Preparation method of niraparib intermediate (S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate

Abstract

The invention discloses a preparation method of a niraparib intermediate (S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate, and belongs to the technical field of medicine synthesis. According to the method, 4-(3-pyridyl) aniline is taken as an initial raw material, and a target product is prepared through amino protection, pyridinium salt synthesis, hydroboration reduction, ruthenium catalysis asymmetric hydrogenation, deprotection / salification and t-butyloxycarbonylation reaction in sequence. The chiral center is directly constructed by innovatively adopting the ruthenium-catalyzed asymmetric hydrogenation reaction, so that the method has excellent stereoselectivity, and the obvious defects of the traditional resolution process are overcome; by optimizing reaction conditions and post-treatment processes, high-yield and high-purity product preparation is realized; the whole technological process is easily available in raw materials, simple to operate and suitable for industrial production; meanwhile, the method has the characteristics of environmental protection, economy and high efficiency.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester. Background Art

[0002] Niraparib, whose chemical name is 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide, has the following structural formula:

[0003]

[0004] Niraparib It is a highly selective PARP1 / 2 inhibitor jointly developed by Tesaro and Merck. It was first approved in the United States in March 2017, becoming the world's first PARP inhibitor that can be used for the maintenance treatment of platinum-sensitive recurrent epithelial ovarian cancer / fallopian tube cancer / primary peritoneal cancer without the need for BRCA (breast cancer susceptibility gene) mutation testing. It specifically inhibits PARP enzyme activity, blocks the DNA damage repair pathway of tumor cells, and produces a "synthetic lethality" effect on tumor cells with homologous recombination repair deficiency (HRD), significantly prolonging patients' progression-free survival (PFS). Its breakthrough lies in: as the only PARP inhibitor currently approved for the maintenance treatment of the entire population of first-line ovarian cancer, it is not restricted by BRCA / HRD biomarkers, covers a wider patient population, and demonstrates huge clinical value and market potential.

[0005] (S)-tert-Butyl 3-(4-aminophenyl)piperidine-1-carboxylate (NLM) is a key chiral intermediate of niraparib, and its structural formula is as follows:

[0006]

[0007] The synthesis process of NLMs directly impacts drug cost and environmental performance. Current NLM preparation methods can be broadly categorized into two types: racemate synthesis and chiral resolution techniques, and direct chiral skeleton construction techniques. The first type of method focuses on racemate synthesis. For example, the route reported in Organic Process Research & Development, 2011, 15, 831-840, uses 3-pyridineboronic acid and 4-nitrobromobenzene as starting materials. Suzuki coupling and platinum oxide-catalyzed reduction yield the 4-(piperidin-3-yl)aniline racemate, which is then protected with Boc and resolved with L-dibenzoyltartaric acid to obtain the target product. Similarly, Chinese patent CN106432055A utilizes 1-benzyl-3-(4-nitrophenyl)pyridinium halide as a starting material and prepares the racemate via Pd / C catalytic hydrogenation. However, this route requires additional resolution and carries a high risk of amino side reactions.

[0008] For the key step of chiral resolution, Chinese patent CN106432056A innovatively uses D-phenylglycine derivatives as resolving agents, while patent CN106432057A uses a binaphthol phosphate derivative as a resolving agent. This significantly improves the stereoselectivity and yield of NLM, but still fails to solve the fundamental problem of enantiomer waste. The reaction equation for the resolution process is as follows:

[0009]

[0010] Chinese patent CN106749180A proposes an alternative route, which uses benzyl-protected 3-piperidone as the starting material, prepares the racemate through triflate esterification, Suzuki coupling and hydrogenation reduction, and then separates the tartaric acid derivative salt of the target isomer using tartaric acid derivatives. After the isomer is freed, it reacts with Boc anhydride to obtain the target product.

[0011] However, these synthetic methods generally have significant limitations. High starting material costs, low resolution efficiency (unsatisfactory ee values), and low yields (often requiring multiple resolutions and purifications) severely restrict the feasibility of industrial production. More importantly, chemical resolution methods produce a large number of useless enantiomers, resulting in a serious waste of resources. Therefore, although a variety of NLM synthesis routes have been reported, existing methods have significant deficiencies in both economic efficiency and environmental performance.

