CN110156751B - Novel method for preparing nilapanib and intermediate thereof - Google Patents
Novel method for preparing nilapanib and intermediate thereof Download PDFInfo
- Publication number
- CN110156751B CN110156751B CN201910450429.3A CN201910450429A CN110156751B CN 110156751 B CN110156751 B CN 110156751B CN 201910450429 A CN201910450429 A CN 201910450429A CN 110156751 B CN110156751 B CN 110156751B
- Authority
- CN
- China
- Prior art keywords
- mmol
- reaction
- nilapanib
- yield
- azo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The invention discloses a novel method for preparing Nilaparib (Niraparib) and an intermediate thereof, which takes 2-aminobenzamide and (S) -4- (piperidine-3-yl) aniline as raw materials, and synthesizes the Nilaparib serving as a PARP inhibitor through two steps of reactions of oxidative dehydrogenation coupling and paraformaldehyde addition cyclization under the promotion of microwave, wherein the total yield is 81%. The synthesis method is simple and convenient, mild in reaction conditions, short in reaction time, high in product yield, low in cost and easy to obtain the raw material 2-aminobenzamide, and low in production cost, provides an efficient and simple method for synthesizing the 2H-indazole compound, and has a potential industrial application prospect.
Description
Technical Field
The invention relates to a new method for manufacturing nilapanib and an intermediate thereof, belonging to the field of pharmaceutical chemistry manufacturing processes.
Background
Nilapanib (Niraparib) is an adenosine diphosphate ribose polymerase (PARP) inhibitor developed by the american Tesaro company, approved for marketing by the U.S. Food and Drug Administration (FDA) on 3 months in 2017 under the trade name zejua, and is mainly used for maintenance therapy of ovarian cancer and treatment of breast cancer. The chemical name of the compound is (S) -2- [4- (piperidine-3-yl) phenyl ] -2H-indazole-7-formamide, and the chemical structure is as follows:
the literature reports that the synthesis method of nilapanib mainly comprises the following steps:
(1) (ADP-ribose) polymerases (PARP) inhibitors disclosed in world patent No. 17/07/2008 (WO 2008/084261A1), which is prepared from 3-methyl-2-nitrobenzoic acid by esterification and NBS/(BzO)2Benzyl bromide, N-methylmorpholine-N-oxide (NMMO) oxidation, condensation with 4- (piperidin-3-yl) aniline, treatment of the ring with sodium azide, treatment with NH3The nilapanib is prepared by ammonolysis, and the total yield is 8.8%; a synthetic method for preparing niraparib disclosed in the Chinese patent No. 03/01/2017 (CN 106467513A), wherein active MnO is adopted2/65% HNO3Directly oxidizing methyl in the esterification product into aldehyde, replacing sodium azide with triethyl phosphite to realize ring closure, and preparing the nilapanib by formamide ammoniation and N-acetyl-L-leucine chiral resolution, wherein the total yield is 11.7%; 31-th-chinese patent (CN 106749181a) in 2017 by reacting the esterification product with DMF-DMA, NaIO4The corresponding benzaldehyde is prepared by the reaction, ammonium bicarbonate and methyl ester are adopted for ammonolysis, and the preparation method of (S) -4- (piperidine-3-yl) aniline is improved, and the total yield is 52.0%.
In the world patent (ADP-ribose) polymerase (PARP) inhibition disclosed in the 17 th day of world patent publication (WO 2008/084261A1) at 07/2008, 3-methylbenzoic acid is used as a raw material, 3-methyl-2-aminobenzoic acid is prepared through nitration, esterification and catalytic hydrogenation, acetylation and cyclization of sodium nitrite/concentrated hydrochloric acid are carried out to obtain 2H-indazole-7-formate, and then the nilaparib is prepared according to the method (3); or diazotizing by using nitronium tetrafluoroborate, carrying out Schiemann reaction to form corresponding difluorobenzene derivatives, and then preparing the nilapanib according to the method (1).
