Synthesis method of niraparil intermediate

Abstract

The invention relates to the field of medicine synthesis, in particular to a synthesis method of a niraparil intermediate. The synthesis method of the niraparil intermediate comprises the following steps: mixing a first compound, a second compound, a catalyst, potassium carbonate and a first solvent in a protective atmosphere, and carrying out catalytic coupling reaction to obtain a third compound, and mixing the third compound, glucose, an enzyme, a coenzyme, glucose dehydrogenase and a second solvent, and carrying out an enzyme catalytic reduction reaction to obtain the nirapalide intermediate. The synthesis method of the niraparil intermediate can be used for effectively preparing a target compound, and has the advantages of simplicity in operation, environment friendliness, high yield, high selectivity, low cost and the like.

Description

Technical Field

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

[0002] Niraparib is an oral poly(ADP-ribose) polymerase (PARP) inhibitor primarily used to treat specific types of malignancies. Its core indication is maintenance therapy for advanced epithelial ovarian cancer and related cancers, and it is the first once-daily PARP inhibitor approved for maintenance therapy in patients with recurrent ovarian cancer (regardless of BRCA mutation status). After its global launch in multiple countries, it has been recommended by several authoritative guidelines, including those of the American Society of Clinical Oncology and the Chinese Society of Clinical Oncology, for first-line maintenance therapy of advanced ovarian cancer. The compound shown in formula (II) is a key intermediate of niraparib, with the following specific structural formula:

[0003]

[0004] A current patent (CN 119751337 A) reports a method for synthesizing (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester. Using 4-bromophenylboronic acid and cyclopentenone as raw materials, a multi-step reaction yields (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester. The first step uses the expensive metal rhodium, and the intermediate produced in the first step has low optical purity. The fourth step uses a NaBH4 / TFA reduction system, which poses significant process safety risks and generates a large amount of wastewater. Furthermore, the synthetic route is lengthy and has high production costs. The specific synthetic route of this patent is shown below:

[0005]

[0006] Patent (CN 117964546 B) reports a method for synthesizing (3S)-(4-bromophenyl)piperidine. In this route, (4-bromophenyl)piperidine is resolved by L-tartaric acid salt formation to obtain (3S)-(4-bromophenyl)piperidine. The byproduct (3R)-(4-bromophenyl)piperidine is protected with Boc, racemized under basic conditions, and then the L-tartaric acid salt formation resolution method is repeated three times to finally obtain (3R)-(4-bromophenyl)piperidine. The overall yield of the resolution is 38%-53%. This production process is relatively cumbersome and inconvenient to operate, and the highest overall yield is only 53%. The specific synthetic route of this patent is shown below:

[0007]

[0008] The literature (Organic Process Research & Development 2011, 15, 831-840) reports on...

[0009] The method for synthesizing (S)-3-(4-aminophenyl)piperidine involves using 3-pyridineboronic acid and 4-nitrobromobenzene as starting materials, and obtaining (S)-3-(4-aminophenyl)piperidine through a multi-step reaction. The specific synthetic route is shown below:

[0010]

[0011] The above-disclosed methods for preparing niraparib intermediates (3S)-3-(4-bromophenyl)piperidine, (3S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester, or (S)-3-(4-aminophenyl)piperidine all suffer from problems such as low yield, poor stereoselectivity, and high production costs. In addition, isomer impurities in the intermediates can also affect the quality of the active pharmaceutical ingredient. Summary of the Invention

[0012] In view of this, the present invention aims to provide a method for synthesizing niraparib intermediates to solve the problem of low yield in the prior art for synthesizing niraparib intermediates.

[0013] To solve the above-mentioned technical problems, this application is implemented as follows:

[0014] This invention provides a method for synthesizing a niraparib intermediate, comprising the following steps:

[0015] (1) Under a protective atmosphere, the first compound shown in formula (Ⅰ), the second compound shown in formula (Ⅱ), the catalyst, potassium carbonate and the first solvent are mixed and subjected to a catalytic coupling reaction to obtain the third compound shown in formula (Ⅲ);

[0016] (2) Mix the third compound shown in formula (III), glucose, enzyme, coenzyme, glucose dehydrogenase and second solvent, and carry out an enzyme-catalyzed reduction reaction to obtain the niraparib intermediate shown in formula (IV);

[0017] The first compound represented by formula (Ⅰ), the second compound represented by formula (Ⅱ), the third compound represented by formula (Ⅲ), and the niraparib intermediate represented by formula (Ⅳ) are shown below:

[0018]

[0019] Wherein, R is F, Cl, Br, I, -NH2, -NO2, or -NHAc;

[0020] X is -Br, -Cl, or -I;

[0021] PG can be Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), PMB (p-methoxybenzyl), or Trt (triphenylmethyl).

