Synthesis method of niraparib

Abstract

The invention discloses a synthesis method of niraparib, and the synthesis route is specifically as follows: # imgabs0 #, wherein x is one of Br, I and Cl.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing niraparib. Background Art

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

[0003] The active ingredient of niraparib is the free base, the English chemical name is (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide, the Chinese translation is (S)-2-[4-(3-piperidinyl)phenyl]-2H-indazole-7-carboxamide, and the active ingredient is its p-toluenesulfonate, the chemical structure is as follows:

[0004]

[0005] In the prior art, due to the complexity and particularity of the molecular structure of niraparib, the yield of the chemical total synthesis process is low and the large-scale production is difficult, which leads to its high price. As a first-line maintenance treatment drug that needs to be used for a long time, it still has a certain burden on patients in ordinary families. Therefore, the development of an efficient and concise synthesis route can effectively reduce the production cost of niraparib, making the price of its drugs more in line with the economic affordability of ordinary consumers, thereby helping to improve market competitiveness.

[0006] Since the first synthesis of niraparib using existing technology in 2009, multiple synthesis routes have been reported so far. The synthesis strategies mainly include the following four:

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

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

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

[0010] (4) Asymmetric synthesis based on kinetic resolution.

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

[0012] (1) WO2008084261A1 includes amide-substituted indazole and benzotriazole derivatives, which describe three racemization synthesis strategies for niraparib. However, the synthetic route is long and complicated, and the reagent cost is 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 a high process cost and is not conducive to large-scale production.

[0014] (3) WO2014088983A1 achieves asymmetric synthesis of niraparib by dynamic kinetic resolution. This method has certain limitations. The selected enzyme requires specific cultivation, and the synthesis route is long and the cost is high.

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

[0016] Therefore, the asymmetric synthesis method of niraparib has unresolved problems such as a long and complicated synthesis route, low yield, and high reagent cost. Summary of the invention

[0017] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a method for synthesizing niraparib, so as to solve the problems of long synthesis route, complicated steps, low yield and high reagent cost when preparing niraparib by asymmetric synthesis in the prior art.

[0018] In order to solve the above technical problems, the present invention adopts the following technical solutions:

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

[0020]

[0021] Wherein, x is one of Br, I and Cl.

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

[0023] Step 1: (3S, 8S, 8aS)-8-(4-bromophenyl)-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridin-5-one (Compound 1) and N-tert-butyl-1H-indazole-7-carboxamide (Compound 2) undergo carbon-nitrogen coupling reaction 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 Ullmann reaction or 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) is subjected to a selective reduction reaction to obtain 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) is subjected to hydrogenation reaction under a hydrogen atmosphere to obtain 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) is subjected to deprotection and salt-forming reactions to obtain niraparib p-toluenesulfonate monohydrate (Compound 6).

[0027] Preferably, in step 1:

[0028] When the Ullmann reaction is used to achieve carbon-nitrogen coupling, DMAC or DMI is used as a solvent, CuBr or CuI is used as a catalyst, and 8-hydroxyquinoline is used as a ligand; the reaction temperature is 100°C to 120°C, and the reaction time is 24h to 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 the Buchwald-hartwig amination reaction is used to achieve carbon-nitrogen coupling, toluene is used as solvent, Pd(OAc)2 is used as catalyst, and DPPF is used as ligand; the reaction temperature is 100-120°C, 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°C to 90°C, the reaction time is 20min to 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°C to 30°C, the reaction time is 1h to 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% calculated by mass percentage; the reaction temperature is 15°C to 25°C, and the reaction time is 24h to 72h; the hydrogenation reagent is hydrogen, and the mass ratio of compound 4 to the catalyst is 1:(0.1 to 0.2).

[0037] Preferably, in step 4:

[0038] When performing the deprotection reaction, the reaction solvent is toluene, the reaction temperature is 30°C to 50°C, and the reaction time is 5 to 6 hours;

[0039] When performing the salt-forming reaction, the reaction solvent is xylene, the reaction temperature is 15°C to 20°C, and the reaction time is 5 to 6 hours;

[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. The present application has carefully designed a synthetic route for the target compound, starting from the carbon-nitrogen coupling reaction of (3S, 8S, 8aS)-8-(4-bromophenyl)-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridine-5-one and N-tert-butyl-1H-indazole-7-carboxamide, and selecting the Ullmann reaction or the Buchwald-Hartwig amination reaction to realize the connection between compound 1 and compound 2, and successfully introducing the indazole part into the oxazolopyridine structure to form the intermediate compound 3; then, by selectively reducing compound 3, the keto group on the oxazolopyridine ring is further reduced to a hydroxyl group, and this process also avoids unnecessary effects on other functional groups; then, the obtained compound 3 is subjected to a hydrogenation reaction in a hydrogen environment, aiming to further simplify the substituents on the piperidine ring, that is, to remove the hydroxyl group and the phenyl group, thereby ensuring the specificity and efficiency of the reaction; finally, by deprotection and salt formation reactions, the monohydrated niraparib p-toluenesulfonate is successfully synthesized.

