Method for preparing chiral intermediate of niraparib by means of chemical-enzymatic method

Abstract

The present application provides a method for preparing a chiral intermediate of Niraparib by means of a chemical-enzymatic method. The method provided by the present application comprises: subjecting compound II, as a starting material, to a Michael addition reaction to obtain compound III; then, subjecting compound III to enzymatic resolution using an ester hydrolase to obtain chiral compound IV, with an ee value of up to 99%; and finally, subjecting compound IV to cyclization and amide reduction reactions to obtain chiral intermediate I of Niraparib. The route features simple operation and low cost, and can be applied to industrial production.

Description

A method for preparing a chiral intermediate of niraparib by chemical-enzymatic method TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological catalysis, and particularly relates to a method for preparing a chiral intermediate of niraparib by chemical-enzymatic method. BACKGROUND

[0002] Niraparib is a polyadenosine diphosphate-ribopolymerase inhibitor drug developed by GlaxoSmithKline. In March 2017, niraparib was approved for marketing in the United States by the FDA and is used for maintenance treatment of recurrent, epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

[0003] There is only one chiral site in the structure of niraparib, and the control of this chirality is the key and difficulty in the synthesis of niraparib. Through retrosynthetic analysis, it is known that this chiral site is mainly introduced by (S)-3-(4-bromophenyl)piperidine (compound I, CAS 1335523-82-4), and the preparation of compound I will directly affect the chirality of niraparib and its commercialization.

[0004] Patent WO2014088984A1 discloses a method for preparing key intermediate I, and the synthetic route is as follows:

[0005] Compound 1 is used as a starting material, and compound 5 is obtained through acylation, esterification, epoxidation, rearrangement and other reactions. Compound 6 is obtained by reacting compound 5 with sodium bisulfite, and finally intermediate I is obtained by catalyzing compound 6 with transaminase, with an ee value of 99.3%. In this route, the rearrangement reaction needs to first prepare an azide reagent with trimethylsulfoxonium iodide and KOt-Bu, and then slowly drop into the reaction system. The enzymatic reaction needs to be carried out under nitrogen protection, and the reaction time is as long as 46 hours.

[0006] Literature J. Am. Chem. Soc. 2022, 144, 21088-21095 reports a method for preparing key intermediate I. In this synthesis method, compound 7 is first converted into chiral compound 8 under the catalysis of imine reductase (IRED), glucose dehydrogenase (GDH) and 6-hydroxy-D-nicotine oxidase (6-HDNO), with an enantiomeric excess (ee value) of 99%, and then the allyl group is removed under the catalysis of metal catalyst RhCl(PPh3)3 under nitrogen protection. In this synthesis method, three enzymes are used for asymmetric reduction, and the temperature of the dealkylation reaction reaches 100℃.

[0007] Therefore, it is urgent to develop a method for preparing the chiral intermediate I of niraparib, which is simple to operate, low in cost and easy to industrialize. SUMMARY

[0008] The present application provides a simple, low-cost, and easy-to-industrialize method for preparing a chiral intermediate I of niraparib.

[0009] In a first aspect, the present application provides a method for preparing a chiral intermediate I (i.e., compound I) of niraparib. The method comprises the following steps: first, Michael addition reaction of compound II with acrylonitrile to obtain compound III; second, chiral compound IV obtained by ester hydrolytic enzyme resolution of compound III; third, compound V obtained by ring closure of chiral compound IV; and finally, niraparib chiral intermediate I obtained by amide reduction reaction of compound V. The synthetic route is shown below:

[0010] wherein R is selected from methyl, ethyl, n-propyl, or isopropyl.

[0011] In some embodiments, the Michael addition reaction requires the addition of a base, wherein the base is sodium tert-butoxide, sodium tert-amylate, sodium methoxide, sodium hydroxide, potassium carbonate, potassium tert-butoxide, or potassium hydroxide, preferably sodium tert-butoxide.

[0012] In some embodiments, the solvent for the Michael addition reaction is tetrahydrofuran, dimethyl sulfoxide, 2-methyltetrahydrofuran, or toluene, preferably tetrahydrofuran.

[0013] In some embodiments, the ester hydrolytic enzyme is derived from Pseudomonas putida, Pseudomonas pseudoalcaligenes, Pseudomonas oleovorans DSM50188, Candida Antarctica, or homologues thereof, preferably Candida Antarctica.

[0014] In some embodiments, the ester hydrolytic enzyme participates in the catalytic reaction in the form of ester hydrolytic enzyme powder, ester hydrolytic enzyme clear liquid, ester hydrolytic enzyme homogenate, cells containing ester hydrolytic enzyme, ester hydrolytic enzyme immobilized cells, ester hydrolytic enzyme immobilized enzyme, etc., preferably ester hydrolytic enzyme powder.

[0015] In some embodiments, the ester hydrolytic enzyme expression recipient strain is selected from Escherichia coli, yeast, Streptomyces, or Bacillus subtilis, preferably Escherichia coli.