[0022] The reaction process of this invention is as follows:

[0023]

[0024] In some specific embodiments, the mass ratio of the first compound to the second compound is 1.5:1 to 1:1, preferably 1.3:1 to 1.1:1.

[0025] In some specific embodiments, the mass ratio of the first compound to the catalyst is 1000:1 to 10:1, preferably 100:1 to 10:1.

[0026] In some specific embodiments, the ratio of the first compound to the solvent is 1g:5mL to 1g:20mL, preferably 1g:10mL to 1g:15mL.

[0027] In some specific embodiments, the mass ratio of the first compound to the potassium carbonate is 5:1 to 1:1, preferably 3:1 to 2:1.

[0028] In some specific embodiments, the catalyst comprises [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)2Cl2).

[0029] In some specific embodiments, the solvent includes 1,4-dioxane and water.

[0030] In some specific embodiments, the volume ratio of 1,4-dioxane to water is 50:1 to 5:1, preferably 30:1 to 10:1.

[0031] In some specific embodiments, the temperature of the catalytic coupling reaction is 70–100°C, preferably 80–90°C, and the time of the catalytic coupling reaction is 12–96 h, preferably 20–80 h.

[0032] In some specific embodiments, the mass ratio of the third compound to the enzyme is 1000:1 to 1:1, preferably 100:1 to 10:1.

[0033] In some specific embodiments, the mass ratio of the third compound to the coenzyme is 10000:1 to 10:1, preferably 1000:1 to 100:1.

[0034] In some specific embodiments, the mass ratio of the third compound to the glucose dehydrogenase is 1000:1 to 10:1, preferably 100:1 to 10:1.

[0035] In some specific embodiments, the mass ratio of the third compound to the glucose is 10:1 to 1:1, preferably 8:1 to 5:1.

[0036] In some specific embodiments, the ratio of the third compound to the second solvent is 1g:5mL to 1g:20mL, preferably 1g:10mL to 1g:15mL.

[0037] In some specific embodiments, the second solvent includes phosphate buffer and organic solvent.

[0038] In some specific embodiments, the pH of the phosphate buffer solution is 7.2.

[0039] In some specific embodiments, the volume ratio of the phosphate buffer solution to the organic solvent is 100:1 to 1:1, preferably 50:1 to 10:1.

[0040] In some specific embodiments, the enzyme includes olefin reductase.

[0041] In some embodiments, the ene reductase includes ES-ERED-101, ES-ERED-102, ES-ERED-103, ES-ERED-104, ES-ERED-105, ES-ERED-106, ES-ERED-107, ES-ERED-108, ES-ERED-109, ES -ERED-110, ES-ERED-111, ES-ERED-112, ES-ERED-113, ES-ERED-114, ES-ERED-115, ES-ERED-116, ES-ERED-117, ES-ERED-118, ES-ERED-119 or ES-ERED-120.

[0042] In some specific embodiments, the coenzyme includes reduced nicotinamide adenine dinucleotide phosphate (NADPH) or nicotinamide adenine dinucleotide (NADH).

[0043] In some specific embodiments, the temperature of the enzyme-catalyzed reduction reaction is 20–60°C, and the time of the enzyme-catalyzed reduction reaction is 12–96 h.

[0044] In some specific embodiments, the protective atmosphere includes nitrogen.

[0045] The beneficial technical effects of the present invention through the above technical solution are as follows:

[0046] The method for synthesizing niraparib intermediates of the present invention can effectively prepare the target compound and has the advantages of simple operation, green and environmentally friendly, high yield, high selectivity and low cost.

[0047] Other features and advantages of the present invention will be described in detail in the following detailed description section. Detailed Implementation

[0048] The present invention will be further described in detail below through examples. All raw materials used in the examples are commercially available.

[0049] In the examples, the olefin reductase reagent was obtained from Suzhou Hanmei Biotechnology Co., Ltd., and the coenzyme was obtained from Bangtai Bioengineering (Shenzhen) Co., Ltd.

[0050] Example 1

[0051] The synthesis of the third compound shown in formula (III), 5-(4-bromophenyl)-3,4-dihydropiperidine-1(2H)-carboxylic acid tert-butyl ester, includes the following steps:

[0052]

[0053] Under nitrogen protection, 50 g of 4-bromophenylboronic acid pinacol ester, 46.3 g of 5-bromo-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, 0.1 g of Pd(dppf)2Cl2, 28 g of K2CO3, 500 mL of 1,4-dioxane, and 50 mL of water were mixed and stirred at 85 °C. After 24 hours, the reaction was terminated, and the mixture was extracted twice with 250 mL of ethyl acetate. The organic phases were combined, dried, and evaporated to dryness to give 52 g of 5-(4-bromophenyl)-3,4-dihydropiperidine-1(2H)-carboxylic acid tert-butyl ester with a purity of 98.5% and a yield of 87%.