(3) (ADP-ribose) polymerases (PARP) inhibitors disclosed in the world patent No. 17/07/2008 (WO 2008/084261A1), starting from 2H-indazole-7-carboxylate, by reaction with NH3Aminolysis, nucleophilic substitution with 4-bromofluorobenzene, Suzuki coupling with 3-pyridine boric acid, Flower reaction and hydrogenation reaction to prepare the Nilaparib.
(4) A Chinese patent (CN 106496187A) in 15/03/2017 discloses a synthesis method for preparing a PARP inhibitor niraparib, which is characterized in that 2-methyl aminobenzoate is used as a raw material, diazotized, coupled with 3-phenylpiperidine-1-tert-butyl formate, and Re2(CO)10The nilapanib is prepared by NaOAc catalytic cyclization, formamide aminolysis, Boc protection removal and L- (+) -tartaric acid chiral resolution, and the total yield is 14.8%.
(5) A Chinese patent (CN 106632244A) of 10.05.2017 discloses a novel synthesis method for preparing an anticancer drug, namely niraparib, which takes 3-formyl-2-nitrobenzoate as a raw material and reduces the methyl ester into amine and NaNO by iron powder2HCl diazotization, Na2SO3Reducing to hydrazine, addition cyclization, coupling with (S) -3- (4-bromophenyl) piperidine-1-tert-butyl formate, aminolysis with formamide and Boc protection removal to obtain the nilapanib with the total yield of 26.8%.
(6) Disclosed in the patent of 18 Japanese America, 5.2017 (US 2017/0137403A1) (registered N-2 arylation of indoles), 1H-indazole-7-carboxylic acid was used as a starting material, and nilapanib was obtained in a total yield of 76.0% by amidating with tert-butylamine, coupling with tert-butyl (S) -3- (4-bromophenyl) piperidine-1-carboxylate, and removing the N-tert-butyl of the amide and the Boc-protecting group of piperidine.
(J Am Chem Soc), 2017, 139(2): 623-626, (Selective aryl formation of group fragmentation from the [2+2] cyclic products of 3-triflyloxyyarynes) reported by (Selective aryl formation of 2-trifluoromethane sulfonate) as raw material, forming 3-trifluorooxybenzene intermediate under the action of benzyl magnesium bromide, reacting with 1- (tert-butyldimethylsiloxy) -1,2, 2-trimethoxyethylene to generate [2+2] cycloaddition product, forming 2, 3-benzene alkyne intermediate through ring opening by Grob cleavage, performing [3+2] cycloaddition reaction with 3- {4- [1- (tert-butoxycarbonyl) piperidin-3-yl ] phenyl } -1,2, 3-oxadiazol-3-onium-5-ol to obtain 2, 2-dimethoxy-2- {2- {4- [1- (tert-butyloxycarbonyl) piperidin-3-yl ] phenyl } -2H-indazol-7-yl } acetic acid methyl ester, and finally, the racemic nilapanib is synthesized through deprotection and ammonolysis, wherein the total yield is 14.2%.
In the above methods, the long synthesis routes of the methods (1) to (3) have low utilization rate of (S) -3- (4-aminophenyl) -piperidine-1-carboxylic acid tert-butyl ester, and sodium azide used in the construction of the indazole ring is very unsafe. The methods (4) and (5) have long synthesis routes and low total reaction yield, and a large amount of wastewater and waste residues are generated by diazotization and reduction reactions, so that the method is not environment-friendly and is not beneficial to industrial production. The method (6) has short synthetic route and high total reaction yield, but the raw material source is not easy. The method (7) has a novel synthetic route, but the raw material source is not easy, and a large amount of isomer 2H-indazole-4-methyl acetate can be generated in the [3+2] cycloaddition reaction, so that the total reaction yield is not high, and the method is not suitable for industrial production.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel method for preparing nilapanib and an intermediate thereof, the preparation method takes 2-aminobenzamide and (S) -4- (piperidine-3-yl) aniline as raw materials, and the nilapanib serving as a PARP inhibitor is synthesized by two steps of reactions of oxidative dehydrogenation coupling and paraformaldehyde addition cyclization under the promotion of microwave, and the total yield reaches 81%. Compared with the literature method, the synthesis method is simple and convenient, the raw material 2-aminobenzamide is cheap and easy to obtain, the total reaction yield is high, the production cost is reduced, the reaction condition is mild, the reaction time is short, and the method has potential industrial application prospects.
