A method of synthesizing niraparib

Abstract

This invention discloses a method for synthesizing niraparib, the specific synthetic route of which is as follows: ; where x is one of Br, I, and Cl.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for synthesizing niraparib. Background Technology

[0002] Niraparib is a poly(ADP-ribose) polymerase (PARP) 1,2 inhibitor. PARP-1 and PARP-2 are involved in DNA repair and are used for maintenance therapy in adult patients with recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have partially or completely responded to platinum-based chemotherapy.

[0003] Niraparib's active ingredient is a free base, chemically named (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide, and its active ingredient is its p-toluenesulfonate, with the chemical structure shown below:

[0004]

[0005] In existing technologies, the complexity and uniqueness of niraparib's molecular structure result in low yields and high difficulties in large-scale production during total chemical synthesis, leading to its persistently high price. As a first-line maintenance therapy drug requiring long-term use, it still places a significant burden on patients from ordinary families. Therefore, developing an efficient and concise synthetic route can effectively reduce the production cost of niraparib, making its price more affordable for ordinary consumers and thus contributing to its market competitiveness.

[0006] Since the first synthesis of niraparib using existing technology in 2009, multiple synthetic routes have been reported to date. The main synthetic strategies include the following four:

[0007] (1) Asymmetric synthesis based on chemical resolution;

[0008] (2) Asymmetric synthesis based on chiral supercritical chromatographic resolution;

[0009] (3) Asymmetric synthesis based on chiral chromatographic resolution;

[0010] (4) Asymmetric synthesis based on dynamic splitting.

[0011] In recent years, several synthetic patents have reported methods for the asymmetric synthesis of niraparib based on kinetic resolution.

[0012] (1)WO2008084261A1 includes amide-substituted indazole and benzotriazole derivatives, which describes three racemic synthetic strategies for niraparib, but the synthetic routes are long and complicated, and the reagent costs are high.

[0013] (2) WO2009087381A1 includes a pharmaceutically acceptable salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, wherein the chirality of the active ingredient 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide is achieved by supercritical chromatography, which has high process costs and is not conducive to scale-up production.

[0014] (3) In WO2014088983A1, the asymmetric synthesis of niraparib was achieved by dynamic kinetic resolution. This method has certain limitations. The selected enzymes need to be cultured in a specific way, and the synthesis route is long and the cost is high.

[0015] (4) CN106749181A prepared chiral fragments through kinetic resolution, and then completed the asymmetric synthesis of niraparib. However, this method has a low yield, and sodium azide is used in the synthesis process, which is dangerous in scale-up preparation.

[0016] Therefore, the asymmetric synthesis of niraparib still faces unresolved challenges, such as long and cumbersome synthetic routes, low yields, and high reagent costs. Summary of the Invention

[0017] In view of the above-mentioned shortcomings of the prior art, the purpose of this invention is to provide a method for synthesizing niraparib, so as to solve the problems of long synthetic routes, complicated steps, low yield and high reagent cost when using asymmetric synthesis to prepare niraparib in the prior art.

[0018] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0019] A method for synthesizing niraparib, the specific synthetic route of niraparib is as follows:

[0020]

[0021] Where x is one of Br, I, or Cl.

[0022] Preferably, niraparib is synthesized through the following steps:

[0023] Step 1: (3S,8S,8aS)-8-(4-bromophenyl)-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridin-5-one (compound 1) undergoes a carbon-nitrogen coupling reaction with N-tert-butyl-1H-indazole-7-carboxamide (compound 2) to obtain N-tert-butyl-2-(4-((3R,8aR)-5-oxy-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide (compound 3); wherein the carbon-nitrogen coupling reaction is achieved by the Ullmann reaction or the Buchwald-Hartwig amination reaction;

[0024] Step 2: N-tert-butyl-2-(4-((3R,8aR)-5-oxy-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide (compound 3) undergoes a selective reduction reaction to give N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (compound 4);

[0025] Step 3: N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (compound 4) was hydrogenated in a hydrogen atmosphere to give N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (compound 5);

[0026] Step 4: N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (compound 5) was subjected to deprotection and salt formation reactions in sequence to give nirapanib p-toluenesulfonate monohydrate (compound 6).