[0012] The second type of method attempts to bypass the resolution step and directly construct a chiral center. For example, Chinese patent CN109265390A uses cheap and readily available (S)-phenylethylamine as the starting material and constructs a chiral center through three key reactions: first, a substitution reaction with 3-bromochloropropane occurs, followed by condensation with p-nitrophenylacetic acid, and finally, a ring closure under alkaline conditions to form a piperidine skeleton. Subsequently, the target product is obtained through steps such as reduction of the amide and nitro groups and Boc protection. The significant advantage of this route is that it avoids the chiral resolution step and precious metal catalytic coupling process in traditional processes, significantly reducing the cost of raw materials. However, its industrial application still faces major challenges, because the ring closure step yield of this route is only 30%, and equal amounts of diastereoisomers are generated as by-products, resulting in low atom utilization, which seriously restricts its industrial feasibility.

[0013] In summary, the NLM synthesis processes reported so far generally lack stereoselectivity and have problems such as low yield, low atom utilization, and high preparation cost. Therefore, the development of an NLM synthesis process with high stereoselectivity, good atom economy, no need for splitting, and controllable cost has important industrial application value. Summary of the Invention

[0014] In response to the problems existing in the prior art, the present application provides a new method for preparing the niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester, which directly constructs the chiral center through asymmetric catalytic hydrogenation, combines the protecting group strategy with catalyst innovation, and realizes efficient and green NLM total synthesis, providing a new path for the large-scale production of niraparib.

[0015] In order to achieve the above-mentioned object, the technical solution adopted by the present invention is as follows: a method for preparing a niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester, the synthetic route of which is as follows:

[0016]

[0017] Wherein, -PG is an amino protecting group;

[0018] The specific preparation steps are:

[0019] 1) Dissolving 4-(3-pyridyl)aniline and an alkaline reagent in an organic solvent, reacting with an amino protecting reagent, introducing an amino protecting group on the amino group, and obtaining intermediate II;

[0020] 2) Dissolving intermediate II and benzyl chloride in a solvent and subjecting to a reflux reaction to generate a pyridinium salt intermediate III;

[0021] 3) After adding intermediate III to the reaction solvent, cooling to 5-10°C, adding sodium borohydride to react; then keeping the temperature at 10-15°C for 1-2 hours to obtain tetrahydropyridine intermediate IV;

[0022] 4) Dissolving intermediate IV and an acid reagent in a reaction solvent, adding a Ru catalyst under nitrogen protection, replacing hydrogen to react, completing asymmetric hydrogenation reduction of the double bond to obtain intermediate V;

[0023] 5) Dissolving intermediate V in a reaction solvent, removing the benzyl group by Pd / C catalytic hydrogenolysis, and removing the amino protecting group thereon simultaneously during the hydrogenolysis process or by subsequent acid treatment, adjusting the pH to alkaline, extracting, and purifying the salt to obtain intermediate VI;

[0024] 6) The intermediate VI is dissolved in a reaction solvent, reacted with di-tert-butyl dicarbonate, and then crystallized and purified to obtain the target product, which is recorded as NLM.

[0025] Further, in step 1), the amino protecting agent is selected from any one of benzyl chloroformate, allyl chloroformate, di-tert-butyl dicarbonate, acetyl chloride or acetic anhydride, trifluoroacetyl chloride or trifluoroacetic anhydride, benzyl chloride or benzyl bromide, 4-methoxybenzyl chloride, 4-methoxybenzyl bromide, and phthalic anhydride, the molar ratio of 4-(3-pyridyl)aniline to the amino protecting agent is 1:1 to 1.3, the reaction temperature with the amino protecting agent is 0 to 30°C, and the reaction time is 2 to 20h; the amino protecting group is any one of benzyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl, p-methoxybenzyl, and phthaloyl.

[0026] Further, in step 1), the alkaline reagent used is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, and potassium phosphate, or any one or several organic bases selected from triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and 4-dimethylaminopyridine, and several refers to a combination of two or more substances, the same below; the molar ratio of 4-(3-pyridyl)aniline to the alkaline reagent is 1:1 to 2; the organic solvent used is selected from any one or several of dichloromethane, tetrahydrofuran, methyl tert-butyl ether, dioxane, and toluene.

