Synthetic method of Rucaparib
By simplifying the Rucaparib synthesis method, catalytic oxidation cyclosynthesis reaction and hydrogen catalysis, the problems of acidic materials and expensive raw materials in the prior art were solved, and efficient and safe industrial production was achieved.
Patent Information
- Application Number
- CN202411384665.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-30
- Publication Date
- 2025-01-17
AI Technical Summary
The existing Rucaparib synthesis method has problems with the use of a large number of acidic materials, violent exothermic reactions, expensive raw materials and precious metal catalysts, which leads to complex steps and is not conducive to industrial production.
Using methyl 3-amino-4-bromo-5-fluorobenzoate as raw material, the use of heteropoly is made by catalytic oxidative cyclosynthesis reaction, acidic hydrolysis protection, condensation reaction, double bond reduction, nitro reduction and cyclic amidation reaction. Acid ionic liquid catalysts and hydrogen catalysis simplifies the reaction route and improves efficiency and safety.
It has achieved simplification of the reaction route, the cheap and easy-to-get raw materials, the simplicity of operation steps, safety and environmental protection, and reduced production costs and is suitable for large-scale industrial production.
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Figure CN119320392A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic chemical synthesis and drug synthesis, and particularly relates to a preparation method of Rucaparib. Background Art
[0002] Rucaparib (trade name Rubraca) is a poly(ADP-ribose) polymerase inhibitor. A large number of clinical trials have shown that it has few toxic side effects, clear effects and good tolerance. It can be used for the potential treatment of cancer, including solid tumors such as breast cancer and ovarian cancer. The drug is used as a monotherapy for patients with refractory advanced ovarian cancer. Its structural formula is as follows.
[0003]
[0004] At present, there are three main routes for the synthesis of Rucaparib. 5-Fluoro-2-methylbenzoic acid 1 is used as a raw material, and after nitration and esterification, it is condensed with DMF-DMA to obtain intermediate 2, and then catalytic hydrogenation reduction cyclization is performed to obtain the key indole intermediate 3. Among them, both routes 1 and 2 need to go through intermediate 4. In route 1, compound 3 reacts with 1-dimethylamino-2-nitroethylene under acid catalysis and then is reduced to obtain intermediate 4; in route 2, compound 3 introduces an aldehyde group at the 3rd position of the indole ring through the Velsmeier reaction and then condenses with nitromethane to obtain intermediate 4. In addition, in route 3, compound 3 is condensed with N-(2-acetaldehyde)phthalimide 8 under the catalysis of trifluoroacetic acid to obtain intermediate 9. Then, intermediate 4 and intermediate 9 are lactamized after catalytic hydrogenation and lactamized after phthalimide deprotection to obtain tricyclic intermediate 5. Finally, intermediate 5 was sequentially subjected to bromination, coupling, and reductive amination reactions to synthesize the target compound Rucaparib.
[0005]
[0006] The above routes have the following problems: 1. Many steps in the route require a large amount of acidic materials, which produces a large amount of acidic wastewater, and has great environmental pressure; 2. The temperature is high and accompanied by a violent exothermic process when reacting with DMFDMA, and a large amount of nitrogen-containing wastewater is produced in the post-treatment, which poses safety and environmental risks; 3. The raw material 1-dimethylamino-2-nitroethylene is expensive; 4. Expensive metal catalysts are used in the coupling reaction. Therefore, these synthetic routes not only have long steps and complex operations, but are also not conducive to industrial scale-up production in terms of safety, environmental protection, and operation.
[0007] Many deficiencies in the prior art restrict the large-scale industrial production and cost reduction of Rucaparib. Therefore, it is necessary to develop a synthesis method of Rucaparib that is easy to control, safe, environmentally friendly, simple to operate, high in yield, and suitable for industrial production. Summary of the invention
[0008] In view of the drawbacks of the prior art, the present invention provides a method for preparing Rucaparib, wherein the raw materials used in the method are cheap and easily available, the reaction route is short, the reaction efficiency is high, the operation steps are simple, safe and environmentally friendly, the cost is low, the yield is high, and it is conducive to realizing industrial production.
