Method for preparing PARP inhibitor niraparib key intermediate

Abstract

The invention provides a method for preparing a PARP inhibitor niraparib key intermediate, and relates to the field of organic synthetic chemistry. The method comprises the following steps: S1, carrying out a reaction on a p-nitrophenyl magnesium bromide Grignard reagent and anhydrous tetrahydrofuran in a 0 DEG C ice bath under the protection of nitrogen; s2, slowly dropwise adding a 3-piperidone (C6H11NO) / tetrahydrofuran solution into a reaction system; s3, stirring for 1h after dropwise adding, and adding saturated ammonium chloride for quenching after TLC monitoring; s4, extracting with ethyl acetate for three times, combining organic layers, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product; s5, heating and refluxing the crude product and trifluoroacetic acid (C2HF3O2) / dichloromethane (CH2Cl2) until the reaction is complete; and S6, carrying out rotary evaporation to remove dichloromethane (CH2Cl2), and adding water and sodium hydroxide (NaOH) to adjust the pH value. According to the method, N-protected 3-piperidone (C6H11NO) is used as an initial raw material, the Niraparib key intermediate with the purity reaching 90% is obtained through Grignard reaction, elimination reaction and asymmetric hydrogenation, and the method is simple, convenient and easy to operate and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of organic synthetic chemistry, and in particular to a method for preparing a key intermediate of the PARP inhibitor niraparib. Background Art

[0002] Niraparib (MK-4827) is chemically named 2_{4_[(3S)_3-piperidinyl]phenyl}-2H-indole-7-carboxamide (11). Currently, the drug is undergoing clinical trials in the United States for the treatment of different tumors, including two phase 3 clinical trials for the treatment of ① platinum-sensitive ovarian cancer (US clinical trial registration number NCT01847274); Negative, BRCA1 / 2 positive breast cancer (U.S. clinical trial registration number NCT01905592). Compared with the existing technology, the present invention discloses a new method for synthesizing (S)-3-p-aminophenylpiperidine chiral intermediates.

[0003] After searching, Route 1 (see WO2008084261, Journal of Medicinal Chemistry, 2009, 52(22), 7170-7185); Organic Process Research & Development, 2011, 15⑷, 831-840.): The total yield of the reaction of this route is not high, and the separation and purification of the product is difficult.

[0004] Route 2 (see WO2008084261) In this route, expensive transition metals are used in both the Suzuki coupling reaction and the reduction of the pyridine ring, resulting in high costs. In particular, in the final step, the chiral product is resolved, and at least half of the enantiomers become waste, resulting in reduced yields and increased costs, making it unsuitable for large-scale industrial production.

[0005] Route 3 (see WO2008084261, Journal of Medicinal Chemistry, 2009, 52(22), 7170-7185); Organic Process Research & Development, 2011, 15(4), 831-840) The starting material 3-pyridineboronic acid used in this route is difficult to prepare, has poor stability, requires high storage conditions, and is expensive. Expensive transition metals are used in two consecutive steps, and chiral separation is performed in the final step. Similarly, about half of the enantiomers cannot be utilized. Therefore, if the intermediate is produced on a large scale according to this route, it will result in high production costs.

[0006] Traditional synthetic routes have significant defects, including reliance on expensive transition metal catalysts (such as palladium and platinum), resulting in excessively high costs, inefficient chiral resolution processes resulting in at least 50% enantiomer waste, poor stability and high prices of key raw materials such as 3-pyridineboronic acid, and low yields and difficult purification in multi-step reactions. In particular, existing methods use nitration / reduction to construct amino groups or split to obtain chiral centers, which not only have poor atom economy but also suffer from harsh raw material storage conditions, metal residue risks, and uncontrollable large-scale production costs, which seriously restrict the feasibility of industrial production of key intermediates of niraparib. Summary of the Invention

[0007] (1) Technical problems solved

[0008] In view of the shortcomings of the existing technology, the present invention provides a method for preparing a key intermediate of the PARP inhibitor niraparib, which solves the problem of using expensive raw materials or obtaining chiral products through chiral resolution in the existing technology.