[0027] Preferably, in step 1), the amino protecting agent used is benzyl chloroformate or di-tert-butyl dicarbonate; and the amino protecting group is benzyloxycarbonyl or tert-butyloxycarbonyl.

[0028] Furthermore, in step 2), the solvent used is selected from one or more of acetonitrile, water, toluene, and dioxane; the molar ratio of intermediate II to benzyl chloride is 1:1 to 1.1, the reflux reaction temperature is 80 to 110° C., and the reaction time is 15 to 25 h.

[0029] Furthermore, in step 3), the reaction solvent used is selected from one or more of methanol, ethanol, tetrahydrofuran, dioxane, and water; the molar ratio of intermediate III to sodium borohydride is 1:1.2-2, and the reaction temperature after adding sodium borohydride does not exceed 15°C.

[0030] Furthermore, in step 4), the reaction solvent used is selected from one or more of methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, tetrahydrofuran, and 2-methyltetrahydrofuran; the Ru catalyst is [RuCl(p-cymene)((S)-DM-SEGPHOS)]Cl, Ru(OAc)2(R)-BINAP,

[0031] Any one of [(S)-SEGPHOS]Ru(OAc)2; the molar ratio of the intermediate IV and the Ru catalyst is 1:0.002-0.01; after replacing the hydrogen, the reaction is carried out at a pressure of 0.5-2MPa and 40-90°C for 15-25h.

[0032] Furthermore, in step 5), the reaction solvent used is selected from any one or more of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, and dichloromethane; the hydrogenolysis process is carried out at a pressure of 0.05 to 0.2 MPa and 40 to 80° C., and the reaction time is 8 to 20 h.

[0033] Furthermore, in step 5), the acid reagent used for acid hydrolysis is selected from any one of hydrochloric acid, phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, and the reaction process of acid treatment to remove the amino protecting group is carried out at 0-30°C and the reaction time is 3-4h; the acid reagent used for salt purification is selected from any one of L-tartaric acid and L-dibenzoyltartaric acid; the molar ratio of the intermediate V and the acid reagent is 1:1-1.1.

[0034] Furthermore, in step 6), the reaction solvent used is selected from any one or more of dichloromethane, tetrahydrofuran, and toluene; the molar ratio of intermediate VI to di-tert-butyl dicarbonate is 1:0.9-1.1, and the reaction temperature of intermediate VI and di-tert-butyl dicarbonate is 0-5°C and the reaction time is 1-5h.

[0035] The beneficial effects of the present invention are:

[0036] 1. This application utilizes ruthenium-catalyzed asymmetric hydrogenation to directly construct chiral centers, which exhibits excellent stereoselectivity and overcomes the drawbacks of traditional resolution processes, such as cumbersome purification steps, low resolution efficiency, insufficient product yield, and unsatisfactory ee values. Furthermore, after optimizing the catalyst system, efficient conversion can be achieved at low catalyst dosages, significantly improving atom utilization and reducing by-product formation, fully aligning with the sustainable development principles of green chemistry.

[0037] 2. This application uses commercially available 4-(3-pyridyl)aniline as the starting reactant, which is widely available and inexpensive. Through a carefully designed synthetic route and precisely optimized reaction conditions, efficient conversion of key steps is ensured. The total yield of the five main steps involved in the preparation of intermediate VI using 4-(3-pyridyl)aniline as the starting material is greater than 75%.