[0009] The technical solution of the present invention is: a method for preparing Rucaparib, comprising:
[0010] (1) subjecting methyl 3-amino-4-bromo-5-fluorobenzoate 10 and compound 11 to a catalytic oxidation cyclization reaction under the action of a catalyst and an oxidant to obtain an indole compound 12,
[0011]
[0012] Wherein, PG is any one of benzyl, p-methylbenzyl, p-methoxybenzyl, and benzyloxycarbonyl;
[0013] (2) deprotecting compound 12 by acidic hydrolysis to obtain compound 13,
[0014]
[0015] (3) a step of condensing compound 13 and nitromethane to obtain compound 14,
[0016]
[0017] (4) subjecting compound 14 to double bond reduction, nitro group reduction, halogen reduction and cyclic amidation reaction under the action of a catalyst and hydrogen catalytic hydrogenation to obtain Rucaparib,
[0018]
[0019] Preferably, in step (1), the catalyst is a heteropolyacid ionic liquid catalyst, wherein the heteropolyacid ionic liquid catalyst is selected from [MIMPS]3PW 12 O 40 、[MIMPS]3PMo 12 O 40 、[PyPS]3PW 12 O 40 、[PyPS]3PMo 12 O 40 、[TEAPS]3PW 12 O 40 、[TEAPS]3PMo 12 O 40 Any one of the above, whose chemical structures are: The oxidant is selected from any one of hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, and cyclohexyl hydroperoxide.
[0020] Preferably, in step (1), the molar ratio of methyl 3-amino-4-bromo-5-fluorobenzoate 10, compound 11, oxidant, and catalyst is 1:1-2:3-6:0.01-0.05; the reaction temperature is 60-120°C; and the reaction time is 8-20h.
[0021] Preferably, in step (2), the reaction is carried out in the presence of an acid, the acid being selected from any one of hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid; the reaction system uses an organic solvent as a solvent, the organic solvent being selected from any one of methanol, ethanol, acetone and acetonitrile.
[0022] Preferably, in step (2), the molar ratio of compound 12 to acid is 1:3-10; the reaction temperature is 20-70°C; and the reaction time is 4-12h.
[0023] Preferably, in step (3), the reaction is carried out in the presence of a base, and the base is selected from any one of ammonium acetate, sodium carbonate, sodium bicarbonate, and potassium carbonate.
[0024] Preferably, in step (3), the molar ratio of compound 13, nitromethane and base is 1:10-20:3-8; the reaction temperature is 60-110°C; and the reaction time is 2-8h.
[0025] Preferably, in step (4), the catalyst is selected from any one of platinum carbon (platinum content 1%-10wt%), palladium carbon (palladium content 1%-10wt%), and Raney nickel; the reaction system uses an organic solvent as a solvent, and the organic solvent is selected from any one of methanol, ethanol, propanol, acetonitrile, acetone, and tetrahydrofuran.
[0026] Preferably, in step (4), the mass ratio of compound 14 to catalyst is 1:0.01-1; the molar ratio of compound 14 to hydrogen is 1:5-20; the reaction temperature is 20-80°C; and the reaction time is 5-20h.