The invention is realized by the following technical scheme:
a novel process for the preparation of nilapanib and intermediates thereof comprising the steps of:
(1) adding 10mmol of 2-aminobenzamide, 10-20 mmol of (S) -4- (piperidine-3-yl) aniline, 20-30 mmol of oxidant, 0.5-2 mmol of catalyst, 1-3 mmol of ligand and 20-40 mL of solvent into a special microwave reaction bottle provided with a drying tube and a condensing tube, and heating to 30-60 ℃ for 5 min-18 h. Cooling the reaction solution to room temperature, suction-filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) to obtain intermediate (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide;
(2) adding 5mmol of (S) -2- [ [4- (piperidine-3-yl) phenyl ] azo ] benzamide, 10-20 mmol of paraformaldehyde, 0.25-1.5 mmol of catalyst, 0.5-1 mmol of additive and 20-40 mL of solvent into a special microwave reaction bottle provided with a drying tube and a condensing tube, and heating to 60-100 ℃ for reaction for 10 min-20 h. And cooling the reaction liquid to room temperature, carrying out suction filtration, distilling the filtrate under reduced pressure to remove the solvent, and recrystallizing the residue with ethanol to obtain the nilapanib.
In the invention, the oxidant in the step (1) is hydrogen peroxide, tert-butyl hydroperoxide (TBHP), silver carbonate or iodobenzene diacetate, and TBHP is preferred. The catalyst is cuprous chloride, cuprous bromide or cupric bromide, preferably cuprous bromide. The ligand is pyridine, or 8-hydroxyquinoline, or 1, 10-phenanthroline, and pyridine is preferred. The solvent is 1, 2-Dichloroethane (DCE), Tetrahydrofuran (THF) or toluene, preferably toluene. The heating mode is conventional heating or microwave heating, and the microwave heating is preferred because the microwave heating reaction time is short, the obtained reaction liquid has high purity, few side reactions and high yield; the reaction can be completed after microwave heating for 10-20 min.
The catalyst in the step (2) is dichloro (p-methyl isopropylphenyl) ruthenium (II) dimer ([ Ru (p-cymene) Cl)2]2) Or cobalt (III) acetylacetonate (Co (acac)3) Or ([ Ru (p-cymene) Cl)2]2)/(Co(acac)3) Preferably ([ Ru (p-cymene) Cl)2]2)/(Co(acac)3). The additive is water, acetic acid, sodium acetate or sodium dihydrogen phosphate,acetic acid is preferred. The solvent is toluene, dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF) or 1, 4-dioxane, preferably 1, 4-dioxane. The heating mode is conventional heating or microwave heating, and the microwave heating is preferred because the microwave heating reaction time is short, the obtained reaction liquid has high purity, few side reactions and high yield; the reaction can be completed after microwave heating for 10-30 min.
