CN104326985A - Preparation method of linifanib - Google Patents

Preparation method of linifanib Download PDF

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CN104326985A
CN104326985A CN201410494691.5A CN201410494691A CN104326985A CN 104326985 A CN104326985 A CN 104326985A CN 201410494691 A CN201410494691 A CN 201410494691A CN 104326985 A CN104326985 A CN 104326985A
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洪健
许忻
王景炳
徐艳超
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An Run Pharmaceutical Technology (suzhou) Co Ltd
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An Run Pharmaceutical Technology (suzhou) Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

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Abstract

The invention provides a preparation method of linifanib. The preparation method includes following steps: (a) carrying out a reaction between a compound represented as the formula (I) and hydrazine hydrate to obtain the compound represented as the formula (II) and carrying out a reaction between the compound represented as the formula (II) and di-tert-butyl dicarbonate ester to obtain the compound represented as the formula (III); (b) carrying out a reaction between compound represented as the formula (IV), a phosgenation reagent and the compound represented as the formula (V) to obtain the compound represented as the formula (VI); (c) carrying out a chemical exchange reaction to the compound represented as the formula (VI) through a one-pot method to obtain the compound represented as the formula (VII), and carrying out a coupling reaction between the compound represented as the formula (VII) and the compound represented as the formula (III) without separation and purification to obtain the compound represented as the formula (VIII); and (d) carrying out a deprotective reaction to the compound represented as the formula (VIII) to obtain the linifanib. The method is reduced in reaction steps, is reduced in cost, is increased in yield, can be used in industrialized large-scale production. A reaction route of the method is described as follows.

Description

Preparation method of Linifangni
Technical Field
The invention relates to the field of drug synthesis, and more particularly relates to a preparation method of a small-molecule chemical drug Linifanib.
Background
The chemical name of the Linifanib (ABT-869) is N- [4- (3-amino-1H-indazol-4-yl) phenyl ] -N' - (2-fluoro-5-methylphenyl) urea, and the Linifanib (ABT-869) is a multi-target receptor tyrosine kinase inhibitor with a novel structure developed by Yapei company. Linifib acts strongly and selectively on Vascular Endothelial Growth Factor (VEGF) and Platelet Derived Growth Factor (PDGF), inhibiting the growth of tumor cells by inhibiting tumor angiogenesis. The preclinical research result shows that the antitumor activity of the compound is remarkable, and the compound shows good pharmacokinetic properties in different animals. Various malignant tumors including kidney cancer, liver cancer, colon cancer, breast cancer, non-small cell lung cancer, leukemia and the like are currently clinically researched, and the research on the late hepatocellular carcinoma enters a phase III clinical test.
The existing technical method for synthesizing the Linifanib is to react a compound with a biboronic acid pinacol ester to generate a compound of a formula (VII), and the compound of the formula (VII) is separated and purified and then is subjected to a coupling reaction with a compound of a formula (III). However, such a method has the following disadvantages: (1) the reaction steps are long, the reaction comprises two steps of palladium-catalyzed chemical exchange and coupling reaction, a borate intermediate compound (VII) needs to be separated and purified, and the post-treatment is troublesome; (2) the cost is high, and expensive catalysts are needed in both palladium catalytic reactions, so that the method cannot be widely applied. For example, reference may be made to Journal of Medicinal Chemistry, 50(7), 1584-.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention provides a synthesis method of Rini Fanib, which adopts a one-pot method as a key step, has short reaction steps, does not need intermediate treatment, saves the cost and improves the efficiency.
