CN112047929A - Preparation method of 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine - Google Patents
Preparation method of 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine Download PDFInfo
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- CN112047929A CN112047929A CN202011037814.4A CN202011037814A CN112047929A CN 112047929 A CN112047929 A CN 112047929A CN 202011037814 A CN202011037814 A CN 202011037814A CN 112047929 A CN112047929 A CN 112047929A
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a preparation method of erdamitinib (Erdafitinib) intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine, which takes 2, 4-dinitroaniline as a starting raw material to prepare a target intermediate through basic unit reactions such as substitution, reduction, cyclization and the like in sequence. The preparation process has the advantages of easily available raw materials, rapidness, convenience, economy, environmental friendliness and suitability for large-scale production, and provides a new preparation way for industrialization of erdastinib.
Description
Technical Field
The invention belongs to the technical field of organic synthesis route design and preparation of raw material medicines and intermediates thereof, and particularly relates to a preparation method of an erdastinib intermediate which can be used for treating advanced or metastatic bladder cancer.
Background
Erdamitinib (Erdafitinib) is an FGFR inhibitor discovered by Astex pharmaceuticals and developed by poplar pharmaceuticals under the grand flag of the american pharmaceutical university. The drug has once been qualified by us FDA for breakthrough therapy approval and priority. Erdafitinib obtained us FDA approval for marketing in 2019 in month 4 under the trade name Balversa. Balversa is the first FDA approved FGFR kinase inhibitor in the united states as an oral pan FGFR inhibitor that is useful in the treatment of locally advanced or metastatic bladder cancer in adult patients. Because the medicine is not yet on the market formally in China and does not have a standard Chinese translation name, the applicant translates the medicine into Ervatinib.
The chemical name of ervatinib is: n is a radical of1- (3, 5-dimethoxyphenyl) -N2- (1-methylethyl) -N1- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl]1, 2-ethyldiamine.
International patents WO2011135376, WO2012073017 and WO2019109069 report synthetic routes and preparation methods of erdastinib or analogs thereof. The basic synthesis thought is that substituted quinoxaline mother nucleus is used as a raw material, on one hand, halogen substitution is formed on quinoxaline, and then quinoxaline pyrazole intermediate is formed by carrying out Suzuki carbon-carbon coupling reaction on different halogen functional groups and a borate derivative of a 1-methylpyrazole ring; on the other hand, another halogen functional group on the quinoxaline and the side chain amino group are subjected to substitution reaction to form another amino group side chain. Of course, the formation of the side chain of the amino group can also be completed by converting the nitro group on the quinoxaline ring into the amino group and then performing an amino substitution reaction with the corresponding halohydrocarbon.
The synthesis methods of ervatinib and derivatives thereof described in the prior documents are examined, although the preparation methods of quinoxaline mother nucleus and amino side chain amine are different, the linking sequence and time of the quinoxaline mother nucleus, pyrazole and amino side chain are different, and the selection of the reaction of a basic unit in the preparation process is different, the quinoxaline and pyrazole side chain are prepared by adopting the steps of firstly halogenating and then carrying out carbon-carbon coupling reaction with the borate of pyrazole; the synthetic route is shown as follows:
it can be seen that one of the key technologies in the synthesis of erdamatinib is to solve the synthesis of two intermediates a or B that overcome positional isomerism that may occur when linking pyrazoles.
How to efficiently and quickly prepare the core intermediate 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline (A) or 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (B) has very important practical significance for preparing erdintinib. Therefore, the research adopts a new synthesis technology, overcomes position isomerism of amino and timely reduction and conversion of nitro, and conveniently and quickly prepares a target intermediate. The preparation technology provides a new valuable way for the industrial production of the erdasatinib bulk drug.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and provides a preparation method of an improved Erdasatinib (Erdacitinib) intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I) according to a synthesis concept of green chemistry, wherein the preparation method is novel in design and simple in steps, is beneficial to quality improvement and industrial production of the medicine, and can promote economic and technical development of the bulk drug.