[0027] Preferably, in step 1:

[0028] When carbon-nitrogen coupling is achieved using the Ullman reaction, DMAC or DMI is used as the solvent, CuBr or CuI is used as the catalyst, and 8-hydroxyquinoline is used as the ligand; the reaction temperature is 100℃~120℃, and the reaction time is 24h~48h; the molar ratio of compound 1, compound 2, K3PO4 or Cs2CO3, catalyst, and 8-hydroxyquinoline is 1:(0.96~1.2):3:(0.1~0.5):(0.2~1).

[0029] Preferably, in step 1:

[0030] When carbon-nitrogen coupling is achieved by the Buchwald-Hartwig amination reaction, toluene is used as the solvent, Pd(OAc)2 as the catalyst, and DPPF as the ligand; the reaction temperature is 100-120℃, and the reaction time is 12-48h; the molar ratio of compound 1, compound 2, NaO-t-Bu or Cs2CO3, Pd(OAc)2, and DPPF is 1:(1.2-1.5):(1.5-3):(0.05-0.2):(0.075-0.3).

[0031] Preferably, in step 2:

[0032] When the reducing agent is (EtO)3SiH or BH3, the reaction solvent is THF, the catalyst is NaBEt3H; the reaction temperature is 70℃~90℃, the reaction time is 20min~10h, and the molar ratio of compound 3, NaBEt3H and reducing agent is 1:(0.05~0.2):3.

[0033] Preferably, in step 2:

[0034] When the reducing agent is DIBAL-H, the reaction solvent is THF; the reaction temperature is 20℃~30℃, the reaction time is 1h~3h, and the molar ratio of compound 3 to the reducing agent is 1:(3-3.5).

[0035] Preferably, in step 3:

[0036] The reaction solvent is one of MeOH, EA or EtOH; the catalyst is one of Pd / C or Pd(OH)2 / C, and the Pd content in the catalyst is 5% to 20% by mass percentage; the reaction temperature is 15℃ to 25℃, and the reaction time is 24h to 72h; the hydrogenation agent is hydrogen gas, and the mass ratio of compound 4 to catalyst is 1:(0.1 to 0.2).

[0037] Preferably, in step 4:

[0038] During the deprotection reaction, the solvent was toluene, the reaction temperature was 30℃~50℃, and the reaction time was 5~6h.

[0039] When carrying out the salt formation reaction, the reaction solvent is xylene, the reaction temperature is 15℃~20℃, and the reaction time is 5~6h;

[0040] The molar ratio of compound 5 to MSA and p-TsOH is 1:20:1.5.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] 1. This application describes a carefully designed synthetic route for the target compound. It begins with a carbon-nitrogen coupling reaction between (3S,8S,8aS)-8-(4-bromophenyl)-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridin-5-one and N-tert-butyl-1H-indazole-7-carboxamide. The connection between compound 1 and compound 2 is achieved through either the Ullmann reaction or the Buchwald-Hartwig amination reaction, successfully introducing the indazole moiety into the oxazolopyridine structure to form intermediate compound 3. Subsequently, compound 3 is selectively reduced to a hydroxyl group on the oxazolopyridine ring, avoiding unnecessary impact on other functional groups. Then, compound 3 is hydrogenated under hydrogen atmosphere to further simplify the substituents on the piperidine ring, i.e., removing the hydroxyl and phenyl groups, ensuring the specificity and efficiency of the reaction. Finally, through deprotection and salt formation reactions, nirapanib p-toluenesulfonate monohydrate is successfully synthesized.