The technical scheme adopted by the invention is as follows: a synthetic method of Linifanib comprises the following steps: (a) enabling a compound of a formula (I) and hydrazine hydrate to perform a ring closing reaction in an organic solvent at a reflux temperature to obtain a compound of a formula (II), and enabling the compound of the formula (II) and di-tert-butyl dicarbonate to perform a reaction in the organic solvent at 20-40 ℃ under the catalytic action of alkali to obtain a compound of a formula (III); (b) carrying out a phosgenation reaction on the compound of formula (IV) and a phosgenation reagent in an organic solvent at 20-80 ℃ to obtain a phosgenation reaction product, and carrying out a reaction on the phosgenation reaction product and p-iodoaniline of formula (V) in the organic solvent at 20-70 ℃ to obtain a compound of formula (VI); (c) performing a chemical exchange reaction on the compound of the formula (VI) obtained in the step (b) and pinacol diboron in an organic solvent at 20-120 ℃ under the action of a palladium catalyst by adopting a one-pot method to obtain a solution of the compound of the formula (VII), or performing a reaction on the compound of the formula (VI) and magnesium metal in the organic solvent at a reflux temperature, cooling a reaction solution to 20-40 ℃ after the reaction is completed, adding zinc halide to further perform a chemical exchange reaction to obtain a solution of the compound of the formula (VII), and performing a coupling reaction on the compound of the formula (III) obtained in the step (a) in the solution of the compound of the formula (VII) and the compound of the formula (VII) under the action of a palladium catalyst or a nickel catalyst at 20-120 ℃ to obtain the compound of the formula (VIII); or carrying out chemical exchange reaction on the compound of the formula (VI) and an organic lithium reagent zinc halide in an organic solvent at-70 to-90 ℃ to obtain a compound of a formula (VII), wherein the compound of the formula (VII) and the compound of the formula (III) obtained in the step (a) are subjected to coupling reaction in the organic solvent under the action of a palladium catalyst or a nickel catalyst at 20 to 120 ℃ to obtain the compound of the formula (VIII); (d) subjecting the compound of formula (VIII) obtained in step (c) to a deprotection reaction to obtain linafanib; the reaction route of the method is as follows:
preferably, the step (b) can be performed by a one-pot method, which comprises the following steps: carrying out light gasification reaction on a compound shown in a formula (IV) and a light gasification reagent in an organic solvent at the temperature of 20-80 ℃, obtaining a reaction solution containing a light gasification reaction product after the reaction is finished, and reacting p-iodoaniline shown in a formula (V) and the light gasification reaction product in the reaction solution at the temperature of 20-70 ℃ to obtain a compound shown in a formula (VI);
further, in the step (a), the organic solvent used in the ring closure reaction is selected from n-butanol, t-butanol, isobutanol, and the like, but is not limited thereto, and the ring closure reaction time is 1 to 4 hours.
Furthermore, in the step (a), the base used for the reaction of the compound of formula (II) and di-tert-butyl dicarbonate is selected from one or more of 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, potassium tert-butoxide, and sodium hydrogen, the organic solvent used is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, toluene, ethyl acetate, diethyl ether, and 1, 4-dioxane, and the reaction time is 1-3 hours.
Still further, in the step (b), the phosgenation reagent is phosgene, diphosgene, triphosgene or N, N' -Carbonyldiimidazole (CDI), the organic solvent used in the phosgenation reaction and the organic solvent used in the reaction of the phosgenation reaction product and the p-iodoaniline compound of the formula (V) are respectively and independently selected from one or more of ethyl acetate, tetrahydrofuran, acetonitrile, diethyl ether, toluene, 1, 4-dioxane and dichloromethane, the time of the phosgenation reaction is 3-5 hours, and the time of the reaction of the phosgenation reaction product and the p-iodoaniline is 4-6 hours.
Preferably, in step (c), the palladium catalyst is selected from PdCl2(dppf)、Pd/C、Pd(OAc)2、Pd(PPh3)4、PdCl2(PPh3)2、PdCl2(CH3CN)2、Pd2(dba)3One or more of the nickel catalyst and the nickel catalyst are NiCl2(dppe), but is not limited thereto.
Further, in the step (c), the organic solvent used in the chemical exchange reaction of the compound of formula (VI) with the pinacol ester of diboronic acid, the organic solvent used in the chemical exchange reaction of the compound of formula (VI) with magnesium metal and zinc halide, and the organic solvent used in the coupling reaction are independently selected from one or more of dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dioxane, dichloroethane, acetonitrile and toluene.
