CN111646940B - Preparation method of bosutinib intermediate - Google Patents

Preparation method of bosutinib intermediate Download PDF

Info

Publication number
CN111646940B
CN111646940B CN201910160456.7A CN201910160456A CN111646940B CN 111646940 B CN111646940 B CN 111646940B CN 201910160456 A CN201910160456 A CN 201910160456A CN 111646940 B CN111646940 B CN 111646940B
Authority
CN
China
Prior art keywords
reaction
compound
solvent
temperature
bosutinib
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201910160456.7A
Other languages
Chinese (zh)
Other versions
CN111646940A (en
Inventor
张贵民
张现利
冯岩
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lunan Pharmaceutical Group Corp
Original Assignee
Lunan Pharmaceutical Group Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lunan Pharmaceutical Group Corp filed Critical Lunan Pharmaceutical Group Corp
Priority to CN201910160456.7A priority Critical patent/CN111646940B/en
Publication of CN111646940A publication Critical patent/CN111646940A/en
Application granted granted Critical
Publication of CN111646940B publication Critical patent/CN111646940B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a synthesis method of a bosutinib intermediate. The method comprises the steps of: a: and (3) carrying out reflux reaction on the compound 1 and the compound 2 under the condition of controlling the temperature in the presence of a solvent A, concentrating the reaction solution under reduced pressure until the reaction is finished, and recrystallizing the obtained solid from a solution B to obtain an intermediate 1'. B: and (3) adding the intermediate 1' into the solvent C, performing temperature-controlled cyclization reaction, cooling the reaction liquid to room temperature after the reaction is finished, and adding the solvent D for crystallization to obtain the target product of the compound shown in the formula I. Compared with the prior art, the 7- (4-methylpiperazine-1-yl) propoxy-6-methoxy-4-oxo-1, 4-dihydro-3-quinoline carbonitrile is provided as a key intermediate for synthesizing bosutinib. The intermediate can be used for obtaining the bosutinib only through two simple steps of subsequent reaction, long-time reflux is avoided, the reaction time is effectively shortened, and the purity of the obtained product is higher.

