CN107235958A - A kind of synthetic method for preparing PARP inhibitor Niraparib - Google Patents

Abstract

A novel synthetic method for preparing the PARP inhibitor Niraparib, the method comprising using the starting material methyl anthranilate through diazo coupling, cyclization, amidation, de-BOC, and chiral resolution to obtain Niraparib with a purity of 99.85%. . The method of the invention is simple and easy to operate, and is a method suitable for industrial production.

Description

A kind of synthetic method for preparing PARP inhibitor Niraparib

technical field

The invention belongs to the technical field of drug synthesis, and relates to a synthesis method for preparing PARP inhibitor Niraparib.

Background technique

Niraparib is an oral poly ADP-ribose polymerase (PARP) inhibitor, which can inhibit the repair of DNA damage in cells and is suitable for cancers with BRCA1/2 gene mutations, such as ovarian cancer and breast cancer, developed by Tesaro, an American biotechnology company. research and development. For cancer cells with BRCA gene mutations, if PARP activity is further inhibited, these cells will generate a lot of DNA damage when they divide, leading to the death of cancer cells. The chemical name of Niraparib is 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide, and a phase III clinical trial called NOVA has been completed. Niraparib shows very good curative effect. In the trial, the researchers recruited more than 500 patients with ovarian cancer recurrence after platinum-based chemotherapy, and divided the patients into two groups according to whether the germ cells had BRCA gene mutations. In the group with germline BRCA mutations, the median progression-free survival of patients treated with niraparib was 21 months, which was significantly longer than the 5.5 months in the control group.

At present, the patent documents related to the synthesis method of Niraparib in the prior art include Preparation of pharmaceutically acceptable salts of (3S)-3-[4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl]piperidines as inhibitors of poly(ADP-ribose)polymerase(PARP), Preparation of piperidinylphenylindazolylcarboxamide for useas poly(ADP-ribose)polymerase inhibitors, etc., which disclose a chemical synthesis route, as follows, and discuss the discovery process of Niraparib in detail.

The synthetic route uses 3-methyl-2-nitrobenzoic acid as the starting material, and obtains compound A through esterification with methanol under the condition of acid chloride, and A is heated to reflux in the CCl4 solution of benzoyl peroxide and NBS for 12 Hours, bromination to give compound B. Compound C was obtained by oxidation of B with acetonitrile and N-methylmorpholine-N-oxide aqueous solution. Compound C and tert-butyl-3-(4-aminophenyl)piperidine-1-carboxylate were stirred and refluxed in ethanol solution to obtain compound D. Compound D reacts with a mixture of sodium azide and DMF to form intermediate E through cyclization. Compound E is acylated in a methanol solution with NH3 at 60°C to obtain intermediate F. Compound F is dissolved in ethyl acetate and dioxane solution Hydrochloric acid was added to remove the BOC group to obtain intermediate G, which was resolved by Chiralpak AS-H normal phase chiral chromatographic column to obtain the target compound S-type conformer Niraparib. The synthetic route is relatively long, and Niraparib obtained by using Chiralpak AS-H normal phase chiral chromatographic column is not easy to achieve large-scale industrial production, and unstable and difficult post-processing raw materials such as sodium azide are used in the reaction, which limits industrialization Safe Production.

Contents of the invention

In order to overcome the above-mentioned deficiencies in the prior art, the object of the present invention is to improve a synthetic method for preparing the PARP inhibitor Niraparib, the route is novel, multiple brand-new intermediates are obtained in the synthetic process, and the properties of the intermediates are stable and easy to operate , easy to realize industrialized mass production.

In order to achieve the above object, the realization process of the present invention is as follows:

A synthetic method for preparing PARP inhibitor Niraparib, the synthetic route is as follows:

Wherein the compound (I) is the PARP inhibitor Niraparib.