Further, the organic solvent used in the chemical exchange reaction of the compound of formula (VI) with the organolithium reagent and the zinc halide is one or more selected from n-hexane, cyclohexane, toluene, diethyl ether and methyl tert-butyl ether. The organolithium reagent is selected from n-butyllithium, isobutyllithium or sec-butyllithium.
Preferably, in the step (c), the reaction time of the chemical exchange reaction is 1.5 to 5 hours,
more preferably, in step (c), the coupling reaction time is 2 to 5 hours.
Preferably, in step (d), the deprotection reagent used for the deprotection reaction is trifluoroacetic acid or hydrochloric acid.
More preferably, in step (d), the deprotection reaction is carried out at a temperature of 20 to 50 ℃ for 2 to 6 hours.
The invention also provides an intermediate for preparing the rilifarnib, which has a structural formula shown as the following formula (III):
compared with the prior art, the invention has the following advantages: the invention provides a new synthesis method of Rini's Fannel, the key steps of the method adopt a one-pot method, namely, the separation of intermediate products is not needed between the chemical exchange reaction and the coupling reaction, namely, the separation and purification of the compound of formula (VII) are not needed, and the next reaction is directly carried out in the solution after the reaction, thus reducing the steps of reaction treatment and purification, shortening the steps and time of the whole reaction and saving the solvent. In addition, in the two-step reaction of the one-pot method, the palladium catalyst only needs to be fed once, and the coupling reaction can also be carried out by using the cheaper nickel catalyst, so that the expensive palladium catalyst is saved, the cost of the raw material medicine can be further greatly reduced, and the production period is shortened.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1
A compound of formula (II) was synthesized.
Example 1-1: adding hydrazine hydrate (1.01g, 20mmol) dropwise into n-butanol (50ml) solution of compound (5g, 20mmol) of formula (I) at room temperature, stirring for 10 min, and heating the solution to 105 deg.C and refluxing for 2 hr; after the reaction is finished, the solvent is evaporated under reduced pressure, water (30ml) is added after the reaction is cooled to room temperature, light yellow solid is separated out, stirring is continued for half an hour, filtering is carried out, the filter cake is washed by water for three times (100ml multiplied by 3), and drying is carried out, so that the light yellow solid, namely the compound of the formula (II) (5.1g, the yield is 98 percent) is obtained.
1H-NMR(400MHz,DMSO-d6,ppm):5.05(s,2H),6.91-6.95(m,1H),7.29(d,J＝8.4Hz,1H),7.35(d,J＝7.2Hz,1H),11.79(s,1H)。
Examples 1 to 2: hydrazine hydrate (1.01g, 20mmol) is added dropwise to a solution of the compound of formula (I) (5g, 20mmol) in tert-butanol (50ml) at room temperature, after stirring for 10 minutes, the solution is heated to 83 ℃ and refluxed for 4 hours; after the reaction is finished, the solvent is evaporated under reduced pressure, water (30ml) is added after the reaction is cooled to room temperature, light yellow solid is separated out, stirring is continued for half an hour, filtering is carried out, the filter cake is washed by water for three times (100ml multiplied by 3), and drying is carried out, so that the light yellow solid, namely the compound of the formula (II) (4.9g, the yield is 94 percent) is obtained.
Example 2
A compound of formula (III) was synthesized.
Example 2-1: the prepared compound of the formula (II) (4.1g, 15.9mmol) and 4-dimethylaminopyridine (0.16g,1.3mmol) were dissolved in dichloromethane (240ml) at room temperature, a solution of di-tert-butyl dicarbonate (3.47g, 15.9mmol) in dichloromethane (120ml) was added dropwise with stirring over 2 hours, after completion of the addition, the reaction solution was washed three times with water (100 ml. times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, the clear solution was evaporated to dryness, the resulting solid was washed three times with petroleum ether (100 ml. times.3), and a white solid, i.e., the compound of the formula (III) (4.3g, yield 76%) was obtained by suction filtration.