[0027] The present invention uses 3-amino-4-bromo-5-fluorobenzoic acid methyl ester as a raw material, and obtains the target product through catalytic oxidation cyclization reaction, acid hydrolysis deprotection, condensation reaction, double bond reduction, nitro reduction, halogen reduction and cycloamidation reaction. Compared with the prior art, the present invention has the following beneficial effects: (1) a heteropolyacid ionic liquid catalyst is used in the catalytic oxidation cyclization reaction step, and the synthesis method is simple, highly active, can be recycled and reused multiple times, and is green and environmentally friendly; finally, double bond reduction, nitro reduction, halogen reduction and cycloamidation reaction are achieved through a one-step reaction, and the efficiency is high. (2) the raw materials used in the method are cheap and easy to obtain, the reaction route is short, the reaction efficiency is high, the process operation is simple, the conditions are easy to control, it is safe and environmentally friendly, the cost is low, the yield is high, and it is conducive to large-scale industrial use. BRIEF DESCRIPTION OF THE DRAWINGS
[0028] Figure 1 The data are the reaction yields of the activity repeatability test of the catalytic heteropolyacid ionic liquid using Group E in Example 3 as the template reaction. DETAILED DESCRIPTION
[0029] The present invention is further described below by way of examples, but the patent rights are not limited to these examples.
[0030] The preparation method of Rucaparib of the present invention uses 3-amino-4-bromo-5-fluorobenzoic acid methyl ester as a raw material, and obtains the target product through catalytic oxidation cyclization reaction, acidic hydrolysis deprotection, condensation reaction, double bond reduction, nitro reduction, halogen reduction and cycloamidation reaction, and specifically comprises the following steps:
[0031] Step 1: Using 3-amino-4-bromo-5-fluorobenzoic acid methyl ester 10 as raw material and compound 11 through catalytic oxidation cyclization reaction to obtain indole compound 12.
[0032]
[0033] Wherein, PG is any one of benzyl, p-methylbenzyl, p-methoxybenzyl, and benzyloxycarbonyl.
[0034] Under stirring conditions, methyl 3-amino-4-chloro-5-fluorobenzoate 10, compound 11, an oxidant and a heteropolyacid ionic liquid catalyst are added to the reactor in sequence. The temperature is raised to the target reaction temperature and the reaction is maintained for a certain period of time. After the reaction is completed, the temperature is lowered to room temperature. A non-protonic weakly polar solvent is added to the reactor. After stirring to dissolve the product, the heteropolyacid ionic liquid catalyst is filtered and recovered, which can be recycled and reused. The concentrated filtrate can be further recrystallized by ethanol or purified by column chromatography to obtain compound 12.
[0035] Step 2: Compound 12 is deprotected by acidic hydrolysis to obtain compound 13.
[0036]
[0037] Under stirring conditions, compound 12 and acid are added to the organic solvent in sequence. The temperature is raised to the target reaction temperature and the reaction is maintained for a certain period of time. After the reaction is completed, the temperature is lowered to room temperature, and a base is added to adjust the pH to 7-8. Water is added to the reactor, and the mixture is extracted with ethyl acetate. The organic phases are combined and washed with saturated brine. Finally, the solvent is dried and drained to obtain compound 13.
[0038] Step 3: Compound 14 is obtained by condensing compound 13 and nitromethane.
[0039]
[0040] Under stirring conditions, compound 13, nitromethane and base were added to the reactor in sequence. The temperature was raised to the target reaction temperature and the reaction was maintained for a certain period of time. After the reaction was completed, the temperature was lowered to room temperature. Water was added to the reactor, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, and finally the solvent was drained after drying to obtain compound 14.
[0041] Step 4: Compound 14 is subjected to double bond reduction, nitro group reduction, halogen reduction and cyclic amidation under catalytic hydrogenation to obtain Rucaparib.
[0042]
[0043] Compound 14 and a catalyst are sequentially added to an organic solvent, and then hydrogen is added. The temperature is raised to the target reaction temperature and then kept for a certain period of time. After the reaction is completed, the temperature is lowered to room temperature, and the catalyst is recovered by filtration and can be reused. After the filtrate is concentrated, it can be further purified by ethanol recrystallization or column chromatography to obtain Rucaparib.
[0044] For the preparation method of the heteropolyacid ionic liquid catalyst used in the examples, refer to the relevant literature (An eco-benign and highly efficient procedure for N-acylation catalyzed by heteropolyanion-based ionic liquids using carboxylic acid under solvent-free conditions, Tetrahedron 70 (2014) 2237-2245.).
