CN111606910A - Synthesis process of antitumor drug Sapanisiertib - Google Patents
Synthesis process of antitumor drug Sapanisiertib Download PDFInfo
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Abstract
The invention discloses a synthesis process of an antitumor drug Sapanisiertib, which comprises the following steps: the method comprises the following steps: performing carboxyl halogenation reaction on the compound I and a halogenating reagent in a proper solvent to obtain a compound II; step two: reacting the compound II with a methylating agent in a proper solvent under the action of alkali to obtain a compound III; step three: reacting the compound III with the compound IV in a proper solvent to obtain a compound V; step four: reacting the compound IV with a cyclization reagent in a suitable solvent to obtain a compound VI; step five: reacting the compound VI with acid or Lewis acid to obtain a compound VII; step six: carrying out reduction reaction on the compound VII to obtain a compound VIII; step seven: reaction of compound VIII with cyanogen bromide in a solvent gives Sapanisiertib. The preparation method of the synthesis process has the advantages of cheap and easily-obtained raw materials, simple operation, stable process, easy control, convenient post-treatment, safety, environmental friendliness, higher yield, lower production cost and the like, has the commercial production potential of the Sapanisertib bulk drug, and generates good economic benefit.
Description
Technical Field
The invention relates to a synthesis process, in particular to a synthesis process of an antitumor drug Sapanisiertib.
Background
The chemical name of Sapanisiertib is 3- (2-amino-5-benzoxazolyl) -1- (1-methylethyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine, and the structural formula is shown as the following formula.
Sapanisiertib, also known as TAK-228, MLN0128 and INK128, is a small-molecule antitumor inhibitor which is researched in Wutian pharmaceutical in Japan and is targeted at the target of mammalian target of rapamycin (mTOR) in phase II. The current clinical test results show that the antitumor activity effect on various solid tumors, lymphomas and multiple myeloma is good.
The synthesis methods of Sapanisiertib reported so far include the following two.
1. Patent WO2013/23184 reports that the compound 1: 2-amino-4-bromophenol is used as a starting material, and undergoes cyclization reaction with cyanogen bromide to obtain a compound 2, the compound 2 undergoes a Gopu boronization reaction to obtain a derivative boric acid ester 3, the boric acid ester 3 is hydrolyzed by acid to obtain corresponding boric acid 4, and the compound 5: 3-bromo-1H-pyrazolo [3,4-d]Carrying out N-alkylation reaction on a pyrazole ring by using pyrimidine-4-amine and bromo-isopropane to prepare an N-alkylated compound 6; the compound 6 and boric acid ester 3 or boric acid 4 are subjected to Suzuki coupling reaction to obtain Sapanisiertiib. The method has 5 steps of reaction, and heavy metal palladium catalytic reagent is used in two steps of reaction, so that the material cost is high; secondly, the operation of the post-treatment and purification process of the palladium catalytic reaction is more complicated, and the operation is specifically shown as the following formula:
2. patent CN102653540 reports that compound 7: methoxybenzoic acid is used as a starting material and reacts with oxalyl chloride to obtain a compound 8, the compound 8 and malononitrile are subjected to condensation reaction to obtain a compound 9, the compound 9 and dimethyl sulfate are subjected to etherification reaction to obtain a compound 10, the compound 10 and hydrazine hydrate are subjected to ring closure to obtain a compound 11, the compound 11 and formamide are subjected to ring closure to obtain a compound 12, the compound 12 and bromoisopropane are subjected to N-alkylation reaction on a pyrazole ring to prepare a compound 13, the compound 13 is subjected to methyl removal under an acidic condition to obtain a compound 14, the compound 14 is nitrified to obtain a compound 15, the compound 15 is subjected to hydrogenation reduction to obtain a compound 16, and the compound 16 and cyanogen bromide are subjected to ring closure to. The method has 10 reaction steps, has a long synthetic route, relates to nitration reaction and hydrogenation reduction reaction, is not easy to carry out amplification preparation, and is specifically shown as the following formula:
disclosure of Invention
The invention aims to provide a synthesis process of an anti-tumor drug Sapanisiertib, so as to solve the problems in the background technology.