[0043] 2. The synthetic route designed in this application not only takes into account the construction of the molecular structure, but also takes into account the purity, yield and convenience of subsequent processing of the product, reduces the difficulty of the reaction in each step, and the conditions of the entire reaction route are very mild. In addition, 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, efficient conversion from starting materials to target products is achieved, making it have a good prospect for industrial application. DETAILED DESCRIPTION

[0044] The present invention will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by ordinary technicians in this field based on the present invention belong to the scope of protection of the present invention.

[0045] Unless otherwise indicated in specific cases in the present invention, the numerical ranges listed herein include the upper and lower limits, and all integers and fractions within the range, and are not limited to the specific values ​​listed when defining the range.

[0046] 1. A method for synthesizing niraparib

[0047] The specific synthetic route is as follows:

[0048]

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

[0050] In order to prepare the target product, it is necessary to consider making the product have a high purity, yield and convenience of subsequent processing, while also taking into account the prospects for industrialization of the synthetic route. The present application designs its synthetic route, starting from the carbon-nitrogen coupling reaction of (3S, 8S, 8aS)-8-(4-bromophenyl)-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridine-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 selected to achieve the connection between (3S, 8S, 8aS)-8-(4-bromophenyl)-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridine-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 the advantages of mild reaction conditions and wide practicality. Through this process, the indazole part was successfully introduced into the oxazolopyridine structure to form 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. Then, the intermediate was subjected to a selective reduction reaction to reduce the keto group on the oxazolopyridine ring to a hydroxyl group. The key to this step is to select a suitable reducing agent to ensure the selectivity and efficiency of the reaction while avoiding unnecessary effects on other functional groups. Therefore, the present application optimizes 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 is subjected to a hydrogenation reaction under a hydrogen environment, aiming to further simplify the substituents on the piperidine ring, that is, to remove the hydroxyl group and the phenyl group. This step also needs to consider ensuring the specificity and efficiency of the reaction, so the present application screens and optimizes both the catalyst and the reaction conditions, and finally obtains N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide. In order to obtain the final target product, niraparib p-toluenesulfonate monohydrate, N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide needs to be deprotected and salt-formed. The purpose of deprotection is to remove the protecting group so as to expose the active functional group; and the salt-formation reaction is to improve the physical properties of the drug, such as solubility and stability, thereby improving 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. Finally, the present application successfully synthesized niraparib p-toluenesulfonate monohydrate. This reaction route not only takes into account the construction of the molecular structure, but also takes into account the purity, yield and convenience of subsequent processing of the product, making it have a good prospect for industrial application.

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

[0052] Step 1: (3S, 8S, 8aS)-8-(4-bromophenyl)-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridin-5-one (Compound 1) and N-tert-butyl-1H-indazole-7-carboxamide (Compound 2) undergo carbon-nitrogen coupling reaction 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 Ullmann reaction or 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) is subjected to a selective reduction reaction to obtain 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) is subjected to hydrogenation reaction under a hydrogen atmosphere to obtain 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) is subjected to deprotection and salt-forming reactions to obtain niraparib p-toluenesulfonate monohydrate (Compound 6).

[0056] In some embodiments of the present application, the present application considers many reactions that can achieve carbon-nitrogen coupling, but these reactions all have certain disadvantages. For example, although the Chan-Lam coupling reaction has mild conditions, it has more by-products and requires further purification steps. In addition, the reaction system is sensitive to moisture and requires strict water removal. The operation is relatively complicated and the yield is unstable, especially when constructing a complex multi-functional structure such as the present application. The yield is very unsatisfactory. The Suzuki-Miyaura coupling reaction is mainly used for carbon-carbon coupling. Although it can also be used for carbon-nitrogen coupling in some cases, it requires the pre-preparation of boric acid esters, which increases the reaction steps, the catalyst cost is relatively high, and there are more by-products. It can be seen that other carbon-nitrogen coupling reactions either have harsh reaction conditions, or have more by-products, or require additional preparation steps, which are not conducive to the efficient synthesis of complex multi-functional molecules. Therefore, from the perspective of industrialization, the present application can select the Ullmann reaction. In step 1:

[0057] When the Ullmann reaction is used to achieve carbon-nitrogen coupling, DMAC (N,N-dimethylacetamide) or DMI (1,3-dimethyl-2-imidazolidinone) is used as a solvent, CuBr or CuI is used as a catalyst, and 8-hydroxyquinoline is used as a ligand; the reaction temperature is 100°C to 120°C, and the reaction time is 24h to 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 the present application, the present application also considers using the Buchwald-Hartwig amination reaction to achieve carbon-nitrogen coupling, because it has been found through experiments that the Buchwald-Hartwig amination reaction can achieve highly stereoselective and regioselective carbon-nitrogen coupling by selecting suitable ligands and catalysts in the present application. This is particularly important for complex multi-functional molecules such as the target product of the present application, which can ensure the high purity and high yield of the target product. At the same time, in the present application, the oxazolopyridine structure contains multiple sensitive functional groups, and the Buchwald-Hartwig reaction can proceed smoothly without destroying these functional groups. Moreover, the Buchwald-Hartwig reaction can be carried out under mild conditions and does not require extreme temperature or pressure, which helps to maintain the stability of the reaction system in the present application and reduce the occurrence of side reactions. Therefore, in step 1:

[0059] When the Buchwald-hartwig amination reaction is used to achieve carbon-nitrogen coupling, toluene is used as solvent, Pd(OAc)2 (palladium acetate) is used as catalyst, and DPPF (1,1'-bis(diphenylphosphino)ferrocene) is used as ligand; the reaction temperature is 100°C to 120°C, and the reaction time is 12h to 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 to 1.5):(1.5 to 3):(0.05 to 0.2):(0.075 to 0.3).

[0060] In some embodiments of the present application, the present application reduces the keto group on the oxazolopyridine ring to a hydroxyl group through 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 to select a suitable reducing agent and reaction conditions to ensure the selectivity and specificity of the reaction. By selecting a specific reducing agent, the present 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 to avoid side reactions or decomposition that may be caused by high temperature or strong acid-base conditions. At the same time, the present application also found that in this process, the reaction product obtained has high purity. Due to the high selectivity of the reaction and the small number of by-products, the target product can be more easily separated and purified. In step 2:

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

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

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

[0064] In some embodiments of the present application, the intermediate is subjected to a hydrogenation reaction under a hydrogen environment to remove the hydroxyl group and the phenyl group, and finally obtain N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide. In this process, the hydrogenation reaction can efficiently convert unsaturated bonds into saturated bonds under the action of a catalyst (such as palladium on carbon). At the same time, by controlling the reaction conditions, the selectivity and rate of the reaction can be accurately controlled to avoid excessive 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 calculated by mass percentage, the Pd content in the catalyst Pd / C is 5wt%~20wt%, and the Pd content in the catalyst Pd(OH)2 / C is 5wt%~20wt%; the reaction temperature is 15°C~25°C, and the reaction time is 24h~72h; the hydrogenation reagent is hydrogen, and the mass ratio of compound 4 to the catalyst is 1:(0.1~0.2).

[0066] In some embodiments of the present application, the present application utilizes a deprotection step to remove the protecting group so as to expose the active functional group, and 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, the present application selects p-toluenesulfonic acid to react with the target molecule, which can effectively form the desired salt form.

[0067] In step 4:

[0068] During the deprotection reaction, compound 5 is subjected to a deprotection reaction with MSA (methanesulfonic acid), the reaction solvent is toluene, the reaction temperature is 30° C. to 50° C., and the reaction time is 5 to 6 h;

[0069] When performing the salt-forming reaction, the product obtained by the deprotection reaction is reacted with p-TsOH (p-toluenesulfonic acid) to form a salt, the reaction solvent is xylene, the reaction temperature is 15° C. to 20° C., and the reaction time is 5 to 6 hours;

[0070] The molar ratio of compound 5 to MSA and p-TsOH is 1:20:1.5.