[0043] 2. The synthetic route designed in this application not only considers the construction of molecular structure, but also takes into account the purity, yield and convenience of subsequent processing of product, reducing the difficulty of each step of the reaction. The entire reaction route is under very mild conditions. Furthermore, the design of the entire synthetic route fully considers the characteristics and requirements of each step of the reaction. By precisely controlling the reaction conditions and selecting appropriate reagents, the efficient conversion from starting materials to target products is achieved, making it a promising candidate for industrial application. Detailed Implementation

[0044] This invention will describe the technical solutions of the embodiments of the invention clearly and completely. Obviously, the described embodiments are only some embodiments of the invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on this invention are within the scope of protection of this invention.

[0045] Unless otherwise specified in the specific circumstances, the numerical ranges listed herein include upper and lower limits, as well as all integers and fractions within that range, but are not limited to the specific values ​​listed when the range is defined.

[0046] I. A method for synthesizing niraparib

[0047] The specific synthesis route is as follows:

[0048]

[0049] Wherein, x is one of Br, I, and Cl. More preferably, x is Br.

[0050] To obtain the target product, it is necessary to consider high purity, yield, and ease of subsequent processing, while also taking into account the industrial applicability of the synthetic route. This application designs a synthetic route that begins with a carbon-nitrogen coupling reaction between (3S,8S,8aS)-8-(4-bromophenyl)-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridin-5-one and N-tert-butyl-1H-indazole-7-carboxamide. In the carbon-nitrogen coupling step, the Ullmann reaction or the Buchwald-Hartwig amination reaction is chosen to achieve the connection between (3S,8S,8aS)-8-(4-bromophenyl)-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridin-5-one and N-tert-butyl-1H-indazole-7-carboxamide. Both methods are effective means of forming carbon-nitrogen bonds, especially the Buchwald-Hartwig amination reaction, which has advantages such as mild reaction conditions and wide applicability. Through this process, the indazole moiety was successfully introduced into the oxazolopyridine structure, forming the intermediate N-tert-butyl-2-(4-((3R,8aR)-5-oxy-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide. Next, the intermediate was selectively reduced to reduce the ketone group on the oxazolopyridine ring to a hydroxyl group. The key to this step is selecting a suitable reducing agent to ensure the selectivity and efficiency of the reaction, while avoiding unnecessary impact on other functional groups. Therefore, this application optimized the reaction process to obtain N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide. Subsequently, the obtained compound was hydrogenated in a hydrogen atmosphere to further simplify the substituents on the piperidine ring, i.e., to remove the hydroxyl and phenyl groups. This step also required consideration of ensuring the specificity and efficiency of the reaction; therefore, the catalyst and reaction conditions were screened and optimized in this application, ultimately yielding N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide. To obtain the final target product—niraparib p-toluenesulfonate monohydrate—N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide required deprotection and salt formation reactions. The purpose of deprotection is to remove the protecting group to expose the active functional group; while the salt formation reaction is to improve the physical properties of the drug, such as solubility and stability, thereby increasing its bioavailability. In this process, selecting an appropriate acid (such as p-toluenesulfonic acid) to react with the target molecule can effectively form the desired salt form. Ultimately, this application successfully synthesized niraparib p-toluenesulfonate monohydrate. This reaction route not only considers the construction of the molecular structure, but also takes into account the purity, yield and convenience of subsequent processing of the product, making it a promising candidate for industrial application.

[0051] In some embodiments of this application, niraparib is synthesized through the following steps:

[0052] Step 1: (3S,8S,8aS)-8-(4-bromophenyl)-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridin-5-one (compound 1) undergoes a carbon-nitrogen coupling reaction with N-tert-butyl-1H-indazole-7-carboxamide (compound 2) to obtain N-tert-butyl-2-(4-((3R,8aR)-5-oxy-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide (compound 3); wherein the carbon-nitrogen coupling reaction is achieved by the Ullmann reaction or the Buchwald-Hartwig amination reaction;

[0053] Step 2: N-tert-butyl-2-(4-((3R,8aR)-5-oxy-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide (compound 3) undergoes a selective reduction reaction to give N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (compound 4);

[0054] Step 3: N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (compound 4) was hydrogenated in a hydrogen atmosphere to give N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (compound 5);

[0055] Step 4: N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (compound 5) was subjected to deprotection and salt formation reactions in sequence to give nirapanib p-toluenesulfonate monohydrate (compound 6).