In order to achieve the purpose, the invention provides the following technical scheme:
a synthesis process of an antitumor drug Sapanisiertib comprises the following steps:
the method comprises the following steps: performing carboxyl halogenation reaction on the compound I and a halogenating reagent in a proper solvent to obtain a compound II;
step two: reacting the compound II with a methylating agent in a proper solvent under the action of alkali to obtain a compound III;
step three: reacting the compound III with the compound IV in a proper solvent to obtain a compound V;
step four: reacting the compound IV with a cyclization reagent in a suitable solvent to obtain a compound VI;
step five: reacting the compound VI with acid or Lewis acid to obtain a compound VII;
step six: carrying out reduction reaction on the compound VII to obtain a compound VIII;
step seven: reaction of compound VIII with cyanogen bromide in a solvent gives Sapanisiertib.
As a further scheme of the invention: in the first step, the halogenating reagent is selected from one or more of oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphosgene, phosgene, phenyl chloroformate, phosphorus tribromide, phosphorus oxybromide and dibromohydantoin; preferably one or more of oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphosgene and phosgene;
in the first step, a suitable solvent is one or more selected from toluene, chlorobenzene, xylene, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, tetraglyme, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diphenyl ether; preferably one or more selected from dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane;
the molar ratio of the compound IV to the feeding amount of the halogenating agent in the step is 1: 1-1: 10, preferably 1: 1-1: 3; most preferably 1: 1.1-1: 1.5;
the reaction temperature in the first step is-20 ℃ to 100 ℃, and preferably 0 ℃ to 30 ℃.
As a still further scheme of the invention: the methylation reagent in the second step is one or more of dimethyl sulfate, methyl iodide, dimethyl carbonate, trimethylsilylated diazomethane and diazomethane; preferably one or more selected from dimethyl sulfate and methyl iodide;
the alkali in the second step is selected from one or more of sodium hydride, sodium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 1, 8-diazabicycloundecen-7-ene (DBU); preferably one or more selected from sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine and diisopropylethylamine;
in the second step, a suitable solvent is selected from one or more of toluene, chlorobenzene, xylene, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, tetraglyme, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diphenyl ether; preferably one or more selected from toluene, chlorobenzene, xylene, 1, 2-dichloroethane, tetrahydrofuran and dioxane;
the molar ratio of the compound II to the charge amount of the malononitrile in the step is 1: 1-1: 3, preferably 1: 1-1: 1.2, and the molar ratio of the compound II to the charge amount of the methylating agent is 1: 1-1: 10, most preferably 1: 2-1: 1.3; the feeding amount of the compound II and the alkali is 1: 1-1: 10, preferably 1: 2-1: 5, and most preferably 1: 2.5-1: 3.5;
the condensation reaction temperature of the compound II and the malononitrile in the step is 0-100 ℃, preferably 10-30 ℃; the temperature of the methylation reaction is 0-100 ℃, preferably 30-80 ℃.
As a still further scheme of the invention: in the third step, a suitable solvent is selected from one or more of methanol, ethanol, isopropanol, ethylene glycol, glycerol, tert-butanol, dichloromethane, toluene, ethylbenzene, chlorobenzene, nitrobenzene, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide; preferably one or more selected from methanol, ethanol, isopropanol and ethylene glycol;
the molar ratio of the compound III to the compound IV in the step III is 1: 1-1: 5, preferably 1: 1-1: 1.2; most preferably 1: 1-1: 1.05;
and the reaction temperature in the third step is-20 to 60 ℃, preferably 0 to 25 ℃.
As a still further scheme of the invention: the cyclizing agent in the step four is selected from one or more of formamidine acetate, formamidine hydrochloride, formamide, trimethyl orthoformate, triethyl orthoformate, formic acid, s-triazine, N-dimethylformamide, N-dimethylformamide dimethyl acetal and the like, and preferably from one or more of formamidine acetate, formamidine hydrochloride, formamide and N, N-dimethylformamide dimethyl acetal;
in the fourth step, the temperature of the pyrimidine cyclization reaction is 50-160 ℃, preferably 100-120 ℃.