In order to achieve the purpose, the main technical scheme provided by the invention is as follows: a preparation method of an erdaminib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I),
the preparation method comprises the following steps: the preparation method comprises the following steps: 2, 4-dinitroaniline (II) and 2-bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone (III) are subjected to substitution reaction to prepare 1- (1-methyl-1H-pyrazol-4-yl) -2- [ (2, 4-dinitro) phenylamino ] ethanone (IV), 1- (1-methyl-1H-pyrazol-4-yl) -2- [ (2, 4-dinitro) phenylamino ] ethanone (IV) and metal indium are subjected to reduction cyclization reaction under the action of hydrochloric acid to prepare an ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I); the synthetic route is shown as follows:
in addition, the invention also provides the following auxiliary technical scheme:
the feeding ratio of the condensation reaction is 2, 4-dinitroaniline (II) (1 equivalent) and 2-bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone (III) (0.5-1.5 equivalents), and preferably 2, 4-dinitroaniline (II) (1 equivalent) and 2-bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone (III) (1 equivalent).
The solvent for the substitution reaction is methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, toluene or water, preferably water.
The temperature of the substitution reaction is 50-150 ℃, and preferably 100-110 ℃.
The feeding ratio of the reduction cyclization reaction is 1- (1-methyl-1H-pyrazol-4-yl) -2- [ (2, 4-dinitro) phenylamino ] ethanone (IV) (1 equivalent), indium (4-5 equivalents) and hydrochloric acid (6-8 equivalents), and the preferable materials are 1- (1-methyl-1H-pyrazol-4-yl) -2- [ (2, 4-dinitro) phenylamino ] ethanone (IV) (1 equivalent), indium (4.5 equivalents) and hydrochloric acid (7 equivalents)
The solvent for the reductive cyclization reaction is methanol, ethanol, isopropanol, toluene, tetrahydrofuran, dioxane, N-dimethylformamide or water, preferably water.
The temperature of the reduction cyclization reaction is 50-150 ℃, and preferably 100-110 ℃.
Using the target intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I) prepared above, reference is made to WO2011135376A1, whereby idatinib can be conveniently prepared according to the following reaction scheme:
the preparation method of the erdaminib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I) uses 2, 4-dinitroaniline (II) as a starting material, and sequentially carries out substitution, reduction, cyclization and other reactions, so that the raw materials in the preparation process are easy to obtain, quick, convenient, economical and environment-friendly, and are suitable for large-scale industrial production.
Detailed Description
The following non-limiting detailed description of the present invention is provided in connection with several preferred embodiments. Wherein, the preparation of the raw materials 2, 4-dinitroaniline (II) and 2-bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone (III) are respectively referred to in Synthetic Communications,31(7), 1123-1127; 2001 "and" Journal of Medicinal Chemistry,61(3), "1001-" 1018; 2018 "preparation method of the same compound.
The first embodiment is as follows:
adding 9.2g (50 mmol) of 2, 4-dinitroaniline (II), 10.5g (50 mmol) of 2-bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone (III) and 150mL of water into a reaction bottle, heating to 100-110 ℃, and carrying out reflux stirring reaction for 3-4 hours. Cooling to room temperature, extracting with ethyl acetate for three times, drying, and concentrating to obtain light yellow oily substance 1- (1-methyl-1H-pyrazol-4-yl) -2- [ (2, 4-dinitro) phenylamino]13.4g of ethanone (IV), yield 87.9%, EI-MS M/z 306[ M + H ]]+。
Example two:
1- (1-methyl-1H-pyrazol-4-yl) -2- [ (2, 4-dinitro) phenylamino group is added into a reaction bottle]Ethanone (IV) (7.6g,25mmol), metallic indium (12.6g, 0.11mol), 2N hydrochloric acid (87.5mL, 0.175mol), and 100mL of water. Heating to 100-110 ℃, and carrying out reflux stirring reaction for 5-6 hours. Cooling to room temperature, extracting with dichloromethane for three times, combining organic phases, washing with saturated sodium bicarbonate, saturated common salt water and water in sequence, drying, recovering the solvent by reduced pressure distillation, recrystallizing the obtained residue with ethyl acetate/n-hexane (volume ratio 1:2) to obtain 4.6g of light yellow solid 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I), the yield is 81.4%, EI-MS M/z is 226[ M + H ] M/z]+。