[0038] 3. The synthetic route designed in this application uses a low-cost solvent system and a simple post-treatment method to obtain a high-purity product, which significantly reduces production costs and has good potential for industrial application;

[0039] 4. The synthetic route designed in this application uses a small amount of metal catalyst, effectively controls heavy metal residues, reduces environmental pollution, and the entire process complies with green environmental protection requirements, embodying the production concept of sustainable development;

[0040] 5. This application achieves a smooth transition from laboratory to industrial production by optimizing reaction conditions and post-processing procedures. The key steps have low equipment requirements, a wide operating window for process parameters, and excellent stability of intermediates, making them particularly suitable for large-scale continuous production and significantly reducing the risk of technology scale-up. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 This is the related substance spectrum of intermediate VI ((S)-4-(piperidin-3-yl)aniline) prepared in Example 1;

[0042] Figure 2 This is the chiral purity spectrum of intermediate VI ((S)-4-(piperidin-3-yl)aniline) prepared in Example 1;

[0043] Figure 3 is the NMR spectrum of intermediate VI ((S)-4-(piperidin-3-yl)aniline) prepared in Example 1;

[0044] Figure 4 is the mass spectrum of intermediate VI ((S)-4-(piperidin-3-yl)aniline) prepared in Example 1;

[0045] Figure 5 This is the related substance spectrum of (S)-tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate prepared in Example 1;

[0046] Figure 6 This is the chiral purity spectrum of (S)-tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate prepared in Example 1;

[0047] Figure 7 is the NMR spectrum of (S)-tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate prepared in Example 1;

[0048] Among them, NLM-6 represents intermediate VI, NLM-6E represents the chiral isomer of intermediate VI, NLM represents (S)-tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate, and NLM-E is the chiral isomer of NLM. DETAILED DESCRIPTION

[0049] In order to enable those skilled in the art to better understand the technology, mass spectrometry and other solutions of the present invention, the technical solutions of the present invention are further described below in conjunction with the accompanying drawings and examples.

[0050] Example 1

[0051] This example discloses the preparation process of the niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester, and the specific steps are as follows:

[0052] 1) Preparation of 4-(3-pyridyl)aniline (Compound I)

[0053] The preparation route is as follows:

[0054]

[0055] The preparation process is as follows: 4-bromoaniline (31.6 g, 0.18 mol, 1.0 eq), (Bpin)2 (56.1 g, 0.22 mol, 1.2 eq), and potassium acetate (54.2 g, 0.55 mol, 3.0 eq) were dissolved in 150 mL of 1,4-dioxane. After nitrogen replacement, PdCl2(PPh3)2 (6.5 g, 9.2 mmol, 0.05 eq) was added. The mixture was heated to 90°C under nitrogen protection and allowed to react for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, water was added, and the mixture was filtered through celite. The filter cake was rinsed with 30 mL of 1,4-dioxane. The filtrate was transferred to a reaction flask, and 3-bromopyridine (34.9 g, 0.22 mol, 1.2 eq), sodium carbonate (48.7 g, 0.46 mol, 2.5 eq), and 90 mL of water were added. After nitrogen substitution, PdCl2(PPh3)2 (3.2 g, 4.6 mmol, 0.025 eq) was added. The reaction was heated to 85°C under nitrogen for 6 h. After completion of the reaction, the reaction was cooled to room temperature, and 300 mL of water was added with stirring to precipitate a solid, which was then filtered. The filter cake was added with 100 mL of water and slurried at room temperature for 2 h, then filtered. The filter cake was dissolved in 15 mL of isopropyl acetate, and 240 mL of n-heptane was slowly added dropwise. After addition, the mixture was stirred at 5°C for 1 h, filtered, and dried under vacuum to obtain Compound I as a pale yellow solid (29.1 g, 93% yield).

[0056] 1H NMR(400MHz, DMSO-d6)8.77(d,J=2.1Hz,1H),8.40(dd,J=1.4,4.7Hz,1H),7.93-7 .89(m,1H),7.67-7.52(m,1H),7.45-7.39(m,2H),6.69-6.64(m,2H),5.33(s,2H).

[0057] 2) Preparation of (S)-4-(piperidin-3-yl)aniline (Intermediate VI)

[0058] The preparation route is as follows:

[0059]

[0060] The preparation process is:

[0061] i. Dissolve compound I (50 g, 0.29 mol, 1.0 eq), triethylamine (Et2N, 50.5 g, 0.50 mol, 1.7 eq), and 4-dimethylaminopyridine (DMAP, 3.6 g, 0.03 mol, 0.1 eq) in 350 mL of tetrahydrofuran. Under nitrogen, cool to 5°C and add di-tert-butyl dicarbonate (Boc2O, 76.9 g, 0.35 mol, 1.2 eq) dropwise. After addition, warm to room temperature and stir for 8 h. After completion of the reaction, concentrate under reduced pressure to remove the organic solvent. The residue is dissolved in 400 mL of ethyl acetate and washed sequentially with 300 mL of 10% citric acid solution, 300 mL of saturated sodium bicarbonate solution, and 200 mL of water. Concentrate under reduced pressure to dryness to obtain intermediate II (79.1 g). The crude product is used directly in the next reaction.