As a still further scheme of the invention: in the step five, the acid or Lewis acid is selected from one or more of hydrochloric acid, sulfuric acid, hydroiodic acid, aqueous hydrobromic acid, acetic acid solution, aluminum trichloride, stannic chloride, titanium tetrachloride, boron trichloride, boron tribromide, trifluoroacetic acid, boron trifluoride ether, polyphosphoric acid and the like, and preferably one or more of sulfuric acid, hydroiodic acid, aqueous hydrobromic acid, acetic acid solution, aluminum trichloride, boron trichloride and boron tribromide;
and fifthly, the temperature of the methyl removal reaction in the step five is 50-160 ℃, and preferably 100-120 ℃.
As a still further scheme of the invention: in the sixth step, the reduction system is selected from one or more of palladium catalytic hydrogenation reduction, raney nickel catalytic hydrogenation reduction, a zinc powder/ammonium chloride/hydrochloric acid system, a zinc powder/ammonium chloride/acetic acid system, an iron powder/hydrochloric acid/acetic acid system, raney nickel catalytic hydrazine hydrate transfer hydrogenation reduction, palladium catalytic ammonium formate transfer hydrogenation reduction and the like, and preferably one or more of raney nickel catalytic hydrogenation reduction, a zinc powder/ammonium chloride/hydrochloric acid system, a zinc powder/ammonium chloride/acetic acid system, an iron powder/ammonium chloride/acetic acid system and an iron powder/hydrochloric acid/acetic acid system.
As a still further scheme of the invention: the solvent in the seventh step is selected from one or more of methanol, ethanol, isopropanol, glycol, glycerol, tert-butanol, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide; preferably one or more selected from methanol, ethanol, isopropanol and ethylene glycol;
the reaction temperature in the seventh step is-20 to 60 ℃, preferably 0 to 25 ℃.
Compared with the prior art, the invention has the beneficial effects that:
compared with the prior art, the preparation method of the Sapanisertib has the advantages of cheap and easily-obtained raw materials, simple operation, stable process, easy control, convenient post-treatment, safety, environmental friendliness, high yield, low production cost and the like, has the commercial production potential of the Sapanisertib bulk drug, and generates good economic benefit.
Drawings
FIG. 1 is a reaction scheme of a synthesis process of an antitumor drug Sapanisiertib.
FIG. 2 shows the hydrogen nuclear magnetic resonance spectrum of Sapanisirtib in the synthesis process of the antitumor drug Sapanisirtib.
Shown in the figure: i4-methoxy-3-nitrobenzoic acid, II 4-methoxy-3-nitrobenzoyl chloride, III 2- (methoxy (4-methoxy-3-nitrophenyl) methylene) malononitrile, IV isopropylhydrazine hydrochloride, V5-amino-1-isopropyl-3- (4-methoxy-3-nitrophenyl) -1H-pyrazole-4-carbonitrile, VI 1-isopropyl-3- (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine, VII 1-isopropyl-3- (4-hydroxy-3-nitrophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine, VIII 1-isopropyl-3- (4-hydroxy-3-aminophenyl) -1H pyrazolo [3,4-d ] pyrimidin-4-amine.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Referring to fig. 1-2, in an embodiment of the present invention, a synthesis process of an anti-tumor drug, sapaniertib, includes the following steps:
the method comprises the following steps: performing carboxyl halogenation reaction on the compound I and a halogenating reagent in a proper solvent to obtain a compound II;
step two: reacting the compound II with a methylating agent in a proper solvent under the action of alkali to obtain a compound III;
step three: reacting the compound III with the compound IV in a proper solvent to obtain a compound V;
step four: reacting the compound IV with a cyclization reagent in a suitable solvent to obtain a compound VI;
step five: reacting the compound VI with acid or Lewis acid to obtain a compound VII;
step six: carrying out reduction reaction on the compound VII to obtain a compound VIII;
step seven: reacting the compound VIII with cyanogen bromide in a solvent to obtain Sapanisiertiib;
in the first step, the halogenating reagent is selected from one or more of oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphosgene, phosgene, phenyl chloroformate, phosphorus tribromide, phosphorus oxybromide and dibromohydantoin; preferably one or more of oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphosgene and phosgene.
