CN110713497A - Preparation method of Brigatinib intermediate 2-aminophenyldimethylphosphine oxide - Google Patents
Preparation method of Brigatinib intermediate 2-aminophenyldimethylphosphine oxide Download PDFInfo
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Abstract
The invention provides a preparation method of an intermediate 2-aminophenyldimethylphosphine oxide of Brigatinib, belonging to the technical field of organic synthesis and comprising the following steps: reacting the intermediate I-1 and the intermediate I-2 in the step (1) in the presence of a catalyst at a certain temperature to obtain an intermediate I-3; reacting the intermediate I-3 with a methyl Grignard reagent in a first solvent at low temperature to obtain a crude product of the intermediate I; reacting the crude intermediate I product with acid in a second solvent to form salt of the intermediate I, and recrystallizing to obtain a pure product of the salt of the intermediate I; and (4) carrying out alkaline hydrolysis on the pure salt of the intermediate I, and extracting with a third solvent to obtain the pure salt of the intermediate I. The first step of coupling reaction has mild conditions, the formed intermediate is directly subjected to the next step of reaction without separation and purification, the obtained crude product forms salt with proper acid to form better solid, the intermediate with high purity is obtained by recrystallization, the intermediate I pure product is obtained by free extraction under alkaline conditions, and the cost is reduced by more than 50% compared with the prior art.
Description
Field of the method
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2-aminophenyldimethylphosphine oxide serving as an intermediate of Brigatinib.
Background method
Lung Cancer is one of the leading causes of Cancer death worldwide, and Cancer patients who die of lung Cancer are the most, whether in men or women, according to the 2017 Cancer statistics (Cancer Facts & regulations 2017) published by the American Cancer society. Of the lung cancers, about 85% of cases are non-small cell lung cancers. Among them, about 3-5% of non-small cell lung cancers present ALK fusion proteins, depending on the composition of tumor histology and molecular biology, and this mutation leads to tumor growth. Current treatments for this segment of patients are limited, leaving their survival hope very elusive once mainstream therapy is not effective.
Brigatinib (Brigatinib, research and development code: AP26113) is also known as butkitabine and Brigatinib. Is a new generation multi-target oral inhibitor independently developed by the Nippon martian pharmaceutical company, and has the inhibition effect on multiple targets such as ALK, EGFR, ROS-1 and the like.
In 2017, 28 months 4, a new drug for lung cancer, Brigatinib, from Wutian, Japan pharmaceutical company is approved by FDA to be on the market. Brigatinib is a new drug for the treatment of ALK + non-small cell lung cancer patients resistant or intolerant to crizotinib. As a potent ALK inhibitor, the compound can inhibit ALK and ALK fusion protein, thereby inhibiting the growth of tumors. Brigatinib demonstrates good inhibitory effects in both in vitro and in vivo assays. Thus, it has also been qualified in tandem with U.S. FDA-issued breakthrough therapy accreditation and orphan drug.
The formula of Brigatinib is as follows:
the production process route of Brigatinib is as follows (WO2016065028A1)
Synthesis of intermediate IV:
synthesis of intermediate III
Synthesis of Brigatinib:
the prior art reports that the synthesis process of Brigatinib starts from o-iodoaniline (I-01) and reacts with dimethyl phosphine oxide (I-02) under the catalysis of palladium acetate to obtain a compound key intermediate (I); reacting the intermediate I with a key starting material (II) under the action of proper base catalysis to obtain a key Intermediate (IV); reacting the compound III-01 with the compound III-02 to obtain an intermediate III-03, and then carrying out palladium catalytic hydrogenation reduction to obtain a compound (III); the intermediate (III) and the Intermediate (IV) react under the action of alkali catalysis to obtain Brigatinib.