[0062] ii. Dissolve Intermediate II (79.1 g, 0.29 mol, 1.0 eq) in a mixture of 240 mL of toluene and 240 mL of water. Add benzyl chloride (PhCH2Cl, 37.0 g, 0.29 mol, 1.0 eq) and heat to 80°C under reflux for 20 h. After completion of the reaction, cool to room temperature and allow to stand for stratification. Separate the aqueous phase containing Intermediate III (the -Bn attached to Intermediate III is a benzyl group). Add 240 mL of water, cool to 5°C, and slowly add sodium borohydride (NaBH4, 14.4 g, 0.38 mol, 1.3 eq) in portions. If bubbling occurs, adjust the addition rate to keep the reaction temperature below 15°C. After addition, maintain the reaction at 10°C for 2 h. After the reaction is completed, 70 mL of water is added to the reaction solution, and after stirring at room temperature for 30 min, 400 mL of ethyl acetate is added and filtered. The filtrate is allowed to stand for stratification, and the aqueous phase is extracted with 400 mL of ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain intermediate IV (104.5 g). The crude product is directly used in the next reaction.

[0063] iii. Dissolve Intermediate IV (104.5 g, 0.29 mol, 1.0 eq) and acetic acid (1.7 g, 28.7 mmol, 0.1 eq) in 500 mL of tert-butyl alcohol. After nitrogen replacement, bubble the mixture for 5 min. Add (S)-RUCL[(p-isopropyltoluene)(DM-SEGPHOS)]CL ([RuCl(p-cymene)((S)-DM-SEGPHOS)]-Cl, 0.9 g, 0.86 mmol, 0.003 eq) under a nitrogen stream. Replace the atmosphere with hydrogen, increase the pressure to 1 MPa, raise the temperature to 80°C, and react with vigorous stirring for 20 h. After completion of the reaction, cool to room temperature, filter, and dilute the filtrate with 500 mL of methyl tert-butyl ether. Wash with saturated sodium bicarbonate solution (500 mL x 2). Concentrate the organic phase under reduced pressure to dryness to obtain Intermediate V (89.3 g), which is used directly in the next reaction.

[0064] iv. Dissolve intermediate V (89.3 g, 0.24 mol, 1.0 eq) in 450 mL of methanol, add 10% Pd / C (4.5 g, 5 wt%), replace the atmosphere with nitrogen, then hydrogen, and heat to 60°C. Stir and react at 0.1 MPa for 8 h. After completion of the reaction, cool to room temperature and filter. Add hydrochloric acid (102 mL, 1.22 mol, 5.0 eq) dropwise to the filtrate. Stir and react at room temperature for 4 h. After completion of the reaction, adjust the pH to 12 with 4N sodium hydroxide solution. Extract with ethyl acetate (400 mL x 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness. The residue was dissolved in 80 mL of methanol and stirred until clear. A methanol solution (40 mL) of L-tartaric acid (36.6 g, 0.24 mol, 1.0 eq) was slowly added dropwise. After addition, the mixture was cooled to 0°C and stirred for 4 h. Filtered and the filter cake rinsed with 10 mL of cold methanol. The filter cake was transferred to a flask, 120 mL of water was added, and 4N sodium hydroxide solution was added dropwise to adjust the pH to 12. Ethyl acetate (160 mL x 2) was added for extraction. The organic phases were combined and concentrated to dryness under reduced pressure. 40 mL of ethyl acetate was added and stirred at reflux for 30 min. 400 mL of n-hexane was slowly added. After reflux and stirring for 30 min, the mixture was slowly cooled to 5°C, stirred for 3 h, filtered, and dried to obtain Intermediate VI as a white solid (40.3 g) with a purity of 99% and an ee of 99%. The total yield over five steps was 78%.