[0056] In some embodiments of this application, numerous reactions capable of achieving carbon-nitrogen coupling are considered. However, these reactions all have certain drawbacks. For example, the Chan-Lam coupling reaction, although under mild conditions, produces many byproducts, requiring further purification steps. Furthermore, the reaction system is sensitive to moisture, necessitating strict dehydration, making the operation complex and the yield unstable, especially when constructing complex multifunctional structures as described in this application, where the yield is far from ideal. The Suzuki-Miyaura coupling reaction is primarily used for carbon-carbon coupling. While it can also be used for carbon-nitrogen coupling in certain situations, it requires the prior preparation of borate esters, increasing the reaction steps, resulting in higher catalyst costs and more byproducts. Therefore, other carbon-nitrogen coupling reactions either have harsh reaction conditions, produce many byproducts, or require additional preparation steps, all of which are detrimental to the efficient synthesis of complex multifunctional molecules. Therefore, considering industrialization prospects, this application chooses the Ullman reaction. In step 1:

[0057] When carbon-nitrogen coupling is achieved using the Ullman reaction, DMAC (N,N-dimethylacetamide) or DMI (1,3-dimethyl-2-imidazolinone) is used as the solvent, CuBr or CuI as the catalyst, and 8-hydroxyquinoline as the ligand. The reaction temperature is 100℃~120℃, and the reaction time is 24h~48h. The molar ratio of compound 1, compound 2, K3PO4 or Cs2CO3, catalyst, and 8-hydroxyquinoline is 1:(0.96~1.2):3:(0.1~0.5):(0.2~1).

[0058] In some embodiments of this application, the Buchwald-Hartwig amination reaction is also considered for carbon-nitrogen coupling. Experiments have shown that the Buchwald-Hartwig amination reaction, with the selection of suitable ligands and catalysts, can achieve highly stereoselective and regioselective carbon-nitrogen coupling. This is particularly important for the complex multifunctional molecule of the target product, ensuring high purity and high yield. Furthermore, in this application, the oxazolopyridine structure contains multiple sensitive functional groups, and the Buchwald-Hartwig reaction can proceed smoothly without damaging these functional groups. Moreover, the Buchwald-Hartwig reaction can be carried out under mild conditions, without the need for extreme temperatures or pressures, which helps maintain the stability of the reaction system and reduce the occurrence of side reactions. Therefore, in step 1:

[0059] When carbon-nitrogen coupling is achieved using the Buchwald-Hartwig amination reaction, toluene is used as the solvent, Pd(OAc)2 (palladium acetate) as the catalyst, and DPPF (1,1'-bis(diphenylphosphine)ferrocene) as the ligand; the reaction temperature is 100℃~120℃, and the reaction time is 12h~48h; the molar ratio of compound 1, compound 2, NaO-t-Bu (sodium tert-butoxide) or Cs2CO3, Pd(OAc)2, and DPPF is 1:(1.2~1.5):(1.5~3):(0.05~0.2):(0.075~0.3).

[0060] In some embodiments of this application, the ketone group on the oxazolopyridine ring is reduced to a hydroxyl group via a selective reduction reaction to obtain N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide. The key to this process is selecting a suitable reducing agent and reaction conditions to ensure the selectivity and specificity of the reaction. By selecting a specific reducing agent, this application can achieve selective reduction of specific functional groups without affecting other sensitive groups. The entire selective reduction reaction is usually carried out under mild conditions, avoiding side reactions or decomposition that may be caused by high temperatures or strong acid / base conditions. Furthermore, this application has found that the reaction product obtained in this process has high purity, and due to the high selectivity of the reaction, there are fewer byproducts, making it easier to separate and purify the target product. In step 2:

[0061] When the reducing agent is (EtO)3SiH (triethoxysilane) or BH3 (borane), the reaction solvent is THF (tetrahydrofuran), and the catalyst is NaBEt3H (sodium ethylborohydride); the reaction temperature is 70℃~90℃, the reaction time is 20min~10h, and the molar ratio of compound 3, NaBEt3H, and reducing agent is 1:(0.05~0.2):3. The reaction temperature can be 70℃, 80℃, 90℃, etc., and all ranges and sub-ranges between these values; the reaction time can be 20min, 30min, 1h, 4h, 6h, 8h, 10h, etc., and all ranges and sub-ranges between these values; the molar ratio of compound 3, NaBEt3H, and reducing agent can be 1:0.05:3, 1:0.1:3, 1:0.15:3, 1:0.2:3, etc., and all ranges and sub-ranges between these values. It should be understood that, in the implementation plan, any of the above scopes can be combined with any other scopes.

[0062] In some embodiments of this application, in step 2:

[0063] When the reducing agent is DIBAL-H (diisobutylaluminum hydride), the reaction solvent is THF; the reaction temperature is 20℃~30℃, the reaction time is 1h~3h, and the molar ratio of compound 3 to the reducing agent is 1:(3-3.5). The reaction temperature can be 20℃, 25℃, 30℃, etc., and all ranges and sub-ranges between these values; the reaction time can be 1h, 2h, 3h, etc., and all ranges and sub-ranges between these values; the molar ratio of compound 3 to the reducing agent can be 1:3, 1:3.2, 1:3.5, etc., and all ranges and sub-ranges between these values. It should be understood that, in the embodiments, any of the above ranges can be combined with any other range.

[0064] In some embodiments of this application, the intermediate is hydrogenated in a hydrogen atmosphere to remove the hydroxyl and phenyl groups, ultimately yielding N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide. In this process, the hydrogenation reaction can efficiently convert unsaturated bonds to saturated bonds with the aid of a catalyst (such as palladium on carbon). Simultaneously, by controlling the reaction conditions, the selectivity and rate of the reaction can be precisely controlled, avoiding over-hydrogenation or other side reactions. In step 3:

[0065] The reaction solvent is one of MeOH (methanol), EA (ethyl acetate), or EtOH (ethanol); the catalyst is one of Pd / C or Pd(OH)2 / C, and the Pd content in the Pd / C catalyst is 5wt% to 20wt%, and the Pd content in the Pd(OH)2 / C catalyst is 5wt% to 20wt% by mass percentage; the reaction temperature is 15℃ to 25℃, and the reaction time is 24h to 72h; the hydrogenation agent is hydrogen gas, and the mass ratio of compound 4 to catalyst is 1:(0.1 to 0.2).

[0066] In some embodiments of this application, a deprotection step is used to remove protecting groups to expose active functional groups; while the salt formation reaction is to improve the physical properties of the drug, such as solubility and stability, thereby increasing its bioavailability. In this process, this application selects p-toluenesulfonic acid to react with the target molecule, which can effectively form the desired salt form. In step 4:

[0067] During the deprotection reaction, compound 5 undergoes a deprotection reaction with MSA (methanesulfonic acid) in toluene as the solvent, at a temperature of 30℃ to 50℃, for a time of 5 to 6 hours.

[0068] During the salt formation reaction, the product obtained from the deprotection reaction reacts with p-TsOH (p-toluenesulfonic acid) to form a salt. The reaction solvent is xylene, the reaction temperature is 15℃~20℃, and the reaction time is 5~6h.

[0069] The molar ratio of compound 5 to MSA and p-TsOH is 1:20:1.5.

