A method for preparing a high-purity niraparib intermediate

Abstract

The invention discloses a method for preparing a niraparib intermediate, wherein 4-bromophenylboronic acid and cyclopentenone undergo 1,4-asymmetric addition reaction under a catalyst, and then undergo addition elimination reaction, Beckmann rearrangement reaction, lactam reduction reaction, and Boc protection to obtain (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester. The preparation method of the invention provides a new synthetic route for a high-purity niraparib intermediate, improves stereoselectivity, avoids the use of expensive transaminase, etc., has lower production cost, and the product has a good yield and high chiral purity.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and specifically relates to a method for preparing tert-butyl (3S)-3-(4-bromophenyl)piperidine-1-carboxylate, an intermediate of the anti-tumor drug niraparib. Background Art

[0002] Niraparib Tosilate is an oral poly ADP ribose polymerase (PARP) inhibitor that inhibits cell repair of DNA damage. It is suitable for maintenance treatment of adult patients with advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have achieved complete remission or partial remission to first-line platinum-containing chemotherapy. Niraparib plays an important role in the maintenance treatment of ovarian cancer. Compared with Olaparib, this drug covers a wider population in the maintenance treatment of ovarian cancer and is also effective as a first-line maintenance treatment for non-BRAC populations. Compared with Olaparib and Rucaparib, this drug only needs to be taken orally once a day, which is more convenient.

[0003] The chemical name of niraparib tosylate is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide-4-methylbenzenesulfonate, and the chemical structure is as follows:

[0004]

[0005] At present, there are many literature reports on the preparation method of niraparib. WO2014088983 and WO2014088984 respectively disclose a method for preparing niraparib (see the reaction equation below), which uses succinic anhydride as the starting material, synthesizes the key intermediate 4-(3S-piperidin-3-yl)bromobenzene through multiple steps, and then reacts with an indazole compound to produce niraparib. In this method, the synthesis steps of the intermediate 4-(3S-piperidin-3-yl)bromobenzene are relatively long, and active reagents such as metals are used many times, which makes the operation difficult and is not conducive to production. Although the valerolactam ring-closing reaction achieves good yield and stereoselectivity, it uses expensive special transaminases and the reaction conditions are harsh.

[0006]

[0007] The document dx.doi.org / 10.1021 / op400233z reports that the intermediate 4-(3S-piperidin-3-yl)bromobenzene is synthesized from p-bromophenylacetic acid through 7 steps of reaction (see the reaction equation below), in which highly reactive unsafe reagents such as methyl lithium, DIBAL, and methanesulfonyl chloride are used, and expensive transaminase reagents are also required. The process is long, the yield is low, and the chiral purity of the obtained product is low.

[0008]

[0009] The document doi.org / 10.1038 / s41596-019-0209-8 reported the synthesis of niraparib intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester by Suzuki-Miyaura coupling reaction (see the reaction equation below): 3-chloro-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and 4-bromophenylboronic acid pinacol ester were subjected to rhodium-catalyzed asymmetric coupling reaction and hydrogenation reaction to produce (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester. The intermediate 3-chloro-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in this method is expensive and has a low market supply, making it difficult to industrialize; in addition, the document reported that the yield of the intermediate obtained was 86% and the chiral purity was only 96%.

[0010]

[0011] The preparation methods of the niraparib intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester disclosed in the above prior art all have the problems of high material cost, low yield, poor stereoselectivity, etc. The prepared intermediates are not high in optical purity, which brings challenges to the subsequent production of high-quality APIs. The isomer impurities contained in the intermediates will also further react to generate other impurities in subsequent reactions that are difficult to remove, and additional purification methods are usually required to sacrifice some yields to improve the purity of the final API. In addition, the increase in chiral impurities in the final product also brings greater challenges and difficulties to the detection of APIs.

