CN113968844A - Novel method for synthesizing 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline - Google Patents

Novel method for synthesizing 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline Download PDF

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CN113968844A
CN113968844A CN202010721263.7A CN202010721263A CN113968844A CN 113968844 A CN113968844 A CN 113968844A CN 202010721263 A CN202010721263 A CN 202010721263A CN 113968844 A CN113968844 A CN 113968844A
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bromo
pyrazol
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夏吉利
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Suzhou Jianghua Biotechnology Co ltd
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    • 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
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Abstract

The invention relates to a novel method for synthesizing 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline, which specifically comprises the following steps: reacting 2-halogeno-1- (1-methyl-1H-pyrazol-4-yl) ethyl ketone formula (II) with 4-bromo-2-nitroaniline formula (III) to obtain 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethyl ketone formula (IV), and then reducing, cyclizing and oxidizing to obtain 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline formula (I). Compared with the traditional method, the method has the advantages of low cost, easy control of reaction, simple post-treatment, continuous operation, high overall yield, economy, environmental protection and the like, and is a novel method for synthesizing the 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline.

Description

Novel method for synthesizing 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline
Technical Field
The invention relates to the field of pharmaceutical chemicals and medicines, in particular to a synthesis method of an anticancer drug erdasatinib key intermediate, and specifically relates to a novel method for synthesizing 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline.
Background
Erdafitinib (erdafitinib), chemical name N1- (3, 5-dimethoxyphenyl) -N2-isopropyl-N1- (3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl) ethane-1, 2-diamine, developed by Yansen under the Juglans of Strong Shengji, approved by the US FDA to be marketed in the US on 4/12 of 2019, can block fibroblast growth factor receptor activity, and is clinically used for treating locally advanced disease progression or metastatic bladder cancer during or after platinum chemotherapy. The structural formula is as follows:
Figure BDA0002600097630000011
patent WO2006/97918 reports a synthesis method of a key intermediate 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline formula (I), 2-hydroxyquinoxaline is brominated by bromine to obtain 7-bromo-2-hydroxyquinoxaline, then the 7-bromo-2-chloroquinoxaline is reacted with phosphorus oxychloride to obtain reaction 7-bromo-2-chloroquinoxaline, and the reaction is further reacted with 1-methylpyrazole-4-boronic acid pinacol ester by SUZUKI to obtain the erda tinib key intermediate 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline formula (I), wherein the reaction formula is as follows:
Figure BDA0002600097630000021
the above-mentioned route uses liquid bromine and phosphorus oxychloride in the reaction process, and has the disadvantages of large danger coefficient and poor environmental friendliness in the synthesis process.
In order to overcome the defects in the prior art, the invention provides a novel method for synthesizing 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline, which comprises the steps of reacting an easily obtained 2-halo-1- (1-methyl-1H-pyrazol-4-yl) acetic ketone formula (II) with a 4-bromo-2-nitroaniline formula (III), to obtain 2- ((4-bromine-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethyl ketone formula (IV), and then carrying out reduction, cyclization and oxidation to obtain 7-bromine-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline formula (I).
Compared with the traditional method, the method has the advantages of low cost, easy control of reaction, simple post-treatment, continuous operation, high overall yield, economy, environmental protection and the like, and is a novel method for synthesizing the 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline.
The specific synthetic route of the invention is summarized as follows:
Figure BDA0002600097630000022
wherein:
x is bromine or chlorine (hereinafter X is as defined herein)
In order to achieve the purpose, the invention provides the following technical scheme, and the novel method for synthesizing the 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline specifically comprises the following steps:
1) preparation of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone formula (IV)
Dissolving 2-halo-1- (1-methyl-1H-pyrazol-4-yl) ethanone formula (II) in a suitable solvent, adding 4-bromo-2-nitroaniline formula (III) and a base in appropriate equivalents, reacting completely at a suitable temperature, and carrying out appropriate post-treatment to obtain 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone formula (IV); wherein:
the raw materials are 2-halogeno-1- (1-methyl-1H-pyrazol-4-yl) ethyl ketone formula (II) and 4-bromo-2-nitroaniline formula (III); suitable solvents are toluene, tetrahydrofuran, ethanol, dioxane, acetonitrile, DMF and the like, preferably toluene, tetrahydrofuran, ethanol, dioxane, acetonitrile, DMF; the molar ratio of the 2-halo-1- (1-methyl-1H-pyrazol-4-yl) acetic acid formula (II) to the amount of the 4-bromo-2-nitroaniline formula (III) is 1: 0.9-1: 1.1, preferably 1: 0.95-1: 1.05; the reaction temperature is 20-100 ℃, and preferably 60-100 ℃; the base is diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate and the like, preferably diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate and the like; the molar ratio of the used amount of the alkali to the 4-bromo-2-nitroaniline of formula (III) is 1: 0.5-1: 2, preferably organic amine 1: 1.1-1: 1.5, inorganic base 1: 0.6-1: 1;
2) preparation of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline of formula (I)
Figure BDA0002600097630000031
Dissolving 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) acetone formula (IV) into a proper solvent, adding a Pd catalyst and a hydrogen source, filtering after complete reaction, adding an oxidant, reacting completely at a proper temperature, and performing proper post-treatment to obtain 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline formula (I); wherein:
suitable solvents are ethyl acetate, ethanol, dioxane, acetonitrile, DMF and the like, preferably ethyl acetate, ethanol; the Pd catalyst is Pd/C, palladium hydroxide, preferably Pd/C, palladium hydroxide; the hydrogen source is hydrogen, ammonium formate, preferably hydrogen, ammonium formate; the oxidant is Pd/C, active manganese dioxide, preferably internal Pd/C, active manganese dioxide; the reaction temperature is 60-100 ℃.
The invention provides a new method for synthesizing 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline, which has the advantages of low cost, easy control of reaction, simple post-treatment, continuous operation, high overall yield, economy, environmental protection and the like.
Detailed description of the preferred embodiments
The present invention will be further described by the following examples, however, the present invention is not limited to the following examples, which do not limit the scope of the present invention in any way. Certain changes and modifications within the scope of the claims, which may be made by one skilled in the art, are also considered to be within the scope of the invention.
The present invention will be described in more detail below by way of examples.
Example 1
(1) Preparation of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone
406g of 2-bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone, 434g of 4-bromo-2-nitroaniline and 130g of potassium carbonate are added into 4.5L of DMF, the mixture is stirred at the temperature of 60-70 ℃ until the reaction is completed, the organic solvent is recovered by filtration, dichloromethane and water are added into the residue, the mixture is kept stand for layering, an organic layer is taken for concentration, and 623.8g of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone is obtained, wherein the yield is 92%.1HNMR(CDC l3)δ:8.24-8.21(d,1H),7.97-7.95(s，1H)，7.93-7.91(s，1H)，7.42-7.39(dd，1H)，6.73-6.71(d，1H)，4.24-4.21(s，2H)，3.96-3.94(s,3H)
(2) Preparation of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline
Adding 340g of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone into 3L of ethanol, adding 10g of 5% Pd/C hydrogen for replacement for three times, carrying out hydrogenation reaction at 40-50 ℃, filtering and recovering Pd/C after complete reaction, adding 10g of 5% Pd/C again, heating to reflux, stirring until complete reaction, concentrating to obtain a solid, and recrystallizing the solid with ethanol water to obtain 241g of 7-bromo-2- (1-methyl-1H-pyrazole) white-like solid-4-yl) quinoxaline in a yield of 83.4% and a purity of 99%.1HNMR(DMSO)δ:9.33(s,1H),8.63(s,1H),8.29(s，1H),8.19-8.16(d,1H),7.96-7.92(m,1H),7.85-7.88(d,1H),3.96(s,3H)。
Example 2
(1) Preparation of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone
330g of 2-chloro-1- (1-methyl-1H-pyrazol-4-yl) ethanone, 434g of 4-bromo-2-nitroaniline and 180g of diisopropylethylamine are added into 4.5L of DMF, the temperature is controlled to 90-100 ℃, the mixture is stirred until the reaction is completed, the organic solvent is recovered by filtration, dichloromethane and water are added into the residue, the mixture is kept stand and layered, an organic layer is taken for concentration, and ethyl acetate is beaten to obtain 594g of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone, wherein the yield is 87.6%.1HNMR(CDCl3)δ:8.24-8.21(d,1H),7.97-7.95(s，1H)，7.93-7.91(s，1H)，7.42-7.39(dd，1H)，6.73-6.71(d，1H)，4.24-4.21(s，2H)，3.96-3.94(s,3H)
(2) Preparation of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline
Adding 340g of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone into 4L of ethyl acetate, adding 10g of 5% Pd/C hydrogen for replacement for three times, carrying out hydrogenation reaction at 50-60 ℃, filtering and recovering Pd/C after the reaction is completed, adding 150g of active manganese dioxide, heating to reflux, stirring until the reaction is completed, filtering, decolorizing filtrate with active carbon, concentrating and recovering an organic solvent to obtain a solid, recrystallizing with ethanol water to obtain 229.4g of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline which is a white-like solid, wherein the yield is 79.1%, and the purity is 99.2%.1HNMR(DMSO)δ:9.33(s,1H),8.63(s,1H),8.29(s，1H),8.19-8.16(d,1H),7.96-7.92(m,1H),7.85-7.88(d,1H),3.96(s,3H)。
Example 3
(1) Preparation of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone
406g of 2-bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone, 434g of 4-bromo-2-nitroaniline and 424g of cesium carbonate are added into 5L of acetonitrile, the temperature is controlled to be 90-100 ℃, the mixture is stirred until the reaction is complete, an organic solvent is recovered by filtration, dichloromethane and water are added into residues, the mixture is kept stand for layering, an organic layer is taken for concentration, ethyl acetate is beaten to obtain 616.3g of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone, and the yield is 90.9%. 1HNMR (CDCl3) delta 8.24-8.21(d,1H),7.97-7.95(s, 1H), 7.93-7.91(s, 1H), 7.42-7.39(dd, 1H), 6.73-6.71(d, 1H), 4.24-4.21(s, 2H), 3.96-3.94(s,3H)
(2) Preparation of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline
Adding 340g of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethyl ketone into 4L of ethanol, adding 3g of 5% palladium hydroxide and 315g of ammonium formate, carrying out hydrogenation reaction at 50-60 ℃, filtering and recovering palladium hydroxide after complete reaction, heating and concentrating to recover an organic solvent, washing off redundant ammonium formate with water, adding 4L of ethyl acetate and 150g of active manganese dioxide into the residue, heating to reflux, stirring until complete reaction, filtering, decolorizing the filtrate with active carbon, concentrating and recovering the organic solvent to obtain a solid, recrystallizing with ethanol water to obtain 240.2g of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline, the yield was 83.1% and the purity 98.9%.1HNMR(DMSO)δ:9.33(s,1H),8.63(s,1H),8.29(s，1H),8.19-8.16(d,1H),7.96-7.92(m,1H),7.85-7.88(d,1H),3.96(s,3H)。
Example 4
(1) Preparation of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone
Adding 33g of 2-chloro-1- (1-methyl-1H-pyrazol-4-yl) ethanone, 43.4g of 4-bromo-2-nitroaniline and 20g of triethylamine into 500mL of acetonitrile, controlling the temperature to be 70-80 ℃, stirring until the reaction is complete, cooling, filtering triethylamine hydrochloride, recovering an organic solvent from a filtrate, adding dichloromethane and water into a residue, standing and layering, concentrating an organic layer, pulping ethyl acetate to obtain 54.9g of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone, wherein the yield is 80.9%. 1HNMR (CDCl3) delta 8.24-8.21(d,1H),7.97-7.95(s, 1H), 7.93-7.91(s, 1H), 7.42-7.39(dd, 1H), 6.73-6.71(d, 1H), 4.24-4.21(s, 2H), 3.96-3.94(s,3H)
(2) Preparation of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline
34g of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone is added into 400mL of ethanol, 0.3g of 5% palladium hydroxide is added for hydrogen replacement for three times, hydrogenation reaction is carried out at 30-40 ℃, after the reaction is completed, palladium hydroxide is filtered and recovered, 1g of 5% Pd/C is added, the temperature is raised to reflux, the reaction is completed, an organic solvent is concentrated and recovered to obtain a solid, and recrystallization is carried out by using ethanol water to obtain white-like solid 24.6g of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline, wherein the yield is 83.1%, and the purity is 99.3%.1HNMR(DMSO)δ:9.33(s,1H),8.63(s,1H),8.29(s，1H),8.19-8.16(d,1H),7.96-7.92(m,1H),7.85-7.88(d,1H),3.96(s,3H)。