In the route, an intermediate I is a core intermediate in the whole preparation of Brigatinib, the product quality and the price of the intermediate I are key factors influencing the development of bulk drugs, and the existing methods for producing the intermediate I mainly comprise the following steps:
1. a method for synthesizing an intermediate I is disclosed in the primary patent WO2012/151561, and the synthetic route thereof is as follows:
the method adopts 2-iodoaniline and dimethyl phosphine oxide to react in a palladium catalytic system, and the reaction has several obvious defects: firstly, an intermediate I-02 used in the reaction is a non-commercial intermediate, the price is very high, the market unit price is about 2.0 ten thousand yuan per kilogram, the intermediate is viscous liquid with low melting point, and the production and purification of the intermediate can meet the requirement of the project after high vacuum rectification; secondly, dimethyl formamide is adopted in the coupling reaction, the reaction is carried out for 3-5 hours at 150 ℃, the reaction system needs an anaerobic reaction, otherwise, the o-iodoaniline serving as the raw material and the product generated in the reaction are easily oxidized to form brown to black impurities which are difficult to separate, and the intermediate obtained through thin-layer chromatography separation and purification is a brown to brown solid with low purity, and has certain influence on the subsequent production of the raw material medicaments.
2. Zilu pharmacy discloses a process for preparing intermediate I (patent CN 106928275).
The method adopts reaction of o-iodoaniline and dimethyl phosphine oxide, the reaction conditions are similar to those of the first method, after the reaction is finished, the intermediate crude product reacts with concentrated hydrochloric acid to form hydrochloride, the hydrochloride is purified, column chromatography purification is avoided, the original process is greatly improved, but the use of the intermediate I-02 avoids the intermediate having higher production cost.
Disclosure of Invention
Aiming at the defect of high production cost in the prior art, the invention aims to provide a preparation method of 2-aminophenyldimethylphosphine oxide serving as an intermediate of Brigatinib.
A preparation method of 2-aminophenyldimethylphosphine oxide serving as an intermediate of Brigatinib comprises the following steps:
reacting the intermediate I-1 and the intermediate I-2 in the step (1) in a catalyst at a certain temperature to obtain an intermediate I-3, wherein the reaction time is 5-20 hours, preferably, the reaction time in the step (1) is 12 hours;
reacting the intermediate I-3 in the step (2) with a methyl Grignard reagent in a first solvent at low temperature to obtain a crude product of the intermediate I, wherein the reaction time is 3-10 hours, preferably 6 hours;
reacting the crude intermediate I product with acid in a second solvent to form salt of the intermediate I, and recrystallizing to obtain a pure salt of the intermediate I, wherein the reaction time is 3-5 hours, preferably 4 hours;
and (4) carrying out alkaline hydrolysis on the pure salt of the intermediate I, and extracting with a third solvent to obtain the pure salt of the intermediate I.
In the technical scheme of the application: 2-halogenated aniline is used as a raw material and reacts with phosphite ester to prepare 2-aminophenyl phosphite ester with better crystallinity, then the 2-aminophenyl phosphite ester reacts with methyl Grignard reagent to obtain an intermediate I crude product, the crude product and proper acid form stable salt, the stable salt is recrystallized to obtain high-purity salt, and the salt is decomposed under an alkaline condition to obtain an intermediate I; the method comprises two steps of synthetic reaction, wherein the first step of coupling reaction has mild conditions, the formed intermediate is directly subjected to the next step of reaction without separation and purification, a crude product obtained after the reaction is salified with a proper acid to form a good solid, the intermediate with high purity is obtained by recrystallization, and the pure product of the intermediate I is obtained by free extraction under an alkaline condition; the raw materials used in the method are common commercial raw materials or reagents, the obtained product has good quality, and the cost is reduced by more than 50% compared with the prior art.
The synthetic process route is as follows:
wherein X in the intermediate I-1 involved in the first step of reaction is bromine or iodine; r in the intermediate I-2 is C1-C6 aliphatic hydrocarbon.
Preferably, in the step (1), the catalyst is one or more of tetratriphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, bis (dibenzylideneacetone) palladium, bis acetonitrile palladium chloride and bis triphenylphosphine palladium dichloride; the amount of the catalyst is 0.001-5.0% of the feeding amount.
Preferably, the amount of the catalyst is 0.003-0.05% of the charge amount.
More preferably, the amount of the catalyst is 0.005-0.01% of the charged amount.