In the first step, a suitable solvent is one or more selected from toluene, chlorobenzene, xylene, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, tetraglyme, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diphenyl ether; preferably one or more selected from dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane.
The molar ratio of the compound IV to the feeding amount of the halogenating agent in the step is 1: 1-1: 10, preferably 1: 1-1: 3; most preferably 1:1.1 to 1: 1.5.
The reaction temperature in the first step is-20 ℃ to 100 ℃, and preferably 0 ℃ to 30 ℃.
The methylation reagent in the second step is one or more of dimethyl sulfate, methyl iodide, dimethyl carbonate, trimethylsilylated diazomethane and diazomethane; preferably one or more selected from dimethyl sulfate and methyl iodide.
The alkali in the second step is selected from one or more of sodium hydride, sodium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 1, 8-diazabicycloundecen-7-ene (DBU); preferably one or more selected from sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine and diisopropylethylamine.
In the second step, a suitable solvent is selected from one or more of toluene, chlorobenzene, xylene, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, tetraglyme, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diphenyl ether; preferably one or more selected from toluene, chlorobenzene, xylene, 1, 2-dichloroethane, tetrahydrofuran and dioxane.
The molar ratio of the compound II to the charge amount of the malononitrile in the step is 1: 1-1: 3, preferably 1: 1-1: 1.2, and the molar ratio of the compound II to the charge amount of the methylating agent is 1: 1-1: 10, most preferably 1: 2-1: 1.3; the molar ratio of the compound II to the alkali is 1: 1-1: 10, preferably 1: 2-1: 5, and most preferably 1: 2.5-1: 3.5.
The condensation reaction temperature of the compound II and the malononitrile in the step is 0-100 ℃, preferably 10-30 ℃; the temperature of the methylation reaction is 0-100 ℃, preferably 30-80 ℃.
In the third step, a suitable solvent is selected from one or more of methanol, ethanol, isopropanol, ethylene glycol, glycerol, tert-butanol, dichloromethane, toluene, ethylbenzene, chlorobenzene, nitrobenzene, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide; preferably one or more selected from methanol, ethanol, isopropanol, and ethylene glycol.
The molar ratio of the compound III to the compound IV in the step III is 1: 1-1: 5, preferably 1: 1-1: 1.2; most preferably 1:1 to 1: 1.05.
And the reaction temperature in the third step is-20 to 60 ℃, preferably 0 to 25 ℃.
The cyclizing agent in the step four is selected from one or more of formamidine acetate, formamidine hydrochloride, formamide, trimethyl orthoformate, triethyl orthoformate, formic acid, s-triazine, N-dimethylformamide, N-dimethylformamide dimethyl acetal and the like, and preferably from one or more of formamidine acetate, formamidine hydrochloride, formamide and N, N-dimethylformamide dimethyl acetal.
In the fourth step, the temperature of the pyrimidine cyclization reaction is 50-160 ℃, preferably 100-120 ℃.
In the step five, the acid or Lewis acid is selected from one or more of hydrochloric acid, sulfuric acid, hydroiodic acid, aqueous hydrobromic acid, acetic acid solution, aluminum trichloride, stannic chloride, titanium tetrachloride, boron trichloride, boron tribromide, trifluoroacetic acid, boron trifluoride ether, polyphosphoric acid and the like, and preferably one or more of sulfuric acid, hydroiodic acid, aqueous hydrobromic acid, acetic acid solution, aluminum trichloride, boron trichloride and boron tribromide.
And fifthly, the temperature of the methyl removal reaction in the step five is 50-160 ℃, and preferably 100-120 ℃.