[0045] The present invention also provides a method for preparing compound 11, wherein cinnamaldehyde derivative 15 undergoes a condensation reaction with ethylene glycol under the action of p-toluenesulfonic acid to obtain acetal compound 16, and finally compound 11 is obtained by oxidizing with potassium permanganate and performing dihydroxylation.
[0046]
[0047] Example 1: Preparation of Compound 16a
[0048]
[0049] Under stirring conditions, 8.0 g of cinnamaldehyde derivative 15a, 30 ml of ethylene glycol, 0.3 g of p-toluenesulfonic acid and 100 ml of toluene were added to the reactor in sequence. After the temperature reached 110°C, the reaction was kept warm for 8 hours. During the warming process, a reflux water separator was used to separate water. After the reaction was completed, the temperature was lowered to room temperature, 80 ml of ethyl acetate and 100 ml of water were added to the reactor, and the mixture was separated after stirring for 15 minutes. The aqueous phase was extracted three times with 50 ml of ethyl acetate, and the organic phases were combined and washed with 150 ml of saturated brine. Finally, the solvent was drained after drying to obtain 9.2 g of compound 16a with a yield of 99%. 1 H NMR(400M Hz, CDCl3) δ7.40(d,J=8.0Hz,2H),7.32-7.21(m,5H),7.22(d,J=8.0Hz,2H),6.79(d,J=16.0Hz,1H),6.62 (dd,J=6.0,16.0Hz,1H),5.43(d,J=6.0Hz,1H),4.12-3.93(m,4H),3.68(s,2H),3.60(s,2H),2.08(s,3H).
[0050] Example 2: Preparation of Compound 11a
[0051]
[0052] Under stirring conditions, 9.3 g of compound 16a, 0.1 g of sodium hydroxide and 80 ml of acetone were added to the reactor in sequence. After cooling to 0°C, the mixture was kept warm. 190 ml of 3% potassium permanganate aqueous solution was slowly added dropwise. After the addition was complete, the mixture was kept warm for 4 hours. After the reaction was completed, 100 ml of ethyl acetate and 100 ml of water were added to the reactor. The mixture was stirred for 15 minutes and then separated. The aqueous phase was extracted three times with 80 ml of ethyl acetate, and the organic phases were combined and washed with 100 ml of saturated brine. Finally, the solvent was drained after drying to obtain 8.8 g of compound 11a with a yield of 85%. 1HNMR(400M Hz, CDCl3) δ7.35(d,J=8.0Hz,2H),7.32-7.21(m,5H),7.27(m,2H),5.33(d,J=6.6Hz,1H),5.00(brs,2H) ,4.68(d,J=5.6Hz,1H),4.40(t,J=6.0Hz,1H),4.04-3.85(m,4H),3.68(s,2H),3.55(s,2H),2.10(s,3H).
[0053] Example 3: Preparation of Compound 12a
[0054]
[0055] The experiment was divided into seven groups, AG group comparison experiments, each group did not add catalyst or added different types of heteropoly acid ionic liquid catalysts
[0056] Group A: No catalyst added
[0057] Group B: [MIMPS] 3PMo 12 O 40
[0058] Group C: [MIMPS] 3PW 12 O 40
[0059] Group D: [PyPS]3PMo 12 O 40
[0060] Group E: [PyPS]3PW12O 40
[0061] Group F: [TEAPS] 3PMo 12 O 40
[0062] Group G: [TEAPS] 3PW 12 O 40
[0063] The specific experimental methods are as follows:
[0064] Under stirring conditions, 101.0 g of methyl 3-amino-4-chloro-5-fluorobenzoate, 1.6 g of compound 11a, 20 mmol of tert-butyl hydroperoxide and 0.12 mmol of heteropolyacid ionic liquid catalyst were added to the reactor in sequence. The temperature was raised to 90° C. and the reaction was kept warm for 12 h. After the reaction was completed, the temperature was lowered to room temperature. Ethyl acetate was added to the reactor, the product was dissolved by stirring, and the heteropolyacid ionic liquid catalyst was recovered by filtration and recycled. The concentrated filtrate was further recrystallized by ethanol or purified by column chromatography to obtain compound 12a.1 H NMR(400M Hz,DMSO-d6)δ11.55(s,1H),7.82(d,J=8.2Hz,2H),7.68(d,J=8.2Hz,2H),7.38(dd,J=2.4,10.0Hz,1H), 7.30-7.22(m,5H),6.11(s,1H),4.25-4.09(m,4H),3.90(s,3H),3.65(s,2H),3.61(s,2H),2.10(s,3H).