Preferably, the certain temperature in the step (1) is 30-150 ℃.
More preferably, the certain temperature in step (1) is 60-120 ℃.
More preferably, the certain temperature in step (1) is 80-100 ℃.
Preferably, the methyl Grignard reagent in step (2) is methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide; the dosage of the methyl Grignard reagent is 1-3 molar equivalents of the intermediate I-3; the concentration of the methyl Grignard reagent is 1.0-3.0 mole/L.
Preferably, in the step (2), the first solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran and toluene; the amount of the first solvent is 5 to 10 times by volume, and the amount of the first solvent is 5 to 10 times by volume, preferably 7 times by volume, of the amount of the intermediate I-3 and the methyl Grignard reagent.
Preferably, the low temperature in step (2) is-78-50 ℃.
More preferably, the low temperature in step (2) is-40-30 ℃.
More preferably, the low temperature in the step (2) is-20-20 ℃.
Preferably, in the step (3), the acid is concentrated hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid, the concentration of the acid is 36.5% -100%, and the amount of the acid is 1-5 molar equivalents of the crude product of the intermediate I.
More preferably, the acid is used in an amount of 1.2 to 3.5 molar equivalents of the crude intermediate I.
More preferably, the acid is used in an amount of 1.5 to 2.5 molar equivalents of the crude intermediate I.
Preferably, the second solvent in step (3) is one or more of N-hexane, cyclohexane, N-heptane, isooctane, petroleum ether, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, methyl tert-butyl ether, methyl cyclopentyl ether, isopropyl ether, toluene, xylene, methanol, ethanol and isopropanol; the dosage of the second solvent is 1-10 times of the volume of the first solvent.
More preferably, the second solvent is ethyl acetate, dichloromethane or tetrahydrofuran.
Preferably, the base in the step (4) is sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably potassium carbonate, sodium hydroxide or potassium hydroxide; the dosage of the alkali is 1-3 equivalent of the pure product of the salt of the intermediate I, and the concentration of the alkali is 10-100%.
Preferably, in the step (4), the third solvent is one or more of ethyl acetate, isopropyl acetate, dichloromethane, toluene and methyl tert-butyl ether, the dosage of the third solvent is 5-20 times of the volume, and the dosage of the third solvent is 5-20 times of the volume of the pure product of the salt of the alkaline hydrolysis intermediate I.
More preferably, the third solvent in step (4) is ethyl acetate and dichloromethane.
In the method scheme of the application:
compared with the prior art, the method has the beneficial effects that:
(1) 2-halogenated aniline is used as a raw material and reacts with phosphite ester to prepare 2-aminophenyl phosphite ester with better crystallinity, then the 2-aminophenyl phosphite ester reacts with methyl Grignard reagent to obtain an intermediate I crude product, the crude product and proper acid form stable salt, the stable salt is recrystallized to obtain high-purity salt, and the salt is decomposed under an alkaline condition to obtain an intermediate I; the method comprises two steps of synthetic reaction, wherein the first step of coupling reaction has mild conditions, the formed intermediate is directly subjected to the next step of reaction without separation and purification, a crude product obtained after the reaction is salified with a proper acid to form a good solid, the intermediate with high purity is obtained by recrystallization, and the pure product of the intermediate I is obtained by free extraction under an alkaline condition;
(2) the raw materials used in the method are common commercial raw materials or reagents, the obtained product has good quality, and the cost is reduced by more than 50% compared with the prior art;
(3) a new synthesis way is created, 2-aminophenyldimethylphosphine oxide is prepared under a very mild condition, and the intermediate is the most key intermediate for producing Brigatinib;
(4) the method has mild reaction conditions, the quality of the intermediate is easy to control, and the key intermediate quality standard which meets Brigatinib raw material medicine can be produced at lower cost, so that the method is suitable for industrial large-scale production of the intermediate I;
(5) the preparation process is efficient and environment-friendly.
Detailed Description
In order that those skilled in the art will better understand the method embodiments of the present invention, the present invention will be further described in detail with reference to the following specific examples.