[0012] In summary, it is necessary to develop a method for preparing niraparib intermediates that is simple in process operation, high in purity and yield, and environmentally friendly and suitable for large-scale production. However, improving the optical purity of compounds through reactions is a complex process that requires comprehensive consideration of multiple factors such as catalysts, solvents, temperature, pressure, reaction time, etc. in each reaction step. Summary of the invention

[0013] In view of the defects of the prior art such as complex processes, the technicians of the present invention have designed and verified a method for preparing a niraparib intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester (compound of Formula I) with high yield, high purity, low cost and significantly improved operating conditions through bold assumptions, a large number of experimental explorations and continuous revisions of the scheme.

[0014] The invention provides a method for preparing a niraparib intermediate. The method uses readily available starting materials, ensures good reproducibility of the synthesis route, has simple unit operations, is economical and cost-effective, has mild reaction conditions, high chiral purity, greatly improves the overall reaction yield, and has controllable quality, thereby meeting the synthesis requirements of a medicinal niraparib bulk drug.

[0015] The present invention provides a method for preparing a niraparib intermediate shown in formula I.

[0016]

[0017] The chemical reaction route is as follows:

[0018]

[0019] The method is characterized in that the chiral center is constructed by Michael addition reaction catalyzed by (S)-binap-Rhodium (I), comprising the following steps:

[0020] (1) Under nitrogen protection, in the presence of a (S)-binap-Rhodium (I) catalyst, 4-bromophenylboronic acid (compound of formula II) and 2-cyclopentenone (compound of formula III) undergo an addition reaction to obtain (S)-3-(4-bromophenyl)cyclopentanone (compound of formula IV);

[0021] The (S)-binap-Rhodium (I) catalyst described above can be produced in situ (the catalyst is generated by other compounds during the reaction process) by using (S)-binap (a chiral diphosphine ligand, the full name is (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) and a metal rhodium catalyst with reference to the prior art, or it can be obtained by purchasing commercial reagents.

[0022] When the (S)-binap-Rhodium(I) catalyst is generated in situ, the reaction ratio of (S)-binap to the metal rhodium catalyst is generally (1-1.2):1; preferably (1.05-1.1):1; more preferably 1.05:1. The metal rhodium catalyst can be selected from acetylacetonatobis(ethylene)rhodium(I), Rh(acac)(C 2 H 4 ) 2 ), Bis(norbornadiene)rhodium(I)tetrafluoroborate, [Rh(C 7 H 8 ) 2 ]BF 4 ), bis(1,5-cyclooctane)rhodium hexafluorophosphate ({Rh(COD) 2}PF 6 ), dihydroxy(1,5-cyclooctadiene)rhodium(I) ([Rh(cod)(OH)] 2), chlorobis(ethylene)rhodium(I)dimer, preferably acetylacetonatobis(ethylene)rhodium(I), Rh(acac)(C 2 H 4 ) 2 ), Bis(norbornadiene)rhodium(I)tetrafluoroborate, [Rh(C 7 H 8 ) 2 ]BF 4 ).

[0023] (2) The compound of formula IV is subjected to addition elimination reaction with hydroxylamine hydrochloride to obtain (S)-3-(4-bromophenyl)cyclopentanone oxime (compound of formula V);

[0024] (3) the compound of formula V is subjected to Beckmann rearrangement reaction in the presence of a catalytic agent to obtain (S)-5-(4-bromophenyl)piperidin-2-one (compound of formula VI);

[0025] (4) The compound of formula VI is subjected to lactam reduction to obtain the niraparib intermediate 4-(3S-piperidin-3-yl)bromobenzene (compound of formula VII);

[0026] (5) The compound of formula VII is subjected to Boc protection to obtain the niraparib intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester (compound of formula I) shown in formula (I);

[0027] In the above preparation method, step (1) is the addition reaction of 2-cyclopentenone and phenylboronic acid.