The chemical reaction formula of the invention is as follows:
in the oxidative dehydrogenation coupling reaction of the invention, Ag is used in the presence of a catalyst CuBr/pyridine2CO3、PhI(OAc)2The asymmetric aromatic azo compound can be synthesized by oxidative dehydrogenation coupling reaction of two aromatic amines by using hydrogen peroxide and TBHP as oxidants, wherein the yield of the product obtained by using TBHP as the oxidant is highest. Among the various Cu salt catalysts used in the experiments, CuBr has the best catalytic performance. The oxidative dehydrogenation coupling reaction of the arylamine can be promoted by microwave heating, the reaction is only carried out for 10-20 min, the yield of the asymmetric azo product reaches 87%, the reaction is carried out for 18h by conventional heating, and the yield of the asymmetric azo product is 74%. The ligand has great influence on the catalytic activity of CuBr, and pyridine as the ligand enables CuBr to more effectively catalyze the oxidative dehydrogenation coupling reaction of two aromatic amines, so that an asymmetric azo product is obtained with good yield. When the dosage of the oxidant is insufficient, the oxidative dehydrogenation coupling reaction cannot be well completed, and the yield of the asymmetric azo product is very low; when the dosage of the oxidant is equal to the total amount of the two aromatic amines, the yield of the asymmetric azo product is the highest; the use of an excessive amount of the oxidizing agent causes further oxidation of the azo compound, resulting in a decrease in the yield of the asymmetric azo product. The yield of the asymmetric azo product gradually increases with the amount of CuBr. The yield of the asymmetric azo product is reduced by reducing or increasing the using amount of pyridine. Ethanol and tetrahydrofuran are used as solvents, but the yield of the asymmetric azo product is low. (S) -4- (piperidin-3-yl) aniline is in excess, and the yield of asymmetric azo products is low; 2-aminobenzeneThe yield of the asymmetric azo product is not obviously increased due to excessive amide. With the increase of the reaction temperature, the yield of the asymmetric azo product is gradually increased, and the yield of the asymmetric azo product is reduced to a certain extent when the reaction temperature is overhigh. The microwave radiation time is too short, and the yield of the asymmetric azo product is lower; the microwave irradiation time is too long, the generated by-products are increased, and the yield of the asymmetric azo product is reduced.
In the addition cyclization reaction of the present invention, [ Ru (p-cymene) Cl ] is used alone2]2Or Co (acac)3As a catalyst, although the catalyst has certain catalytic activity on the addition cyclization reaction of the azo compound and the paraformaldehyde, the yield of the target product is low. [ Ru (p-cymene) Cl2]2And Co (acac)3The catalytic activity of the catalyst is obviously improved, the reaction is only carried out for 10-30 min under the promotion of microwave, the yield of the target product is up to 93%, and the yield of the target product is 86% after the conventional heating reaction is carried out for 20 h. The target product can be obtained with better yield by using 1, 4-dioxane, DMF and DMSO as reaction media. The addition cyclization reaction can be realized without using an additive, but the yield of a target product is not high; adding HOAc, NaOAc and NaH2PO4、H2O has a certain accelerating effect on the addition cyclization reaction, and the reaction effect is best when HOAc is added. Increasing [ Ru (p-cymene) Cl in catalyst2]2The yield of the target product is not obviously changed by the dosage of the compound; increasing Co (acac)3The yield of the target product is reduced. The yield of the target product is obviously improved along with the increase of the dosage of the paraformaldehyde, and the yield of the target product is not obviously increased after the dosage of the paraformaldehyde is increased by 2-3 times of that of the azo compound. The reaction temperature is increased to facilitate the progress of addition cyclization reaction. The reaction time is short, the addition cyclization reaction can not be completely carried out, and the yield of the target product is low; the reaction time is prolonged, and the yield of the target product has no obvious change.
Compared with the literature method, the synthesis method is simple and convenient, the total reaction yield is high, the used raw material 2-aminobenzamide is cheap and easy to obtain, the production cost is reduced, the reaction condition is mild, and the reaction time is short. The invention provides an efficient, simple and convenient method for synthesizing the 2H-indazole compound, and has potential industrial application prospect.
Detailed Description
Example 1: preparation of intermediate (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide
2-aminobenzamide (1.36 g, 10 mmol), (S) -4- (piperidin-3-yl) aniline (1.76 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), pyridine (0.24 g, 3 mmol), iodobenzene diacetate (6.44 g, 20 mmol), toluene (20 mL) were added to a microwave-dedicated reaction flask equipped with a drying tube and a condensing tube, and reacted at 50 ℃ for 15 min under microwave irradiation. The reaction solution was cooled to room temperature, filtered under suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100: 1) to give (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide (2.12 g, 69%) as a yellow solid.