In the sixth step, the reduction system is selected from one or more of palladium catalytic hydrogenation reduction, raney nickel catalytic hydrogenation reduction, a zinc powder/ammonium chloride/hydrochloric acid system, a zinc powder/ammonium chloride/acetic acid system, an iron powder/hydrochloric acid/acetic acid system, raney nickel catalytic hydrazine hydrate transfer hydrogenation reduction, palladium catalytic ammonium formate transfer hydrogenation reduction and the like, and preferably one or more of raney nickel catalytic hydrogenation reduction, a zinc powder/ammonium chloride/hydrochloric acid system, a zinc powder/ammonium chloride/acetic acid system, an iron powder/ammonium chloride/acetic acid system and an iron powder/hydrochloric acid/acetic acid system.
The solvent in the seventh step is selected from one or more of methanol, ethanol, isopropanol, glycol, glycerol, tert-butanol, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide; preferably one or more selected from methanol, ethanol, isopropanol, and ethylene glycol.
The reaction temperature in the seventh step is-20 to 60 ℃, preferably 0 to 25 ℃.
Compared with the prior art, the preparation method of the Sapanisertib has the advantages of cheap and easily-obtained raw materials, simple operation, stable process, easy control, convenient post-treatment, safety, environmental friendliness, high yield, low production cost and the like, has the commercial production potential of the Sapanisertib bulk drug, and generates good economic benefit.
The first embodiment is as follows: preparation of 4-methoxy-3-nitrobenzoyl chloride
4-methoxy-3-nitrobenzoic acid (compound I) (98.6g,0.50mols,1.0eq), N-dimethylformamide (0.914g,0.0125mols,0.025eq) and dichloromethane (600ml, 6V) were added to a 1L three-necked reaction flask at room temperature with stirring turned on. The temperature was reduced in an ice-water bath, oxalyl chloride (95.2g, 0.75mols,1.5eq) was added dropwise at 20 ℃. After the addition, the temperature was naturally raised to room temperature and stirred for 20 hours. The reaction was concentrated under reduced pressure at 45 ℃ to remove dichloromethane to give 4-methoxy-3-nitrobenzoyl chloride as a yellow oil (108.2g, 0.502mols) in 100.4% yield, which was used directly in the next reaction.
Example two: preparation of 2- (methoxy (4-methoxy-3-nitrophenyl) methylene) malononitrile
4-methoxy-3-nitrobenzoyl chloride (compound II) (108.2g,0.50mols,1.0eq), malononitrile (33.0g,0.50mols,1.0eq), and tetrahydrofuran (1100ml, 10V) were added to a 2L three-necked reaction flask at room temperature with stirring turned on. Under the protection of nitrogen, cooling in an ice-water bath, dropwise adding N, N-diisopropylethylamine (193.9g,1.50mols,3.0eq) at 25 ℃, naturally heating to room temperature, and stirring for 3 hours. At room temperature, dimethyl sulfate (157.7g,1.25mols,2.5eq) was heated to 75 ℃ and stirred for 22 hours.
The reaction mixture was cooled to room temperature, poured into an ice-water mixture (1100ml), and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (600ml, 6V), and the organic phase was washed successively with 1M aqueous hydrochloric acid (1500ml, 15V) and saturated brine (600ml, 6V), and concentrated under reduced pressure at 45 ℃. The concentrated residue was added with anhydrous methanol (200ml,. about.2V) and stirred at room temperature for crystallization for 6 hours. Filtration and drying gave 2- (methoxy (4-methoxy-3-nitrophenyl) methylene) malononitrile as a yellow solid (112.6g, 0.434mols) in 86.9% yield.
Example three: preparation of 5-amino-1-isopropyl-3- (4-methoxy-3-nitrophenyl) -1H-pyrazole-4-carbonitrile
2- (methoxy (4-methoxy-3-nitrophenyl) methylene) malononitrile (compound III) (77.77g,0.3mols,1.0eq), isopropylhydrazine hydrochloride (compound IV) (33.18g,0.3mols,1.0eq) and absolute ethanol (650ml, 8V) were added to a 1L three-necked reaction flask at room temperature, stirring was turned on, and triethylamine (33.4g, 0.33mols,1.1eq) was added. The reaction was heated to 60 ℃ and stirred for 3 hours.