The synthetic steps are described in detail below:

first step:

Mix methyl anthranilate with sulfuric acid solution, then slowly add sodium nitrite dropwise, the reaction temperature is -10°C to 10°C, and the brown-red diazonium salt formed is then mixed with tert-butyl-3-phenylpiperidine-1 - tert-butyl formate carries out coupling reaction in 10% sodium hydroxide solution environment to obtain intermediate (II), and the structure of intermediate (II) is

Step two:

Under the catalysis of intermediate (II) dirhenium decacarbonyl [Re ₂ (CO) ₁₀ ] and sodium acetate [NaOAc], the cyclization of the azobenzene structure of intermediate (II) is catalyzed, and the cyclization is formed in a methanol solvent system Indazole ring, obtain intermediate (III), realize the indazole structure in one-step construction intermediate (III), the structure of intermediate (III) is

third step:

Dissolve the intermediate (III) in anhydrous DMF at 0°C, add sodium methoxide and formamide, raise the temperature to 40°C for 3.5 hours, and form the amide structure in the intermediate (IV) after aminolysis of the methyl ester to obtain the crude product Intermediate (IV), then add the crude intermediate (IV) to a mixed solvent of dioxane-water (volume ratio 8:1) at room temperature, raise the temperature to 101°C, add activated carbon after the solid is completely dissolved, and reflux , suction filtration while hot, filtrate, leave standstill, suction filtration, dry, obtain intermediate (IV), the structure of intermediate (IV) is:

the fourth step:

Intermediate (IV) reacts with trifluoroacetic acid in dichloromethane to remove the BOC protecting group, using dichloromethane as a solvent, the molar ratio of substances is intermediate (IV): dichloromethane: trifluoroacetic acid = 1:5 : 1, stirred at room temperature for about 3 hours and reacted completely, evaporated to dryness to obtain racemic intermediate (V), the structure of intermediate (V) is

the fifth step:

Dissolve the racemic intermediate (V) in an organic solvent under reflux, add L-(+)-tartaric acid, cool down and crystallize, separate the solid crystal to obtain Niraparib.L-(+)-tartrate, dissolve it in water , add sodium hydroxide solution to alkalinize, then add ethyl acetate to extract, wash, and dry to obtain compound (I) PARP inhibitor Niraparib, its structural formula is The mass ratio of the organic solvent to the racemic intermediate (V) is 10 to 20:1; the mass ratio of the L-(+)-tartaric acid to the Niraparib intermediate 4 is 0.5 to 5:1, preferably 3 ~4:1.

The organic solvent used in the chemical resolution process of the racemic intermediate (V) in the fifth step is tetrahydrofuran, methanol, ethanol, acetone, ethyl acetate or several mixtures in any proportion, preferably ethanol and ethyl acetate. The crystal temperature is -10～0℃.

In the fourth step, the de-BOC protection reaction to prepare the racemic intermediate (V) uses a solvent selected from tetrahydrofuran, dioxane, methylene chloride, chloroform, toluene, o-xylene, p-xylene, m- Xylene, acetonitrile or a mixture of mixtures in any proportion, preferably dichloromethane, the temperature used for de-BOC is room temperature.

In the first step described, the preparation of diazonium salt by methyl anthranilate can use potassium nitrite, calcium nitrite, silver nitrite, sodium nitrite, barium nitrite, ethyl nitrite, isoamyl nitrite Esters, isobutyl nitrite, isopropyl nitrite, tert-butyl nitrite, n-butyl nitrite, and n-propyl nitrite are used as diazotization reagents, preferably sodium nitrite.

Compared with the prior art, the present invention has the advantages of:

1) The starting material methyl anthranilate used in the present invention is a raw material commonly used in the field of organic drug synthesis, which is cheap and easy to obtain;

2) The synthesis route of the present invention is short and the steps are simple.

3) The present invention only adopts operation methods such as extraction, drying, filtration, crystallization and recrystallization in each intermediate link, and the post-processing is simple and convenient, and it is relatively easy to realize large-scale production;

4) The route of the present invention is novel, and a plurality of brand-new intermediates are obtained in the synthesis process, and the properties of the intermediates are stable, the operation is simple, and it is easy to realize industrialized large-scale production.

Description of drawings

Fig. 1 is the HPLC chromatogram of the final product Niraparib of the present invention.

detailed description

The present invention is further described below in conjunction with the examples, but the present invention is not limited to the following examples.