Example 2: preparation of intermediate (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide
2-aminobenzamide (1.36 g, 10 mmol), (S) -4- (piperidin-3-yl) aniline (1.76 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), pyridine (0.24 g, 3 mmol), silver carbonate (5.51 g, 20 mmol), toluene (20 mL) were added to a microwave-dedicated reaction flask equipped with a drying tube and a condensing tube, and reacted at 50 ℃ for 15 min under microwave irradiation. The reaction solution was cooled to room temperature, filtered under suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100: 1) to give (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide (1.92 g, 62%) as a yellow solid.
Example 3: preparation of intermediate (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide
2-aminobenzamide (2.72 g, 20 mmol), (S) -4- (piperidin-3-yl) aniline (1.76 g, 10 mmol), cuprous bromide (0.28 g, 2 mmol), pyridine (0.24 g, 3 mmol), TBHP (3.86 g, 30 mmol), toluene (30 mL) were added to a microwave-dedicated reaction flask equipped with a drying tube and a condensing tube, and reacted at 40 ℃ for 20 min under microwave irradiation. The reaction solution was cooled to room temperature, filtered under suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100: 1) to give (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide (2.25 g, 73%) as a yellow solid.
Example 4: preparation of intermediate (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide
2-aminobenzamide (1.36 g, 10 mmol), (S) -4- (piperidin-3-yl) aniline (1.76 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), pyridine (0.24 g, 3 mmol), TBHP (2.58 g, 20 mmol), toluene (20 mL) were added to a microwave-dedicated reaction flask equipped with a drying tube and a condensing tube, and reacted at 50 ℃ for 15 min under microwave irradiation. The reaction solution was cooled to room temperature, filtered under suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100: 1) to give (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide (2.68 g, 87%) as a yellow solid.
Example 5: preparation of intermediate (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide
2-aminobenzamide (1.36 g, 10 mmol), (S) -4- (piperidin-3-yl) aniline (1.76 g, 10 mmol), cuprous chloride (0.10 g, 1 mmol), pyridine (0.24 g, 3 mmol), TBHP (2.58 g, 20 mmol), toluene (20 mL) were added to a microwave-dedicated reaction flask equipped with a drying tube and a condensing tube, and reacted at 50 ℃ for 15 min under microwave irradiation. The reaction solution was cooled to room temperature, filtered under suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100: 1) to give (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide (2.31 g, 75%) as a yellow solid.
Example 6: preparation of intermediate (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide
In a microwave-dedicated reaction flask equipped with a drying tube and a condensing tube, 2-aminobenzamide (1.36 g, 10 mmol), (S) -4- (piperidin-3-yl) aniline (1.76 g, 10 mmol), copper bromide (0.23 g, 1 mmol), 8-hydroxyquinoline (0.44 g, 3 mmol), TBHP (2.58 g, 20 mmol), tetrahydrofuran (30 mL) were added and reacted at 60 ℃ for 10min under microwave irradiation. The reaction solution was cooled to room temperature, filtered under suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100: 1) to give (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide (1.72 g, 56%) as a yellow solid.
Example 7: preparation of intermediate (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide
2-aminobenzamide (1.36 g, 10 mmol), (S) -4- (piperidin-3-yl) aniline (1.76 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), pyridine (0.24 g, 3 mmol), TBHP (2.58 g, 20 mmol), toluene (20 mL) were added to a microwave-dedicated reaction flask equipped with a drying tube and a condensing tube, and reacted at 50 ℃ for 18h with ordinary heating. The reaction solution was cooled to room temperature, filtered under suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100: 1) to give (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide (2.28 g, 74%) as a yellow solid.