[0065] Table 1 Comparative experimental results of groups A-G
[0066] Group Heteropolyacid ionic liquid catalyst Yield Group A Without catalyst 15％ Group B <![CDATA[[MIMPS]3PMo 12 THE 40 ]]> 78％ Group C <![CDATA[[MIMPS]3PW 12 THE 40 ]]> 88％ Group D <![CDATA[[PyPS]3PMo 12 THE 40 ]]> 82％ Group E <![CDATA[[PyPS]3PW 12 THE 40 ]]> 90％ Group F <![CDATA[[TEAPS]3PMo 12 THE 40 ]]> 32％ Group G <![CDATA[[TEAPS]3PW 12 THE 40 ]]> 45％
[0067] The following conclusions can be drawn from the data in Table 1: the experimental results without catalyst (Group A) are significantly worse than those with heteropoly acid ionic liquid catalyst (Group BG); the catalytic activity of heteropoly acid ionic liquid containing PyPS is higher than that of heteropoly acid ionic liquid containing MIMPS and TEAPS; 12 O 40 The catalytic activity of heteropolyacid ionic liquids is significantly higher than that of PMo 12 O 40 The heteropolyacid ionic liquid of the AG group has the highest catalytic activity [PyPS]3PW 12 O 40 (Group E).
[0068] Example 4: Catalyst recycling during the preparation of compound 12a
[0069] The activity repeatability test of the catalyst heteropolyacid ionic liquid was carried out using Group E in Example 3 as a template reaction, and the ionic liquid was reused 4 times. The yield data of the reaction is shown in Figure 1 .
[0070] Depend on Figure 1 The data in this paper can lead to the following conclusion: the catalytic activity of heteropolyacid ionic liquid catalysts decreases and loses to a certain extent during the recycling process, but they can still be recycled more than 4 times.
[0071] Example 5: Preparation of Compound 13a
[0072]
[0073] Under stirring conditions, 2.2 g of compound 12a and 20 ml of methanol were added to the reactor in sequence, and 5 ml of 1 mol / L hydrochloric acid was slowly added dropwise, and the reaction was carried out at room temperature for 8 hours. After the reaction was completed, the pH was adjusted to 7-8 with sodium carbonate solution, 20 ml of ethyl acetate and 20 ml of water were added to the reactor, and the mixture was separated after stirring for 15 minutes. The aqueous phase was extracted three times with 10 ml of ethyl acetate, and the organic phases were combined and washed with 15 ml of saturated brine. Finally, the solvent was drained after drying to obtain 1.9 g of compound 13a, with a yield of 95%. 1 H NMR (400MHz, DMSO-d6) δ11.71(s,1H),9.70(s,1H),7.87(d,J=8.2Hz,2H),7.71(d,J=8.2Hz,2H),7. 49(dd,J=2.4,10.0Hz,1H),7.33-7.21(m,5H),3.94(s,3H),3.69(s,2H),3.63(s,2H),2.12(s,3H).