Description

Preparation method of bosutinib intermediate
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a bosutinib intermediate.
Background
Bosutinib (Bosutinib), chemical name 4- [ (2, 4-dichloro-5-methoxyphenyl) amino ] -6-methoxy-7- [3- (4-methyl-1-piperazine) propoxy ] -3-quinolinecarbonitrile monohydrate, developed by the company of wheatstone pharmacy (Wyeth Pharmaceuticals), is a powerful dual-inhibitor of protein kinase Scr/Ab1, and is competitive with a substrate in cells, inhibits phosphorylation of epidermal growth factor receptor tyrosine kinase (EGFR-TK), blocks transduction of tumor cell signals, and thus inhibits growth of tumor cells, and induces apoptosis. The year 2010 9 menstrual European Union approved for the treatment of Chronic Myelogenous Leukemia (CML). On 9/4 2012, the drug was approved by the FDA in the united states for marketing under the trade name Bosulif. The product is an oral tablet, and is mainly used for patients with chronic, acceleration or rapid change Ph chromosome positive CML which are intolerant or resistant to other treatments including Imatinib (Imatinib). The CAS number is 380843-75-4, and the chemical structure is as follows:
there are many reports on the research of Guan Boshu tenib preparation method, and besides the continuous improvement of the side chain functional group conversion method and conversion sequence, the research of the mother nucleus quinoline-3-carbonitrile cyclization mode is also reported. Mainly comprises the following synthetic routes:
route one: patent CN100354263C, WO2003093241, US20030212276A1, CN1750824a and literature j.med.chem.,2004,47,1599-1601 report that 3-fluoro-4-methoxyaniline is used as a raw material, a quinoline ring intermediate is first constructed by a Doebner-Miller reaction with ethyl (ethoxymethylene) cyanoacetate, then a 4-chloro-3-quinolinecarbonitrile derivative is produced by a chlorination reaction with a chlorinating agent such as phosphorus oxychloride, phosphorus trichloride or thionyl chloride, and finally bosutinib is produced by a two-step Ullmann reaction. The route is the mainstream method for preparing the bosutinib at present, and although the cyclization reaction needs high temperature and long-time reflux, the process has the characteristics of classical reaction and stable process. In addition, since 3-fluoro-4-methoxyaniline is adopted as a starting material, stronger reaction conditions are required when the 2, 4-dichloro-5-methoxyaniline and the 1- (3-hydroxypropyl) -4-methylpiperazine part are finally introduced through Ullmann reaction, the yield is lower, the industrialization prospect of the process is limited, and the total yield of the route is 19.6%.
Route two: patent CN100354263C, WO2003093241, US20030212276A1 and literature biorg. Med. Chem.,16 (2008) 405-412 uses methyl 2-amino-4-fluoro-5-methoxybenzoate as a raw material, which is reacted with DMF-DMA first and then acetonitrile under the action of butyllithium to construct a quinoline ring intermediate, and then bosutinib is prepared according to the above method. However, butyl lithium is used in the construction of quinoline ring, and the reaction is required at-78 ℃ and the conditions are more severe; and the Ullmann reaction is also adopted to prepare a target product, so that the method is not suitable for industrial scale-up operation, and the total yield of the route is 20.2%.
Route three: the literature bioorg.med.chem.lett.,10 (2000) 2477-2480 and j.med.chem.,2001,44,3965-3977 report that 4-hydroxy-3-methoxybenzoic acid methyl ester is used as a raw material, isopropyl protection is introduced by reaction with 2-bromopropane, nitrosation with nitric acid, reduction of iron powder-ammonium chloride, reaction with DMF-DMA, cyclization with acetonitrile under the action of butyllithium to construct a quinoline ring intermediate, and the intermediate is subjected to a phosphorus oxychloride chlorination reaction, an aluminum trichloride deisopropyl protection reaction, and a three-step substitution reaction to obtain bosutinib. The route adopts a linear synthesis strategy, so that the reaction steps are greatly prolonged, butyl lithium is required to be used for reaction at the temperature of minus 78 ℃, and the conditions are relatively harsh.
The industrial journal of the literature, 2013,44 (11), 1086-1088, likewise employs isopropyl to protect phenolic hydroxyl groups, but employs 3-ethoxy-2-nitrile-acrylic acid to introduce quinoline rings, and employs a method of introducing aniline fragments first and then alkyl side chains. The method has longer reaction steps, and does not need to adopt Dowtherm A as a solvent for reaction at 250 ℃ during cyclization, thus being not suitable for industrial scale-up operation.
Route four: patent CN101792416B and literature molecular 2010,15,4261-4266 still take 4-hydroxy-3-methoxybenzoic acid methyl ester as raw materials, react with 1-bromo-3-chloropropane, then react with cyanoacetaldehyde diethyl acetal after nitric acid nitration and iron powder-ammonium chloride reduction, cyclize under the action of sodium hydroxide to construct a quinoline ring intermediate, and finally prepare the bosutinib according to a conventional method. However, the route adopts a linear synthesis mode, the introduction and removal of isopropyl protecting groups prolong the synthesis steps, the operation is complicated, and the total yield is only 13.5%.
WO2015198249A1 does not have obvious advantages by using a strategy of reacting with 4-methylpiperazine and then preparing the target product by the clasp in this way.