Example 1
A preparation method of 2-aminophenyldimethylphosphine oxide serving as an intermediate of Brigatinib comprises the following steps:
reacting the intermediate I-1 and the intermediate I-2 in the step (1) in the presence of a catalyst at a certain temperature, specifically 150 ℃, so as to obtain an intermediate I-3, wherein the reaction time is 20 hours; the catalyst is palladium tetratriphenylphosphine; the amount of the catalyst is 0.001 percent of the feeding amount;
reacting the intermediate I-3 with a methyl Grignard reagent in a first solvent at low temperature to obtain a crude product of the intermediate I, wherein the reaction time is 10 hours; the first solvent is tetrahydrofuran, and the dosage of the first solvent is 5 times of the volume; the medium and low temperature is-78 ℃;
reacting the crude intermediate I product with acid in a second solvent to form salt of the intermediate I, and recrystallizing to obtain a pure salt of the intermediate I, wherein the reaction time is 3 hours; the acid is concentrated hydrochloric acid with the concentration of 36.5 percent, and the dosage of the acid is 5 molar equivalents of the crude product of the intermediate I; the second solvent is ethyl acetate, and the dosage of the second solvent is 1 time of the volume of the first solvent;
extracting the pure product of the salt of the alkaline hydrolysis intermediate I by using a third solvent to obtain the pure product of the intermediate I, wherein the alkali is sodium bicarbonate, and the concentration is 100%; the third solvent is ethyl acetate, and the dosage of the third solvent is 20 times of the volume.
Example 2
A preparation method of 2-aminophenyldimethylphosphine oxide serving as an intermediate of Brigatinib comprises the following steps:
reacting the intermediate I-1 and the intermediate I-2 in the step (1) in the presence of a catalyst at a certain temperature, specifically 30 ℃, to obtain an intermediate I-3, wherein the reaction time is 5 hours; the catalyst is palladium dichloride; the amount of the catalyst is 5% of the feeding amount;
reacting the intermediate I-3 with a methyl Grignard reagent in a first solvent at low temperature to obtain a crude product of the intermediate I, wherein the reaction time is 8 hours; the first solvent is 2-methyltetrahydrofuran, and the dosage of the first solvent is 6 times of the volume; the medium and low temperature is-40 ℃;
reacting the crude intermediate I product with acid in a second solvent to form salt of the intermediate I, and recrystallizing to obtain a pure intermediate I salt product, wherein the reaction time is 4 hours; the acid is sulfuric acid, the concentration is 40%, and the using amount of the acid is 1 molar equivalent of the intermediate I crude product; the second solvent is dichloromethane, and the dosage of the second solvent is 2 times of the volume of the first solvent;
extracting the pure product of the salt of the alkaline hydrolysis intermediate I by using a third solvent to obtain the pure product of the intermediate I, wherein the alkali is sodium carbonate, and the concentration of the alkali is 80%; the third solvent is isopropyl acetate, and the dosage of the third solvent is 18 times of the volume.
Example 3
A preparation method of 2-aminophenyldimethylphosphine oxide serving as an intermediate of Brigatinib comprises the following steps:
reacting the intermediate I-1 and the intermediate I-2 in the step (1) in the presence of a catalyst at a certain temperature, specifically 60 ℃, to obtain an intermediate I-3, wherein the reaction time is 15 hours; the catalyst is palladium acetate; the amount of the catalyst is 0.003 percent of the feeding amount;
reacting the intermediate I-3 with a methyl Grignard reagent in a first solvent at low temperature to obtain a crude product of the intermediate I, wherein the reaction time is 6 hours; the first solvent is toluene, and the dosage of the first solvent is 8 times of the volume; the medium and low temperature is-20 ℃;
reacting the crude intermediate I product with acid in a second solvent to form salt of the intermediate I, and recrystallizing to obtain a pure intermediate I salt product, wherein the reaction time is 5 hours; the acid is methanesulfonic acid, the concentration is 60%, and the use amount of the acid is 1.2 molar equivalent of the intermediate I crude product; the second solvent is tetrahydrofuran, and the dosage of the second solvent is 5 times of the volume of the first solvent;
extracting the pure product of the salt of the alkaline hydrolysis intermediate I by using a third solvent to obtain the pure product of the intermediate I, wherein the alkali is potassium carbonate, and the concentration of the alkali is 60%; the third solvent is ethyl acetate and dichloromethane, and the amount of the third solvent is 16 times of the volume.