1H-NMR(400MHz,CDCl3,ppm):1.69(s,9H),4.96(s,2H),7.11-7.15(m,1H),7.64(d,1H,J＝7.6Hz),8.11-8.13(m,1H)。
Example 2-2: the prepared compound of the formula (II) (4.1g, 15.9mmol) and triethylamine (3.2g,31.8mmol) were dissolved in toluene (120ml) at 40 ℃, a solution of di-tert-butyl dicarbonate (3.47g, 15.9mmol) in toluene (60ml) was added dropwise with stirring over 1 hour, after completion of the addition, the reaction solution was washed three times with water (100 ml. times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, the clear solution was evaporated to dryness, the resulting solid was washed three times with petroleum ether (100 ml. times.3), and a white solid, i.e., the compound of the formula (III) (3.8g, yield 67%) was obtained by suction filtration.
Examples 2 to 3: the prepared compound of the formula (II) (4.1g, 15.9mmol) and potassium tert-butoxide (1.8g,15.9mmol) were dissolved in tetrahydrofuran (120ml) at 20 ℃, a solution of di-tert-butyl dicarbonate (3.47g, 15.9mmol) in tetrahydrofuran (60ml) was added dropwise with stirring over 3 hours, after completion of the addition, the reaction mixture was washed three times with water (100 ml. times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, the clear solution was evaporated to dryness, the resulting solid was washed three times with petroleum ether (100 ml. times.3), and a white solid, i.e., the compound of the formula (III) (3.1g, yield 55%) was obtained by suction filtration.
Example 3
Synthesis of a Compound of formula (VI)
Example 3-1: diphosgene (4.4g, 22mmol) was dissolved in ethyl acetate (60ml) under nitrogen, the resulting solution was stirred at 0 ℃ and a solution of the compound of formula (IV) (i.e. 2-fluoro-5-methylaniline) (5.0g, 40mmol) in ethyl acetate (80ml) was added dropwise thereto, and the reaction was carried out at 70 ℃ for 4 hours after completion of the addition. After cooling to room temperature, a solution of iodoaniline (8.76g, 40mmol) in ethyl acetate (40ml) was added dropwise with stirring at room temperature, and after completion of the addition, the reaction mixture was reacted at 60 ℃ for 5 hours, whereupon a large amount of white solid precipitated, the reaction mixture was filtered while hot, and the filter cake was washed with hot ethanol (40ml) and dried to obtain a white solid, i.e., the compound of formula (VI) (11.70g, 72% yield).
1H-NMR(400MHz,DMSO-d6,ppm):2.27(s,3H),6.80-6.83(m,1H),7.08-7.13(m,1H),7.31(d,J＝8.8Hz,2H),7.61(d,J＝8.4Hz,2H),7.94-7.97(m,1H),8.49(d,J＝2.0Hz,1H),9.15(s,1H)。
Example 3-2: triphosgene (4.3g, 13.3mmol) was dissolved in tetrahydrofuran (60ml) under nitrogen protection, the resulting solution was stirred at 0 ℃ and a solution of the compound of formula (IV) (i.e., 2-fluoro-5-methylaniline) (5.0g, 40mmol) in tetrahydrofuran (80ml) was added dropwise thereto, and the reaction was carried out at 80 ℃ for 3 hours after completion of the addition. After cooling to room temperature, a tetrahydrofuran (40ml) solution of iodoaniline (8.76g, 40mmol) was added dropwise with stirring at room temperature, and after completion of the dropwise addition, the reaction mixture was reacted at 70 ℃ for 4 hours, whereupon a large amount of white solid precipitated, the reaction mixture was filtered while hot, and the filter cake was washed with hot ethanol (40ml) and dried to obtain a white solid, i.e., the compound of formula (VI) (10.2g, yield 63%).