Route five: patent WO2005019201, CN1835923A and Org. Process Res. Dev.,2013,17,500-504 disclose a process comprising the steps of using 2-methoxy-5-nitrophenol as a raw material, sequentially carrying out substitution and reduction reaction to obtain a substituted aniline intermediate, synthesizing the substituted aniline intermediate with 2-cyano-N- (2, 4-dichloro-5-methoxyphenyl) acetamide and triethyl orthoformate by a Combes quinoline synthesis method to obtain a key intermediate, and finally dehydrating and closing the ring under the action of phosphorus oxychloride to obtain a target product. The route adopts a convergent method for synthesis, shortens the reaction steps, has higher total yield of 44.0 percent, and the reaction conditions of each step are more suitable for industrial production, but in the last step of ring-closing reaction system, the high temperature and long-time reflux (105 ℃/16 h) are required due to poor solubility of each material, so that the reaction time is longer, and the production period is prolonged.
Route six: patent WO2009149622A1, CN200810038964 and literature Synthesis,2015,47,3133-3138 take 3-methoxy-4- (3-chloropropyloxy) acetophenone as raw materials, and after 4-methylpiperazine substitution, nitric acid nitration, bromine bromination, sodium cyanide substitution and iron powder reduction, quinoline ring is constructed by the reduced iron powder and triethyl orthoformate, and finally the bosutinib is obtained by reacting the reduced iron powder with 2, 4-dichloro-5-methoxyaniline after phosphorus oxychloride. However, the route adopts a linear synthesis strategy, and a large amount of iron mud can be generated by ferrite reduction, so that the environment pollution is easy to generate, and the total yield is 13.4%.
Route seven: the same research subject group takes 4-hydroxy-3-methoxybenzoic acid methyl ester as a raw material in literature Heterycles, vol.89, no.12,2014, and sequentially carries out 1-bromo-3-chloropropane substitution, bromous, alkali hydrolysis of ester, thionyl chloride chlorination, cyanoethyl acetate condensation, high-temperature decarboxylation, trimethyl orthoformate condensation and ammonia ammonolysis reaction, then a quinoline mother nucleus intermediate is prepared by closing a ring under high-temperature conditions, and finally a target product is prepared by substitution reaction, but the route is applied to dangerous products such as bromine, and the like, has long synthesis steps and is not suitable for industrialized amplification production.
Route eight: another synthetic strategy is disclosed in document Organic Preparations and Procedures International,47:207-213,2015: the preparation method comprises the steps of using 4-hydroxy-3-methoxybenzoic acid methyl ester as a raw material, sequentially carrying out 1-bromo-3-chloropropane substitution, nitric acid nitration, alkali hydrolysis of ester, oxalyl chloride substitution, cyanoethyl acetate condensation, high-temperature decarboxylation, DMF-DMA condensation and Raney Ni hydrogenation cyclization to prepare a quinoline mother nucleus intermediate, and finally carrying out substitution reaction to prepare a target product, wherein the method is applied to dangerous goods such as nitric acid, oxalyl chloride and the like, the Raney Ni hydrogenation operation is complex, and meanwhile, the synthesis steps are long, so that the method is not suitable for industrialized large-scale production.
Route nine: patent CN104876865a uses isoxazole ring to prepare a quinoline mother nucleus intermediate, but the reaction time is longer and the purity of the obtained product is lower because the reaction reagent is weaker in alkali treatment of isoxazole.
In summary, in the reported technical methods for preparing bosutinib, the main problems are:
1. the high temperature and long time reflux are needed when constructing the quinoline ring, and the two key steps for preparing the bosutinib through Ullmann reaction both need stronger reaction conditions, so that the problem of higher equipment requirement is solved;
2. butyl lithium is applied when constructing quinoline ring, and the reaction is required to be carried out at the temperature of minus 78 ℃, so that the reaction condition is harsher;
3. the linear synthesis strategy is adopted, and the introduction and removal of the protecting group prolong the synthesis step, and simultaneously, the operation is complicated and the total yield is lower;
4. the application of dangerous goods such as ferrite, bromine, nitric acid, oxalyl chloride and the like is not only easy to produce environmental pollution, but also has more severe operation and is not suitable for industrialized amplified production.
7- (4-methylpiperazin-1-yl) propoxy-6-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarbonitrile can be used as a key intermediate in the bosutinib synthesis process, and its chemical structure is as follows:
the intermediate only needs to undergo a chlorination reaction with phosphorus oxychloride and then undergo a nucleophilic substitution reaction with 2, 4-dichloro-5-methoxyaniline to prepare bosutinib. The process can effectively avoid the problems that in the first route, the two key steps for preparing the bosutinib through Ullmann reaction need stronger reaction conditions and higher equipment requirements, and in the fifth route, the materials are poor in solubility and high in temperature and long in reflux, so that the reaction time is longer, the production period is prolonged, and the purity of the obtained product is lower.
Based on the intermediate, a brand new synthetic route for preparing the bosutinib (shown in the following chart) can be developed: 2-methoxy-5-nitrophenol is used as a raw material, 3- (4-methylpiperazine-1-yl) propoxy-4-methoxyaniline (1) is prepared by two steps of substitution reaction and reduction reaction in sequence, 7- (4-methylpiperazine-1-yl) propoxy-6-methoxy-4-oxo-1, 4-dihydro-3-quinoline formonitrile (I) is generated by Doebner-Miller reaction with (ethoxymethylene) cyanoacetic acid ethyl ester (2), the corresponding quinoline mother nucleus intermediate is prepared by reacting with phosphorus oxychloride, and finally bosutinib is prepared by nucleophilic substitution reaction with 2, 4-dichloro-5-methoxyaniline. The synthesis method for preparing the quinoline ring intermediate (I) from the key intermediate 1 is not reported.