The reaction solution is decompressed and concentrated to 2-3 times of volume at 50 ℃, water (400ml, 5V) and methanol (80ml, 1V) are added, and the mixture is stirred for 2 hours at room temperature. Filtration, elution of the filter cake with a mixed solvent of methanol/water (1/2,140ml, 2V), and drying gave the finished 5-amino-1-isopropyl-3- (4-methoxy-3-nitrophenyl) -1H-pyrazole-4-carbonitrile as a yellow solid (86.1g,0.286mols) in 95.3% yield.
Example four: preparation of 1-isopropyl-3- (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine
5-amino-1-isopropyl-3- (4-methoxy-3-nitrophenyl) -1H-pyrazole-4-carbonitrile (compound V) (60.3g,0.2mols,1.0eq), formamidine acetate (104.1g,1.0mols,5.0eq) and ethylene glycol monoethyl ether (600ml, 10V) were added to a 1L three-necked reaction flask at room temperature with stirring. The reaction was heated to 120 ℃ and stirred for 10 hours.
The reaction was allowed to cool to room temperature, water (900ml,15V) and ethyl acetate (600ml, 10V) were added and stirred for 10 minutes. The layers were separated by standing and the aqueous phase was extracted 2 times with 300ml (. about.5V) each time of ethyl acetate. The combined organic phases were washed 2 times with 100ml (. about.2V) of saturated saline each time. The organic phase was concentrated under reduced pressure at 70 ℃ to no distillate, and the concentrated residue was crystallized from methanol (120ml,. about.2V) and water (300ml,5V), filtered, and dried to give 1-isopropyl-3- (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine as a yellow solid (56.1g,0.171mols), 85.4% yield.
Example five: preparation of 1-isopropyl-3- (4-hydroxy-3-nitrophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine
1-isopropyl-3- (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (compound VI) (49.2g,0.15mols,1.0eq), 48% aqueous hydrobromic acid (150ml,3V) and acetic acid (250ml, 5V) were added to a 1L three-necked reaction flask at room temperature, stirred with stirring, and heated to 120 ℃ under reflux for 12 hours.
The reaction was allowed to cool to room temperature, poured into a mixture of ice and water (500ml,. about.10V), stirred for 10 minutes, and extracted 3 times with 300ml (. about.6V) of dichloromethane. The organic phases were combined and washed 2 times with 250ml (. about.5V) of water each time; saturated aqueous sodium bicarbonate (300ml, 6V) was washed 1 time. The organic phase was concentrated under reduced pressure at 45 ℃ to no distillate. The concentrated residue was crystallized by the addition of water (300ml,. about.6V) and methanol (50ml,. about.1V). Filtration and drying gave 1-isopropyl-3- (4-hydroxy-3-nitrophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine as a yellow solid (42.9g,0.136mols) in 91.0% yield.
Example six: preparation of 1-isopropyl-3- (4-hydroxy-3-aminophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine
1-isopropyl-3- (4-hydroxy-3-nitrophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (compound VII) (37.7g,0.12mols,1.0eq), Raney nickel (7.5g, 20% W/W), triethylamine (6.1g,0.06mols, 0.5eq), and methanol (377ml,10V) were added to a 1L three-necked reaction flask at room temperature, stirred with stirring, and stirred at 45 ℃ under a hydrogen atmosphere of 1 atmosphere for 20 hours.
The reaction system was cooled to room temperature, the reaction solution was filtered through a sand core funnel loaded with diatomaceous earth (50g) to remove the Raney nickel catalyst, and the filtrate was concentrated under reduced pressure at 45 ℃ until no fraction was obtained. Water (180ml,. about.5V) and methylene chloride (220ml,. about.6V) were added to the concentrated residue and stirred for 10 minutes. The layers were separated by standing and the aqueous phase was extracted once with dichloromethane (220ml, 6V). The combined organic phases were washed 1 time with saturated aqueous sodium chloride (180ml,. about.5V) and concentrated to no distillate at 45 ℃ under reduced pressure. To the concentrated residue was added n-heptane (180ml,. about.5V) and stirred at room temperature for 2 hours. Filtration and drying gave 1-isopropyl-3- (4-hydroxy-3-aminophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine as an off-white solid (33.6g,0.118mols) in 95.5% yield.