Example 4
A preparation method of 2-aminophenyldimethylphosphine oxide serving as an intermediate of Brigatinib comprises the following steps:
reacting the intermediate I-1 and the intermediate I-2 in the step (1) in the presence of a catalyst at a certain temperature, specifically 80 ℃, to obtain an intermediate I-3, wherein the reaction time is 10 hours; the catalyst is [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride; the amount of the catalyst is 0.005 percent of the feeding amount;
reacting the intermediate I-3 with a methyl Grignard reagent in a first solvent at low temperature to obtain a crude product of the intermediate I, wherein the reaction time is 3 hours; the first solvent is tetrahydrofuran and 2-methyltetrahydrofuran, and the dosage of the first solvent is 10 times of the volume; the medium and low temperature is 50 ℃;
reacting the crude intermediate I product with acid in a second solvent to form salt of the intermediate I, and recrystallizing to obtain a pure intermediate I salt product, wherein the reaction time is 4 hours; the acid is trifluoroacetic acid, the concentration is 80%, and the using amount of the acid is 1.5 molar equivalents of the crude product of the intermediate I; the second solvent is n-hexane, and the dosage of the second solvent is 6 times of the volume of the first solvent;
extracting the pure product of the salt of the alkaline hydrolysis intermediate I by using a third solvent to obtain the pure product of the intermediate I, wherein the alkali is sodium hydroxide and the concentration is 20%; the third solvent is dichloromethane, and the dosage of the third solvent is 12 times of the volume.
Example 5
A preparation method of 2-aminophenyldimethylphosphine oxide serving as an intermediate of Brigatinib comprises the following steps:
reacting the intermediate I-1 and the intermediate I-2 in the step (1) in the presence of a catalyst at a certain temperature, specifically 100 ℃, to obtain an intermediate I-3, wherein the reaction time is 6 hours; the catalyst is bis (dibenzylideneacetone) palladium; the amount of the catalyst is 0.05 percent of the feeding amount;
reacting the intermediate I-3 with a methyl Grignard reagent in a first solvent at low temperature to obtain a crude product of the intermediate I, wherein the reaction time is 4 hours; the first solvent is tetrahydrofuran and toluene, and the dosage of the first solvent is 6 times of the volume; the medium-low temperature is 30 ℃;
reacting the crude intermediate I product with acid in a second solvent to form salt of the intermediate I, and recrystallizing to obtain a pure intermediate I salt product, wherein the reaction time is 4 hours; the acid is trifluoromethanesulfonic acid, the concentration is 100%, and the amount of the acid is 2.5 molar equivalents of the crude product of the intermediate I; the second solvent is petroleum ether, and the dosage of the second solvent is 8 times of the volume of the first solvent;
extracting the pure product of the salt of the alkaline hydrolysis intermediate I by using a third solvent to obtain the pure product of the intermediate I, wherein the alkali is potassium hydroxide and the concentration is 40%; the third solvent is toluene, and the dosage of the third solvent is 5 times of the volume.