In summary, 7- (4-methylpiperazine-1-yl) propoxy-6-methoxy-4-oxo-1, 4-dihydro-3-quinoline carbonitrile is used as a key intermediate in the bosutinib synthesis process, so that a process route more suitable for industrial scale-up production is explored for the bosutinib, and the problem to be solved at present is still solved.
Disclosure of Invention
In order to make the bosutinib more suitable for industrial production, the invention provides a preparation method of a bosutinib intermediate, and particularly relates to a preparation method of 7- (4-methylpiperazine-1-yl) propoxy-6-methoxy-4-oxo-1, 4-dihydro-3-quinoline carbonitrile shown as a formula I.
The specific technical scheme of the invention is as follows:
a preparation method of 7- (4-methylpiperazin-1-yl) propoxy-6-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarbonitrile shown in formula I comprises the following steps:
a: and (3) carrying out reflux reaction on the compound 1 and the compound 2 under the condition of controlling the temperature in the presence of a solvent A, concentrating the reaction solution under reduced pressure until the reaction is finished, and recrystallizing the obtained solid from a solution B to obtain an intermediate 1'.
B: and (3) adding the intermediate 1' into the solvent C, performing temperature-controlled cyclization reaction, cooling the reaction liquid to room temperature after the reaction is finished, and adding the solvent D for crystallization to obtain the target product of the compound shown in the formula I.
Preferably, the solvent A in the step A is one or two of tetrahydrofuran, acetonitrile, N-heptane, 1, 4-dioxane, toluene, octane, N, N-dimethylformamide, xylene and dimethyl sulfoxide, wherein toluene is particularly preferred.
Preferably, the molar ratio of compound 1 to compound 2 in step a is 1:1.0 to 2.0, of which 1 is particularly preferred: 1.2.
preferably, the solvent B in step A is one or both of methanol and ethanol, with methanol being particularly preferred.
Preferably, the mass-volume ratio of the compound 1 to the recrystallization solvent B in the step A is 1:1 to 5 g/mL, of which 1 is particularly preferred: 3, g/mL.
Preferably, the solvent C in the step B is one or two of N-methyl pyrrolidone, biphenyl ether and sulfolane, and the added solvent can completely dissolve the intermediate 1'.
Preferably, the reaction temperature in step B is 200 to 260 ℃.
Preferably, the mass to volume ratio of compound 1 to solvent D described in step B is 1: 25-30 g/mL.
Preferably, the solvent D in the step B is one or two of petroleum ether, n-hexane, cyclohexane, n-pentane and n-heptane, wherein n-hexane is particularly preferred, and the solvent is added in such an amount that no new crystals are precipitated.
The invention has the technical effects that:
1. the intermediate can be used for obtaining the bosutinib only through two simple steps of subsequent reaction, long-time reflux is avoided, the reaction time is effectively shortened, and the purity of the obtained product is higher.
2. The intermediate has simple synthetic route and high yield (more than 86 percent) and purity (more than 99.8 percent).
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The invention adopts HPLC to measure the purity of I, and the chromatographic conditions are as follows: [ chromatographic column: ultimate XB-C 18 (4.6 mm. Times.150 mm,3.0 μm); mobile phase a:0.02% aqueous trifluoroacetic acid; mobile phase B: methanol: acetonitrile (1:1), gradient elution (0.fwdarw.30 min: B15%. Fwdarw.50%; 30.fwdarw.50 min: B50%. Fwdarw.80%; 50.fwdarw.60 min: B80%. Fwdarw.15%); column temperature: 40 ℃; detection wavelength: 216nm; flow rate: 1.0 mL/min -1 The method comprises the steps of carrying out a first treatment on the surface of the Sample injection amount: 10 mu L]。
Example 1
Adding compound 1 (55.88 g,0.20 mol) and compound 2 (40.60 g,0.24 mol) into toluene (300 mL), controlling the temperature to reflux for 5h, cooling the reaction solution to room temperature, concentrating under reduced pressure to dryness, recrystallizing the obtained solid with methanol (165 mL), filtering, collecting a filter cake, adding the obtained filter cake into diphenyl ether-biphenyl (V) Biphenyl ether ：V Bidiphenyl =3: 1,500 mL), heating to 245-250 ℃ for reaction for 3h, cooling the reaction solution to room temperature, adding positive reagentHexane (1500 mL) is crystallized for 2-3 h, crystallization is finished, filtering is carried out, a filter cake is collected, and the obtained filter cake is decompressed and dried at 40 ℃ to obtain the target product of the compound shown in the formula I, wherein the yield is 93.4%, and the purity is 99.92%.
Example 2
Adding compound 1 (55.88 g,0.20 mol) and compound 2 (33.83 g,0.20 mol) into toluene (300 mL), controlling the temperature to reflux for 5h, cooling the reaction solution to room temperature, concentrating under reduced pressure to dryness, recrystallizing the obtained solid with methanol (100 mL), filtering, collecting a filter cake, adding the obtained filter cake into diphenyl ether-biphenyl (V) Biphenyl ether ：V Biphenyl =3: 1,500 mL), controlling the temperature to 245-250 ℃ for 3h, cooling the reaction liquid to room temperature, adding n-hexane (1400 mL) for crystallization for 2-3 h, ending crystallization, filtering, collecting a filter cake, and drying the obtained filter cake under reduced pressure and vacuum at 40 ℃ to obtain the target product of the compound shown as the formula I, wherein the yield is 91.5%, and the purity is 99.90%.