Example seven: preparation of Sapanisertib
1-isopropyl-3- (4-hydroxy-3-aminophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (compound VIII) (28.4g,0.100mols,1.0eq) and methanol (250ml, 8V) were added to a 2L three-necked reaction flask at room temperature with stirring turned on. The temperature was reduced in an ice-water bath, cyanogen bromide (11.1g, 0.105mols,1.05eq) was added in portions at 30 ℃. After the addition, the temperature was naturally raised to room temperature and stirred for 20 hours.
And (3) controlling the temperature to be 30 ℃, dropwise adding a 5% sodium hydroxide solution into the reaction system until the pH value is 7-8, quenching the reaction, and adding water (300ml, 10V). The system is decompressed and concentrated at 40 ℃ to remove methanol to about 5-6 times of volume, and the mixture is naturally cooled to room temperature and stirred for 2 hours. Filtration and cake washing with water (150ml, 5V) and ethyl acetate (120ml, 4V) followed by drying gave the finished Sapanisiertib as a white solid (29.6g, 0.0957mols), 95.7% yield, 99.6% HPLC purity.
1H NMR(DMSO-d6,400MHz):＝1.50(d,J＝6.4Hz,6H),5.06(m,1H),7.26 (s,1H),7.41(d,J＝1.2Hz,1H),7.46(d,J＝8Hz,1H),7.56(s,1H),8.23(s,1H).
MS:[M+H]+＝310.05。
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes in the embodiments and/or modifications of the invention can be made, and equivalents and modifications of some features of the invention can be made without departing from the spirit and scope of the invention.
Claims (8)
1. A synthesis process of an antitumor drug Sapanisiertib is characterized by comprising the following steps: the synthesis process comprises the following steps:
the method comprises the following steps: performing carboxyl halogenation reaction on the compound I and a halogenating reagent in a proper solvent to obtain a compound II;
step two: reacting the compound II with a methylating agent in a proper solvent under the action of alkali to obtain a compound III;
step three: reacting the compound III with the compound IV in a proper solvent to obtain a compound V;
step four: reacting the compound IV with a cyclization reagent in a suitable solvent to obtain a compound VI;
step five: reacting the compound VI with acid or Lewis acid to obtain a compound VII;
step six: carrying out reduction reaction on the compound VII to obtain a compound VIII;
step seven: reaction of compound VIII with cyanogen bromide in a solvent gives Sapanisiertib.
2. The process for the synthesis of an antitumor drug Sapanisiertib according to claim 1, characterized in that: in the first step, the halogenating reagent is selected from one or more of oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphosgene, phosgene, phenyl chloroformate, phosphorus tribromide, phosphorus oxybromide and dibromohydantoin; preferably one or more of oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphosgene and phosgene;
in the first step, a suitable solvent is one or more selected from toluene, chlorobenzene, xylene, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, tetraglyme, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diphenyl ether; preferably one or more selected from dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane;
the molar ratio of the compound IV to the feeding amount of the halogenating agent in the step is 1: 1-1: 10, preferably 1: 1-1: 3; most preferably 1: 1.1-1: 1.5;
the reaction temperature in the first step is-20 ℃ to 100 ℃, and preferably 0 ℃ to 30 ℃.
3. The process for the synthesis of an antitumor drug Sapanisiertib according to claim 1, characterized in that: the methylation reagent in the second step is one or more of dimethyl sulfate, methyl iodide, dimethyl carbonate, trimethylsilylated diazomethane and diazomethane; preferably one or more selected from dimethyl sulfate and methyl iodide;
the alkali in the second step is selected from one or more of sodium hydride, sodium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 1, 8-diazabicycloundecen-7-ene (DBU); preferably one or more selected from sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine and diisopropylethylamine;
in the second step, a suitable solvent is selected from one or more of toluene, chlorobenzene, xylene, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, tetraglyme, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diphenyl ether; preferably one or more selected from toluene, chlorobenzene, xylene, 1, 2-dichloroethane, tetrahydrofuran and dioxane;
the molar ratio of the compound II to the charge amount of the malononitrile in the step is 1: 1-1: 3, preferably 1: 1-1: 1.2, and the molar ratio of the compound II to the charge amount of the methylating agent is 1: 1-1: 10, most preferably 1: 2-1: 1.3; the feeding amount of the compound II and the alkali is 1: 1-1: 10, preferably 1: 2-1: 5, and most preferably 1: 2.5-1: 3.5;
the condensation reaction temperature of the compound II and the malononitrile in the step is 0-100 ℃, preferably 10-30 ℃; the temperature of the methylation reaction is 0-100 ℃, preferably 30-80 ℃.