Example three:
under the protection of nitrogen, 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I) (2.25g,10mmol), 3, 5-dimethoxy-1-bromobenzene (4.34g,20mmol), potassium tert-butoxide (0.11g,1mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (1.9g,3mmol) and ethylene glycol dimethyl ether 50mL are added into a reaction flask, stirred at room temperature for 30 minutes, palladium acetate (0.2g,1mmol) is added into the reaction flask, and the reaction is carried out for 1 hour under microwave heating to 135 ℃. Cooling to room temperature, adding aqueous solution of potassium carbonate to quench the reaction, extracting with ethyl acetate for three times, combining organic phases, washing with saturated brine and water in sequence, and drying with anhydrous sodium sulfate. Vacuum concentrating to dry to obtain off-white solid N- (3, 5-dimethoxyphenyl) -3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (V)2.7g with the yield of 74.6 percent and EI-MS M/z of 362[ M + H ])]+。
Example four:
under the protection of nitrogen and at 0-5 ℃, N- (3, 5-dimethoxyphenyl) -3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (V) (1.8g and 5mmol), tert-butylammonium bromide (1.15g and 2.5mmol), potassium hydroxide (4.2g and 75mmol), tetrahydrofuran (100 mL) and water (5 mL) are added into a reaction bottle. The reaction was warmed to room temperature and stirred for 2 hours. N- (2-chloroethyl) -2-propylamine hydrochloride (1.6g,10mmol) was added thereto, and the reaction was stirred at 55 ℃ for 6 hours. Cooling to room temperature, adding dilute hydrochloric acid to adjust the pH value to be neutral, extracting with dichloromethane for three times, separating an organic phase, washing with saturated saline water and water in sequence, and drying with anhydrous magnesium sulfate. Vacuum concentrating to dryness and recrystallizing with isopropanol to obtain white solid ervatinib (VI)1.9g with yield of 81.5%, EI-MS M/z:447[ M + H ]]+；1H NMR(DMSO-d6)8.96(s,1H),8.55(s,1H),8.21(s,1H),7.76(d,J＝9.4Hz,1H),7.27(m,1H),7.14(d,J＝2.4Hz,1H),6.47(d,J＝2.0Hz,2H),6.41(s,1H),3.90(m,5H),3.74(s,6H),3.35(brs,1H),2.80((t,J＝12.92,6.46Hz,2H),2.71(t,J＝12.2,6.10Hz,1H),0.96(d,J＝6.12Hz,6H)。
It should be noted that the above-mentioned preferred embodiments are merely illustrative of the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (7)
1. A preparation method of Erdafitinib (Erdafitinib) intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine, wherein the chemical structural formula of the intermediate is as follows:
the preparation method is characterized by comprising the following steps: 2, 4-dinitroaniline and 2-bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone are subjected to substitution reaction to prepare 1- (1-methyl-1H-pyrazol-4-yl) -2- [ (2, 4-dinitro) phenylamino ] ethanone; the 1- (1-methyl-1H-pyrazol-4-yl) -2- [ (2, 4-dinitro) phenylamino ] ethanone and metal indium are subjected to reduction cyclization reaction under the action of hydrochloric acid to prepare the erdamitinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine.
2. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the feeding ratio of the condensation reaction is 2, 4-dinitroaniline (1 equivalent) and 2-bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone (0.5-1.5 equivalent).
3. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the solvent of the substitution reaction is methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, toluene or water.
4. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the temperature of the substitution reaction is 50-150 ℃.
5. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the feeding ratio of the reduction cyclization reaction is 1- (1-methyl-1H-pyrazol-4-yl) -2- [ (2, 4-dinitro) phenylamino ] ethanone (1 equivalent), indium (4-5 equivalents) and hydrochloric acid (6-8 equivalents).
6. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the solvent of the reduction cyclization reaction is methanol, ethanol, isopropanol, toluene, tetrahydrofuran, dioxane, N-dimethylformamide or water.
7. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the temperature of the reduction cyclization reaction is 50-150 ℃.
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Application publication date: 20201208 |