Example 3
Compound 1 (55.88 g,0.20 mol), compound 2 (67.68 g,0.40 mol) are added into toluene (300 mL), the temperature is controlled to reflux for 5h, the reaction liquid is cooled to room temperature, the reaction liquid is concentrated to dryness under reduced pressure, the obtained solid is recrystallized by methanol (200 mL), the filtration is carried out, a filter cake is collected, the obtained filter cake is added into diphenyl ether (500 mL), the temperature is controlled to 245-250 ℃ for reaction for 3h, the reaction liquid is cooled to room temperature, n-hexane (1700 mL) is added for crystallization for 2-3 h, the crystallization is finished, the filtration is carried out, the filter cake is collected, and the obtained filter cake is dried under reduced pressure and vacuum at 40 ℃ to obtain the compound of the target product formula I, and the yield is 91.6%, and the purity is 99.88%.
Example 4
Adding compound 1 (55.88 g,0.20 mol) and compound 2 (20.07 g,0.16 mol) into toluene (300 mL), controlling the temperature to reflux for reaction for 5h, cooling the reaction liquid to room temperature, concentrating under reduced pressure to dryness, recrystallizing the obtained solid by methanol (280 mL), filtering, collecting a filter cake, adding the obtained filter cake into biphenyl (500 mL), controlling the temperature to 245-250 ℃ for reaction for 3h, cooling the reaction liquid to room temperature, adding n-hexane (1450 mL), crystallizing for 2-3 h, filtering, collecting the filter cake, and drying the obtained filter cake under reduced pressure at 40 ℃ in vacuum to obtain the compound of the target product formula I, wherein the yield is 90.3%, and the purity is 99.85%.
Example 5
Adding compound 1 (55.88 g,0.20 mol) and compound 2 (71.05 g,0.40 mol) into toluene (300 mL), controlling the temperature to reflux for 5h, cooling the reaction solution to room temperature, concentrating under reduced pressure to dryness, recrystallizing the obtained solid with methanol (55 mL), filtering, collecting a filter cake, adding the obtained filter cake into diphenyl ether-sulfolane (V) Biphenyl ether ：V Sulfolane (TMP) =3: 1,500 mL), controlling the temperature to 210-215 ℃ for 3h, cooling the reaction liquid to room temperature, adding n-hexane (1500 mL) for crystallization for 2-3 h, filtering after crystallization, collecting a filter cake, and drying the obtained filter cake under reduced pressure and vacuum at 40 ℃ to obtain the target product of the compound shown as the formula I, wherein the yield is 89.9%, and the purity is 99.89%.
Example 6
Compound 1 (55.88 g,0.20 mol), compound 2 (40.60 g,0.24 mol) were added to 1, 4-dioxane (300 mL), the temperature was controlled to reflux reaction for 5h, the reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, the obtained solid was recrystallized from ethanol (165 mL), filtered, the filtrate was collected, and the obtained cake was added to biphenyl-sulfolane (V Biphenyl ：V Sulfolane (TMP) =3: 1,500 mL), controlling the temperature to 200-205 ℃ for 3h, cooling the reaction liquid to room temperature, adding n-heptane (1500 mL) for crystallization for 2-3 h, ending crystallization, filtering, collecting a filter cake, and drying the obtained filter cake under reduced pressure and vacuum at 40 ℃ to obtain the target product of the compound shown as the formula I, wherein the yield is 88.4%, and the purity is 99.85%.
Example 7
Compound 1 (55.88 g,0.20 mol), compound 2 (40.60 g,0.24 mol) were added to octane (300 mL), the temperature was controlled to reflux for 5h, the reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, the obtained solid was recrystallized from methanol (130 mL), filtered, and the obtained cake was added to N-methylpyrrolidone-sulfolane (V) N-methylpyrrolidone ：V Sulfolane (TMP) =3: 1,500 mL), controlling the temperature to 230-235 ℃ for 3h, cooling the reaction liquid to room temperature, adding petroleum ether (1700 mL) for crystallization for 2-3 h, filtering after crystallization, and drying the obtained filter cake under reduced pressure and vacuum at 40 ℃ to obtain the target product of the compound shown as the formula I, wherein the yield is 88.0%, and the purity is 99.87%.
Example 8
Compound 1 (55.88 g,0.20 mol), compound 2 (40.60 g,0.24 mol) are added into N-heptane (300 mL), the temperature is controlled to reflux for 5h, the reaction liquid is cooled to room temperature, the reaction liquid is concentrated to dryness under reduced pressure, the obtained solid is recrystallized by ethanol (165 mL), the obtained solid is filtered, the obtained filter cake is added into N-methylpyrrolidone (500 mL), the temperature is raised to 195-200 ℃ for reaction for 3h, the reaction liquid is cooled to room temperature, N-pentane (1500 mL) is added for crystallization for 2-3 h, after crystallization is finished, the filtration is carried out, the obtained filter cake is dried under reduced pressure at 40 ℃ and vacuum, thus obtaining the compound of the target product formula I, the yield is 88.1%, and the purity is 99.83%.
Example 9
And adding xylene (300 mL) into a compound 1 (55.88 g,0.20 mol) and a compound 2 (40.60 g,0.24 mol), controlling the temperature to reflux for reaction for 5h, cooling the reaction liquid to room temperature, concentrating the reaction liquid under reduced pressure to dryness, recrystallizing the obtained solid by ethanol (100 mL), filtering, adding sulfolane (500 mL) into the obtained filter cake, heating to 260-265 ℃ for reaction for 3h, cooling the reaction liquid to room temperature, adding cyclohexane (1400 mL) for crystallization for 2-3 h, ending crystallization, filtering, collecting the filter cake, and drying the obtained filter cake under reduced pressure at 40 ℃ in vacuum to obtain the compound of the target product formula I, wherein the yield is 87.6% and the purity is 99.82%.