[0009] (2) Technical solution

[0010] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0011] A method for preparing a key intermediate of the PARP inhibitor niraparib comprises the following steps:

[0012] S1. Add p-nitrophenylmagnesium bromide Grignard reagent and anhydrous tetrahydrofuran (C4H8O) to the reaction flask, protect with nitrogen (N2), and cool to 0°C in an ice-water bath;

[0013] S2. Prepare 3-piperidone (C5H 11 NO) was diluted with anhydrous tetrahydrofuran (C4H8O), added to the dropping funnel, and slowly added dropwise to the reaction flask;

[0014] S3. After the addition was complete, the reaction was continued with stirring for 1 hour. The reaction was complete by TLC. Saturated aqueous ammonium chloride (NH4Cl(aq)) solution was added with stirring.

[0015] S4: Extract with ethyl acetate (C4H8O2) for three times, combine the organic layers, add an appropriate amount of anhydrous sodium sulfate (Na2SO4) to dry, filter, and spin dry the solvent to obtain a crude product;

[0016] S5. The crude product obtained in step S4, trifluoroacetic acid (C2HF3O2), and dichloromethane (CH2Cl2) were added to the reaction flask, heated, and refluxed. The reaction of the raw materials was detected to be complete and the reaction was stopped;

[0017] S6. The dichloromethane (CH2Cl2) was spin-dried, water was added first, and then an aqueous solution of sodium hydroxide (NaOH) was added to adjust the pH value of the solution;

[0018] S7. The mixture was extracted with ethyl acetate (C4H8O2), the organic layer was collected, dried over anhydrous sodium sulfate (Na2SO4), filtered, and the solvent was dried to give a crude product;

[0019] S8. The product [Rh(cod)2]OTf (2 mol%) obtained from steps S1 to S7, JosiPhos (2.2 mol%), triethylamine (5 equivalents) and anhydrous tetrahydrofuran (C4H8O) / methanol (CH3OH) (2:1) were added to an autoclave;

[0020] S9. Atm hydrogen (H2) was introduced to react, and the reaction was complete by TLC. The reaction was stopped, filtered, the solvent was dried, 1N hydrochloric acid (HCl) (100 mL) was added, and then extracted with ethyl acetate (C4H8O2) (100 mL), the aqueous layer was collected, and the organic layer was discarded;

[0021] S10. The pH value of the aqueous layer was adjusted with an aqueous sodium hydroxide (NaOH) solution, and then extracted with ethyl acetate (C4H8O2). The organic layer was collected, dried with anhydrous sodium sulfate (Na2SO4), filtered, the solvent was dried, and silica gel column chromatography was performed.

[0022] Furthermore, in both step S1 and step S2, the amount of anhydrous tetrahydrofuran (C4H8O) is 300 ml. When the anhydrous tetrahydrofuran (C4H8O) is added dropwise to the reaction flask in step S2, the temperature is controlled at 0°C-5°C and the entire amount is added dropwise within 60 minutes.

[0023] Furthermore, in step S3, the amount of saturated ammonium chloride aqueous solution (NH4Cl(aq)) is 300 ml, and when ethyl acetate (C4H8O2) is used for extraction in step S1, the amount of ethyl acetate (C4H8O2) is 200 ml each time.

[0024] Furthermore, in step S6, the water content is 250 ml, the content of the sodium hydroxide (NaOH) solution is 20%, and the pH is adjusted to 7-9.

[0025] Furthermore, when ethyl acetate (C4H8O2) is used for extraction in step S7, 250 ml is used each time, and extraction is performed three times in total.

[0026] Furthermore, the reaction time in step S9 is 2 hours, the amount of 1N hydrochloric acid (HCl) is 100 ml, and the amount of ethyl acetate (C4H8O2) is 100 ml.