[0054] Example 2

[0055] The synthesis of the third compound shown in formula (III), 5-(4-aminophenyl)-3,4-dihydropiperidine-1(2H)-carboxylic acid tert-butyl ester, includes the following steps:

[0056]

[0057] Under nitrogen protection, 50 g of 4-aminophenylboronic acid pinacol ester, 46.3 g of 5-bromo-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, 0.1 g of Pd(dppf)2Cl2, 28 g of K2CO3, 500 mL of 1,4-dioxane, and 50 mL of water were mixed and stirred at 90 °C. After 30 hours, the reaction was terminated, and the mixture was extracted twice with 250 mL of ethyl acetate. The organic phases were combined, dried, and evaporated to dryness to obtain 56.3 g of 5-(4-aminophenyl)-3,4-dihydropiperidine-1(2H)-carboxylic acid tert-butyl ester with a purity of 98.7% and a yield of 90%.

[0058] Example 3

[0059] The method for synthesizing the niraparib intermediate shown in formula (Ⅳ) includes the following steps:

[0060]

[0061] In phosphate buffer (pH = 7.2, 100 mL), 10 g of 5-(4-bromophenyl)-3,4-dihydropiperidin-1(2H)-carboxylic acid tert-butyl ester (prepared in Example 1), 0.1 g of olefin reductase ES-ERED-104, 0.01 g of coenzyme (NADH), 10 mL of methyl tert-butyl ether, 0.1 g of glucose dehydrogenase, and 10 g of glucose were added and mixed. The mixture was stirred at 45 °C for 18 hours, and then the reaction was terminated. The mixture was extracted twice with dichloromethane (250 mL), the organic phases were combined, dried, and evaporated to dryness. The mixture was then slurried with ethanol (10 mL) for 2 hours, filtered, and the filter cake was washed with a small amount of ethanol and dried to obtain (R)-3-(4-bromophenyl)piperidin-1-carboxylic acid tert-butyl ester (8.4 g) with a purity of 99.3% and an ee (optical purity) of 99.8%, and a yield of 83.5%.

[0062] Example 4

[0063] The method for synthesizing the niraparib intermediate shown in formula (Ⅳ) includes the following steps:

[0064]

[0065] In phosphate buffer (pH = 7.2, 100 mL), 10 g of 5-(4-bromophenyl)-3,4-dihydropiperidin-1(2H)-carboxylic acid tert-butyl ester (prepared in Example 1), 0.05 g of olefin reductase ES-ERED-107, 0.01 g of coenzyme (NADH), 10 mL of isopropyl ether, 0.1 g of glucose dehydrogenase, and 10 g of glucose were added and mixed. The mixture was stirred at 37 °C for 38 hours, and then the reaction was terminated. The mixture was extracted twice with dichloromethane (250 mL), the organic phases were combined, dried, and evaporated to dryness. The mixture was then slurried with 10 mL of ethanol for 2 hours, filtered, and the filter cake was washed with a small amount of ethanol and dried to obtain (R)-3-(4-bromophenyl)piperidin-1-carboxylic acid tert-butyl ester (8.4 g) with a purity of 99.1%, ee of 99.8%, and a yield of 82.5%.

[0066] Example 5

[0067] The method for synthesizing the niraparib intermediate shown in formula (Ⅳ) includes the following steps:

[0068]

[0069] In phosphate buffer (pH = 7.2, 100 mL), 10 g of 5-(4-aminophenyl)-3,4-dihydropiperidine-1(2H)-carboxylic acid tert-butyl ester (prepared in Example 2), 0.05 g of olefin reductase ES-ERED-108, 0.01 g of coenzyme (NADH), 20 mL of acetone, 0.1 g of glucose dehydrogenase, and 10 g of glucose were added and mixed. The mixture was stirred at 45 °C for 24 hours. After that, the reaction was terminated, and the mixture was extracted twice with dichloromethane (250 mL). The organic phases were combined, dried, and evaporated to dryness. The mixture was then slurried with 10 mL of ethanol for 2 hours, filtered, and the filter cake was washed with a small amount of ethanol and dried to obtain (R)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester (8.4 g) with a purity of 99.1%, an ee of 99.7%, and a yield of 80.4%.