Example 10
Adding tetrahydrofuran (300 mL) into compound 1 (55.88 g,0.20 mol) and compound 2 (40.60 g,0.24 mol), controlling the temperature to reflux for 5h, cooling the reaction solution to room temperature, concentrating the reaction solution under reduced pressure to dryness, recrystallizing the obtained solid with ethanol (150 mL), filtering, collecting filtrate, adding the obtained filter cake into diphenyl ether-N-methylpyrrolidone (V) Biphenyl ether ：V N-methylpyrrolidone =3: 1,500 mL), controlling the temperature to 205-210 ℃ for 3h, cooling the reaction liquid to room temperature, adding n-heptane (1500 mL) for crystallization for 2-3 h, filtering after crystallization, collecting a filter cake, and drying the obtained filter cake under reduced pressure and vacuum at 40 ℃ to obtain the target product of the compound shown as the formula I, wherein the yield is 87.3%, and the purity is 99.85%.
Example 11
Compound 1 (55.88 g,0.20 mol), compound 2 (40.60 g,0.24 mol) were added to acetonitrile (300 mL), the temperature was controlled to reflux for 5h, the reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, the obtained solid was recrystallized from methanol (165 mL),filtering, adding N-methylpyrrolidone-biphenyl (V) N-methylpyrrolidone ：V Biphenyl =3: 1,500 mL), controlling the temperature to 200-205 ℃ for 3h, cooling the reaction liquid to room temperature, adding petroleum ether (1600 mL) for crystallization for 2-3 h, filtering after crystallization, and drying the obtained filter cake under reduced pressure and vacuum at 40 ℃ to obtain the target product of the compound shown as the formula I, wherein the yield is 87.5%, and the purity is 99.80%.
Example 12
Adding compound 1 (55.88 g,0.20 mol) and compound 2 (40.60 g,0.24 mol) into N, N-dimethylformamide (300 mL), controlling the temperature to reflux for 5h, cooling the reaction solution to room temperature, concentrating under reduced pressure to dryness, recrystallizing the obtained solid with ethanol (300 mL), filtering, collecting filtrate, adding the obtained filter cake into sulfolane-N-methylpyrrolidone (V) Sulfolane (TMP) ：V N-methylpyrrolidone =3: 1,500 mL), controlling the temperature to 220-225 ℃ for 3h, cooling the reaction liquid to room temperature, adding n-pentane (1500 mL) for crystallization for 2-3 h, ending crystallization, filtering, collecting a filter cake, and drying the obtained filter cake under reduced pressure and vacuum at 40 ℃ to obtain the target product of the compound shown as the formula I, wherein the yield is 87.2%, and the purity is 99.81%.
Example 13
Adding xylene (300 mL) into a compound 1 (55.88 g,0.20 mol) and a compound 2 (40.60 g,0.24 mol), controlling the temperature to reflux for reaction for 5h, cooling the reaction liquid to room temperature, concentrating under reduced pressure to dryness, recrystallizing the obtained solid by methanol (280 mL), filtering, adding the obtained filter cake into N-methylpyrrolidone (500 mL), controlling the temperature to 195-200 ℃ for reaction for 3h, cooling the reaction liquid to room temperature, adding petroleum ether (1400 mL) for crystallization for 2-3 h, filtering, and drying the obtained filter cake under reduced pressure at 40 ℃ in vacuum to obtain the compound of the target product formula I, wherein the yield is 87.0% and the purity is 99.80%.
Example 14
Compound 1 (55.88 g,0.20 mol) and compound 2 (40.60 g,0.24 mol) are added into dimethyl sulfoxide (300 mL), the temperature is controlled to reflux for 5h, the reaction liquid is cooled to room temperature, the mixture is concentrated to dryness under reduced pressure, the obtained solid is recrystallized by ethanol (50 mL), the mixture is filtered, the filtrate is collected, the obtained filter cake is added into sulfolane (500 mL), the temperature is controlled to 255-260 ℃ for 3h, the reaction liquid is cooled to room temperature, n-heptane (1500 mL) is added for crystallization for 2-3 h, the crystallization is finished, the filtration is carried out, the filter cake is collected, and the obtained filter cake is dried under reduced pressure at 40 ℃ and vacuum, thus obtaining the compound of the target product formula I, the yield is 86.9%, and the purity is 99.78%.
Comparative example 1
Methyl 4- (3- (4-methylpiperazino) -1-propoxy) -5-methoxy-2-aminobenzoate (1.5 g,4.45 mmol) and isoxazole (0.62 g,9 mmol) were dissolved in 20mL ethanol, adjusted to pH 12 by addition of sodium hydroxide solution and reacted at room temperature for 5h. The solvent was distilled off under reduced pressure, pH was adjusted to neutrality with dilute hydrochloric acid, and filtration was carried out to give 7- (3- (4-methylpiperazino) -1-propoxy) -4-keto-6-methoxyquinoline-3-carbonitrile as a solid in 85% yield, 99.65% yield.
Comparative example 2
Methyl 4- (3- (4-methylpiperazino) -1-propoxy) -5-methoxy-2-aminobenzoate (1.5 g,4.45 mmol) and isoxazole (0.62 g,9 mmol) were dissolved in ethanol, adjusted to pH 12 by the addition of sodium hydroxide solution and reacted at room temperature for 5h. Concentrating under reduced pressure to dryness, recrystallizing the obtained solid with methanol, filtering, collecting filter cake, and adding the obtained filter cake into diphenyl ether-biphenyl (V) Biphenyl ether ：V Bidiphenyl =3: 1,500 mL), heating to 245-250 ℃ for reaction for 3h, cooling the reaction liquid to room temperature, adding n-hexane (1500 mL) for crystallization for 2-3 h, ending crystallization, filtering, and drying the obtained filter cake under reduced pressure and vacuum at 40 ℃ to obtain the target product of the compound shown as the formula I, wherein the yield is 78%, and the purity is 99.90%.