[0071] 2. Embodiment

[0072] (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

[0073] Embodiment 1:

[0074] Under 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 added into a 50 mL two-necked flask, 4 mL of DMAC was added to dissolve, the whole system was frozen with liquid nitrogen, and then vacuum treated with a vacuum pump for 20 min, and then CuBr (2.64 mg, 0.0184 mmol) was quickly added under argon atmosphere, and vacuum treated with a vacuum pump for 20 min under liquid nitrogen conditions, then the liquid nitrogen was removed and argon was introduced to completely restore the reaction system to room temperature, and finally reacted at 110 ° C for 24 h. After the reaction is completed, wait for the system to return to room temperature, add 50 mL of water and mix thoroughly with the reaction system, use ethyl acetate (3×50 mL) for extraction, combine the organic phases, wash the organic phases with water (6×50 mL), and finally wash the organic phases with saturated sodium chloride solution, dry the water in the organic phase with anhydrous Na2SO4 solid, filter, and concentrate the filtrate under reduced pressure. Purify by column chromatography to obtain 42.15 mg of light yellow solid with a yield of 90% and a purity of 98%.

[0075] Example 2

[0076] The method was adjusted based on Example 1, except that the carbon-nitrogen coupling was carried out by Buchwald-hartwig amination reaction, 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 24h.

[0077] Examples 3 to 6 were reacted according to the raw material ratio in Example 1 and the reaction conditions in Table 1. Examples 7 to 8 were reacted according to the raw material ratio in Example 2 and the reaction conditions in 1.

[0078] Table 1

[0079]

[0080] The products prepared in Examples 1 to 8 were analyzed, and the 1H NMR data analysis results 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 were 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).

[0081] (2) Synthesis of N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide

[0082] 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 testing.

[0083] Example 9: Under argon atmosphere, weighed N-tert-butyl-2-(4-((3R,8aR)-5-oxyl-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide (20 mg, 0.0393 mmol) was added into a 50 mL reaction flask, 6 mL of THF was added to dissolve, and 7 μL of BH3-DMS solution (8.96 mg, 0.118 mmol) was added. The reaction mixture was refluxed at 90°C for 20 min. The reaction solution was quenched with HCl, the pH was adjusted to about 10 with a NaOH aqueous solution, and extracted with ethyl acetate (3×10 mL). The organic phases were combined, the water in the organic phase was dried over anhydrous Na2SO4 solid, and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 15.50 mg of a light yellow solid with a yield of 80% and a purity of 98%.

[0084] Example 10: Under an argon atmosphere, weighed 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), (EtO)3SiH (38.77 mg, 0.236 mmol) were added to a 10 mL schlenk tube, and 6.0 mL THF was added to dissolve, and the whole system was placed at 80 ° C for 6 hours. After the reaction system was cooled to room temperature, DCM was added to dissolve, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 23.24 mg of a light yellow solid with a yield of 60% and a purity of 98%.

[0085] Example 11: Under argon atmosphere and room temperature, weighed N-tert-butyl-2-(4-((3R,8aR)-5-oxyl-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridin-8-yl)phenyl)-2H-indazole-7-carboxamide (20 mg, 0.039 mmol) was added into a 50 mL reaction flask, 6 mL of THF was added to dissolve, DIBAL-H (19.56 mg, 0.138 mmol) was added, and the mixture was stirred at 25°C for 2 h. The mixture was cooled to 0°C in an ice bath, diluted with methyl tert-butyl ether, followed by the addition of water, 15% NaOH, and water. The mixture was stirred at 25°C for 1 h. Anhydrous MgSO4 was added and stirred for 5 min. The mixture was filtered through diatomaceous earth, the filter cake was washed with methyl tert-butyl ether, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 11.72 mg of a light yellow solid with a yield of 60% and a purity of 98%.

[0086] (3) Synthesis of N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide

[0087] 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.

[0088] Example 12: N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (10 mg, 0.020 mmol) and 10% Pd / C (2 mg) were added into a 50 mL reaction flask, 4 mL MeOH was added to dissolve, and the reaction was hydrogenated under a hydrogen environment at 25 °C 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 light yellow solid with a yield of 90% and a purity of 98%.

[0089] Example 13: N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (10 mg, 0.020 mmol) and 5% Pd / C (2 mg) were added into a 50 mL reaction flask, 4 mL MeOH was added to dissolve, and the mixture was hydrogenated under a hydrogen environment at 25°C 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 light yellow solid with a yield of 85% and a purity of 98%.

[0090] Example 14: N-(tert-butyl)-2-(4-(1-(2-hydroxy-1-phenylethyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (10 mg, 0.020 mmol) and 10% Pd(OH)2 / C (2 mg) were added into a 50 mL reaction flask, 4 mL of MeOH was added to dissolve, and the mixture was hydrogenated under a hydrogen environment at 25°C 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 light yellow solid with a yield of 85% and a purity of 98%.