Example 8: preparation of nilapanib
Adding (S) -2- [ [4- (piperidine-3-yl) phenyl group into a special microwave reaction bottle with a drying tube and a condensing tube]Azo group]Benzamide (1.04 g, 5 mmol), paraformaldehyde (0.60 g, 20 mmol), Co (acac)3(0.18 g, 0.5 mmol), acetic acid (0.03 g, 0.5 mmol) and 1, 4-dioxane (30 mL) were reacted at 100 ℃ for 30 min under microwave irradiation. The reaction solution was cooled to room temperature, filtered under suction, the solvent was removed from the filtrate by distillation under the reduced pressure, and the residue was recrystallized from ethanol to give nilapanib (0.83 g, 52%) as a white solid.
Example 9: preparation of nilapanib
Adding (S) -2- [ [4- (piperidine-3-yl) phenyl group into a special microwave reaction bottle with a drying tube and a condensing tube]Azo group]Benzamide (1.04 g, 5 mmol), paraformaldehyde (0.30 g, 10 mmol), [ Ru (p-cymene) Cl2]2(0.30 g, 0.5 mmol)，Co(acac)3(0.18 g, 0.5 mmol), sodium dihydrogen phosphate (0.06 g, 0.5 mmol) and DMF (40 mL) were reacted at 90 ℃ for 30 min under microwave irradiation. The reaction solution was cooled to room temperature, filtered under suction, the solvent was removed from the filtrate by distillation under the reduced pressure, and the residue was recrystallized from ethanol to give nilapanib (1.12 g, 70%) as a white solid.
Example 10: preparation of nilapanib
Adding (S) -2- [ [4- (piperidine-3-yl) phenyl group into a special microwave reaction bottle with a drying tube and a condensing tube]Azo compoundsBase of]Benzamide (1.04 g, 5 mmol), paraformaldehyde (0.45 g, 15 mmol), [ Ru (p-cymene) Cl2]2(0.15 g, 0.25 mmol)，Co(acac)3(0.18 g, 0.5 mmol), acetic acid (0.03 g, 0.5 mmol) and 1, 4-dioxane (20 mL) were reacted at 100 ℃ for 20 min under microwave irradiation. The reaction solution was cooled to room temperature, filtered under suction, the solvent was removed from the filtrate by distillation under the reduced pressure, and the residue was recrystallized from ethanol to give nilapanib (1.49 g, 93%) as a white solid.
Example 11: preparation of nilapanib
Adding (S) -2- [ [4- (piperidine-3-yl) phenyl group into a special microwave reaction bottle with a drying tube and a condensing tube]Azo group]Benzamide (1.04 g, 5 mmol), paraformaldehyde (0.45 g, 15 mmol), [ Ru (p-cymene) Cl2]2(0.30 g, 0.5 mmol)，Co(acac)3(0.18 g, 0.5 mmol), water (0.01 g, 0.5 mmol) and DMSO (30 mL), and reacted at 100 ℃ for 10min under microwave irradiation. The reaction solution was cooled to room temperature, filtered under suction, the solvent was removed from the filtrate by distillation under the reduced pressure, and the residue was recrystallized from ethanol to give nilapanib (1.25 g, 78%) as a white solid.
Example 12: preparation of nilapanib
Adding (S) -2- [ [4- (piperidine-3-yl) phenyl group into a special microwave reaction bottle with a drying tube and a condensing tube]Azo group]Benzamide (1.04 g, 5 mmol), paraformaldehyde (0.45 g, 15 mmol), [ Ru (p-cymene) Cl2]2(0.15 g, 0.25 mmol)，Co(acac)3(0.18 g, 0.5 mmol), acetic acid (0.03 g, 0.5 mmol) and 1, 4-dioxane (20 mL) were reacted by heating at 100 ℃ for 20 h. The reaction solution was cooled to room temperature, filtered under suction, the solvent was removed from the filtrate by distillation under the reduced pressure, and the residue was recrystallized from ethanol to give nilapanib (1.38 g, 86%) as a white solid.