Examples 3 to 3: to a solution of phosgene (44mmol) in toluene (29.3g, 15 wt.%) under nitrogen with stirring at 0 ℃ was added dropwise a solution of the compound of formula (IV) (i.e. 2-fluoro-5-methylaniline) (5.0g, 40mmol) in toluene (80ml), and after completion of the addition, the reaction was carried out at 60 ℃ for 5 hours. After cooling to room temperature, a toluene (40ml) solution of p-iodoaniline (8.76g, 40mmol) was added dropwise with stirring at room temperature, and after completion of the dropwise addition, the reaction mixture was reacted at 50 ℃ for 6 hours, whereupon a large amount of white solid precipitated, the reaction solution was filtered while hot, and the filter cake was washed with hot ethanol (40ml) and dried to obtain a white solid, i.e., the compound of formula (VI) (10.8g, yield 66%).
Examples 3 to 4: CDI (12.9g, 40mmol) was dissolved in tetrahydrofuran (60ml) under nitrogen, added to a solution of the compound of formula (IV) (i.e. 2-fluoro-5-methylaniline) (5.0g, 40mmol) and triethylamine (4.0g, 40mmol) in tetrahydrofuran (80ml) at 0 deg.C, and reacted at 25 deg.C for 3 hours after completion of the addition. A solution of p-iodoaniline (8.76g, 40mmol) in tetrahydrofuran (40ml) was added dropwise, and the reaction was carried out at 25 ℃ for 4 hours after completion of the addition. The reaction was concentrated, poured into water (500ml), extracted with dichloromethane (100mlx3), dried, concentrated, and purified by column chromatography to give a white solid, i.e. the compound of formula (VI) (8.2g, 50.4% yield).
Example 4
Synthesis of a Compound of formula (VIII)
Example 4-1: under the protection of nitrogen, PdCl is added2(dppf) (0.45g, 0.55mmol) was added to a mixed solution containing the compound of formula (VI) (1.01g, 2.74mmol), pinacol ester diboron (1.04g, 4.10mmol), potassium acetate (1.07g, 10.94mmol) and dimethyl sulfoxide (35ml), and the temperature was raised to 80 ℃ for reaction for 3 hours; the reacted solution was cooled to room temperature, and a solution (7ml) of the compound of the formula (III) synthesized above (0.82g, 2.28mmol) in dimethyl sulfoxide and an aqueous solution (5ml) of sodium carbonate (0.73g, 6.84mmol) which had been subjected to preliminary degassing treatment were addedThe mixture was injected into the above-mentioned solution after the reaction cooled to room temperature, and the temperature was raised to 80 ℃ to react for 3 hours. After completion of the reaction, the temperature was naturally lowered to room temperature, insoluble matter was filtered off, the filter cake was washed with ethyl acetate, water (200ml) was added to the filtrate, ethyl acetate was extracted three times (200 ml. times.3), the organic phases were combined and washed six times with water (1000 ml. times.6), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with silica gel column to obtain a pale yellow solid, i.e., the compound of formula (VIII) (0.523g, yield 69%).
1H-NMR(400MHz,CDCl3,ppm):1.61(s,9H),2.19(s,3H),4.15(s,2H),6.62-6.64(m,1H),6.77-6.81(m,1H),6.99(d,J＝7.2Hz,1H),7.25(d,J＝8.4Hz,2H),7.41(t,J＝8.4Hz,1H),7.51(d,J＝8.4Hz,2H),7.96-7.97(m,2H),8.12(d,J＝2.4Hz,1H),8.92(s,1H)。
Example 4-2: pd (PPh) under nitrogen protection3)4(0.64g, 0.55mmol) was added to a mixed solution containing the compound of the formula (VI) (1.01g, 2.74mmol), pinacol ester diboron (1.04g, 4.10mmol), potassium acetate (1.07g, 10.94mmol) and tetrahydrofuran (35ml), and the temperature was raised to 80 ℃ for 5 hours; the reacted solution was cooled to room temperature, and a tetrahydrofuran solution (7ml) of the compound of formula (III) synthesized above (0.82g, 2.28mmol) and an aqueous solution (5ml) of sodium carbonate (0.73g, 6.84mmol) which had been degassed in advance were injected into the above reacted solution cooled to room temperature, and the temperature was raised to 80 ℃ for reaction for 4 hours. After completion of the reaction, the temperature was naturally lowered to room temperature, insoluble matter was filtered off, the filter cake was washed with ethyl acetate, water (200ml) was added to the filtrate, ethyl acetate was extracted three times (200 ml. times.3), the organic phases were combined and washed six times with water (1000 ml. times.6), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with silica gel column to obtain a pale yellow solid, i.e., the compound of formula (VIII) (0.47g, yield 62%).