[0016] In some embodiments, the enzyme powder concentration of the ester hydrolytic enzyme is 1-10 g / L, or the concentration of cells containing ester hydrolytic enzyme is 10-100 g / L.

[0017] In some embodiments, the ester hydrolase is selected from the ester hydrolases ES-PLE-101 to ES-PLE-137 sold by Shengke Biomedicine (Shanghai) Co., Ltd.

[0018] In some embodiments, the ring closure reaction requires the addition of a reducing agent, wherein the reducing agent is sodium borohydride, Raney nickel, preferably Raney nickel.

[0019] In some embodiments, the reducing agent used in the reduction reaction is selected from sodium 2-hydroxybisdimesitylhydroxyborate, borane tetrahydrofuran, borane dimethyl sulfide, sodium borohydride, lithium aluminum hydride, preferably sodium 2-hydroxybisdimesitylhydroxyborate.

[0020] In some embodiments, the intermediate I can be used to prepare niraparib.

[0021] In a second aspect, the present application provides a new compound, the structure of which is shown in formula III,

[0022] wherein R is selected from methyl, ethyl, n-propyl or i-propyl.

[0023] In a third aspect, the present application provides a new compound, the structure of which is shown in formula IV,

[0024] wherein R is selected from methyl, ethyl, n-propyl or i-propyl.

[0025] The present application has the beneficial effect that it provides a new chemical-enzymatic method for preparing the chiral intermediate I of niraparib. The method has a short route and only uses a single enzyme, is simple to operate, and is more suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 is the nuclear magnetic spectrum of the compound IIIa of Example 1. DETAILED DESCRIPTION

[0027] The technical content of the present application is further described below in combination with specific examples, and the purpose is to better understand the content of the present application, but the protection scope of the present application is not limited thereto.

[0028] Preparation of the compound IIIa of Example 1

[0029] Into a 500 mL three-necked flask, compound IIa (30.0 g, 1.0 eq) was added, tetrahydrofuran 300 mL, the reaction liquid was stirred at 0-2 °C, and sodium tert-butoxide (1.26 g, 0.1 eq) was slowly added dropwise, acrylonitrile (8.37 g, 1.2 eq) was added dropwise, and stirring was carried out for 1.5 hours. The reaction was completed, the temperature was raised to room temperature, 2 mol / L hydrochloric acid was added dropwise to quench the reaction system, then the aqueous phase was extracted with ethyl acetate for 3 times, the organic phase was combined, and concentrated under reduced pressure to obtain 25.9 g of oily liquid compound IIIa. The nuclear magnetic spectrum of compound IIIa is shown in Figure 1.

[0030] Preparation of compound IIIb in Example 2

[0031] Into a 500 mL three-necked flask, compound IIb (31.8 g, 1.0 eq) was added, tetrahydrofuran 300 mL, the reaction liquid was stirred at 0-2 °C, and sodium tert-butoxide (1.26 g, 0.1 eq) was slowly added dropwise, acrylonitrile (8.37 g, 1.2 eq) was added dropwise, and stirring was carried out for 1.5 hours. The reaction was completed, the temperature was raised to room temperature, 2 mol / L hydrochloric acid was added dropwise to quench the reaction system, then the aqueous phase was extracted with ethyl acetate for 3 times, the organic phase was combined, and concentrated under reduced pressure to obtain 25.9 g of oily liquid compound IIIa. The nuclear magnetic spectrum of compound IIIa is shown in Figure 1.

[0032] Preparation of compound IVa in Example 3

[0033] Into a 150 mL three-necked flask, 0.1M pH=8.0 phosphate buffer solution 295 mL, compound IIIa (5 g, 1.0 eq), DMSO 5 mL, ester hydrolase enzyme powder 1.0 g (Shankai Biomedicine (Shanghai) Co., Ltd. ES-PLE-110) were added, and the reaction was carried out at 25 °C for 24 hours. 2 mol / L aqueous hydrochloric acid was added dropwise to adjust the pH of the reaction liquid to 8-9, and then extracted with ethyl acetate for 3 times. The organic phase was combined, and concentrated under reduced pressure to obtain 2.3 g of oily liquid compound IVa, with an ee value of 99.2%.

[0034] Preparation of compound IVa in Example 4

[0035] Into a 150 mL three-necked flask, 0.1M pH=7.6 phosphate buffer solution 295 mL, compound IIIa (5 g, 1.0 eq), DMSO 5 mL, ester hydrolase enzyme powder 1.0 g (Shankai Biomedicine (Shanghai) Co., Ltd. ES-PLE-110) were added, and the reaction was carried out at 25 °C for 24 hours. 2 mol / L aqueous hydrochloric acid was added dropwise to adjust the pH of the reaction liquid to 8-9, and then extracted with ethyl acetate for 3 times. The organic phase was combined, and concentrated under reduced pressure to obtain 2.3 g of oily liquid compound IVa, with an ee value of 99.2%.