[0027] Furthermore, in step S10, the content of the sodium hydroxide (NaOH) solution is 10%, the pH value of the water layer is adjusted to 7-9, and ethyl acetate (C4H8O2) is used for extraction 200 ml each time, and extraction is performed three times in total.

[0028] Furthermore, a (S)-3-p-aminophenylpiperidine chiral intermediate is obtained according to the above-mentioned preparation method.

[0029] (3) Beneficial effects

[0030] The present invention provides a method for preparing a key intermediate of the PARP inhibitor niraparib. It has the following beneficial effects:

[0031] 1. The present invention provides a method for preparing a key intermediate of the PARP inhibitor niraparib. First, the route is relatively short. Compared with CN109810047A / WO2019 / 165981Al / CN106749180A, this strategy does not need to undergo nitration and reduction reaction of S-configured 3-phenylpiperidine to obtain the (S)-3-para-aminophenylpiperidine chiral intermediate, and this route avoids the use of chiral resolution methods to waste enantiomers. Secondly, compared with WO2008084261 and Organic Process Research & Development, 2011, 15(4), 831-840, this route no longer uses unstable boric acid raw materials and expensive coupling strategies. Finally, this method uses asymmetric hydrogenation to construct chirality, which not only avoids the problem of isomer waste faced by chiral resolution in the literature, but also is the first time that this method is used to achieve the synthesis of the intermediate, which is more suitable for large-scale preparation.

[0032] 2. The present invention provides a method for preparing a key intermediate of the PARP inhibitor niraparib, which comprises the steps of: 11 NO) as a starting material through Grignard reaction, elimination reaction, and asymmetric hydrogenation to obtain a key intermediate of Niraparib with a purity of 90%. The method of the invention is simple and easy to operate, and is a method suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Schematic diagram of the process of constructing chiral carbon using the asymmetric hydrogenation method in the present invention;

[0034] Figure 2 Schematic diagram of the multi-step organic synthesis route in the present invention. DETAILED DESCRIPTION

[0035] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0036] Example 1:

[0037] The present invention provides a method for preparing a key intermediate of the PARP inhibitor niraparib, comprising the following steps:

[0038] S1. Add p-nitrophenylmagnesium bromide Grignard reagent and anhydrous tetrahydrofuran (C4H8O) to the reaction flask, protect with nitrogen (N2), and cool to 0°C in an ice-water bath;

[0039] S2. Prepare 3-piperidone (C5H 11 NO) was diluted with anhydrous tetrahydrofuran (C4H8O), added to the dropping funnel, and slowly added dropwise to the reaction flask;

[0040] S3. After the addition was complete, the reaction was continued with stirring for 1 hour. The reaction was complete by TLC. Saturated aqueous ammonium chloride (NH4Cl(aq)) solution was added with stirring.

[0041] S4: Extract with ethyl acetate (C4H8O2) for three times, combine the organic layers, add an appropriate amount of anhydrous sodium sulfate (Na2SO4) to dry, filter, and spin dry the solvent to obtain a crude product;

[0042] S5. The crude product obtained in step S4, trifluoroacetic acid (C2HF3O2), and dichloromethane (CH2Cl2) were added to the reaction flask, heated, and refluxed. The reaction of the raw materials was detected to be complete and the reaction was stopped;

[0043] S6. The dichloromethane (CH2Cl2) was spin-dried, water was added first, and then an aqueous solution of sodium hydroxide (NaOH) was added to adjust the pH value of the solution;

[0044] S7. The mixture was extracted with ethyl acetate (C4H8O2), the organic layer was collected, dried over anhydrous sodium sulfate (Na2SO4), filtered, and the solvent was dried to give a crude product;

[0045] S8. The product [Rh(cod)2]OTf (2 mol%) obtained from steps S1 to S7, JosiPhos (2.2 mol%), triethylamine (5 equivalents) and anhydrous tetrahydrofuran (C4H8O) / methanol (CH3OH) (2:1) were added to an autoclave;