[0070] II. Implementation Examples

[0071] (1) Synthesis of N-tert-butyl-2-(4-((3R,8aR)-5-oxy-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide

[0072] Example 1:

[0073] Under an argon atmosphere, N-tert-butyl-1H-indazole-7-carboxamide (20 mg, 0.0921 mmol), (3S,8aS)-8-(4-bromophenyl)-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridine (32.91 mg, 0.0884 mmol), K3PO4 (58.61 mg, 0.276 mmol), and 8-hydroxyquinoline (5.34 mg, 0.0368 mmol) were weighed and added to a 50 mL double-necked flask. 4 mL of LDMAC was added to dissolve the flask, and the entire system was frozen with liquid nitrogen. Then, the system was vacuum-treated for 20 min using a vacuum pump. Next, CuBr (2.64 mg, 0.0184 mmol) was rapidly added under an argon atmosphere, and the system was vacuum-treated again under liquid nitrogen for another 20 min using a vacuum pump. The liquid nitrogen was then removed, and argon was introduced to completely restore the reaction system to room temperature. Finally, the reaction was carried out at 110 °C for 24 h. After the reaction was completed, the system was allowed to return to room temperature. 50 mL of water was added and thoroughly mixed with the reaction system. Extraction was performed using ethyl acetate (3 × 50 mL). The organic phases were combined and washed with water (6 × 50 mL). Finally, the organic phase was washed with saturated sodium chloride solution. The water in the organic phase was dried with anhydrous Na2SO4 solid, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 42.15 mg of a pale yellow solid, with a yield of 90% and a purity of 98%.

[0074] Example 2

[0075] The experiment was modified from Example 1, with the difference being that the carbon-nitrogen coupling was performed using the Buchwald-Hartwig amination reaction, and the molar ratio of compound 1, compound 2, NaO-t-Bu, Pd(OAc)2, and DPPF was 1:1.2:1.5:0.05:0.075. The reaction temperature was 110°C, and the reaction time was 24 hours.

[0076] Examples 3-6 were carried out according to the raw material ratios in Example 1 and the reaction conditions in Table 1. Examples 7-8 were carried out according to the raw material ratios in Example 2 and the reaction conditions in Table 1.

[0077] Table 1

[0078]

[0079] The products prepared in Examples 1-8 were analyzed. The 1H NMR data of the product N-tert-butyl-2-(4-((3R,8aR)-5-oxy-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide are as follows: 1H NMR (600MHz, CDCl3) δ9.30 (s, 1H), 8.53 (s, 1H), 8.28 (d, J = 6.0Hz, 1H), 7.94 (d, J =6.6Hz,2H),7.85(d,J=7.8Hz,1H),7.59(d,J=6.6Hz,2H),7.46-7.33(m,5H),5.0 1(d,J=6.6Hz,1H),4.96(d,J=9.0Hz,1H),4.15(t,J=7.2Hz,1H),4.05(d,J=9.0Hz ,1H),3.20(t,J=10.8Hz,1H),2.65-2.52(m,2H),2.27-2.16(m,2H),1.60(s,9H).

[0080] (2) Synthesis of N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide

[0081] In this step, N-tert-butyl-2-(4-((3R,8aR)-5-oxy-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide prepared in Example 1 was used as a raw material for the experiment.

[0082] Example 9: Under an argon atmosphere, 20 mg (0.0393 mmol) of N-tert-butyl-2-(4-((3R,8aR)-5-oxy-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide was weighed and added to a 50 mL reaction flask. 6 mL of THF was added to dissolve the carboxylic acid, followed by 7 μL of BH3-DMS solution (8.96 mg, 0.118 mmol). The mixture was refluxed at 90 °C for 20 min. The reaction solution was quenched with HCl, and the pH was adjusted to approximately 10 with NaOH aqueous solution. Extraction was performed using ethyl acetate (3 × 10 mL). The organic phases were combined, and the water in the organic phase was dried over anhydrous Na2SO4 solid. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 15.50 mg of a pale yellow solid, with a yield of 80% and a purity of 98%.

[0083] Example 10: Under an argon atmosphere, N-tert-butyl-2-(4-((3R,8aR)-5-oxy-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide (40 mg, 0.0786 mmol), NaBEt3H (1.92 mg, 0.0157 mmol), and (EtO)3SiH (38.77 mg, 0.236 mmol) were weighed and added to a 10 mL Schlenk tube. 6.0 mL of THF was added to dissolve the solid, and the entire system was reacted at 80 °C for 6 h. After the reaction system cooled to room temperature, DCM was added to dissolve the solid. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 23.24 mg of a pale yellow solid, with a yield of 60% and a purity of 98%.