[0028]

[0029] The synthesis reaction of compound IV is a highly stereoselective 1,4-addition reaction catalyzed by chiral phosphine-rhodium, which is specifically as follows: under nitrogen protection, 4-bromophenylboronic acid (II), chiral phosphine ligand, and metal rhodium catalyst are dissolved in a solvent, stirred and dissolved, and subjected to addition reaction with 2-cyclopentenone (Formula III) to obtain (S)-3-(4-bromophenyl)cyclopentanone (Formula IV); wherein the chiral phosphine ligand is selected from (S)-binap, and the metal rhodium catalyst is mainly selected from acetylacetonatobis(ethylene)rhodium(I), Rh(acac)(C 2 H 4 ) 2), Bis(norbornadiene)rhodium(I)tetrafluoroborate, [Rh(C 7 H 8 )2]BF 4 ), bis(1,5-cyclooctane)rhodium hexafluorophosphate ({Rh(COD)2}PF6), dihydroxy(1,5-cyclooctane)rhodium(I) ([Rh(cod)(OH)]2), chlorobis(ethylene)rhodium(I)dimer, preferably acetylacetonatobis(ethylene)rhodium(I), Rh(acac)(C 2 H 4 ) 2 ), Bis(norbornadiene)rhodium(I)tetrafluoroborate, [Rh(C 7 H 8 )2]BF 4 ); more preferably bis(dicyclopentadiene)rhodium(I)tetrafluoroborate.

[0030] In organic synthesis reactions, chiral ligands are widely used in asymmetric catalysis. They can participate in the construction of catalysts and improve the stereoselectivity of reactions. Selecting appropriate chiral ligands can often achieve better stereoselectivity and catalytic activity in asymmetric catalytic reactions, and can achieve efficient and selective synthesis of enantioselective reactions. In the present invention, (S)-binap is selected as a chiral ligand, and combined with an appropriate catalyst to promote the reaction to obtain a purer single enantiomer.

[0031] It is well known to those skilled in the art that the catalytic performance of a chemical reaction depends not only on the catalyst itself, but also on the catalytic reaction conditions such as reduction mode, atmosphere, solvent, space velocity, pressure, temperature, time, etc., and adjusting one of the conditions alone often cannot achieve the desired effect. It is understandable that in a chemical reaction, the yield and purity of the product often depend on the combined effect of several reaction conditions, and sometimes it is necessary to select a suitable post-treatment method to achieve a relatively more ideal effect. In the present invention, in the step (1) of the preparation method of the above-mentioned niraparib intermediate, the molar ratio of 2-cyclopentenone (Formula III) to 4-bromophenylboronic acid (Formula II) is 1: (1 to 5), preferably 1: (1 to 2); the molar ratio of the metal rhodium catalyst to 2-cyclopentenone is (0.005 to 0.1): 1, preferably (0.01 to 0.05): 1. Furthermore, in step (1) of the preparation method, the molar ratio of the metal rhodium catalyst, 2-cyclopentenone (Formula III), and 4-bromophenylboric acid (Formula II) is (0.005-0.1):1:(1-5), preferably (0.01-0.05):1(1-2).

[0032] In step (1) of the preparation method described above, the solvent is 1,4-dioxane, n-propanol, n-butanol, water or a mixed solvent of any combination of the two, preferably a mixed solvent of 1,4-dioxane and water. The amount of the solvent added is preferably 10-30 times (V / m, volume mass ratio) of 4-bromophenylboronic acid, preferably 10-20 times (V / m) of the solvent. When the solvent is a mixed solvent of 1,4-dioxane and water, the ratio of 1,4-dioxane to water (V / V, volume ratio) is (1-50):1, preferably (5-15):1, more preferably 10:1; the ratio (V / m) of the amount of dioxane-water mixed solvent to 4-bromophenylboronic acid is (5-100):1, preferably (10-30):1, more preferably (10-20):1.

[0033] In the above-mentioned method for preparing the niraparib intermediate, in step (1), the reaction temperature is 10 to 150°C, preferably 90 to 110°C, and more preferably 90 to 100°C.

[0034] In the above-mentioned method for preparing the niraparib intermediate, a base can be added in step (1) to promote the reaction, and the base can be selected from an organic base or an inorganic base, preferably an organic base. The inorganic base can be selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide and potassium hydroxide; the organic base can be selected from triethylamine and N,N-diisopropylethylamine; the molar ratio of the base to 2-cyclopentenone is (0.5-5):1, preferably (1-3):1.

[0035] During the synthesis of compound IV, different catalysts also have a significant effect on the chiral selectivity of the 1,4-asymmetric addition of boronic acid (Formula II) and enone (Formula III).

[0036] In some embodiments of the present invention, the compound IV is prepared by the following method: nitrogen is passed through the reaction bottle for protection, 4-bromophenylboronic acid, (S)-binap, metal rhodium catalyst and solvent are added, 2-cyclopentenone is added after stirring, and the organic base is heated for reaction. After the reaction is completed, ethyl acetate and water are added for extraction and separation, the organic phase is washed with saturated brine and concentrated to dryness under reduced pressure, and then purified with a silica gel short column to obtain compound IV. The above-mentioned silica gel short column purification method is: 30-50 times the weight of the sample to be purified is loaded with silica gel (200-300 mesh) wet or dry, the sample to be purified is loaded (wet or dry), and 10% ethyl acetate / petroleum ether with a volume of 10-20 times the weight of the sample to be purified is used as an eluent for rapid elution, and the eluent is collected and concentrated to dryness under reduced pressure.

[0037] The following table shows the yield and chiral purity of the compound of formula IV under different conditions in step (1) with the same operation.

[0038]

[0039] From the results in the above table, it can be seen that different catalyst-to-reactant feed ratios, solvents, reaction temperatures and other factors have an impact on the yield and purity of the product. The remaining experimental data conducted by the technical personnel of the present invention that are not included in the table also show that the catalyst, solvent, reaction temperature and time have different effects on the yield and purity of the reaction product. The use of acetylacetonatobis(ethylene)rhodium(I) and bis(norbornadiene)rhodium(I)tetrafluoroborate has a high conversion rate and excellent chiral selectivity.

[0040] After a large number of experimental explorations, the technicians of the present invention found that in step (1) of the preparation method of the present invention, when the molar ratio of the rhodium catalyst, formula III, and formula II is (0.01-0.05):1:(1-2), the reaction solvent is a mixed solvent of 1,4-dioxane and water (1,4-dioxane:water=(5-15):1), an organic base is selected to promote the reaction, and the reaction temperature is 90-100°C, the yield and purity of the obtained compound of formula IV are better.

[0041] Steps (2) and (3) in the preparation method of the present invention are Beckmann rearrangement reactions, which include two unit operations: ketoxime generation and Beckmann rearrangement.

[0042]

[0043] The preparation method of the niraparib intermediate described above, in step (2), the compound of formula IV reacts with hydroxylamine hydrochloride in the presence of a reaction reagent, the reaction reagent is selected from sodium acetate or potassium acetate; the reaction solvent is selected from methanol and ethanol; the reaction temperature is selected from 10 to 60° C., preferably 10 to 30° C. The reaction time is 10 min to 2 h, and the product is a ketoximate (formula V) with cis-trans isomers (1:1).

[0044] In some embodiments of the present invention, the preparation method of step (2) is: mixing the compound of formula IV, sodium acetate, solvent, and hydroxylamine hydrochloride and reacting at 10-30° C., adding methyl tert-butyl ether after the reaction is complete, washing with water and saturated sodium chloride solution in sequence, and concentrating the organic layer under reduced pressure to dryness to obtain the compound of formula V. The reaction solvent is selected from methanol and ethanol, preferably methanol.

[0045] In the preparation method described above, the catalytic reagent used for the Beckmann rearrangement reaction in step (3) is selected from p-toluenesulfonic acid, phenyl dichlorophosphate, thionyl chloride, cyanuric chloride, preferably cyanuric chloride and phenyl dichlorophosphate, more preferably phenyl dichlorophosphate; the solvent is selected from dichloromethane, acetonitrile, N,N-dimethylformamide or any combination of the two.

[0046] In some embodiments of the present invention, the operation mode of step (3) is as follows: under nitrogen protection, the compound of formula V is subjected to Beckmann rearrangement reaction in a solvent in the presence of a catalyst, and after the reaction is completed, the solid is cooled and washed out, and the solid is separated and dried to obtain a compound of formula VI. The solvent is selected from dichloromethane, acetonitrile, N,N-dimethylformamide or any combination of the two, preferably acetonitrile; the molar ratio of the compound of formula V to the catalyst is 1:1; the catalyst is selected from p-toluenesulfonic acid, phenyl dichlorophosphate, thionyl chloride, cyanuric chloride, preferably cyanuric chloride and phenyl dichlorophosphate, more preferably phenyl dichlorophosphate.

[0047] In the preparation method of the present invention, (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester (Formula I) is obtained through steps (4) and (5).

[0048]

[0049] The lactam reduction in step (4) of the above-mentioned preparation method is selected from NaBH 4 -BF 3 or NaBH 4 -TFA reaction system generates borane in situ for reaction, preferably NaBH 4 -TFA reaction system; the solvent is selected from tetrahydrofuran; the reaction temperature is 0-5°C.

[0050] In some embodiments of the present invention, the operation mode of step (4) is as follows: under nitrogen protection, sodium borohydride is suspended in anhydrous tetrahydrofuran, a tetrahydrofuran solution of the compound of formula VI (the compound VI is dissolved in anhydrous tetrahydrofuran) is added dropwise at 0-5°C and the reaction is kept warm for 30 minutes, the reaction solution is added to trifluoroacetic acid / tetrahydrofuran solution and reacted for 5 hours, acetone and hydrochloric acid are added, isopropyl acetate and water are added, and the pH is adjusted to 10, extraction is performed, and the organic phase is washed with a saturated sodium chloride solution and concentrated to dryness to obtain the compound of formula VII.

[0051] In step (5) of the preparation method described above, the lactam reduction intermediate 4-(3S-piperidin-3-yl)bromobenzene (Formula VII) can be reacted with di-tert-butyl dicarbonate in the presence of an alkaline agent to obtain the niraparib intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester shown in formula (I), which has better stability and maintains a better solid state. The alkaline agent can be selected from an organic base or an inorganic base, the organic base is mainly selected from triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, and the inorganic base is mainly selected from sodium carbonate, potassium carbonate, cesium carbonate, etc. The solvent is selected from dichloromethane, methyl tert-butyl ether, tetrahydrofuran, acetonitrile or a mixed solvent with an aqueous system, preferably a mixed solution of methyl tert-butyl ether and water. The molar ratio of 4-(3S-piperidin-3-yl)bromobenzene to di-tert-butyl dicarbonate is 1:(1 to 3).

[0052] In some embodiments of the present invention, the operation of step (5) is as follows: di-tert-butyl dicarbonate is added dropwise to a mixed solution of the compound of formula VII, methyl tert-butyl ether, water, and an alkaline agent, and the mixture is separated after the reaction is completed by heat preservation, and the organic phase is washed with water and concentrated to dryness under reduced pressure to obtain a compound of formula I. The alkaline agent is sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine; preferably sodium carbonate and potassium carbonate.

[0053] The preparation method of the niraparib intermediate of the present invention is simple to operate and is suitable for industrial production. By selecting appropriate reaction reagents and controlling the reaction conditions and treatment methods of each step, the intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester has a high yield and a chiral purity that can stably reach more than 99.6%.

[0054] The chemical purity of the key intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester of niraparib obtained by the preparation method of the present invention is not less than 99%, and the content of its enantiomer (3R)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester is less than 0.2%. The chemical purity and chiral purity thereof can be detected by liquid chromatography, and the optional liquid chromatography detection method is as follows:

[0055] 1. HPLC chemical purity detection chromatographic method:

[0056] Chromatographic column: Ascentis Express C18 column (100 mm × 4.6 mm, 2.7 μm);

[0057] Mobile phase A: 0.1% phosphoric acid / water Mobile phase B: acetonitrile

[0058] Gradient elution:

[0059] Time (minutes) Mobile phase B (%) 0 5 20 95 30 95

[0060] Detection wavelength: 210nm

[0061] Flow rate: 1.0ml / min

[0062] Column temperature: 40°C

[0063] Injection volume: 5 μL

[0064] 2. Chromatographic method for chiral purity detection:

[0065] Chromatographic column: Daicel Chiralcel OB-H;

[0066] Mobile phase: n-hexane: isopropanol = 98:2

[0067] Detection wavelength: 220nm

[0068] Flow rate: 0.5ml / min

[0069] Column temperature: 25°C

[0070] Injection volume: 5 μL

[0071] The invention provides a method for preparing a niraparib intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester. Compared with the existing process, the method has simple process operation, high chemical and chiral purity, high yield, low cost, environmental protection and safety, and is suitable for large-scale production.

[0072] Compared with the prior art, the obtained niraparib intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester has higher chiral purity.

[0073] Reference Method Chiral purity of compound VI (%) Org.Process Res.Dev.2011,15,831–840 96%(ee) 10.1038 / s41596-019-0209-8 96%(ee) 10.1038 / ncomms15762 95%(ee) Niraparib intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester obtained by the present invention ≥99.6%(ee)

[0074] According to the relevant drug standards for niraparib tosylate capsules and the ICH Q3a drug development guidelines, the enantiomer content in the niraparib tosylate API should be ≤0.1%, and the chiral center of the enantiomer is introduced by the intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester. Only intermediates with higher purity can be used to synthesize APIs with better quality, and the difficulty of separation and purification in the subsequent API production process can be reduced, thereby increasing the yield and reducing the cost.

[0075] Specifically, the present invention has the following advantages:

[0076] (1) The chemical purity of the niraparib intermediate (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester obtained by the preparation method of the present invention is not less than 99.6%, and the chiral isomer impurity is less than 0.2%, which is more in line with the quality requirements for preparing medicinal niraparib.

[0077] (2) The synthesis route is short and does not use unsafe reagents such as methyl lithium, DIBAL, and methanesulfonyl chloride. The reaction conditions are mild, the operation is simple, and it is environmentally safe.

[0078] (3) The present invention avoids the use of expensive reagents such as transaminase. The materials 4-bromophenylboronic acid and 2-cyclopentenone are both bulk chemicals with low prices. The asymmetric synthesis selectivity is high, and the amount of rhodium catalyst used can be reduced to 1% to 3%, which is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] Figure 1 : 1H-NMR of tert-butyl (3S)-3-(4-bromophenyl)piperidine-1-carboxylate; DETAILED DESCRIPTION

[0080] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below through specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them.

[0081] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0082] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturers.

[0083] Example 1: Synthesis of (S)-3-(4-bromophenyl)cyclopentanone (Formula IV)

[0084] In a 500mL single-mouth bottle, under nitrogen protection, add 4-bromophenylboronic acid (26.9g, 134mmol), (S)-binap (1.441g, 2.314mmol), bis(dicyclopentadiene) tetrafluoroborate rhodium (0.820g, 2.192mmol), add 1,4-dioxane (300ml) and water (30ml), stir for 30min. Add 2-cyclopentenone (10.0g, 121.88mmol), triethylamine (17ml, 122mmol), under nitrogen protection, stir at 95-100℃ for 3-5h, add ethyl acetate (300ml) to dilute the reaction solution, add water (300ml) to extract and separate the liquids. The organic phase was washed with saturated brine (250 ml), concentrated to dryness under reduced pressure, and purified on a silica gel short column () using 10% EtOAc / petroleum ether to obtain 26.52 g of compound IV with a yield of 91.0% and chiral purity >97%.

[0085] Example 2: (S)-3-(4-bromophenyl)cyclopentanone oxime (Formula V)

[0086] Add (S)-3-(4-bromophenyl)cyclopentanone (23.9 g, 100 mmol), 286 ml of methanol, and anhydrous sodium acetate (12.3 g, 150 mmol) to the reaction bottle, add hydroxylamine hydrochloride (10.4 g, 150 mmol) under stirring, and react at 10-30°C for 1 h. Add methyl tert-butyl ether (850 ml) to dilute the reaction liquid, wash with water (286 ml) and saturated sodium chloride (150 ml) in turn, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 24.4 g of white foamy solid with a yield of 96%, which is directly used in the next step without purification.