[0091] (3) Synthesis of Niraparib Monohydrate p-Toluenesulfonate

[0092] 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 a raw material for the experiment.

[0093] Example 15: N-(tert-butyl)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (147.38 mg, 0.46 mmol) was weighed and added into a 50 mL reaction flask, 4 mL of xylene was added to dissolve, and then MSA (0.6 mL, 9.2 mmol) was added. The mixture was stirred and heated to 40°C, aged for 2.5 h, and then cooled to below 20°C. 14 mL of water was added to the reaction system and mixed thoroughly. The aqueous phase was separated, and the aqueous phase was washed with toluene (3×2 mL) and filtered to obtain seed crystals.

[0094] Prepare 0.24 mL of p-TsOH (118.82 mg, 0.69 mmol) aqueous solution, add the seed crystals into a 50 mL reaction flask at 20°C and add the prepared p-TsOH aqueous solution to stir and dissolve, then age for 12 h, filter, and wash with water (3×1 mL). After vacuum drying at 20-25°C, 214.46 mg of off-white solid was obtained, with a yield of 90% and a purity of 98%.

[0095] The product niraparib monohydrate p-toluenesulfonate 1 The results of H NMR data analysis are as follows: 1H NMR (600 MHz, CH3OD) δ8.95 (1H, s), 8.15 (1H, dd, J = 7.1, 1.2 Hz), 8.02 (2H, m), 8.00 (1H, dd, J = 8.3, 1.2 Hz), 7.72 (2H, m), 7.49 (2H, m), 7.25 (1H, dd, J = 8.3, 7.1 Hz), 7.22 (2H, d, J = 8.0 Hz), 3.49-3.43 (2H, m), 2.34 (3H, s), 2.09-2.05 (2H, m), 1.96-1.82 (2H, m).

[0096] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the technical solution. Those skilled in the art should understand that those modifications or equivalent substitutions of the technical solution of the present invention that do not depart from the purpose and scope of the technical solution should be included in the scope of the claims of the present invention.

Claims

1. A method for synthesizing niraparib, characterized in that: The synthetic route of niraparib is as follows: Wherein, x is one of Br, I and Cl.

2. The synthesis method according to claim 1, characterized in that: Niraparib was synthesized by 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 an Ullmann reaction or a Buchwald-Hartwig amination reaction; Step 2: Compound 3 is subjected to a selective reduction reaction to obtain compound 4; Step 3: Compound 4 is subjected to hydrogenation reaction under a hydrogen environment to obtain compound 5; Step 4: Compound 5 is subjected to deprotection and salt-forming reactions in sequence to obtain compound 6.

3. The synthesis method according to claim 2, characterized in that: In step 1: When the Ullmann reaction is used to achieve carbon-nitrogen coupling, DMAC or DMI is used as a solvent, CuBr or CuI is used as a catalyst, and 8-hydroxyquinoline is used as a ligand; the reaction temperature is 100-120°C, 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 the Buchwald-hartwig amination reaction is used to achieve carbon-nitrogen coupling, toluene is used as solvent, Pd(OAc)2 is used as catalyst, and DPPF is used as ligand; the reaction temperature is 100°C to 120°C, and the reaction time is 12h to 48h; the molar ratio of compound 1, compound 2, NaO-t-Bu or Cs2CO3, Pd(OAc)2, and DPPF is 1:(1.2 to 1.5):(1.5 to 3):(0.05 to 0.2):(0.075 to 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°C to 90°C, the reaction time is 20min to 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° C. to 30° C., the reaction time is 1 h to 3 h, 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% to 20% calculated by mass percentage; the reaction temperature is 15 to 25°C, and the reaction time is 24h to 72h; the hydrogenation reagent is hydrogen, and the mass ratio of compound 4 to the catalyst is 1:(0.1 to 0.2).

8. The synthesis method according to claim 2, characterized in that: In step 4: During the deprotection reaction, compound 5 and MSA are subjected to a deprotection reaction, the reaction solvent is toluene, the reaction temperature is 30° C. to 50° C., and the reaction time is 5 to 6 h; When performing the salt-forming reaction, the product obtained by the deprotection reaction is reacted with p-TsOH to form a salt, the reaction solvent is xylene, the reaction temperature is 15° C. to 20° C., and the reaction time is 5 to 6 hours; The molar ratio of compound 5 to MSA and p-TsOH is 1:20:1.5.

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