[0084] Example 11: Under an argon atmosphere and at room temperature, 20 mg (0.039 mmol) of N-tert-butyl-2-(4-((3R,8aR)-5-oxy-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide was added to a 50 mL reaction flask, dissolved in 6 mL of THF, and DIBAL-H (19.56 mg, 0.138 mmol) was added. The mixture was stirred at 25 °C for 2 h, cooled to 0 °C in an ice bath, diluted with methyl tert-butyl ether, and then water, 15% NaOH, and water were added. The mixture was stirred at 25 °C for 1 h, and anhydrous MgSO4 was added and stirred for 5 min. The mixture was filtered through diatomaceous earth, and the filter cake was washed with methyl tert-butyl ether. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 11.72 mg of a pale yellow solid, with a yield of 60% and a purity of 98%.

[0085] (3) Synthesis of N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide

[0086] In this step, N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide prepared in Example 9 was used as a raw material for the reaction.

[0087] Example 12: 10 mg (0.020 mmol) of N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide and 10% Pd / C (2 mg) were weighed and added to a 50 mL reaction flask. 4 mL of MeOH was added to dissolve the flask, and the reaction was carried out at 25 °C under hydrogen atmosphere for 72 h. The mixture was filtered through diatomaceous earth, and the filter cake was washed with hot methanol. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 5.76 mg of a pale yellow solid, with a yield of 90% and a purity of 98%.

[0088] Example 13: 10 mg (0.020 mmol) of N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide and 5% Pd / C (2 mg) were weighed and added to a 50 mL reaction flask. 4 mL of MeOH was added to dissolve the flask, and the reaction was carried out at 25 °C under hydrogen atmosphere for 24 h. The mixture was filtered through diatomaceous earth, and the filter cake was washed with hot methanol. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 5.45 mg of a pale yellow solid, with a yield of 85% and a purity of 98%.

[0089] Example 14: 10 mg (0.020 mmol) of N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide and 10% Pd(OH)2 / C (2 mg) were weighed and added to a 50 mL reaction flask. 4 mL of MeOH was added to dissolve the flask, and the reaction was carried out at 25 °C under hydrogen atmosphere for 24 h. The mixture was filtered through diatomaceous earth, and the filter cake was washed with hot methanol. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 5.45 mg of a pale yellow solid, with a yield of 85% and a purity of 98%.

[0090] (3) Synthesis of niraparib monohydrate p-toluenesulfonate

[0091] In this step, the product N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide prepared in Example 12 was used as the raw material for the experiment.

[0092] Example 15: Weigh out N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (147.38 mg, 0.46 mmol) and add it to a 50 mL reaction flask. Add 4 mL of xylene to dissolve it, then add MSA (0.6 mL, 9.2 mmol), stir and heat to 40 °C, age for 2.5 h, then cool to below 20 °C, add 14 mL of water and mix thoroughly with the reaction system, separate the aqueous phase, wash the aqueous phase with toluene (3 × 2 mL) and filter to obtain seed crystals.

[0093] Prepare 0.24 mL of p-TsOH (118.82 mg, 0.69 mmol) aqueous solution. Add seed crystals to a 50 mL reaction flask at 20 °C, then add the prepared p-TsOH aqueous solution and stir to dissolve. Aging for 12 h is followed by filtration and washing with water (3 × 1 mL). Vacuum drying at 20–25 °C yields 214.46 mg of a off-white solid, with a yield of 90% and a purity of 98%.

[0094] For the product niraparib monohydrate p-toluenesulfonate 1The ¹H NMR data analysis results are as follows: ¹H NMR (600MHz, CH₃OD) δ 8.95 (¹H, s), 8.15 (¹H, dd, J = 7.1, 1.2Hz), 8.02 (2H, m), 8.00 (¹H, dd, J = 8.3, 1.2Hz), 7.72 (2H, m), 7.49 (2H, m), 7.25 (¹H, dd, J = 8.3, 7.1Hz), 7.22 (2H, d, J = 8.0Hz), 3.49–3.43 (2H, m), 2.34 (3H, s), 2.09–2.05 (2H, m), 1.96–1.82 (2H, m).