4. The process for the synthesis of an antitumor drug Sapanisiertib according to claim 1, characterized in that: in the third step, a suitable solvent is selected from one or more of methanol, ethanol, isopropanol, ethylene glycol, glycerol, tert-butanol, dichloromethane, toluene, ethylbenzene, chlorobenzene, nitrobenzene, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide; preferably one or more selected from methanol, ethanol, isopropanol and ethylene glycol;
the molar ratio of the compound III to the compound IV in the step III is 1: 1-1: 5, preferably 1: 1-1: 1.2; most preferably 1: 1-1: 1.05;
and the reaction temperature in the third step is-20 to 60 ℃, preferably 0 to 25 ℃.
5. The process for the synthesis of an antitumor drug Sapanisiertib according to claim 1, characterized in that: the cyclizing agent in the step four is selected from one or more of formamidine acetate, formamidine hydrochloride, formamide, trimethyl orthoformate, triethyl orthoformate, formic acid, s-triazine, N-dimethylformamide, N-dimethylformamide dimethyl acetal and the like, and preferably from one or more of formamidine acetate, formamidine hydrochloride, formamide and N, N-dimethylformamide dimethyl acetal;
in the fourth step, the temperature of the pyrimidine cyclization reaction is 50-160 ℃, preferably 100-120 ℃.
6. The process for the synthesis of an antitumor drug Sapanisiertib according to claim 1, characterized in that: in the step five, the acid or Lewis acid is selected from one or more of hydrochloric acid, sulfuric acid, hydroiodic acid, aqueous hydrobromic acid, acetic acid solution, aluminum trichloride, stannic chloride, titanium tetrachloride, boron trichloride, boron tribromide, trifluoroacetic acid, boron trifluoride ether, polyphosphoric acid and the like, and preferably one or more of sulfuric acid, hydroiodic acid, aqueous hydrobromic acid, acetic acid solution, aluminum trichloride, boron trichloride and boron tribromide;
and fifthly, the temperature of the methyl removal reaction in the step five is 50-160 ℃, and preferably 100-120 ℃.
7. The process for the synthesis of an antitumor drug Sapanisiertib according to claim 1, characterized in that: in the sixth step, the reduction system is selected from one or more of palladium catalytic hydrogenation reduction, raney nickel catalytic hydrogenation reduction, a zinc powder/ammonium chloride/hydrochloric acid system, a zinc powder/ammonium chloride/acetic acid system, an iron powder/hydrochloric acid/acetic acid system, raney nickel catalytic hydrazine hydrate transfer hydrogenation reduction, palladium catalytic ammonium formate transfer hydrogenation reduction and the like, and preferably one or more of raney nickel catalytic hydrogenation reduction, a zinc powder/ammonium chloride/hydrochloric acid system, a zinc powder/ammonium chloride/acetic acid system, an iron powder/ammonium chloride/acetic acid system and an iron powder/hydrochloric acid/acetic acid system.
8. The process for the synthesis of an antitumor drug Sapanisiertib according to claim 1, characterized in that: the solvent in the seventh step is selected from one or more of methanol, ethanol, isopropanol, glycol, glycerol, tert-butanol, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide; preferably one or more selected from methanol, ethanol, isopropanol and ethylene glycol;
the reaction temperature in the seventh step is-20 to 60 ℃, preferably 0 to 25 ℃.
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| CN102653540A (en) * | 2012-03-22 | 2012-09-05 | 盛世泰科生物医药技术(苏州)有限公司 | New synthesis process of new antineoplastic drug INK128 |
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