Example 6
A preparation method of 2-aminophenyldimethylphosphine oxide serving as an intermediate of Brigatinib comprises the following steps:
reacting the intermediate I-1 and the intermediate I-2 in the step (1) in the presence of a catalyst at a certain temperature, specifically 120 ℃, to obtain an intermediate I-3, wherein the reaction time is 10 hours; the catalyst is bis (dibenzylideneacetone) palladium; the amount of the catalyst is 0.01 percent of the feeding amount;
reacting the intermediate I-3 with a methyl Grignard reagent in a first solvent at low temperature to obtain a crude product of the intermediate I, wherein the reaction time is 5 hours; the first solvent is 2-methyltetrahydrofuran and toluene, and the dosage of the first solvent is 8 times of the volume; the medium-low temperature is 20 ℃;
reacting the crude intermediate I product with acid in a second solvent to form salt of the intermediate I, and recrystallizing to obtain a pure intermediate I salt product, wherein the reaction time is 5 hours; the acid is trifluoroacetic acid, the concentration is 100%, and the using amount of the acid is 3.5 molar equivalents of the crude product of the intermediate I; the second solvent is dioxane, and the dosage of the second solvent is 10 times of the volume of the first solvent;
extracting the pure product of the salt of the alkaline hydrolysis intermediate I by using a third solvent to obtain the pure product of the intermediate I, wherein the alkali is sodium methoxide, and the concentration of the alkali is 30%; the third solvent is methyl tert-butyl ether, and the amount of the third solvent is 8 times of the volume.
In the above examples 1 to 6, in the step (1), the catalyst is one or more of tetratriphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, bis (dibenzylideneacetone) palladium, bis-acetonitrile palladium chloride, and bis-triphenylphosphine palladium dichloride; in the step (3), the second solvent is one or more of N-hexane, cyclohexane, N-heptane, isooctane, petroleum ether, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, methyl tert-butyl ether, methyl cyclopentyl ether, isopropyl ether, toluene, xylene, methanol, ethanol and isopropanol; in the step (4), the alkali is sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably potassium carbonate, sodium hydroxide or potassium hydroxide.
Test examples
The synthetic process route is as follows:
the first step is as follows: coupling reaction, Synthesis of dimethyl (2-aminophenyl) phosphite I-03
2-iodoaniline I-01500 g (2.28mole, 1.0 equivalent) and dimethyl phosphite I-02754 g (6.85mole, 3.0 equivalents) were placed in a 5.0L three-necked flask, 3.5L dioxane was added, stirring was carried out until complete dissolution, 1.12kg anhydrous potassium phosphate (5.7mole, 2.5 equivalents) was added, nitrogen substitution was carried out twice, and Pd (dppf) Cl was added under nitrogen protection255.0g (0.068mole, 0.03 equivalent), heating to the internal temperature of 90-100 ℃ under the protection of nitrogen, stirring for reaction for 15 hours, and controlling in thin-layer chromatography until the raw materials are completely converted; after the reaction, cooling to room temperature, concentrating to remove most of the solution, adding 5kg of deionized water, stirring, adding 5kg of ethyl acetate for extraction once, extracting the water phase with 5.0kg of ethyl acetate once, combining the organic phases, adding 0.5kg of anhydrous sodium sulfate, drying for two hours, filtering, and concentrating to dryness to obtain 357g of I-03 crude product, wherein the yield is 78%, and the next reaction is directly carried out without purification.
And (3) map analysis:
1H NMR(400MHz,CDCl3)δ7.38-7.43(m,1H),7.25-7.29(m,1H),6.64-6.72(m,2H),3.75(s,3H),3.72(s,3H).
the second step is that: synthesis of (2-aminophenyl) dimethyl phosphine oxide I by addition reaction
Dissolving 300g (1.50mole, 1.0 equivalent) of crude I03 in 1.8L of dry THF, stirring to form a solution, cooling to an internal temperature of 0-5 ℃ in an ice-water bath under the protection of nitrogen, dropwise adding 1.50L (4.5mole, 3.0 equivalent, 3.0mole/L of THF solution sold on the market) of a methyl magnesium chloride reagent, keeping the internal temperature of the product not more than 10 ℃ in the dropwise adding process, reacting to complete the conversion of the intermediate after the dropwise adding is finished, cooling the reaction system to the internal temperature of 10 ℃ in the ice-water bath, dropwise adding 3.0 equivalent of hydrochloric acid solution until the pH value of the system is neutral, concentrating to remove most of organic solvent, extracting twice by using 5.0L of ethyl acetate, combining organic phases, adding 500g of anhydrous sodium sulfate, drying for 2 hours, filtering, and concentrating to obtain viscous oily matter;
salifying and refining: dissolving the oily matter with dry THF 1.5L, dripping concentrated hydrochloric acid into the solution to precipitate a large amount of yellow to off-white solid, filtering, washing the solid with clean THF, dissolving the obtained hydrochloride solid into 1.5L absolute ethyl alcohol, heating to completely dissolve, cooling to precipitate off-white solid, and detecting the purity to meet the requirement of quality control standard.