[0074] Example 6: Preparation of Compound 14a
[0075]
[0076] Under stirring conditions, 2.0 g of compound 13a, 40 ml of nitromethane and 1.6 g of ammonium acetate were added to the reactor in sequence. The temperature was raised to 100°C and the reaction was kept warm for 3 hours. After the reaction was completed, the temperature was lowered to room temperature. 100 ml of water was added to the reactor, and extraction was performed three times with 50 ml of ethyl acetate. The organic phases were combined and washed with saturated brine. Finally, the solvent was dried and the solvent was drained to obtain 2.0 g of compound 14a with a yield of 90%. 1 H NMR(400M Hz, DMSO-d6) δ11.98(s,1H),7.88(d,J=8.2Hz,2H),7.77(d,J=8.2Hz,2H),7.69(m,2H),7.48(d d,J=2.4,10.0Hz,1H),7.31-7.23(m,5H),3.95(s,3H),3.70(s,2H),3.65(s,2H),2.15(s,3H).
[0077] Example 7: Preparation of Rucaparib
[0078]
[0079] Under stirring conditions, 2.2 g of compound 14a, 50 ml of methanol and 0.2 g of 10 wt% platinum carbon were added to the reactor in sequence, and hydrogen was introduced. The reaction was carried out at room temperature for 8 h. The catalyst was recovered by filtration and reused. After concentrating the filtrate, it was further purified by ethanol recrystallization or column chromatography to obtain 1.2 g of Rucaparib with a yield of 93%. 1 HNMR(400M Hz, DMSO-d6) δ11.64(s,1H),8.21(t,J=5.8Hz,1H),7.56(d,J=8.3Hz,2H),7.44(d,J=8.3Hz,2H),7.40(dd,J= 9.2, 2.4Hz, 1H), 7.30 (dd, J = 9.3, 2.4Hz, 1H), 3.68 (s, 2H), 3.46-3.37 (m, 2H), 3.07-3.01 (m, 2H), 2.25 (s, 3H).
[0080] Example 8: Preparation of Compound 16b
[0081]
[0082] Under stirring conditions, 9.3 g of cinnamaldehyde derivative 15b, 30 ml of ethylene glycol, 0.3 g of p-toluenesulfonic acid and 100 ml of toluene were added to the reactor in sequence. The temperature was raised to 110°C and the reaction was kept warm for 10 hours. During the warming process, a reflux water separator was used to separate water. After the reaction was completed, the temperature was lowered to room temperature, 80 ml of ethyl acetate and 100 ml of water were added to the reactor, and the mixture was separated after stirring for 15 minutes. The aqueous phase was extracted three times with 50 ml of ethyl acetate, and the organic phases were combined and washed with 150 ml of saturated brine. Finally, the solvent was drained after drying to obtain 10.5 g of compound 16b with a yield of 99%. 1 H NMR(400M Hz, CDCl3) δ7.44(d,J=8.0Hz,2H),7.42-7.28(m,5H),7.24(d,J=8.0Hz,2H),6.82(d,J=16.0Hz,1H),6.64 (dd,J=6.0,16.0Hz,1H),5.44(d,J=6.0Hz,1H),5.12(s,2H),4.15-3.99(m,4H),3.71(s,2H),2.30(s,3H).
[0083] Example 9: Preparation of Compound 11b
[0084]
[0085] Under stirring conditions, 10.6 g of compound 16b, 0.1 g of sodium hydroxide and 80 ml of acetone were added to the reactor in sequence. After cooling to 0°C, the mixture was kept warm. 190 ml of 3% potassium permanganate aqueous solution was slowly added dropwise. After the addition was complete, the mixture was kept warm for 6 hours. After the reaction was completed, 100 ml of ethyl acetate and 100 ml of water were added to the reactor. The mixture was stirred for 15 minutes and then separated. The aqueous phase was extracted three times with 80 ml of ethyl acetate, and the organic phases were combined and washed with 100 ml of saturated brine. Finally, the solvent was drained after drying to obtain 10.2 g of compound 11b with a yield of 88%. 1 H NMR(400M Hz, CDCl3) δ7.45-7.30(m,5H),7.39(d,J=8.0Hz,2H),7.28(m,2H),5.41(d,J=6.6Hz,1H),5.09(brs,2H) ,4.73(d,J=5.6Hz,1H),4.55(t,J=6.0Hz,1H),5.09(s,2H),4.09-3.91(m,4H),3.65(s,2H),2.28(s,3H).