1H-NMR(400MHz,CDCl3,ppm):1.61(s,9H),2.19(s,3H),4.15(s,2H),6.62-6.64(m,1H),6.77-6.81(m,1H),6.99(d,J＝7.2Hz,1H),7.25(d,J＝8.4Hz,2H),7.41(t,J＝8.4Hz,1H),7.51(d,J＝8.4Hz,2H),7.96-7.97(m,2H),8.12(d,J＝2.4Hz,1H),8.92(s,1H)。
Examples 4 to 3 inPd (OAc) under the protection of nitrogen2(63mg, 0.28mmol) was added to a mixed solution containing the compound of formula (VI) (1.01g, 2.74mmol), pinacol ester diboron (1.04g, 4.10mmol), potassium acetate (1.07g, 10.94mmol) and dimethylformamide (35ml), and the temperature was raised to 115 ℃ for reaction for 2.5 hours; the reacted solution was cooled to room temperature, Pd/C (30mg,0.27mmol) was added, and after degassing, a solution (7ml) of the compound of formula (III) synthesized above (0.82g, 2.28mmol) in dimethylformamide and sodium carbonate (0.73g, 6.84mmol) in water (5ml) which had been degassed in advance were injected into the above reacted solution cooled to room temperature, and the temperature was raised to 115 ℃ for reaction for 2 hours. After completion of the reaction, the temperature was naturally lowered to room temperature, insoluble matter was filtered off, the filter cake was washed with ethyl acetate, water (200ml) was added to the filtrate, ethyl acetate was extracted three times (200 ml. times.3), the organic phases were combined and washed six times with water (1000 ml. times.6), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with silica gel column to obtain a pale yellow solid, i.e., the compound of formula (VIII) (0.45g, yield 60%).
1H-NMR(400MHz,CDCl3,ppm):1.61(s,9H),2.19(s,3H),4.15(s,2H),6.62-6.64(m,1H),6.77-6.81(m,1H),6.99(d,J＝7.2Hz,1H),7.25(d,J＝8.4Hz,2H),7.41(t,J＝8.4Hz,1H),7.51(d,J＝8.4Hz,2H),7.96-7.97(m,2H),8.12(d,J＝2.4Hz,1H),8.92(s,1H)。
Examples 4 to 4: adding a compound (VI) (14.8g, 40mmol) and ether (80ml) into a 500ml three-necked bottle, introducing nitrogen, cooling to-78 ℃, slowly dropping a 2mol/L n-hexane solution (20ml, 40mmol) of n-butyllithium, stirring for reaction for 30min, adding an ether solution (140ml) of zinc bromide (9g, 40mmol), keeping the temperature and stirring for reaction for 1 hour, slowly raising the temperature to room temperature, and concentrating to dryness to obtain a zinc bromide compound (VII). N, N-dimethylformamide (170ml) was added thereto, and after stirring to dissolve the compound of the formula (III) (14.4g, 40mmol) and tetrakistriphenylphosphine palladium (0.464g, 0.4mmol) were added thereto, and the reaction was stirred at room temperature for 5 hours. TLC showed the reaction was complete, the insoluble material was filtered off, the filter cake was washed with ethyl acetate, water (200ml) was added to the filtrate, ethyl acetate was extracted three times (200ml × 3), the organic phases were combined and washed six times with water (1000ml × 6), dried over anhydrous sodium sulfate, filtered, concentrated, and purified on silica gel column to give a pale yellow solid, compound of formula (VIII) (6.89g, 62% yield).