Salt dissolving: the hydrochloride obtained above was dissolved in 1.5kg of deionized water, the pH of the solution was adjusted to 7.0 to 8.0 with 3.0 equivalents of sodium hydroxide, ethyl acetate was added thereto for 3.0 liters and extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain (2-aminophenyl) dimethylphosphine oxide i189.0g as a pale yellow to off-white solid with a yield of 75%.
And (3) map analysis:
1H NMR(400MHz,DMSO-d6)δ7.10-7.24(m,2H),6.59-6.67(m,1H),6.50-6.57(m,1H),6.14(s,2H),1.63(d,J＝13.30Hz,6H).
the above-mentioned embodiments only express the specific embodiments of the present application, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present application. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the concept of the method of the present application, which fall within the scope of the present application.
Claims (10)
1. A preparation method of 2-aminophenyldimethylphosphine oxide serving as an intermediate of Brigatinib is characterized by comprising the following steps of:
reacting the intermediate I-1 and the intermediate I-2 in the step (1) in the presence of a catalyst at a certain temperature to obtain an intermediate I-3, wherein the reaction time is 5-20 hours;
reacting the intermediate I-3 with a methyl Grignard reagent in a first solvent at low temperature to obtain a crude product of the intermediate I, wherein the reaction time is 3-10 hours;
reacting the crude intermediate I product with acid in a second solvent to form salt of the intermediate I, and recrystallizing to obtain a pure salt of the intermediate I, wherein the reaction time is 3-5 hours;
and (4) carrying out alkaline hydrolysis on the pure salt of the intermediate I, and extracting with a third solvent to obtain the pure salt of the intermediate I.
2. The method according to claim 1, wherein in step (1), the catalyst is one or more of tetratriphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, bis (dibenzylideneacetone) palladium, bis-acetonitrile palladium chloride and bis-triphenylphosphine palladium dichloride; the amount of the catalyst is 0.001-5.0% of the feeding amount.
3. The method according to claim 1, wherein the temperature in step (1) is 30-150 ℃.
4. The method according to claim 1, wherein the methyl Grignard reagent in step (2) is methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide; the dosage of the methyl Grignard reagent is 1-3 molar equivalents of the intermediate I-3; the concentration of the methyl Grignard reagent is 1.0-3.0 mole/L.
5. The method according to claim 1, wherein the first solvent in step (2) is one or more of tetrahydrofuran, 2-methyltetrahydrofuran and toluene; the amount of the first solvent is 5 to 10 times by volume.
6. The method of claim 1, wherein the low temperature in step (2) is-78-50 ℃.
7. The method according to claim 1, wherein the acid in step (3) is concentrated hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid, the concentration of the acid is 36.5% -100%, and the amount of the acid is 1-5 molar equivalents of the crude intermediate I.
8. The method according to claim 1, wherein the second solvent in step (3) is one or more selected from N-hexane, cyclohexane, N-heptane, isooctane, petroleum ether, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, methyl tert-butyl ether, methyl cyclopentyl ether, isopropyl ether, toluene, xylene, methanol, ethanol, and isopropanol; the dosage of the second solvent is 1-10 times of the volume of the first solvent.
9. The process according to claim 1, wherein the base in step (4) is sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably potassium carbonate, sodium hydroxide or potassium hydroxide; the dosage of the alkali is 1-3 equivalent of the pure product of the salt of the intermediate I, and the concentration of the alkali is 10-100%.
10. The method according to claim 1, wherein the third solvent in step (4) is one or more of ethyl acetate, isopropyl acetate, dichloromethane, toluene and methyl tert-butyl ether, and the amount of the third solvent is 5-20 times by volume.
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