[0070] Example 6

[0071] The method for synthesizing the niraparib intermediate shown in formula (Ⅳ) includes the following steps:

[0072]

[0073] In phosphate buffer (pH = 7.2, 100 mL), 10 g of 5-(4-aminophenyl)-3,4-dihydropiperidine-1(2H)-carboxylic acid tert-butyl ester (prepared in Example 2), 0.1 g of olefin reductase ES-ERED-119, 0.01 g of coenzyme (NADH), 15 mL of methyl tert-butyl ether, 0.1 g of glucose dehydrogenase, and 10 g of glucose were added and mixed. The mixture was stirred at 45 °C for 38 hours, and then the reaction was terminated. The mixture was extracted twice with dichloromethane (250 mL), the organic phases were combined, dried, and evaporated to dryness. The mixture was then slurried with ethanol (10 mL) for 2 hours, filtered, and the filter cake was washed with a small amount of ethanol and dried to obtain (R)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester (8.4 g) with a purity of 99.4%, an ee of 99.8%, and a yield of 82.4%.

[0074] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing a niraparib intermediate, characterized in that, Includes the following steps: (1) Under a protective atmosphere, the first compound shown in formula (Ⅰ), the second compound shown in formula (Ⅱ), the catalyst, potassium carbonate and the first solvent are mixed and a catalytic coupling reaction is carried out to obtain the third compound shown in formula (Ⅲ); (2) Mix the third compound shown in formula (III), glucose, enzyme, coenzyme, glucose dehydrogenase and second solvent, and carry out an enzyme-catalyzed reduction reaction to obtain the niraparib intermediate shown in formula (IV); The first compound represented by formula (Ⅰ), the second compound represented by formula (Ⅱ), the third compound represented by formula (Ⅲ), and the niraparib intermediate represented by formula (Ⅳ) are shown below: Wherein, R is F, Cl, Br, I, -NH2, -NO2, or -NHAc; X is -Br, -Cl, or -I; PG can be Boc, Cbz, PMB, or Trt.

2. The method for synthesizing the niraparib intermediate according to claim 1, characterized in that, The mass ratio of the first compound to the second compound is 1.5:1 to 1:1; The mass ratio of the first compound to the catalyst is 1000:1 to 10:1; The ratio of the first compound to the solvent is 1g:5mL to 1g:20mL; The mass ratio of the first compound to the potassium carbonate is 5:1 to 1:

1.

3. The method for synthesizing the niraparib intermediate according to claim 1, characterized in that, The catalyst comprises [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; The solvent comprises 1,4-dioxane and water; The volume ratio of the 1,4-dioxane to the water is 50:1 to 5:

1.

4. The method for synthesizing the niraparib intermediate according to claim 1, characterized in that, The temperature of the catalytic coupling reaction is 70–100°C, and the time of the catalytic coupling reaction is 12–96 h.

5. The method for synthesizing the niraparib intermediate according to claim 1, characterized in that, The mass ratio of the third compound to the enzyme is 1000:1 to 1:1; The mass ratio of the third compound to the coenzyme is 10000:1 to 10:1; The mass ratio of the third compound to the glucose dehydrogenase is 1000:1 to 10:1; The mass ratio of the third compound to the glucose is 10:1 to 1:

1.

6. The method for synthesizing the niraparib intermediate according to claim 1, characterized in that, The ratio of the third compound to the second solvent is 1g:5mL to 1g:20mL; The second solvent includes phosphate buffer and organic solvent; The pH of the phosphate buffer solution is 7.2; The volume ratio of the phosphate buffer solution to the organic solvent is 100:1 to 1:

1.

7. The method for synthesizing the niraparib intermediate according to claim 1, characterized in that, The enzyme includes olefin reductase; The ene reductases include ES-ERED-101, ES-ERED-102, ES-ERED-103, ES-ERED-104, ES-ERED-105, ES-ERED-106, ES-ERED-107, ES-ERED-108, ES-ERED-109, ES-ERED- 110, ES-ERED-111, ES-ERED-112, ES-ERED-113, ES-ERED-114, ES-ERED-115, ES-ERED-116, ES-ERED-117, ES-ERED-118, ES-ERED-119 or ES-ERED-120; The coenzyme includes reduced nicotinamide adenine dinucleotide phosphate or nicotinamide adenine dinucleotide.

8. The method for synthesizing the niraparib intermediate according to claim 1, characterized in that, The enzyme-catalyzed reduction reaction is carried out at a temperature of 20–60°C for 12–96 h.

9. The method for synthesizing the niraparib intermediate according to claim 1, characterized in that, The protective atmosphere includes nitrogen.

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