Example 4-5 to a mixed solution of magnesium turnings (2.2g, 0.15mo1) and tetrahydrofuran (40m1), a compound of formula (VI) (1.4g, 4mmo1) and dibromoethane (0.4m1) were added, the mixture was heated with a hair dryer, the reaction was initiated at the bottom of the flask, a solution of a compound of formula (VI) (14.8g, 40mmo1) in tetrahydrofuran (90m1) was added dropwise, and the mixture was refluxed for 2 hours. Cooling to 20 ℃, adding anhydrous zinc chloride (6.2g, 0.05mo1), continuing the reaction at the same temperature for 1 hour, adding nickel chloride/DPPE catalyst (300mg) and the compound of formula (III) (14.4g, 40mmo1), reacting at 20 ℃ for 2 hours, adding into cold water (600m1), extracting with dichloromethane (100ml × 3), drying the organic phase with anhydrous magnesium sulfate, filtering, evaporating the solvent from the filtrate, filtering, concentrating, purifying with silica gel column to obtain a light yellow solid, namely the compound of formula (VIII) (6.2g, 56% yield).
Example 5
Synthetic lipifarnib
Example 5-1: the compound of the formula (VIII) (0.079g, 0.17mmol) and hydrochloric acid (5ml) were charged into a reaction flask, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated, water (10ml) and dichloromethane (10ml) were added, the PH was adjusted to 8, the solution was separated, the aqueous phase was extracted three times with dichloromethane (15ml × 3), the organic phases were combined, washed 1 time with saturated sodium chloride solution (15ml), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was evaporated to dryness to obtain a white solid, that is, lyfanib (0.053g, yield 81%).
1H-NMR(400MHz,DMSO-d6,ppm):2.29(s,3H),4.36(s,2H),6.79-6.83(m,2H),7.09-7.14(m,1H),7.25-7.30(m,2H),7.41(d,J＝8.4Hz,2H),7.60(d,J＝8.8Hz),8.01-8.03(m,1H),8.55(d,J＝2.4Hz,1H),9.22(s,1H),11.74(s,1H)。
Example 5-2: the compound of the formula (VIII) (0.079g, 0.17mmol) and trifluoroacetic acid (7ml) were added to a reaction flask, and the reaction was stirred at 50 ℃ for 2 hours. After the reaction was completed, the reaction solution was concentrated, water (10ml) and dichloromethane (10ml) were added, the PH was adjusted to 8, the solution was separated, the aqueous phase was extracted three times with dichloromethane (15ml × 3), the organic phases were combined, washed 1 time with saturated sodium chloride solution (15ml), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was evaporated to dryness to obtain a white solid, that is, rilifarnib (0.061g, 93% yield).
While specific embodiments of the present invention have been described above, the present invention is not limited to the above embodiments, and various modifications can be made within the scope of the technical gist of the present invention in the technical field of the present invention, as long as the general knowledge is grasped.