Example

Intermediate (II) The synthesis of intermediate (II) is divided into two steps, the preparation of the first step diazonium salt: 52mL (0.4mol) methyl anthranilate is mixed with 170mL 20% sulfuric acid (0.62mol), cooled to At 10°C, slowly add 42 mL of 30% sodium nitrite (0.4 mol) solution dropwise into the reaction flask. Check the excess nitrous acid with starch potassium iodide test paper to determine the end point of the reaction. The generated brown-red diazonium salt carries out the coupling reaction of the second step with tert-butyl-3-phenylpiperidine-1-carboxylate: get 100g (0.4mol) tert-butyl-3-phenylpiperidine- 1-tert-butyl formate was dissolved in 500mL of 10% sodium hydroxide solution, and was dripped into the above-mentioned diazonium salt under constant stirring, stirred for 5h, left to stand for crystallization, suction filtered, and recrystallized in ethanol to obtain 127g of the intermediate (II ), yield: 78%.

¹ H-NMR (300MHz, DMSO-d6) (ppm) δ: 8.52 (2H, d, J = 7.6Hz), 8.25-8.11 (3H, m), 7.86 (1H, t), 7.51 (2H, d, J＝7.6Hz), 3.91(3H,s), 3.75-3.49(2H,m), 3.38-3.32(2H,m), 2.77-2.67(1H,m), 1.92-1.68(2H,m), 1.58 -1.43(2H,m),1.38(9H,s); ¹³ C-NMR(75MHz,DMSO-d6)δ(ppm):164.6,153.5,150.0,141.1,133.5,128.6,127.5,126.9,123.0,117.0 ,80.1,56.9,51.3,49.2,40.3,30.8,28.2,22.9; MS(ESI)for(M+H) ⁺ :424.2.

Intermediate (III) For the synthesis of Niraparib intermediate 1, 82g (0.2mol) of Niraparib intermediate 1 was mixed with 68mL (0.64mol) of toluene and 16mL (0.4mol) of methanol, stirred and dissolved, and 6.5g of dirhenium decacarbonyl ([Re ₂ (CO) ₁₀ ]10mmol) was added And 5.4g of sodium acetate (0.04mol) as a catalyst, heated to reflux at 150°C for 72 hours, filtered while hot, static crystallization, and vacuum dried at 40°C for 4h to obtain 51.2g of intermediate (III), with a yield of 61%.

¹ H-NMR (300MHz, DMSO-d6) (ppm) δ: 8.51 (1H, s), 8.13 (1H, d, J = 7.1Hz), 7.95 (1H, d, J = 8.3Hz), 7.91 (2H ,d,J=8.4Hz),7.39(2H,d,J=8.4Hz),7.18(1H,t,J=7.2Hz),4.30-4.10(2H,m),4.00(3H,s),2.85 -2.70(3H,m),2.11-2.03(1H,m),1.83-1.75(1H,m),1.73-1.53(2H,m overlapped to H ₂ O signal),1.48(9H,s).

¹³ CNMR (75MHz, DMSO-d6) δ (ppm): 167.3, 153.4, 145.3, 136.8, 128.4, 126.7, 125.1, 124.1, 120.8, 112.0, 80.0, 57.0, 51.3, 49.0, 40.3, 30.5, 28.1, 22.8; MS(ESI)for(M+H) ⁺ :436.2.

Intermediate (IV) 17.2g (41mmol) of intermediate (III) was dissolved in 100mL of anhydrous DMF at 0°C, 13mL (328mmol) of formamide and 3.3g (62mmol) of sodium methoxide were added to the solution, and the temperature was raised to 40°C for reaction 3.5h. The reaction solution was cooled to room temperature, poured into 400 mL of water, stirred for 1 h, filtered with suction, and dried to obtain 17.23 g of crude intermediate (IV) (theoretical yield was 13.78 g), with a yield of 87%. Add 10.0 g of the crude product of Compound 3 to 80 mL of dioxane-water (volume ratio 8:1) mixed solvent at room temperature, raise the temperature to 101 ° C, add 0.2 g (mass fraction 2%) of activated carbon after the solid is completely dissolved, and continue Reflux for 0.5h, suction filter while it is hot, cool the filtrate to 0°C, let stand for 2h (precipitate white needle-like crystals), suction filter and dry to obtain intermediate (IV).

¹ H-NMR (300MHz, DMSO-d6) (ppm) δ: 9.04 (1H, br.s), 8.51 (1H, s), 8.31 (1H, d, J=6.8Hz), 7.91 (1H, d, J=8.3Hz),7.84(2H,d,J=8.2Hz),7.42(2H,d,J=8.2Hz),7.31-7.22(1H,m),5.95(1H,br,s),4.40- 4.05(2H,m),2.90-2.70(3H,m),2.15-2.00(1H,m),1.85-1.75(1H,m),1.75-1.50(2H,moverlapped to H ₂ O signal),1.48( 9H,s);

¹³ CNMR (75MHz, DMSO-d6) δ (ppm): 168.2, 153.4, 143.6, 136.8, 128.9, 126.5, 125.1, 124.3, 120.8, 115.1, 80.0, 57.0, 49.3, 40.5, 30.7, 28.4, 22.5; MS ( ESI)for(M+H) ⁺ :421.2

Intermediate (V) The synthesis of 18g intermediate (IV) (42mmol) was added in 180mL dichloromethane, after fully mixing, 50mL trifluoroacetic acid solution was added dropwise one by one, after stirring for 24h, 80mL sodium hydroxide aqueous solution was added, standing for stratification, The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 11.2 g of intermediate (V), with a molar yield of 83.33%.

¹ H-NMR (300MHz, DMSO-d6) (ppm) δ9.28 (1H, s), 8.57 (1H, br, s), 8.06 (2H, d, J=7.2Hz), 8.04 (2H, d, J=8.4Hz), 7.88(2H,br.s),7.49(2H,d,J=8.4Hz),7.27(1H,dd,J=8.4,7.2Hz),3.08-2.94(2H,m), 2.77-2.67(1H,m),2.76-2.73(2H,m),1.75-1.47(4H,m).

¹³ C-NMR (75MHz, DMSO-d6) δ (ppm): 168.2, 143.4, 136.7, 128.8, 126.4, 125.1, 123.9, 120.9, 115.2, 52.2, 48.8, 43.5, 30.8, 25.1,

MS(ESI)for(M+H) ⁺ :321.2.

Compound (I) Niraparib Synthesis, adding 100g of intermediate (V) to 1000mL of absolute ethanol, adding 50g of L-(+)-tartaric acid and heating to reflux for 0.5h, then cooling the system to -10-0°C for crystallization, and filtering to obtain a solid; The solid was purified by recrystallization with 200 mL of ethanol to obtain 66.89 g of L-(+)-tartrate salt of Niraparib, with a molar yield of 45.5%.

Add 4.5 g of L-(+)-tartrate salt of Niraparib to 22.5 mL of pure water, then add 1.3 g of sodium hydroxide solution in a water bath at room temperature, mix well, add 45.0 mL of ethyl acetate, and stir at room temperature for 3 h until clarification. Stand to separate and separate, the aqueous phase was extracted with 45.0 mL ethyl acetate, and the organic phase was combined; washed with 15 mL water and 15 mL saturated sodium chloride solution successively, dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated to dilute crystals, and the crystals Obtain compound (I) Niraparib 2.88g after drying, the yield of this step reaction is 94.2%, and the total reaction yield is 14.78%, and the purity of compound (I) Niraparib measured by HPLC is 99.85% (chromatogram as shown in Figure 1 below), Using Daicel's AD-3 150mm×2.1mm chiral column measured ee value is 99.7%. ¹ H-NMR (300MHz, DMSO-d6) (ppm) δ9.28 (1H, s), 8.57 (1H, br, s), 8.06 (2H, d, J=7.2Hz), 8.04 (2H, d, J=8.4Hz), 7.88(2H,br.s),7.49(2H,d,J=8.4Hz),7.27(1H,dd,J=8.4,7.2Hz),3.08-2.94(2H,m), 2.77-2.67(1H,m),2.76-2.73(2H,m),1.75-1.47(4H,m).

¹³ C-NMR (75MHz, DMSO-d6) δ (ppm): 168.2, 143.4, 136.7, 128.8, 126.4, 125.1, 123.9, 120.9, 115.2, 52.2, 48.8, 43.5, 30.8, 25.1, MS (ESI) for ( M+H) ⁺ :321.2.

Claims (9)

1. A synthetic method for preparing PARP inhibitor Niraparib, the synthetic route is as follows: Wherein the compound (I) is the PARP inhibitor Niraparib. 2. a kind of synthetic method preparing PARP inhibitor Niraparib according to right 1 is characterized in that, methyl anthranilate is mixed with sulfuric acid solution, then slowly add sodium nitrite dropwise, reaction temperature-10 ℃ to 10 ℃, after the brownish-red diazonium salt generated, carry out coupling reaction with tert-butyl-3-phenylpiperidine-1-carboxylic acid tert-butyl ester in 10% sodium hydroxide solution environment to obtain intermediate (II), intermediate ( II) The structure is 3. a kind of synthetic method preparing PARP inhibitor Niraparib according to claim 1, is characterized in that, intermediate (II) is catalyzed in decacarbonyl dirhenium (Re ₂ (CO) ₁₀ ) and sodium acetate (NaOAc) Next, the cyclization of the azobenzene structure of the intermediate (II) is catalyzed, and the indazole ring is formed in the solvent system of methanol to obtain the intermediate (III), and the indazole structure in the intermediate (III) is realized in one step. The structure of body (III) is 4. a kind of synthetic method of preparing PARP inhibitor Niraparib according to claim 1 is characterized in that, intermediate (III) is added sodium methylate, formamide after being dissolved in anhydrous DMF at 0 ℃, is warming up to React at 40°C for 3.5h, form the amide structure in the intermediate (IV) after aminolysis of the methyl ester, and obtain the crude intermediate (IV), and then add the crude intermediate (IV) to dioxane-water ( In a mixed solvent with a volume ratio of 8:1), heat up to 101°C, add activated carbon after the solid is completely dissolved, reflux, and suction filter while it is hot. IV) has a structure of: 5. a kind of synthetic method preparing PARP inhibitor Niraparib according to claim 1 is characterized in that, intermediate (IV) is in dichloromethane, reacts with trifluoroacetic acid to remove BOC protecting group, uses dichloromethane as Solvent, the molar ratio of substance is intermediate (IV): dichloromethane: trifluoroacetic acid = 1:5:1, stirred at room temperature for about 3 hours, the reaction is complete, evaporated to dryness to obtain racemic intermediate (V), intermediate ( The structure of V) is 6. a kind of synthetic method preparing PARP inhibitor Niraparib according to claim 1 is characterized in that, racemic intermediate (V) is dissolved in organic solvent and reflux dissolves, adds L-(+)-tartaric acid, cooling Crystallization, separation of solid crystals to obtain Niraparib.L-(+)-tartrate, dissolve it in water, add sodium hydroxide solution to alkalinize, then add ethyl acetate to extract, wash, concentrate and dry under reduced pressure to obtain the compound (1) PARP inhibitor Niraparib, its structural formula is The mass ratio of the organic solvent to the Niraparib racemic intermediate (V) is 10 to 20:1; the mass ratio of the L-(+)-tartaric acid to the Niraparib racemic intermediate (V) is 0.5 to 5 :1. 7. a kind of synthetic method preparing PARP inhibitor Niraparib according to claim 1 is characterized in that, the organic solvent used in the racemic intermediate (V) chemical resolution process in the described 5th step is THF, Methanol, ethanol, acetone, ethyl acetate or mixtures of several in arbitrary proportions, preferably ethanol and ethyl acetate, and the crystallization temperature is -10 to 0°C. 8. a kind of synthetic method preparing PARP inhibitor Niraparib according to claim 1 is characterized in that, in the described 4th step, de-BOC protection reaction prepares the used solvent of racemic intermediate (V) and is selected from tetrahydrofuran, Dioxane, dichloromethane, chloroform, toluene, o-xylene, p-xylene, m-xylene, acetonitrile or a mixture of mixtures in any proportion, preferably dichloromethane, the temperature used for de-BOC for room temperature. 9. a kind of synthetic method preparing PARP inhibitor Niraparib according to claim 1, is characterized in that, in the described first step, can use potassium nitrite, nitrite by the preparation diazonium salt of methyl anthranilate Calcium nitrate, silver nitrite, sodium nitrite, barium nitrite, ethyl nitrite, isoamyl nitrite, isobutyl nitrite, isopropyl nitrite, tert-butyl nitrite, n-butyl nitrite, N-propyl nitrite was used as a reagent for the diazotization reaction.