[0095] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit the technical solutions. Those skilled in the art should understand that any modifications or equivalent substitutions to the technical solutions of the present invention without departing from the spirit and scope of the present invention should be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing niraparib, characterized in that, The specific synthetic route for niraparib is as follows: ； Where x is Br and Ar is phenyl.

2. The synthesis method according to claim 1, characterized in that, Niraparib was synthesized through the following steps: Step 1: Compound 1 and Compound 2 undergo a carbon-nitrogen coupling reaction to obtain Compound 3; wherein the carbon-nitrogen coupling reaction is achieved by the Ullmann reaction or the Buchwald-Hartwig amination reaction; Step 2: Compound 3 undergoes a selective reduction reaction to obtain compound 4; Step 3: Compound 4 undergoes a hydrogenation reaction in a hydrogen atmosphere to obtain compound 5; Step 4: Compound 5 undergoes deprotection and salt formation reactions sequentially to obtain compound 6.

3. The synthesis method according to claim 2, characterized in that, In step 1: When carbon-nitrogen coupling is achieved using the Ullman reaction, DMAC or DMI is used as the solvent, CuBr or CuI is used as the catalyst, and 8-hydroxyquinoline is used as the ligand; the reaction temperature is 100~120℃, and the reaction time is 24h~48h; the molar ratio of compound 1, compound 2, K3PO4 or Cs2CO3, catalyst, and 8-hydroxyquinoline is 1:(0.96~1.2):3:(0.1~0.5):(0.2~1).

4. The synthesis method according to claim 2, characterized in that, In step 1: When carbon-nitrogen coupling is achieved by the Buchwald-hartwig amination reaction, toluene is used as the solvent, Pd(OAc)2 as the catalyst, and DPPF as the ligand; the reaction temperature is 100℃~120℃, and the reaction time is 12h~48h; the molar ratio of compound 1, compound 2, NaO-t-Bu or Cs2CO3, Pd(OAc)2, and DPPF is 1:(1.2~1.5):(1.5~3):(0.05~0.2):(0.075~0.3).

5. The synthesis method according to claim 3 or 4, characterized in that, In step 2: When the reducing agent is (EtO)3SiH or BH3, the reaction solvent is THF, the catalyst is NaBEt3H; the reaction temperature is 70℃~90℃, the reaction time is 20min~10h, and the molar ratio of compound 3, NaBEt3H and reducing agent is 1:(0.05~0.2):

3.

6. The synthesis method according to claim 3 or 4, characterized in that, In step 2: When the reducing agent is DIBAL-H, the reaction solvent is THF; the reaction temperature is 20℃~30℃, the reaction time is 1h~3h, and the molar ratio of compound 3 to the reducing agent is 1:(3-3.5).

7. The synthesis method according to claim 2, characterized in that, In step 3: The reaction solvent is one of MeOH, EA or EtOH; the catalyst is one of Pd / C or Pd(OH)2 / C, and the Pd content in the catalyst is 5%~20% by mass percentage; the reaction temperature is 15~25℃, and the reaction time is 24h~72h; the hydrogenation agent is hydrogen gas, and the mass ratio of compound 4 to catalyst is 1:(0.1~0.2).

8. The synthesis method according to claim 2, characterized in that, In step 4: During the deprotection reaction, compound 5 reacts with MSA in toluene as the solvent, at a temperature of 30°C to 50°C, for a time of 5 to 6 hours. During the salt formation reaction, the product obtained from the deprotection reaction reacts with p-TsOH to form a salt. The reaction solvent is xylene, the reaction temperature is 15℃~20℃, and the reaction time is 5~6h. The molar ratio of compound 5 to MSA and p-TsOH is 1:20:1.5.

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