[0065] 1H NMR (500MHz, DMSO-d6)6.85(d,J=8.2Hz,2H),6.48(d,J=8.2Hz,2H),4.67(brs,2H),3.40(br s,1H),2.90(s,2H),2.49-2.38(m,3H),1.78(d,J=7.4Hz,1H),1.62-1.60(m,1H),1.44(m,2H).[M+H] + :177.19.

[0066] Figures 1 to 4 They are respectively the related substance spectrum (the main peak is intermediate VI), chiral purity spectrum, NMR spectrum and mass spectrum of intermediate VI ((S)-4-(piperidin-3-yl)aniline).

[0067] 3) Preparation of tert-butyl 4(S)-3-(4-aminophenyl)piperidine-1-carboxylate (NLM)

[0068] The preparation route is as follows:

[0069]

[0070] The specific preparation process is:

[0071] Intermediate VI (50 g, 0.28 mol, 1.0 eq) was dissolved in 300 mL of dichloromethane and cooled to 0°C. A solution of di-tert-butyl dicarbonate (59.3 g, 0.27 mol, 0.97 eq) in dichloromethane (200 mL) was slowly added dropwise. After addition, the mixture was stirred at 0°C for 2 h. After completion of the reaction, 300 mL of water was added, stirred for 30 min, and allowed to stand for stratification. The organic phase was washed with water (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to yield 75.9 g of crude product. To the crude product was added 75 mL of isopropyl acetate, heated until the solution was clear, and 750 mL of n-hexane was added. The mixture was stirred at reflux until the solid dissolved. The temperature was slowly lowered to 0°C, stirred for 2 h, and crystallized. The mixture was filtered and the filter cake was dried to yield 74.4 g of an off-white solid with a yield of 95%, a purity >99%, and an ee value >99%.

[0072] 1 H NMR(500MHz,DMSO-d6)6.88(d,J=8.2Hz,2H),6.50(d,J=8.2Hz,2H),4.87(s,2H),3.96-3.90(m,2H),2.6 9-2.50(m,2H),2.40-2.36(m,1H),1.82-1.79(m,1H),1.68-1.65(m,1H),1.57-1.49(m,1H),1.39(s,9H).

[0073] Figures 5-7 They are respectively the related substance spectrum, chiral purity spectrum and NMR spectrum of (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester prepared in this example.

[0074] Example 2

[0075] In this example, compound 1 was also used as a raw material to prepare (S)-4-(piperidin-3-yl)aniline (intermediate VI), and the same method was used to prepare the final product NLM. The difference between this example and Example 1 is that during the preparation of intermediate VI, the amino protecting group attached to compound 1 was changed from tert-butyloxycarbonyl to benzyloxycarbonyl.

[0076] The preparation route of intermediate VI is as follows:

[0077]

[0078] The specific preparation process is:

[0079] i. Dissolve 4-(3-pyridyl)aniline (Compound I, 34.0 g, 0.20 mol, 1.0 eq) in 280 mL of dichloromethane. Add potassium carbonate (33.2 g, 0.24 mol, 1.2 eq). Under nitrogen, cool to 0°C and add benzyl chloroformate (CbzCl, 37.5 g, 0.22 mol, 1.1 eq) dropwise. After addition, warm to room temperature and stir for 4 h. After completion of the reaction, filter, rinse the filter cake with 50 mL of dichloromethane, and wash the filtrate with saturated Na2CO3 solution (250 mL x 2). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain Intermediate II (59.2 g). The crude product is used directly in the next reaction.

[0080] ii. Dissolve Intermediate II (59.2 g, 0.19 mol, 1.0 eq) in 240 mL of acetonitrile, add benzyl chloride (24.6 g, 0.19 mol, 1.0 eq), and heat to 85°C under reflux for 20 h. After completion of the reaction, cool to room temperature and concentrate to dryness under reduced pressure to obtain Intermediate III. Dissolve in 475 mL of water, cool to 5°C, and slowly add sodium borohydride (9.6 g, 0.25 mol, 1.3 eq) portionwise. If bubbling occurs, adjust the addition rate to keep the reaction temperature below 15°C. After addition, maintain the reaction at 15°C for 1 h. After completion of the reaction, quench the reaction by dropwise addition of 30 mL of 5% citric acid solution. Extract with ethyl acetate (350 mL x 2). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain Intermediate IV (74.5 g). The crude product is used directly in the next reaction.