[0046] S9. Atm hydrogen (H2) was introduced to react, and the reaction was complete by TLC. The reaction was stopped, filtered, the solvent was dried, 1N hydrochloric acid (HCl) (100 mL) was added, and then extracted with ethyl acetate (C4H8O2) (100 mL), the aqueous layer was collected, and the organic layer was discarded;

[0047] S10. The pH value of the aqueous layer was adjusted with an aqueous sodium hydroxide (NaOH) solution, and then extracted with ethyl acetate (C4H8O2). The organic layer was collected, dried with anhydrous sodium sulfate (Na2SO4), filtered, the solvent was dried, and silica gel column chromatography was performed.

[0048] In both step S1 and step S2, the amount of anhydrous tetrahydrofuran (C4H8O) is 300 ml. When adding the anhydrous tetrahydrofuran (C4H8O) dropwise into the reaction flask in step S2, the temperature is controlled at 0°C-5°C and the entire amount of the anhydrous tetrahydrofuran (C4H8O) is added dropwise over 60 minutes.

[0049] In step S3, the amount of saturated ammonium chloride aqueous solution (NH4Cl(aq)) is 300 ml, and when ethyl acetate (C4H8O2) is used for extraction in step S1, the amount of ethyl acetate (C4H8O2) is 200 ml each time.

[0050] In step S6, the water content is 250 ml, the content of sodium hydroxide (NaOH) solution is 20%, and the pH is adjusted to 7-9.

[0051] When ethyl acetate (C4H8O2) is used for extraction in step S7, 250 ml is used each time, and extraction is performed three times in total.

[0052] The reaction time in step S9 is 2 hours, the amount of 1N hydrochloric acid (HCl) is 100 ml, and the amount of ethyl acetate (C4H8O2) is 100 ml.

[0053] In step S10, the content of sodium hydroxide (NaOH) solution is 10%, the pH value of the aqueous layer is adjusted to 7-9, and ethyl acetate (C4H8O2) is used for extraction 200 ml each time, and extraction is performed three times in total.

[0054] According to the above preparation method, a (S)-3-p-aminophenylpiperidine chiral intermediate is obtained.

[0055] Under nitrogen (N2) protection, p-nitrophenylmagnesium bromide Grignard reagent (10 mmol) was added to 100 ml of anhydrous tetrahydrofuran (C4H8O) at 0 ° C, and 3-piperidone (C5H 11NO) (10 mmol) was diluted with 20 ml of tetrahydrofuran and slowly added dropwise to the reaction solution. Stirred for 1 hour after the addition. After the reaction of the raw material was completed, 100 ml of saturated ammonium chloride (NH4Cl) was added to quench the reaction, and extracted with ethyl acetate (C4H8O2) (50 ml * 3). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) (Na2SO4) and concentrated to obtain a crude product. The crude product was further treated with trifluoroacetic acid (C2HF3O2) (20 mol%) / dichloromethane (CH2Cl 2) (100 ml) was heated under reflux until the reaction was complete, dichloromethane (CH2Cl2) was removed by rotary evaporation, and 100 ml of water was added. The pH was adjusted to 7 with a 1M aqueous sodium hydroxide (NaOH) (NaoH) solution, and extracted with ethyl acetate (C4H8O2) (50 ml * 3). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) (Na2SO4) and concentrated to obtain a crude product. The product (containing a double bond p-nitro group) was obtained by silica gel column chromatography. MS-ESI (m / z): 205.1 (M+H) +

