according to claim 1, characterized in that, The step S1 specifically includes: S11, tert-butyl carbamate and tetrahydrofuran were added to a reaction vessel. After nitrogen substitution, water, sodium p-toluenesulfonate, freshly distilled p-bromobenzaldehyde and formic acid were added in sequence, and the mixture was stirred. The reaction solution was filtered, the filter cake was washed with water, and a mixed solvent of hexane and dichloromethane was added and stirred. The mixture was filtered and washed again, and dried under reduced pressure to obtain intermediate 01. Intermediate 01, tetrahydrofuran and potassium carbonate were then added in sequence to a dry reaction vessel, and the mixture was refluxed with stirring. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated to obtain intermediate 02; S12. Add intermediate 02, S-configuration catalyst and toluene to the reaction vessel. After nitrogen replacement and cooling, add methyl acetoacetate SM2 dropwise. After the reaction is completed, quench with a dichloromethane solution of trifluoroacetic acid, add dichloromethane, and wash with a saturated sodium bicarbonate solution and a sodium chloride solution in sequence. After the organic phase is concentrated, add n-heptane for pulping and purification to obtain intermediate 03.

3. The synthetic method of the key intermediate of ipocopan for the indication of paroxysmal nocturnal hemoglobinuria according to claim 2, characterized in that, The step S2 specifically includes: S21, dissolving the intermediate 03 in tetrahydrofuran, adding hydrochloric acid to remove the Boc protecting group, then adding potassium carbonate to adjust to alkalinity, and causing a ring-closure reaction to obtain the intermediate 04; S22. Dissolve the intermediate 04 in tetrahydrofuran, add sodium borohydride for reduction, and obtain the cis-product intermediate 05 of single configuration.

4. The synthesis method of a key intermediate of ipocopan for the indication of paroxysmal nocturnal hemoglobinuria according to claim 3, characterized in that, The step S3 specifically includes: S31, the intermediate 05 is subjected to a Mitsunobu reaction with p-nitrobenzoic acid to flip the chirality of the hydroxyl group, and then hydrolyzed to obtain a single-configuration trans product intermediate 07; S32. Intermediate 07 is subjected to etherification reaction with diethyl sulfate under alkaline conditions to obtain a single-configuration trans product intermediate 08.

5. The synthesis method of the key intermediate of eprifibatide for the indication of paroxysmal nocturnal hemoglobinuria according to claim 2, characterized in that: The catalyst reagent structure selected in step S12 is (S)-3,3'-bis[3,5-bis(trifluoromethyl)phenyl]-1,1'-binaphthyl-2,2'-disulfonimide, and the catalyst dosage is 2%-5% molar equivalent, based on the amount of the intermediate 02.

6. The synthesis method of the key intermediate of ipocopan for the indication of paroxysmal nocturnal hemoglobinuria according to claim 3, wherein: Step S21 adopts a one-pot method of deprotection and ring closure.

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