[0036] Preparation of compound IVa in Example 5

[0037] Into a 150 mL three-necked flask, 295 mL of 0.1M pH=7.6 phosphate buffer solution, compound IIIa (5 g, 1.0 eq), DMSO 5 mL, ester hydrolase enzyme powder 1.0 g (Shengke Biomedicine (Shanghai) Co., Ltd. ES-PLE-111) were added, and the reaction was carried out at 25°C for 24 hours. Then 2 mol / L aqueous hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 8-9. The reaction solution was extracted with ethyl acetate for 3 times, and the organic phase was combined and concentrated under reduced pressure to obtain 2.4 g of oily liquid compound IVa with an ee value of 99.0%.

[0038] Preparation of compound IVb in Example 6

[0039] Into a 150 mL three-necked flask, 295 mL of 0.1M pH=8.0 phosphate buffer solution, compound IIIb (5.25 g, 1.0 eq), DMSO 5 mL, ester hydrolase enzyme powder 1.0 g (Shengke Biomedicine (Shanghai) Co., Ltd. ES-PLE-111) were added, and the reaction was carried out at 25°C for 24 hours. Then 2 mol / L aqueous hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 8-9. The reaction solution was extracted with ethyl acetate for 3 times, and the organic phase was combined and concentrated under reduced pressure to obtain 2.47 g of oily liquid compound IVb with an ee value of 99.3%.

[0040] Preparation of compound V in Example 7

[0041] Under nitrogen protection, compound IVa (4.3 g, 1.0 eq), glacial acetic acid 25.8 mL, Raney nickel 1.08 g were sequentially added into a 150 mL three-necked flask. After the reaction system was replaced with hydrogen for 3 times, the temperature was raised to 90°C, and the reaction was stirred for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and concentrated to obtain a crude product. The crude product was recrystallized with a mixture of anhydrous ethanol and methyl tert-butyl ether to finally obtain 2.5 g of white solid compound V.

[0042] Preparation of compound V in Example 8

[0043] Into a 150 mL three-necked flask, compound IVb (4.5 g, 1.0 eq), glacial acetic acid 25.8 mL, Raney nickel 1.08 g were added successively under nitrogen protection, the reaction system was replaced with hydrogen for 3 times, then the temperature was raised to 90 °C, and the reaction was stirred for 6 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, filtered, and concentrated to obtain a crude product. The crude product was recrystallized with a mixture of anhydrous ethanol and methyl tert-butyl ether to obtain 2.44 g of white solid compound V.

[0044] Preparation of compound I of Example 9

[0045] Into a 150 mL three-necked flask, compound IVb (4.5 g, 1.0 eq), glacial acetic acid 25.8 mL, Raney nickel 1.08 g were added successively under nitrogen protection, the reaction system was replaced with hydrogen for 3 times, then the temperature was raised to 90 °C, and the reaction was stirred for 6 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, filtered, and concentrated to obtain a crude product. The crude product was recrystallized with a mixture of anhydrous ethanol and methyl tert-butyl ether to obtain 2.44 g of white solid compound V.

[0046] The applicant declares that the technical solutions of the present application are illustrated by the above examples, but the present application is not limited to the above examples, that is, the present application does not mean that the present application must rely on the above examples to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific modes, etc. fall within the protection scope and disclosure scope of the present application.

Claims

1. A method for preparing niraparib chiral intermediate I using a chemical-enzymatic process, comprising the following steps: starting with compound II, a Michael addition reaction is first performed with acrylonitrile to generate compound III; compound III is then resolved by an ester hydrolase to obtain compound IV; subsequently, compound IV undergoes self-cyclization to form compound V; and finally, an amide reduction reaction is performed to obtain niraparib chiral intermediate I; the synthetic route of intermediate I is shown below: in, R is selected from methyl, ethyl, n-propyl, or isopropyl.

2. The method as described in claim 1, wherein, The ester hydrolase participates in the catalytic reaction in the form of enzyme powder, enzyme solution, homogenate, enzyme-containing cells, immobilized cells, immobilized enzymes, etc.

3. The method as described in claim 1, wherein, The ester hydrolase expression strains are selected from Escherichia coli, yeast, Streptomyces or Bacillus subtilis.

4. The method of claim 1, wherein, The concentration of the ester hydrolase powder is 1–10 g / L or the concentration of the cells containing the ester hydrolase is 10–100 g / L.

5. The method of claim 1, wherein, The ester hydrolase is ester hydrolase ES-PLE-101 to ES-PLE-137.

6. The method of claim 1, wherein, The reducing agent in the amide reduction reaction is selected from sodium 2-hydrobis(dimethoxyethoxy)aluminate, borane tetrahydrofuran, borane dimethyl sulfide, sodium borohydride, or lithium aluminum hydride.

7. A compound as shown in Formula III, in, R is selected from methyl, ethyl, n-propyl, and isopropyl.

8. A compound as shown in Formula IV, in, R is selected from methyl, ethyl, n-propyl, and isopropyl.

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