Claims (10)

1. A preparation method of a bosutinib intermediate is characterized in that a compound 1, namely 4-methoxy-3- [3- (4-methyl-piperazin-1-yl) -propoxy ] -phenylamine, reacts with a compound 2, namely (ethoxymethylene) cyanoacetic acid ethyl ester to obtain a compound of formula I, namely the bosutinib intermediate;
the reaction formula is as follows:
。
2. the preparation method according to claim 1, wherein the method comprises the following specific steps,
a: reflux-reacting the compound 1 and the compound 2 under the condition of controlling temperature in the presence of a solvent A, concentrating the reaction liquid under reduced pressure until the reaction is finished, and recrystallizing the obtained solid by the solvent B to prepare an intermediate 1';
b: and (3) adding the intermediate 1' into the solvent C, performing temperature-controlled cyclization reaction, cooling the reaction liquid to room temperature after the reaction is finished, and adding the solvent D for crystallization to obtain the target product of the compound shown in the formula I.
3. The process according to claim 2, wherein the solvent A in step A is tetrahydrofuran, acetonitrile, n-heptane, 1, 4-dioxane, toluene, octane,N,N-one or two of dimethylformamide, xylene, dimethyl sulfoxide.
4. The process of claim 2, wherein the molar ratio of compound 1 to compound 2 in step a is 1:1.0 to 2.0.
5. The method according to claim 2, wherein the solvent B in the step a is one or both of methanol and ethanol.
6. The process according to claim 2, wherein the solvent C in step B isN-one or both of methyl pyrrolidone, biphenyl ether, sulfolane.
7. The preparation method according to claim 2, wherein the solvent D in the step B is one or two of petroleum ether, n-hexane, cyclohexane, n-pentane and n-heptane.
8. The process according to claim 2, wherein the reaction temperature in step B is 200 to 260 ℃.
9. The preparation method according to claim 2, wherein the mass-to-volume ratio of the compound 1 to the recrystallization solvent B is 1: 1-5 g/mL.
10. The preparation method according to claim 2, wherein the mass-to-volume ratio of the compound 1 to the solvent D in the step B is 1: 25-30 g/mL.
CN201910160456.7A 2019-03-04 2019-03-04 Preparation method of bosutinib intermediate Active CN111646940B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910160456.7A CN111646940B (en) 2019-03-04 2019-03-04 Preparation method of bosutinib intermediate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910160456.7A CN111646940B (en) 2019-03-04 2019-03-04 Preparation method of bosutinib intermediate