[0086] Example 10: Preparation of Compound 12b
[0087]
[0088] Under stirring conditions, 101.0 g of methyl 3-amino-4-chloro-5-fluorobenzoate, 1.9 g of compound 11b, 25 mmol of tert-butyl hydroperoxide and a heteropolyacid ionic liquid catalyst [PyPS]3PW were added to the reactor in sequence. 12 O 40 0.12mmol, the temperature was raised to 100°C and kept for reaction for 10h. After the reaction was completed, the temperature was lowered to room temperature. Ethyl acetate was added to the reactor, and the product was dissolved by stirring. The heteropolyacid ionic liquid catalyst was recovered by filtration and could be recycled and reused. The concentrated filtrate could be further purified by ethanol recrystallization or column chromatography to obtain 2.2g of compound 12b with a yield of 92%. 1 H NMR(400M Hz,DMSO-d6)δ11.64(s,1H),7.85(d,J=8.2Hz,2H),7.70(d,J=8.2Hz,2H),7.45-7.29(m,5H),7.40(dd,J =2.4,10.0Hz,1H),6.15(s,1H),5.10(s,2H),4.30-4.12(m,4H),3.93(s,3H),3.75(s,2H),2.35(s,3H).
[0089] Example 11: Preparation of Compound 13b
[0090]
[0091] Under stirring conditions, 2.4 g of compound 12b and 20 ml of acetone were added to the reactor in sequence, and 6 ml of 1 mol / L hydrochloric acid was slowly added dropwise, and the reaction was carried out at room temperature for 10 h. After the reaction was completed, the pH was adjusted to 7-8 with sodium carbonate solution, and 25 ml of ethyl acetate and 25 ml of water were added to the reactor, stirred for 15 minutes, and then separated. The aqueous phase was extracted three times with 13 ml of ethyl acetate, and the organic phases were combined and washed with 20 ml of saturated brine. Finally, the solvent was drained after drying to obtain 2.1 g of compound 13b, with a yield of 97%. 1 H NMR(400M Hz, DMSO-d6) δ11.78(s,1H),9.77(s,1H),7.88(d,J=8.2Hz,2H),7.74(d,J=8.2Hz,2H),7.52(d d,J=2.4,10.0Hz,1H),7.47-7.30(m,5H),5.13(s,2H),3.99(s,3H),3.72(s,2H),2.38(s,3H).
[0092] Example 12: Preparation of Compound 14b
[0093]
[0094] Under stirring conditions, 2.2 g of compound 13b, 45 ml of nitromethane and 1.8 g of sodium carbonate were added to the reactor in sequence. The temperature was raised to 105°C and the reaction was kept warm for 5 hours. After the reaction was completed, the temperature was lowered to room temperature. 100 ml of water was added to the reactor, and extraction was performed three times with 50 ml of ethyl acetate. The organic phases were combined and washed with saturated brine. Finally, the solvent was dried and dried to obtain 2.1 g of compound 14b with a yield of 90%. 1 H NMR(400M Hz,DMSO-d6)δ12.05(s,1H),7.90(d,J=8.0Hz,2H),7.79(d,J=8.0Hz,2H),7.73(m,2H),7.55(d d,J=2.4,10.0Hz,1H),7.49-7.32(m,5H),5.18(s,2H),3.97(s,3H),3.75(s,2H),2.41(s,3H).
[0095] Example 13: Preparation of Rucaparib
[0096]
[0097] Under stirring conditions, 2.4 g of compound 14b, 60 ml of ethanol and 0.4 g of 10 wt% palladium on carbon were added to the reactor in sequence, hydrogen was introduced, the temperature was raised to 50°C and the reaction was kept warm for 12 h. The catalyst was recovered by filtration and reused. After concentrating the filtrate, it was further purified by ethanol recrystallization or column chromatography to obtain 1.2 g of Rucaparib with a yield of 95%. 1 H NMR(400M Hz, DMSO-d6) δ11.66(s,1H),8.30(t,J=5.8Hz,1H),7.57(d,J=8.3Hz,2H),7.45(d,J=8.3Hz,2H),7.42(dd,J= 9.2, 2.4Hz, 1H), 7.32 (dd, J = 9.3, 2.4Hz, 1H), 3.69 (s, 2H), 3.48-3.38 (m, 2H), 3.09-3.02 (m, 2H), 2.26 (s, 3H).
Claims
1. A method for preparing Rucaparib, characterized in that: include: (1) subjecting methyl 3-amino-4-bromo-5-fluorobenzoate 10 and compound 11 to a catalytic oxidation cyclization reaction under the action of a catalyst and an oxidant to obtain an indole compound 12, Wherein, PG is any one of benzyl, p-methylbenzyl, p-methoxybenzyl, and benzyloxycarbonyl; (2) deprotecting compound 12 by acidic hydrolysis to obtain compound 13, (3) a step of condensing compound 13 and nitromethane to obtain compound 14, (4) subjecting compound 14 to double bond reduction, nitro group reduction, halogen reduction and cyclic amidation reaction under the action of a catalyst and hydrogen catalytic hydrogenation to obtain Rucaparib, 2. The method according to claim 1, characterized in that In step (1), the catalyst is a heteropolyacid ionic liquid catalyst, wherein the heteropolyacid ionic liquid catalyst is selected from [MIMPS]3PW 12 O 40 、[MIMPS]3PMo 12 O 40 、[PyPS]3PW 12 O 40 、[PyPS]3PMo 12 O 40 、[TEAPS]3PW 12 O 40 、[TEAPS]3PMo 12 O 40 Any one of; the oxidant is selected from any one of hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, and cyclohexyl hydroperoxide.
3. The method according to claim 1, characterized in that In step (1), the molar ratio of methyl 3-amino-4-bromo-5-fluorobenzoate 10, compound 11, oxidant, and catalyst is 1:1-2:3-6:0.01-0.05; the reaction temperature is 60-120° C.; and the reaction time is 8-20 h.
4. The method according to claim 1, characterized in that In step (2), the reaction is carried out in the presence of an acid, which is selected from any one of hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid; the reaction system uses an organic solvent as a solvent, which is selected from any one of methanol, ethanol, acetone and acetonitrile.
5. The method according to claim 1, characterized in that In step (2), the molar ratio of compound 12 to acid is 1:3-10; the reaction temperature is 20-70° C.; and the reaction time is 4-12 h.
6. The method according to claim 1, characterized in that In step (3), the reaction is carried out in the presence of a base, and the base is selected from any one of ammonium acetate, sodium carbonate, sodium bicarbonate, and potassium carbonate.
7. The method according to claim 1, characterized in that In step (3), the molar ratio of compound 13, nitromethane and base is 1:10-20:3-8; the reaction temperature is 60-110°C; and the reaction time is 2-8h.
8. The method according to claim 1, characterized in that In step (4), the catalyst is selected from any one of platinum carbon with a platinum content of 1%-10wt%, palladium carbon with a palladium content of 1%-10wt%, and Raney nickel; the reaction system uses an organic solvent as a solvent, and the organic solvent is selected from any one of methanol, ethanol, propanol, acetonitrile, acetone, and tetrahydrofuran.
9. The method according to claim 1, characterized in that In step (4), the mass ratio of compound 14 to catalyst is 1:0.01-1; the molar ratio of compound 14 to hydrogen is 1:5-20; the reaction temperature is 20-80°C; and the reaction time is 5-20h.