[0081] iii. Dissolve Intermediate IV (74.5 g, 0.187 mol, 1.0 eq) and acetic acid (2.8 g, 46.7 mmol, approximately 0.25 eq) in 300 mL of tert-amyl alcohol. After nitrogen displacement, bubble the mixture through the air for 5-10 min. Add [RuCl(p-cymene)((S)-DM-SEGPHOS)]-Cl (0.6 g, 0.56 mmol, 0.003 eq) under a nitrogen stream. Displace the atmosphere with hydrogen, increase the pressure to 0.8 MPa, raise the temperature to 90°C, and react with vigorous stirring for 20 h. After completion of the reaction, cool to room temperature, filter, and dilute the filtrate with 300 mL of methyl tert-butyl ether. Wash with saturated sodium bicarbonate solution (300 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure to obtain Intermediate V (68.9 g). The crude product is used directly in the next reaction.

[0082] iv. Dissolve Intermediate V (68.9 g, 0.172 mol, 1.0 eq) in 350 mL of methanol, add 10% Pd / C (3.5 g, 5 wt%), replace the atmosphere with nitrogen, then hydrogen, and heat to 55°C. Stir and react at 0.1 MPa for 14 h. After completion of the reaction, cool to room temperature, filter, and concentrate the filtrate to dryness. Dissolve the residue in 90 mL of methanol, stir to dissolve, and slowly add a methanol solution (30 mL) of L-tartaric acid (25.8 g, 0.172 mol, 1.0 eq) dropwise. After addition, cool to 0°C, stir for 4 h, filter, and rinse the filter cake with 10 mL of cold methanol. The filter cake was transferred to a flask, 150 mL of water was added, and 4 N sodium hydroxide solution was added dropwise to adjust the pH to 12. Ethyl acetate (120 mL x 2) was added for extraction. The organic phases were combined and concentrated to dryness under reduced pressure. 30 mL of ethyl acetate was added, and the mixture was refluxed with stirring for 30 minutes. 300 mL of n-hexane was slowly added, and the mixture was refluxed with stirring for 30 minutes. The temperature was then slowly lowered to 0°C, stirred for 4 hours, filtered, and dried to obtain Intermediate VI as a white solid (26.7 g) with a purity of 99% and an ee value of 99%. The total yield over the five steps was 76%.

[0083] The above shows and describes the basic principles, main features, and advantages of the present invention. However, the above is only a specific embodiment of the present invention, and the technical features of the present invention are not limited thereto. Any other implementation methods derived by any person skilled in the art without departing from the technical solution of the present invention are intended to be within the scope of the present invention.

Claims

1. A method for preparing a niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester, characterized in that: The synthetic route is as follows: Wherein, -PG is an amino protecting group; The specific preparation steps are: 1) Dissolving 4-(3-pyridyl)aniline and an alkaline reagent in an organic solvent, reacting with an amino protecting reagent, introducing an amino protecting group on the amino group, and obtaining intermediate II; 2) Dissolving intermediate II and benzyl chloride in a solvent and subjecting to a reflux reaction to generate a pyridinium salt intermediate III; 3) After adding intermediate III to the reaction solvent, cooling to 5-10°C, adding sodium borohydride to react; then keeping the temperature at 10-15°C for 1-2 hours to obtain tetrahydropyridine intermediate IV; 4) Dissolving intermediate IV and an acid reagent in a reaction solvent, adding a Ru catalyst under nitrogen protection, replacing hydrogen to react, completing asymmetric hydrogenation reduction of the double bond to obtain intermediate V; 5) Dissolving intermediate V in a reaction solvent, removing the benzyl group by Pd / C catalytic hydrogenolysis, and removing the amino protecting group thereon simultaneously during the hydrogenolysis process or by subsequent acid treatment, adjusting the pH to alkaline, extracting, and purifying the salt to obtain intermediate VI; 6) The intermediate VI is dissolved in a reaction solvent, reacted with di-tert-butyl dicarbonate, and then crystallized and purified to obtain the target product, which is recorded as NLM.