[0056] The raw material (10 mmol), [Rh(cod)2]OTf (2 mol%), JosiPhos (2.2 mol%), triethylamine (5 eq) and tetrahydrofuran / methanol (CH3OH) (2:1, 50 ml) were added to an autoclave. 50 bar of hydrogen (H2) was introduced and the reaction was carried out at 50°C for 12 h. After the reaction was completed by TLC, the solvent was evaporated and 100 ml of water was added. The mixture was extracted with ethyl acetate (C4H8O2) (50 ml*3). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) (Na2SO4) and concentrated to obtain a crude product. The product (without a double bond to the amino group) was obtained by silica gel column chromatography with an Mp of 96-98°C. 1 H-NMR (400MHz, CD3OD) δ: 7.04 (2H, d, J = 8·4Hz), 6.72 (2H, d, J = 8.4Hz), 3.44-3.33 (2H, m), 3 .05-2.97(2H,m),2.88-2.84,2.07-1.98(2H,m),1.88-1.75(2H,m).MS-ESI(m / z):177(M+H) +13 C-NMR (100MHz, CDCl3) δ: 144.60, 135.20, 127.84, 115.19, 54.47, 46.73, 43.73, 32.36, 27.29.

[0057] Example 2:

[0058] Add p-nitrophenylmagnesium bromide Grignard reagent (12 mmol) and 150 ml of anhydrous tetrahydrofuran (C4H8O) into the reaction flask, and cool to -5°C in an ice-water bath under nitrogen (N2) protection; add 3-piperidone (C5H 11 NO) (12mmol) was diluted with 30ml of anhydrous tetrahydrofuran (C4H8O) and slowly added dropwise to the reaction solution through a dropping funnel, the temperature was controlled at -5℃~0℃, and the dropping time was extended to 90 minutes; the reaction was continued to stir for 1.5 hours after the dropwise addition, and after the reaction was completed by TLC monitoring, 200ml of saturated ammonium chloride aqueous solution (NH4Cl(aq)) was added to quench the reaction; the mixture was extracted with dichloromethane (CH2Cl2) (150ml×3), the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a light yellow crude product; the crude product was dissolved in 120ml of dichloromethane (CH2Cl2), trifluoroacetic acid (C2HF3O2) (15mol%) was added, and the mixture was refluxed at 40℃ for 3 hours. After TLC confirmed that the reaction was complete, the solvent was removed by rotary evaporation; 150ml of water was added to the residue, and 15% sodium carbonate solution was slowly added dropwise to adjust the pH to 7.0-8.0; ethyl acetate (C4H8O2) (150ml×3 ) was extracted with 4% 4-nitropropane, and the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain a light brown solid crude product; the crude product, [Rh(nbd)2]BF4 (1.5 mol%), (R)-Binap (2.0 mol%), triethylamine (4 equivalents), and tetrahydrofuran / isopropanol (3:1, 60 ml) were added to an autoclave; 30 bar of hydrogen (H2) was introduced, and the reaction was carried out at 40°C for 18 hours. After the reaction, the mixture was filtered, and the filtrate was concentrated, 80 ml of water was added, and the pH was adjusted to acidic (pH = 2) with 1 M hydrochloric acid (HCl). The organic layer was washed with ethyl acetate (C4H8O2) (50 ml × 2) and the organic layer was discarded; the aqueous layer was adjusted to pH 7-9 with 10% sodium hydroxide (NaOH) (NaoH), and extracted with ethyl acetate (C4H8O2) (100 ml × 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate (C4H8O2) = 5:1) to obtain a white solid product.