Claims (1)
1. A novel process for the preparation of nilapanib and intermediates thereof, characterized in that it comprises the following steps:
(1) adding 10mmol of 2-aminobenzamide, 10-20 mmol of (S) -4- (piperidine-3-yl) aniline, 20-30 mmol of hydrogen peroxide or tert-butyl hydroperoxide (TBHP), or silver carbonate or iodobenzene diacetate, 0.5-2 mmol of cuprous chloride or cuprous bromide or cupric bromide, 1-3 mmol of pyridine or 8-hydroxyquinoline or 1, 10-phenanthroline, 20-40 mL of 1, 2-Dichloroethane (DCE), or Tetrahydrofuran (THF) or toluene into a special microwave reaction bottle provided with a drying tube and a condensing tube, and reacting for 5 min-18 h by conventional or microwave heating at 30-60 ℃; cooling the reaction solution to room temperature, suction-filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) to obtain intermediate (S) -2- { [4- (piperidin-3-yl) phenyl ] azo } benzamide;
(2) adding 5mmol of (S) -2- [ [4- (piperidine-3-yl) phenyl ] in a special microwave reaction bottle with a drying tube and a condensing tube]Azo group]Benzamide, 10-20 mmol of paraformaldehyde, 0.25-1.5 mmol of dichloro (p-methylisopropylphenyl) ruthenium (II) dimer ([ Ru (p-cymene) Cl)2]2) Or cobalt (III) acetylacetonate (Co (acac)3) Or ([ Ru (p-cymene) Cl)2]2)/(Co(acac)3) 0.5-1 mmol of water, or acetic acid, or sodium acetate, or sodium dihydrogen phosphate, 20-40 mL of toluene, or dimethyl sulfoxide (DMSO), or N, N-Dimethylformamide (DMF), or 1, 4-dioxane, and reacting for 10 min-20 h at 60-100 ℃ by conventional or microwave heating; and cooling the reaction liquid to room temperature, carrying out suction filtration, distilling the filtrate under reduced pressure to remove the solvent, and recrystallizing the residue with ethanol to obtain the nilapanib.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910450429.3A CN110156751B (en) | 2019-05-28 | 2019-05-28 | Novel method for preparing nilapanib and intermediate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910450429.3A CN110156751B (en) | 2019-05-28 | 2019-05-28 | Novel method for preparing nilapanib and intermediate thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110156751A CN110156751A (en) | 2019-08-23 |
| CN110156751B true CN110156751B (en) | 2022-01-18 |
Family
ID=67629359
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910450429.3A Active CN110156751B (en) | 2019-05-28 | 2019-05-28 | Novel method for preparing nilapanib and intermediate thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110156751B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114524800A (en) * | 2022-01-20 | 2022-05-24 | 上海陶术生物科技有限公司 | Synthesis method of nilapanib intermediate |
| CN114920699B (en) * | 2022-05-31 | 2024-03-19 | 甘肃皓天科技股份有限公司 | Method for preparing 6-chloro-2-methyl-2H-indazol-5-amine |
| CN115626891B (en) * | 2022-10-20 | 2024-01-26 | 四川轻化工大学 | Synthesis method of nilaparib key intermediate |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2109608B1 (en) * | 2007-01-10 | 2011-03-23 | Istituto di Richerche di Biologia Molecolare P. Angeletti S.p.A. | Amide substituted indazoles as poly(adp-ribose)polymerase (parp) inhibitors |
| EP2928473B1 (en) * | 2012-12-07 | 2017-06-28 | Merck Sharp & Dohme Corp. | Regioselective n-2 arylation of indazoles |
| CN106496187A (en) * | 2016-09-14 | 2017-03-15 | 陕西科技大学 | A kind of synthetic method for preparing PARP inhibitor Niraparib |
| CN106632244A (en) * | 2016-09-30 | 2017-05-10 | 陕西科技大学 | A novel synthetic method for preparing an anticancer medicine Niraparib |
| CN106467513A (en) * | 2016-09-30 | 2017-03-01 | 陕西科技大学 | A kind of synthetic method preparing Niraparib |