2. The method for preparing the niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester according to claim 1, wherein: In step 1), the amino protecting agent is selected from any one of benzyl chloroformate, allyl chloroformate, di-tert-butyl dicarbonate, acetyl chloride or acetic anhydride, trifluoroacetyl chloride or trifluoroacetic anhydride, benzyl chloride or benzyl bromide, 4-methoxybenzyl chloride, 4-methoxybenzyl bromide, and phthalic anhydride, the molar ratio of 4-(3-pyridyl)aniline to the amino protecting agent is 1:1-1.3, the reaction temperature with the amino protecting agent is 0-30°C, and the reaction time is 2-20h; The amino protecting group is any one of benzyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl, p-methoxybenzyl, and phthaloyl.

3. The method for preparing the niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester according to claim 1, wherein: In step 1), the alkaline reagent used is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, and potassium phosphate, or any one or more organic bases selected from triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and 4-dimethylaminopyridine, and the molar ratio of 4-(3-pyridyl)aniline to the alkaline reagent is 1:1 to 2; The organic solvent used is selected from any one or more of dichloromethane, tetrahydrofuran, methyl tert-butyl ether, dioxane and toluene.

4. The method for preparing the niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester according to claim 2, wherein: In step 1), the amino protecting agent used is benzyl chloroformate or di-tert-butyl dicarbonate; and the amino protecting group is benzyloxycarbonyl or tert-butyloxycarbonyl.

5. The method for preparing the niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester according to claim 1, wherein: In step 2), the solvent used is selected from one or more of acetonitrile, water, toluene, and dioxane; the molar ratio of intermediate II to benzyl chloride is 1:1 to 1.1, the reflux reaction temperature is 80 to 110° C., and the reaction time is 15 to 25 h.

6. The method for preparing the niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester according to claim 1, wherein: In step 3), the reaction solvent used is selected from one or more of methanol, ethanol, tetrahydrofuran, dioxane, and water; the molar ratio of intermediate III to sodium borohydride is 1:1.2-2, and the reaction temperature after adding sodium borohydride does not exceed 15°C.

7. The method for preparing the niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester according to claim 1, wherein: In step 4), the reaction solvent used is selected from one or more of methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, tetrahydrofuran, and 2-methyltetrahydrofuran; The Ru catalyst is any one of [RuCl(p-cymene)((S)-DM-SEGPHOS)]Cl, Ru(OAc)2(R)-BINAP, and [(S)-SEGPHOS]Ru(OAc)2; The molar ratio of the intermediate IV and the Ru catalyst is 1:0.002-0.01; after replacing the hydrogen, the reaction is carried out at a pressure of 0.5-2 MPa and 40-90° C. for 15-25 hours.

8. The method for preparing the niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester according to claim 1, wherein: In step 5), the reaction solvent used is selected from any one or more of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, and dichloromethane; the hydrogenolysis process is carried out at a pressure of 0.05 to 0.2 MPa and 40 to 80° C., and the reaction time is 8 to 20 h.

9. The method for preparing the niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester according to claim 1, wherein: In step 5), the acid reagent used for acid treatment is selected from any one of hydrochloric acid, phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, and the reaction process of removing the amino protecting group by acid treatment is carried out at 0-30° C. and the reaction time is 3-4 h; The acid reagent used for salt formation and purification is selected from any one of L-tartaric acid and L-dibenzoyltartaric acid; the molar ratio of the intermediate V to the acid reagent is 1:1 to 1.

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10. The method for preparing the niraparib intermediate (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester according to claim 1, wherein: In step 6), the reaction solvent used is selected from any one or more of dichloromethane, tetrahydrofuran, and toluene; the molar ratio of intermediate VI to di-tert-butyl dicarbonate is 1:0.9-1.1, and the reaction temperature of intermediate VI and di-tert-butyl dicarbonate is 0-5°C and the reaction time is 1-5h.

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