Claims (5)

1. A new method for synthesizing 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline is characterized in that 2-halo-1- (1-methyl-1H-pyrazol-4-yl) ethanone formula (II) and 4-bromo-2-nitroaniline formula (III) are used as raw materials, and operations such as substitution, reduction, cyclization, oxidation and the like are carried out to prepare 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline formula (I);
Figure FDA0002600097620000011
the specific synthetic route is as follows:
Figure FDA0002600097620000012
wherein:
x is bromine or chlorine (hereinafter X is as defined herein).
2. The novel process for the synthesis of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline according to claim 1, characterized by comprising the following steps:
1) preparation of 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone formula (IV)
Figure FDA0002600097620000013
X is bromine or chlorine
Dissolving 2-halo-1- (1-methyl-1H-pyrazol-4-yl) ethanone formula (II) in a suitable solvent, adding 4-bromo-2-nitroaniline formula (III) and a base in appropriate equivalents, reacting completely at a suitable temperature, and carrying out appropriate post-treatment to obtain 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) ethanone formula (IV);
2) preparation of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline of formula (I)
Figure FDA0002600097620000021
Dissolving 2- ((4-bromo-2-nitrophenyl) amine) -1- (1-methyl-1H-pyrazol-4-yl) acetone formula (IV) into a proper solvent, adding a Pd catalyst and a hydrogen source, filtering after the reaction is completed, adding an oxidant, reacting at a proper temperature completely, and performing proper post-treatment to obtain the 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline formula (I).
3. The novel process for the synthesis of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline formula (I) according to claims 1, 2, characterized in that in step (1) the starting materials are 2-halo-1- (1-methyl-1H-pyrazol-4-yl) ethanone formula (II) and 4-bromo-2-nitroaniline formula (III); suitable solvents are toluene, tetrahydrofuran, ethanol, dioxane, acetonitrile, DMF, and the like; the molar ratio of the 2-halo-1- (1-methyl-1H-pyrazol-4-yl) acetic acid formula (II) to the amount of the 4-bromo-2-nitroaniline formula (III) is 1: 0.9-1: 1.1; the reaction temperature is 20-100 ℃; the alkali is diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate and the like, and the molar ratio of the alkali to the 4-bromo-2-nitroaniline shown in the formula (III) is 1: 0.5-1: 2.
4. the novel process for the synthesis of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline formula (i) according to claims 1, 2, characterized in that in step (2), the suitable solvents ethyl acetate, ethanol, dioxane, acetonitrile, DMF and the like; the Pd catalyst is Pd/C and palladium hydroxide; the hydrogen source is hydrogen gas and ammonium formate; the oxidant is Pd/C and active manganese dioxide; the reaction temperature is 60-100 ℃.
5. The novel process for the synthesis of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline of formula (I) according to claims 1, 2, characterized in that steps (1) (2) can be operated continuously.
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