| CN106831708A (en) * | 2016-11-22 | 2017-06-13 | 西安泰科迈医药科技股份有限公司 | A kind of synthetic method of new oral cancer therapy drug Nirapairb |
| CN106749181A (en) * | 2016-12-21 | 2017-05-31 | 南京艾德凯腾生物医药有限责任公司 | A kind of method for preparing Ni Lapani |
-
2019
- 2019-05-28 CN CN201910450429.3A patent/CN110156751B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors;Philip Jones等;《J. Med. Chem. 》;20091029;第52卷;scheme 3a * |
| Synthesis of (2H)-Indazoles from Azobenzenes UsingParaformaldehyde as a One-Carbon Synthon;Rina Chun等;《Adv. Synth. Catal.》;20190114;第361卷;图1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110156751A (en) | 2019-08-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110156751B (en) | Novel method for preparing nilapanib and intermediate thereof | |
| EP2817289B1 (en) | Asymmetric synthetic processes for the preparation of aminosulfone compounds | |
| Jiang et al. | Highly enantioselective construction of a quaternary carbon center of dihydroquinazoline by asymmetric Mannich reaction and chiral recognition | |
| CN105085373B (en) | A kind of purification process to Apremilast product | |
| CN111171037A (en) | Chiral spiro 3, 2' -pyrrolidine oxidation indole skeleton compound, preparation method and application thereof, intermediate and preparation method | |
| CN114380741B (en) | Preparation method of 4-position alkylated derivative of 2-methylquinoline compound | |
| WO2016055015A1 (en) | Method for preparing sitagliptin intermediate via asymmetrical reduction method | |
| CA2509833A1 (en) | 1-alkyl-3-aminoindazoles | |
| CN108440496B (en) | A method of preparing 2- aminoindole derivatives | |
| WO2010004957A1 (en) | Chiral iridium aqua complex and method for producing optically active hydroxy compound using the same | |
| CN108689907B (en) | Method for preparing 2-nitroindole derivative | |
| WO2016141833A1 (en) | Method for synthesizing medical intermediate phenanthrene compounds using palladium trifluoroacetate | |
| CN107473941A (en) | A kind of allyl alcohol and its method of asymmetric synthesis of cyclopropyl substitution | |
| CN107298683A (en) | A kind of synthetic method of chiral benzodiazepine * compounds | |
| CN107973755B (en) | Preparation method of 3-acetamido quinoxalinone derivative | |
| CN101671357B (en) | (S)-Alpha, Alpha-fluorine-containing diaryl-2-pyrrolidine methanol derivative as well as preparation and applications thereof | |
| JP2022075375A (en) | Method for producing optically active amine compound | |
| WO2015192774A1 (en) | Application of chiral aminophenol ligand in asymmetric synthesis of efavirenz | |
| CN115108980B (en) | Preparation method of No. 4 acylated derivative of 2-methylquinoline compound | |
| JP4643566B2 (en) | Method for allylation of N-acylhydrazone | |
| CN108558878B (en) | Synthesis process of quinoline and derivatives thereof | |
| CN109912538B (en) | Preparation method of antidepressant vortioxetine | |
| CN107383076A (en) | A kind of synthetic method of the chlorophenylboronic acid pinacol ester of 3 amino 4 | |
| CN109776400B (en) | Preparation method of (R) -phenyl (pyridine-2-yl) methanol derivative | |
| CN107721920B (en) | Synthesis method of quinoline amide compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20190823 Assignee: Zhenjiang Renzhi Biotechnology Co.,Ltd. Assignor: JIANGSU FOOD & PHARMACEUTICAL SCIENCE COLLEGE Contract record no.: X2022320000323 Denomination of invention: A New Method for the Preparation of Nilapani and Its Intermediates Granted publication date: 20220118 License type: Common License Record date: 20221210 |