[0087] Example 3: (S)-5-(4-bromophenyl)piperidin-2-one (Formula VI)

[0088] Under nitrogen protection, (S)-3-(4-bromophenyl)cyclopentanone oxime (20 g, 78.7 mmol) and acetonitrile 200 ml were added to the reaction bottle, and phenyl dichlorophosphate (16.6 g, 78.7 mmol) was slowly added, and the temperature was raised to 70-80 ° C. and stirred for 1-2 h. Solids gradually precipitated, cooled to room temperature, filtered and dried to obtain 19 g of off-white solid, i.e. (S)-5-(4-bromophenyl)piperidin-2-one, with a yield of 96%.

[0089] Example 4: 4-(3S-piperidin-3-yl)bromobenzene (Formula VII)

[0090] Under nitrogen protection, add anhydrous tetrahydrofuran (100 ml) and sodium borohydride (9.37 g, 248 mmol) to the reaction bottle, stir to form a sodium borohydride suspension solution, and cool to 0-5°C. (S)-5-(4-bromophenyl)piperidin-2-one (18 g, 70.8 mmol) is stirred and dissolved in anhydrous tetrahydrofuran (120 ml), and the tetrahydrofuran solution of (S)-5-(4-bromophenyl)piperidin-2-one is added to the sodium borohydride suspension solution at 0-5°C, and stirred for 30 minutes, and then trifluoroacetic acid / tetrahydrofuran solution (28.37 g / 80 ml) is slowly added at below 10°C, and stirred for 5 hours at 20-25°C, and acetone (36 ml) is added to quench the reaction, and then 17% hydrochloric acid (100 ml) is added, and stirred for 3 hours at 60°C. Isopropyl acetate (180 ml) and water (100 ml) were added to dilute, and the pH was adjusted to 10. The liquid was separated by extraction, and the organic phase was washed with saturated sodium chloride and concentrated to dryness to obtain 15.8 g of 4-(3S-piperidin-3-yl)bromobenzene (Formula VII) with a yield of 93%.

[0091] Example 5: (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester (Formula I)

[0092] To the reaction flask, add 4-(3S-piperidin-3-yl)bromobenzene (15 g, 62.5 mmol) and methyl tert-butyl ether (350 ml), add 1 mol / L sodium carbonate solution (75 ml, 75 mmol), add di-tert-butyl dicarbonate (13.6 g, 62.5 mmol) dropwise, after the addition is complete, keep at 20-25 ° C for 5 hours, separate the liquids, wash the organic phase with water (150 ml*2) and concentrate to dryness under reduced pressure, and dissolve the residue by heating with petroleum ether (120 ml) and then cool and recrystallize to obtain 19.1 g of (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester, with a yield of 90%, a chemical purity of 99.5%, and a chiral purity of 99.9%.

Claims

1. A method for preparing a niraparib intermediate of formula I, The chemical reaction route is as follows: It is characterized in that The following steps are involved: (1) Under nitrogen protection, in the presence of a (S)-binap-Rhodium (I) catalyst, the compound of formula II is subjected to an addition reaction with the compound of formula III in a solvent to obtain a compound of formula IV; (2) the compound of formula IV is reacted with hydroxylamine hydrochloride to obtain the compound of formula V; (3) subjecting the compound of formula V to Beckmann rearrangement to obtain the compound of formula VI; (4) subjecting the compound of formula VI to lactam reduction to obtain the compound of formula VII; (5) The compound of formula VII is protected by Boc to obtain the niraparib intermediate of formula I.

2. The preparation method according to claim 1, characterized in that: The (S)-binap-Rhodium (I) catalyst described in step (1) is generated in situ using (S)-binap and a metal rhodium catalyst; the ratio of the (S)-binap to the metal rhodium catalyst is (1-1.2):1; preferably (1.05-1.1):1; more preferably 1.05:

1.

3. The preparation method according to claim 2, characterized in that: The metal rhodium catalyst is selected from acetylacetonatobi(ethylene) rhodium, bis(dicyclopentadiene) rhodium tetrafluoroborate, di(1,5-cyclooctanedi) rhodium hexafluorophosphate, dipolymerized hydroxy(1,5-cyclooctadiene) rhodium (I), and di(ethylene) chloride rhodium dimer; preferably acetylacetonatobi(ethylene) rhodium and bis(dicyclopentadiene) rhodium tetrafluoroborate.

4. The preparation method according to any one of claims 2 to 3, characterized in that: In step (1), the molar ratio of the metal rhodium catalyst, the compound of formula III, and the compound of formula II is (0.005-0.1):1:(1-5), preferably (0.01-0.05):1(1-2); the solvent is 1,4-dioxane, n-propanol, n-butanol, water, or a mixed solvent of any combination of the two, preferably a mixed solvent of 1,4-dioxane and water; The reaction temperature of the reaction is 10 to 150°C, preferably 90 to 110°C, and more preferably 90 to 100°C.

5. The preparation method according to any one of claim 4, characterized in that: In step (1), the solvent is a mixed solvent of 1,4-dioxane and water, wherein the volume ratio of 1,4-dioxane to water is (1-50):1, preferably (5-15):1, and more preferably 10:

1.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The preparation method of step (1) is as follows: nitrogen is passed into the reaction flask for protection, 4-bromophenylboronic acid, (S)-binap, a metal rhodium catalyst and a solvent are added, 2-cyclopentenone and an organic base are added after stirring, and then heated for reaction. After the reaction is completed, ethyl acetate and water are added for extraction and separation, the organic phase is washed with saturated brine and concentrated to dryness under reduced pressure, and then purified with a silica gel short column to obtain compound IV.

7. The preparation method according to claim 1, characterized in that: In step (2), the compound of formula IV reacts with hydroxylamine hydrochloride in the presence of a reaction reagent, the reaction reagent is selected from sodium acetate or potassium acetate; the reaction solvent is selected from methanol and ethanol; the reaction temperature is selected from 10 to 60° C., preferably 10 to 30° C.; the reaction time is 10 min to 2 h; the compound of formula V is cis-trans isomers; The preparation method of step (2) is: mixing the compound of formula IV, sodium acetate, solvent and hydroxylamine hydrochloride and reacting at 10-30° C., adding methyl tert-butyl ether after the reaction is complete, washing with water and saturated sodium chloride solution in sequence, and concentrating the organic layer under reduced pressure to dryness to obtain the compound of formula V; the solvent of the reaction is selected from methanol and ethanol, preferably methanol.

8. The preparation method according to claim 1, characterized in that: The catalytic agent in the Beckmann rearrangement reaction in step (3) is selected from p-toluenesulfonic acid, phenyl dichlorophosphate, thionyl chloride, cyanuric chloride, preferably cyanuric chloride and phenyl dichlorophosphate, more preferably phenyl dichlorophosphate; the solvent is selected from dichloromethane, acetonitrile, N,N-dimethylformamide or a mixture of any two thereof.

9. The preparation method according to claim 1, characterized in that: The lactam reduction reaction in step (4) is obtained by in-situ generating borane in a NaBH4-BF3 or NaBH4-TFA reaction system, preferably a NaBH4-TFA reaction system; the solvent of the reaction is tetrahydrofuran, and the reaction temperature is 0-5°C.

10. The preparation method according to claim 1, characterized in that: In the step (5), the reaction operation method is: the compound of formula VII reacts with di-tert-butyl dicarbonate in the presence of an alkaline reagent to obtain the niraparib intermediate shown in formula I; the alkaline reagent is selected from triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, cesium carbonate; the solvent of the reaction is selected from dichloromethane, methyl tert-butyl ether, tetrahydrofuran, acetonitrile or a mixed solvent with a water system, preferably a mixed solution of methyl tert-butyl ether and water; the molar ratio of the compound of formula VII to di-tert-butyl dicarbonate is 1:(1-3).

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