Claims (10)

1. A preparation method of Linifangni is characterized by comprising the following steps:
(a) enabling a compound of a formula (I) and hydrazine hydrate to perform a ring closing reaction in an organic solvent at a reflux temperature to obtain a compound of a formula (II), and enabling the compound of the formula (II) and di-tert-butyl dicarbonate to perform a reaction in the organic solvent under the catalysis of alkali at 20-40 ℃ to obtain a compound of a formula (III);
(b) carrying out a phosgenation reaction on the compound of formula (IV) and a phosgenation reagent in an organic solvent at 20-80 ℃ to obtain a phosgenation reaction product, and reacting the compound of formula (V) and iodoaniline in the organic solvent at 20-70 ℃ to obtain a compound of formula (VI);
(c) performing a chemical exchange reaction on the compound of the formula (VI) obtained in the step (b) and pinacol diboron in an organic solvent at 20-120 ℃ under the action of a palladium catalyst by adopting a one-pot method to obtain a solution of a compound of a formula (VII), or performing a reaction on the compound of the formula (VI) and magnesium metal in the organic solvent at a reflux temperature, cooling a reaction solution to 20-40 ℃ after the reaction is completed, adding zinc halide to further perform a chemical exchange reaction to obtain a solution of a compound of a formula (VII), and performing a coupling reaction on the compound of the formula (III) obtained in the step (a) in the solution of the compound of the formula (VII) and the compound of the formula (VII) under the action of a palladium catalyst or a nickel catalyst at 20-120 ℃ to obtain the compound of the formula (VIII); or,
carrying out chemical exchange reaction on the compound of the formula (VI), an organic lithium reagent and zinc halide in an organic solvent at-70 to-90 ℃ to obtain a compound of a formula (VII), and carrying out coupling reaction on the compound of the formula (VII) and the compound of the formula (III) obtained in the step (a) in the organic solvent under the action of a palladium catalyst or a nickel catalyst at 20 to 120 ℃ to obtain a compound of the formula (VIII);
(d) subjecting the compound of formula (VIII) obtained in step (c) to a deprotection reaction to obtain linafanib;
2. the method of preparing li-fanib of claim 1, wherein: in step (a), the organic solvent used in the ring closure reaction is selected from n-butanol, t-butanol or isobutanol.
3. The method of preparing li-fanib of claim 1, wherein: in the step (a), the base used for the reaction of the compound of the formula (II) and di-tert-butyl dicarbonate is one or more selected from 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, potassium tert-butoxide and sodium hydrogen, and the organic solvent used is one or more selected from dichloromethane, tetrahydrofuran, acetonitrile, toluene, ethyl acetate, diethyl ether and 1, 4-dioxane.
4. The method of preparing li-fanib of claim 1, wherein: in the step (b), the phosgenation reagent is selected from phosgene, diphosgene, triphosgene or N, N' -carbonyldiimidazole, and the organic solvent used in the phosgenation reaction and the organic solvent used in the reaction of the phosgenation reaction product and the p-iodoaniline compound of the formula (V) are respectively and independently selected from one or more of ethyl acetate, tetrahydrofuran, acetonitrile, diethyl ether, toluene, 1, 4-dioxane and dichloromethane.
5. The method of preparing li-fanib of claim 1, wherein: in step (c), the palladium catalyst is selected from PdCl2(dppf)、Pd/C、Pd(OAc)2、Pd(PPh3)4、PdCl2(PPh3)2、PdCl2(CH3CN)2、Pd2(dba)3The nickel catalyst is NiCl2(dppe)。
6. The method of preparing li-fanib of claim 1, wherein: in the step (c), the organic solvent used in the chemical exchange reaction of the compound of formula (VI) and the pinacol ester of diboronic acid, the organic solvent used in the chemical exchange reaction of the compound of formula (VI) with magnesium metal and zinc halide, and the organic solvent used in the coupling reaction are respectively and independently selected from one or more of dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, dichloroethane, acetonitrile and toluene; the organic solvent used in the chemical exchange reaction of the compound shown in the formula (VI), an organic lithium reagent and zinc halide is selected from one or more of n-hexane, cyclohexane, toluene, diethyl ether and methyl tert-butyl ether, and the organic lithium reagent is selected from one or more of n-butyllithium, iso-butyllithium and sec-butyllithium.
7. The method of preparing li-fanib of claim 1, wherein: in the step (c), the reaction time of the chemical exchange reaction is 1.5-5 hours, and the coupling reaction time is 2-5 hours.
8. The method of preparing li-fanib of claim 1, wherein: in step (d), the deprotection reagent used in the deprotection reaction is trifluoroacetic acid or hydrochloric acid.
9. The method of preparing li-fanib of claim 1, wherein: in the step (d), the temperature of the deprotection reaction is 20-50 ℃ and the time is 2-6 hours.
10. An intermediate for the preparation of rilifarnib, characterized in that: has a structural formula shown as the following formula (III),
CN201410494691.5A 2014-09-24 2014-09-24 Preparation method of linifanib Pending CN104326985A (en)

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