[0059] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a key intermediate of the PARP inhibitor niraparib, characterized in that: The following steps are involved: S1. Add p-nitrophenylmagnesium bromide Grignard reagent and anhydrous tetrahydrofuran (C4H8O) to the reaction flask, protect with nitrogen (N2), and cool to 0°C in an ice-water bath; S2. Prepare 3-piperidone (C5H 11 NO) was diluted with anhydrous tetrahydrofuran (C4H8O), added to the dropping funnel, and slowly added dropwise to the reaction flask; S3. After the addition was complete, the reaction was continued with stirring for 1 hour. The reaction was complete by TLC. Saturated aqueous ammonium chloride (NH4Cl(aq)) solution was added with stirring. S4: Extract with ethyl acetate (C4H8O2) for three times, combine the organic layers, add an appropriate amount of anhydrous sodium sulfate (Na2SO4) to dry, filter, and spin dry the solvent to obtain a crude product; S5. The crude product obtained in step S4, trifluoroacetic acid (C2HF3O2), and dichloromethane (CH2Cl2) were added to the reaction flask, heated, and refluxed. The reaction of the raw materials was detected to be complete and the reaction was stopped; S6. The dichloromethane (CH2Cl2) was spin-dried, water was added first, and then an aqueous solution of sodium hydroxide (NaOH) was added to adjust the pH value of the solution; S7. The mixture was extracted with ethyl acetate (C4H8O2), the organic layer was collected, dried over anhydrous sodium sulfate (Na2SO4), filtered, and the solvent was dried to give a crude product; S8. The product obtained from step S1 to step S7 [Rh (cod) 2] OTf (2 mol%), JosiPhos (2.2 mol%), triethylamine (5 equivalents) or diisopropylethylamine (C5H 13 N), 2,6-lutidine (C5H9N), 4-dimethylaminopyridine (C5H8N2) and anhydrous tetrahydrofuran (C4H8O) / methanol (CH3OH) (2:1) were added into the autoclave; S9. Atm hydrogen (H2) was introduced to react, and the reaction was complete by TLC. The reaction was stopped, filtered, the solvent was dried, 1N hydrochloric acid (HCl) (100 mL) was added, and then extracted with ethyl acetate (C4H8O2) (100 mL), the aqueous layer was collected, and the organic layer was discarded; S10. The pH value of the aqueous layer was adjusted with an aqueous sodium hydroxide (NaOH) solution, and then extracted with ethyl acetate (C4H8O2). The organic layer was collected, dried with anhydrous sodium sulfate (Na2SO4), filtered, the solvent was dried, and silica gel column chromatography was performed.

2. A method for preparing a key intermediate of the PARP inhibitor niraparib according to claim 1, characterized in that: In both step S1 and step S2, the amount of anhydrous tetrahydrofuran (C4H8O) is 300 ml. When adding the anhydrous tetrahydrofuran (C4H8O) dropwise into the reaction flask in step S2, the temperature is controlled at 0°C-5°C and the entire amount of the anhydrous tetrahydrofuran (C4H8O) is added dropwise over 60 minutes.

3. The method for preparing a key intermediate of the PARP inhibitor niraparib according to claim 1, characterized in that: In step S3, the amount of saturated ammonium chloride aqueous solution (NH4Cl(aq)) is 300 ml, and when ethyl acetate (C4H8O2) is used for extraction in step S1, the amount of ethyl acetate (C4H8O2) is 200 ml each time.

4. The method for preparing a key intermediate of the PARP inhibitor niraparib according to claim 1, characterized in that: In step S6, the water content is 250 ml, the content of the sodium hydroxide (NaOH) aqueous solution is 20%, and the pH is adjusted to 7-9.

5. The method for preparing a key intermediate of the PARP inhibitor niraparib according to claim 1, characterized in that: When ethyl acetate (C4H8O2) is used for extraction in step S7, trifluoroacetic acid (C2HF3O2), hydrochloric acid (HCl), p-toluenesulfonic acid (C6H4CH3SO3H), formic acid (HCOOH) or acetic acid (CH3COOH) is used, each time with 250 ml, and extraction is performed three times in total.

6. The method for preparing a key intermediate of the PARP inhibitor niraparib according to claim 1, characterized in that: The reaction time in step S9 is 2 hours, the amount of 1N hydrochloric acid (HCl) is 100 ml, and the amount of ethyl acetate (C4H8O2) is 100 ml.

7. The method for preparing a key intermediate of the PARP inhibitor niraparib according to claim 1, characterized in that: In step S10, the content of the sodium hydroxide (NaOH) aqueous solution is 10%, the pH value of the water layer is adjusted to 7-9, and ethyl acetate (C4H8O2) is used for extraction each time, 200 ml, and a total of three extractions are performed.

8. A method according to claim 1 to obtain a (S)-3-p-aminophenylpiperidine chiral intermediate.

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