Publications (2)

Publication Number Publication Date
CN111646940A CN111646940A (en) 2020-09-11
CN111646940B true CN111646940B (en) 2024-01-30

Family

ID=72344566

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910160456.7A Active CN111646940B (en) 2019-03-04 2019-03-04 Preparation method of bosutinib intermediate

Country Status (1)

Country Link
CN (1) CN111646940B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1750824A (en) * 2003-02-21 2006-03-22 惠氏公司 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-3-quinolinecarbonitriles for the treatment of ischemic injury
WO2015198249A1 (en) * 2014-06-27 2015-12-30 Shilpa Medicare Limited Process for preparation of bosutinib

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1750824A (en) * 2003-02-21 2006-03-22 惠氏公司 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-3-quinolinecarbonitriles for the treatment of ischemic injury
WO2015198249A1 (en) * 2014-06-27 2015-12-30 Shilpa Medicare Limited Process for preparation of bosutinib

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
陈洪等.伯舒替尼的合成.中国医药工业杂志.2013,第第44卷卷(第第11期期),1086-1087. *

Also Published As

Publication number Publication date
CN111646940A (en) 2020-09-11

Similar Documents

Publication Publication Date Title
CA2535385A1 (en) Process for the preparation of 4-amino-3-quinolinecarbonitriles
CN104529895B (en) Synthetic method of replacing nitrogen-containing heterocyclic compound
WO2013156835A1 (en) An improved process for the preparation of erlotinib hydrochloride form a
JPS60197684A (en) Benzo(a)quinolizine derivative and its salt
CN111646940B (en) Preparation method of bosutinib intermediate
CN108084161A (en) The preparation method of De Lasha stars and its intermediate
Nyc et al. Synthesis of a biologically active nicotinic acid precursor: 2-amino-3-hydroxybenzoic acid
CN108658981A (en) A kind of synthetic method of the bromo- 4- methoxyl groups hydrogen of 6--pyrazoles [1,5-a] pyridine -3- formonitrile HCNs
NO328873B1 (en) Precursor feed for the preparation of olanzapine.
CN114671867B (en) Preparation method of tocartinib intermediate 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine
CN105254629A (en) Preparation method of moxifloxacin hydrochloride
CN111646939A (en) Preparation method of bosutinib
US10562889B2 (en) Process for the preparation of 1-(arylmethyl)quinazoline-2,4(1H,3H)-diones
CN114380732A (en) Preparation method of fluoro-indole carboxylic acid compounds
US4168313A (en) Phthalidyl 2-(3'-trifluoromethyl-anilino)-pyridine-3-carboxylate and its salts
KR20060079217A (en) Process for the synthesis of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-ethoxy-quinoline-3-carbonitrile
KR101457453B1 (en) Process for preparing gefitinib and an intermediate used for preparing thereof
CN111646955B (en) Method for preparing bosutinib intermediate
CN115433124B (en) Preparation method of 4-chloro-6-methoxy-7-benzyloxy quinoline
US6933388B2 (en) Process for the synthesis of 3-cyano-6-alkoxy-7-nitro-4-quinolones
CN110407735B (en) Synthesis process of 3,4,5, 6-tetrafluoro-N-methylphthalimide
AU2019260015B2 (en) Process for the hydrolysis of quinolone carboxylic esters
Syniugin et al. New method for the synthesis of pyrrolo [2, 3-b] dihydroquinolines
RU2054421C1 (en) Method for production of hydrochlorides of 2-benzyl benzimidazole or 2-styryl benzimidazole
CN105669566A (en) Preparation method of pharmaceutical intermediate N-arylquinazolinyl-amine compounds

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant