CN110386892B - Preparation method of 4-fluoro-5-hydroxy-2-methyl-1H-indole - Google Patents
Preparation method of 4-fluoro-5-hydroxy-2-methyl-1H-indole Download PDFInfo
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Abstract
The invention provides a preparation method of 4-fluoro-5-hydroxy-2-methyl-1H-indole, which comprises the steps of using 2-fluoro-3-halogeno-6-nitrotoluene as a raw material, carrying out substitution reaction on the raw material and alcohol to prepare 2-fluoro-3-GO substituent-6-nitrotoluene, carrying out condensation reaction on the 2-fluoro-3-GO substituent-6-nitrophenyl) -2-alkoxy propylene and orthoacetic acid triester to obtain 1- (2-fluoro-3-GO substituent-6-nitrophenyl) -2-alkoxy propylene, and carrying out reduction-cyclization reaction to obtain 4-fluoro-5-hydroxy-2-methyl-1H-indole. The method disclosed by the invention is safe and green, is simple and convenient to operate, is low in cost, is high in selectivity, and is high in yield and purity of the final product.
Description
Technical Field
The invention relates to a preparation method of 4-fluoro-5-hydroxy-2-methyl-1H-indole, belonging to the technical field of medical chemistry.
Background
Anlotinib Hydrochloride (Anlotinib Hydrochloride) is a novel multi-target tyrosine kinase inhibitor independently developed in China, can effectively inhibit VEGFR, PDGFR, FGFR, c-Kit and other kinases, and has the effects of resisting tumor angiogenesis and inhibiting tumor growth. Anrotinib hydrochloride is qualified in 2015 by the United states FDA for an orphan drug for treating ovarian cancer, is currently used in a phase III study (ALTER-0303) of advanced NSCLC three-line treatment and successfully reaches a treatment endpoint, enters a Chinese CFDA rapid review channel, is expected to become a Chinese advanced NSCLC three-line treatment standard, and has a good treatment prospect in treating ovarian cancer, endometrial cancer and other various cancers such as soft tissue sarcoma, gastric cancer, colorectal cancer, medullary thyroid cancer, differentiated thyroid cancer and esophageal squamous cell carcinoma.
Cediranib (Cediranib), also known as AZD2171, is a potent inhibitor of pan-vascular endothelial growth factor (pan-VEGF) receptor tyrosine kinase developed by Aslicon, and the combination of Cediranib and Olaparib (Olaparib) can be used for treating recurrent ovarian cancer, and the two drugs have good synergistic effect and tolerance, the curative effect is equivalent to that of Nilaparib, but the Cediranib has the advantages of convenient medication, low treatment cost and the like.
And 4-fluoro-5-hydroxy-2-methyl-1H-indole (I) is a key intermediate for preparing the aritinib hydrochloride and the cediranib hydrochloride.
The structural formulas of the aritinib hydrochloride, the cediranib and the 4-fluoro-5-hydroxy-2-methyl-1H-indole (I) are shown as follows;
three synthetic routes to aritinib hydrochloride are described in patent documents CN101809012A, and patent documents CN103275069A and CN102603718A propose methods for preparing cediranib, wherein 4-fluoro-5-hydroxy-2-methyl-1H-indole is used as a key intermediate, but there are few reports on the preparation method of 4-fluoro-5-hydroxy-2-methyl-1H-indole. At present, the preparation method is mainly reported as follows:
patent documents US2011257395 and WO2008053221 describe a preparation method of 4-fluoro-5-hydroxy-2-methyl-1H-indole, 2,3, 4-trifluoronitrobenzene is used as a raw material, tert-butyl acetoacetate is used for preparing 2- (2, 3-difluoro-6-nitrophenyl) -3-oxo-N-butyl acid tert-butyl ester in the presence of strong sodium alkoxide, then the tert-butyl ester is reacted with Triton B (N, N-trimethylbenzene ammonium hydroxide) to replace nitro para-fluorine atoms to prepare 2- (2-fluoro-3-hydroxy-6-nitrophenyl) -3-oxo-N-butyl acid tert-butyl ester, and the tert-butyl ester is hydrolyzed and decarboxylated by aqueous solution of sulfuric acid to obtain 1- (2-fluoro-3-hydroxy-6-nitrophenyl) propyl-2 ketone, the preparation of 4-fluoro-5-hydroxy-2-methyl-1H-indole by reductive cyclization of sodium hydrosulfite is reported to have a total yield of 50.3%, and the reaction process is described as the following synthetic scheme 1.
Chinese patent document CN102603718A uses 2,3, 4-trifluoronitrobenzene as raw material, and ethyl acetoacetate to prepare 2- (2, 3-difluoro-6-nitrophenyl) -3-oxo-n-butyl ethyl butyrate in the presence of strong alkali sodium ethoxide, then hydrolysis decarboxylation is carried out in mixed acid consisting of concentrated hydrochloric acid and glacial acetic acid to obtain 1- (2, 3-difluoro-6-nitrophenyl) propyl-2 ketone, nitro para-fluorine atom is replaced by benzyl alcohol to prepare 1- (3-benzyloxy-2-fluoro-6-nitrophenyl) propyl-2-ketone, 5-benzyloxy-4-fluoro-2-methyl-1H-indole is obtained by reduction cyclization of sodium hydrosulfite, and 4-fluoro-5-hydroxy-2-methyl-1H-indole is obtained by palladium carbon catalysis, the overall yield is reported to be 44.3% and the reaction procedure is described in scheme 2 below.
The two methods have multiple preparation routes, and when the 2,3, 4-trifluoronitrobenzene and the acetoacetate carbanion are subjected to substitution reaction, the fluorine atoms at the ortho-position and the para-position of the nitro group have equivalent reaction activity, low selectivity and high product purification requirement. In addition, the 2,3, 4-trifluoronitrobenzene, strong base, Triton B and the like used in the method have high price, large acid consumption for hydrolysis and decarboxylation, large wastewater amount and poor environmental protection, and are not beneficial to green industrial production and cost reduction.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of 4-fluoro-5-hydroxy-2-methyl-1H-indole, which is safe, green, simple and convenient to operate and low in cost. The method has high selectivity and high yield and purity of the final product.
Description of terms:
a compound of formula II: 2-fluoro-3-halo-6-nitrotoluene;
a compound of formula III: 2-fluoro-3-GO substituent-6-nitrotoluene, wherein GO is benzyloxy, p-methylbenzyloxy or p-methoxybenzyloxy;
a compound of formula IV: 1- (2-fluoro-3-GO substituent-6-nitrophenyl) -2-alkoxypropene, wherein GO is benzyloxy, p-methylbenzyloxy or p-methoxybenzyloxy;
a compound of formula I: 4-fluoro-5-hydroxy-2-methyl-1H-indole.
The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
A preparation method of 4-fluoro-5-hydroxy-2-methyl-1H-indole comprises the following steps:
(1) in a solvent A, in the presence of an acid-binding agent, carrying out substitution reaction on a compound shown in a formula II and alcohol with a general formula of GOH to prepare a compound shown in a formula III;
wherein in the structural formula of the compound shown in the formula II, X is Cl, Br or I; in the structural formula of the alcohol with the general formula of GOH and the compound with the formula III, G has the same meaning and is benzyl, p-methylbenzyl or p-methoxybenzyl;
(2) in a solvent B or in the absence of a solvent, under the action of a catalyst 1, carrying out condensation reaction on a compound shown in a formula III and orthoacetic triester to obtain a compound shown in a formula IV;
wherein, in the structural formula of the compound shown in the formula IV, R is methyl or ethyl, and the meaning of G is the same as that of G in the structural formula of the compound shown in the formula III;
(3) in a solvent C, under the action of a catalyst 2, the compound shown in the formula IV undergoes reduction-cyclization reaction to obtain 4-fluoro-5-hydroxy-2-methyl-1H-indole (I).
According to the present invention, it is preferable that the solvent a in step (1) is one or a combination of two or more of N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, 1, 2-dimethoxyethane, or chlorobenzene; the mass ratio of the solvent A to the compound shown in the formula II is (5-25) to 1; preferably, the mass ratio of the solvent A to the compound of the formula II is (7-15): 1.
According to the invention, preferably, the acid-binding agent in the step (1) is one or a combination of more than two of potassium carbonate, sodium carbonate, cesium carbonate or calcium carbonate.
According to the invention, the molar ratio of the acid-binding agent, the alcohol and the compound of formula II in step (1) is preferably (1.0-2.0): 1.
According to the present invention, it is preferable that the substitution reaction temperature in step (1) is 60 to 150 ℃; preferably, the substitution reaction temperature is 80-110 ℃. The substitution reaction time is 2-10 hours; preferably, the substitution reaction time is 3 to 6 hours.
According to the present invention, preferably, in the step (2), the solvent B is one or a combination of two or more of cyclohexane, N-hexane, petroleum ether, tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, 1, 2-dimethoxyethane, N-dimethylformamide, or orthoacetic acid triester; the mass ratio of the solvent B to the compound shown in the formula III is (3-15) to 1; preferably, the mass ratio of the solvent B to the compound of the formula III is (5-10): 1.
According to the present invention, it is preferred that in step (2), the catalyst 1 is a Lewis acid, preferably zinc chloride, ferric chloride, aluminum chloride or cuprous chloride; the mass of the catalyst 1 is 0.5-10% of that of the compound shown in the formula III; preferably, the mass of the catalyst 1 is 1 to 5 percent of the mass of the compound shown in the formula III.
According to the present invention, it is preferred that the triacetate in step (2) is trimethyl orthoacetate or triethyl orthoacetate; the molar ratio of the orthoacetate triester to the compound of formula III is (1.0-6.0): 1.
According to the present invention, it is preferable that the condensation reaction temperature in the step (2) is 20 to 100 ℃; preferably, the condensation reaction temperature is 60-80 ℃. The condensation reaction time is 2-10 hours; preferably, the condensation reaction time is 3 to 6 hours.
According to the present invention, preferably, the solvent C in step (3) is one or a combination of two or more of methanol, ethanol, acetonitrile, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether or 1, 2-dimethoxyethane; the mass ratio of the solvent C to the compound shown in the formula IV is (5-25) to 1; preferably, the mass ratio of the solvent C to the compound of the formula IV is (8-15): 1.
According to the present invention, it is preferable that the catalyst 2 in the step (3) is palladium carbon or raney nickel; preferably, the mass of the palladium-carbon is 0.5-10% of that of the compound of the formula IV; more preferably, the mass of the palladium carbon is 1 to 5 percent of that of the compound shown in the formula IV, and the mass content of palladium in the palladium carbon is 5 percent; preferably, the mass of the Raney nickel is 5-25% of that of the compound shown in the formula IV; more preferably, the mass of the raney nickel is 10 to 15 percent of that of the compound shown in the formula IV, and the mass content of nickel in the raney nickel is 50 percent.
According to the invention, preferably, in the step (3), the temperature of the reduction-cyclization reaction is 20-100 ℃, the reducing agent used in the reduction reaction in the reduction-cyclization reaction is hydrogen, and the hydrogen pressure is 0.1-0.5 MPa; preferably, the reduction-cyclization reaction temperature is 30-60 ℃, and the hydrogen pressure is 0.2-0.4 MPa. The reduction-cyclization reaction time is 3-10 hours; preferably, the reduction-cyclization reaction time is 4 to 8 hours.
The 4-fluoro-5-hydroxy-2-methyl-1H-indole prepared by the method can be used for preparing the aritinib hydrochloride and the cediranib according to the prior art.
The present invention is depicted as the following synthetic scheme 3:
the invention has the following technical characteristics and beneficial effects:
1. the invention provides a preparation method of 4-fluoro-5-hydroxy-2-methyl-1H-indole, which comprises the steps of using 2-fluoro-3-halo-6-nitrotoluene as a raw material, carrying out substitution reaction on the raw material and alcohol to prepare 2-fluoro-3-GO substituent-6-nitrotoluene, carrying out condensation reaction on the 2-fluoro-3-GO substituent-6-nitrophenyl) -2-alkoxy propylene and orthoacetic acid triester to obtain 1- (2-fluoro-3-GO substituent-6-nitrophenyl) -2-alkoxy propylene, and carrying out reduction-cyclization reaction to obtain 4-fluoro-5-hydroxy-2-methyl-1H-indole.
2. The method has simple and short process flow, can prepare the final product by only 3 steps, has mild reaction conditions and is easy to operate; hydrolysis decarboxylation reaction is not involved, the amount of wastewater is small, and the method is green, safe and environment-friendly; the raw materials are cheap and easy to obtain, and the product cost is low; the obtained product has high purity and yield, the total yield can reach 86 percent, and the method is suitable for green industrial production.
3. The invention fully embodies the concept that the quality is from the design, the related unit operation ensures the reaction specificity and the proper activity of the chemical reaction functional group, the hydroxyl of the alcohol with the general formula of GOH and the single halogen activated by the para-nitro carry out substitution reaction, the selectivity is 100 percent, and multiple active positions in the background technology are avoided; the condensation reaction with the orthoacetic triester can only occur in ortho-methyl activated by nitro, and in the subsequent reduction-cyclization reaction, the nitro is easily reduced into amino, and the alcohol cyclization is removed at the same time to obtain the 4-fluoro-5-hydroxy-2-methyl-1H-indole, so that the reaction selectivity is high.
4. The 4-fluoro-5-hydroxy-2-methyl-1H-indole prepared by the method can be used for preparing the aritinib hydrochloride and the cediranib and has important significance for industrial production.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is a mass percentage unless otherwise specified.
Example 1: preparation of 2-fluoro-3-benzyloxy-6-nitrotoluene (III 1)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 200 g of N, N-dimethylformamide, 23.4 g (0.1 mol) of 2-fluoro-3-bromo-6-nitrotoluene (II 1), 16.2 g (0.15 mol) of benzyl alcohol, 20.7 g (0.15 mol) of potassium carbonate, and the mixture was stirred at 105 to 110 ℃ for 3 hours. Cooling to 20-25 ℃, filtering to remove potassium salt, washing filter cakes with 30 g of solvent, combining filtrates, recovering the solvent by reduced pressure distillation, then adding 0.5 g of activated carbon and 150 g of 80% ethanol into the residue, reacting at 80 ℃, stirring and decoloring for 1 hour, filtering while hot, cooling for recrystallization, filtering, and drying to obtain 24.3 g of 2-fluoro-3-benzyloxy-6-nitrotoluene (III 1), wherein the yield is 93.1%, and the liquid phase purity is 99.3%.
Example 2: preparation of 2-fluoro-3-benzyloxy-6-nitrotoluene (III 1)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 200 g of N, N-dimethylformamide, 28.2 g (0.1 mol) of 2-fluoro-3-iodo-6-nitrotoluene (II 2), 13.0 g (0.12 mol) of benzyl alcohol, 20.7 g (0.15 mol) of potassium carbonate, and the mixture was stirred at 90 to 95 ℃ for 5 hours. Cooling to 20-25 ℃, filtering to remove potassium salt, washing filter cakes with 30 g of solvent, combining filtrates, recovering the solvent by reduced pressure distillation, then adding 0.5 g of activated carbon and 150 g of 80% ethanol into the residue, reacting at 80 ℃, stirring and decoloring for 1 hour, filtering while hot, cooling for recrystallization, filtering, and drying to obtain 24.7 g of 2-fluoro-3-benzyloxy-6-nitrotoluene (III 1), wherein the yield is 94.6%, and the liquid phase purity is 99.4%.
Example 3: preparation of 2-fluoro-3- (4-methoxy) benzyloxy-6-nitrotoluene (III 2)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 200 g of N, N-dimethylformamide, 23.5 g (0.1 mol) of 2-fluoro-3-bromo-6-nitrotoluene (II 1), 16.7 g (0.12 mol) of 4-methoxybenzyl alcohol and 20.7 g (0.15 mol) of potassium carbonate were charged and reacted with stirring at 100 to 105 ℃ for 4 hours. Cooling to 20-25 ℃, filtering to remove potassium salt, washing filter cakes with 30 g of solvent, combining filtrates, recovering the solvent by reduced pressure distillation, then adding 0.5 g of activated carbon and 150 g of 80% ethanol into the residue, reacting at 80 ℃, stirring and decoloring for 1 hour, filtering while hot, cooling for recrystallization, filtering, and drying to obtain 25.7 g of 2-fluoro-3- (4-methoxy) benzyloxy-6-nitrotoluene (III 2), wherein the yield is 88.2%, and the liquid phase purity is 99.2%.
Example 4: preparation of 1- (2-fluoro-3-benzyloxy-6-nitrophenyl) -2-methoxypropene (IV1)
Into a 250 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 100 g of tetrahydrofuran, 13.1 g (0.05 mol) of 2-fluoro-3-benzyloxy-6-nitrotoluene (III 1) obtained in example 1, 18.0 g (0.15 mol) of trimethyl orthoacetate, 0.4 g of zinc chloride, and the reaction was stirred at 65 to 70 ℃ for 5 hours. The solvent and excess trimethyl orthoacetate were recovered by distillation to give 16.1 g of 1- (2-fluoro-3-benzyloxy-6-nitrophenyl) -2-methoxypropene (IV1) as a pale yellow viscous material, which was used directly in example 7.
Example 5: preparation of 1- (2-fluoro-3- (4-methoxy) benzyloxy-6-nitrophenyl) -2-methoxypropene (IV2)
Into a 250 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 100 g of tetrahydrofuran, 14.6 g (0.05 mol) of 2-fluoro-3- (4-methoxy) benzyloxy-6-nitrotoluene (III 2) obtained in example 3, 18.0 g (0.15 mol) of trimethyl orthoacetate, 0.5 g of cuprous chloride, and the reaction was stirred at 65 to 70 ℃ for 5 hours. The solvent and excess trimethyl orthoacetate were recovered by distillation to give 18.2 g of 1- (2-fluoro-3- (4-methoxy) benzyloxy-6-nitrophenyl) -2-methoxypropene (IV2) as a pale yellow viscous mass, which was used directly in example 8.
Example 6: preparation of 1- (2-fluoro-3-benzyloxy-6-nitrophenyl) -2-ethoxypropene (IV3)
Into a 250 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 13.1 g (0.05 mol) of 2-fluoro-3-benzyloxy-6-nitrotoluene (III 1) obtained in example 2, 50.0 g (0.3mol) of triethyl orthoacetate, 0.6 g of zinc chloride, and the mixture was stirred at 75 to 80 ℃ for 5 hours, and excess triethyl orthoacetate was recovered by distillation under reduced pressure to obtain 16.4 g of 1- (2-fluoro-3-benzyloxy-6-nitrophenyl) -2-ethoxypropene (IV3) as a pale yellow viscous substance which was used as it was in example 9.
Example 7: preparation of 4-fluoro-5-hydroxy-2-methyl-1H-indole (I)
150 g of methanol, 16.1 g of light yellow viscous substance 1- (2-fluoro-3-benzyloxy-6-nitrophenyl) -2-methoxypropene (IV1) obtained in example 4 and 0.5 g of 5 wt% palladium carbon catalyst were charged into a 500 ml stainless steel autoclave, and after three times of replacement with nitrogen, hydrogen was introduced to the autoclave while maintaining the system pressure at 0.2 to 0.3MPa and reacting at 55 to 60 ℃ for 4 hours. The nitrogen is replaced three times, the palladium carbon is removed by filtration, the filter cake is washed twice by methanol, 30 g of methanol is used for each time, and the filtrates are combined. The filtrate was distilled to recover the solvent and dried to give 7.53 g of 4-fluoro-5-hydroxy-2-methyl-1H-indole (I) in a yield of 91.3% based on the compound III 1 and a liquid phase purity of 99.5%.
The nuclear magnetic data of the product obtained are as follows:
1HNMR(400MHz,DMSO-d6):ppm
10.82(br,s,1H),8.72(s,1H),6.86(d,1H),6.64(t,1H),6.02-6.04(m,1H),2.28(s,3H).
example 8: preparation of 4-fluoro-5-hydroxy-2-methyl-1H-indole (I)
150 g of acetonitrile, 18.2 g of the pale yellow viscous substance 1- (2-fluoro-3- (4-methoxy) benzyloxy-6-nitrophenyl) -2-methoxypropene (IV2) obtained in example 5 and 2.3 g of a 50 wt% Raney nickel catalyst were charged into a 500 ml stainless steel autoclave, and after nitrogen substitution was carried out three times, hydrogen was introduced into the autoclave while maintaining the system pressure at 0.3 to 0.4MPa, and the reaction was carried out at 50 to 55 ℃ for 5 hours. The nitrogen was replaced three times, the catalyst was removed by filtration, the filter cake was washed twice with 30 g of acetonitrile each time, and the filtrates were combined. The filtrate was distilled to recover the solvent and dried to give 7.40 g of 4-fluoro-5-hydroxy-2-methyl-1H-indole (I) in 89.7% yield based on the compound III 2 and 99.4% purity in the liquid phase.
Example 9: preparation of 4-fluoro-5-hydroxy-2-methyl-1H-indole (I)
150 g of methanol, 16.4 g of the pale yellow viscous substance 1- (2-fluoro-3-benzyloxy-6-nitrophenyl) -2-ethoxypropene (IV3) obtained in example 6 and 0.5 g of a 5 wt% palladium-carbon catalyst were charged into a 500 ml stainless steel autoclave, and after three times of replacement with nitrogen, hydrogen was introduced thereinto to react at 45 to 50 ℃ for 6 hours while maintaining the system pressure at 0.2 to 0.3 MPa. The nitrogen is replaced three times, the palladium carbon is removed by filtration, the filter cake is washed twice by methanol, 30 g of methanol is used for each time, and the filtrates are combined. The filtrate was distilled to recover the solvent and dried to give 7.51 g of 4-fluoro-5-hydroxy-2-methyl-1H-indole (I) in a yield of 91.0% based on the compound III 1 and a liquid phase purity of 99.7%.
Comparative example: preparation of 2-fluoro-3-benzyloxy-6-nitrotoluene (III 1)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 200 g of N, N-dimethylformamide, 23.4 g (0.1 mol) of 2-fluoro-3-bromo-6-nitrotoluene (II 1), 16.2 g (0.15 mol) of benzyl alcohol, 6.9 g (0.05 mol) of potassium carbonate, and the mixture was stirred at 105 to 110 ℃ for 4 hours. Cooling to 20-25 ℃, filtering to remove potassium salt, washing filter cakes with 30 g of solvent, combining filtrates, recovering the solvent by reduced pressure distillation, then adding 0.5 g of activated carbon and 150 g of 80% ethanol into the residue, reacting at 80 ℃, stirring and decoloring for 1 hour, filtering while hot, cooling for recrystallization, filtering, and drying to obtain 19.4 g of 2-fluoro-3-benzyloxy-6-nitrotoluene (III 1), wherein the yield is 74.3%, and the liquid phase purity is 98.2%.
The comparative example shows that the acid-binding agent is suitable in type and amount, and when the acid-binding agent is used for neutralizing halogen acid, the generation of water is avoided, otherwise, the generated water causes the compound shown in the formula II 1 to be hydrolyzed to generate 2-fluoro-3-hydroxy-6-nitrotoluene, further dimerization is caused, and the yield and the purity of the target product are reduced.
Claims (13)
1. A preparation method of 4-fluoro-5-hydroxy-2-methyl-1H-indole comprises the following steps:
(1) in a solvent A, in the presence of an acid-binding agent, carrying out substitution reaction on a compound shown in a formula II and alcohol with a general formula of GOH to prepare a compound shown in a formula III; the solvent A is one or the combination of more than two of N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, 1, 2-dimethoxyethane or chlorobenzene; the acid-binding agent is one or the combination of more than two of potassium carbonate, sodium carbonate, cesium carbonate or calcium carbonate;
wherein in the structural formula of the compound shown in the formula II, X is Cl, Br or I; in the structural formula of the alcohol with the general formula of GOH and the compound with the formula III, G has the same meaning and is benzyl, p-methylbenzyl or p-methoxybenzyl;
(2) in a solvent B or in the absence of a solvent, under the action of a catalyst 1, carrying out condensation reaction on a compound shown in a formula III and orthoacetic triester to obtain a compound shown in a formula IV; the solvent B is one or the combination of more than two of cyclohexane, normal hexane, petroleum ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, 1, 2-dimethoxyethane, N-dimethylformamide or orthoacetic acid triester; the catalyst 1 is Lewis acid;
wherein, in the structural formula of the compound shown in the formula IV, R is methyl or ethyl, and the meaning of G is the same as that of G in the structural formula of the compound shown in the formula III;
(3) in a solvent C, under the action of a catalyst 2, the compound shown in the formula IV undergoes reduction-cyclization reaction to obtain 4-fluoro-5-hydroxy-2-methyl-1H-indole (I); the solvent C is one or the combination of more than two of methanol, ethanol, acetonitrile, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether or 1, 2-dimethoxyethane; the catalyst 2 is palladium carbon or Raney nickel.
2. The process for producing 4-fluoro-5-hydroxy-2-methyl-1H-indole according to claim 1, wherein the mass ratio of the solvent A to the compound of formula II in the step (1) is (5-25): 1.
3. The process for preparing 4-fluoro-5-hydroxy-2-methyl-1H-indole according to claim 1, wherein the molar ratio of the acid-binding agent, alcohol and the compound of formula II in step (1) is (1.0-2.0): 1.0-2.0).
4. The process for producing 4-fluoro-5-hydroxy-2-methyl-1H-indole according to claim 1, wherein the substitution reaction temperature in step (1) is 60 to 150 ℃.
5. The process for preparing 4-fluoro-5-hydroxy-2-methyl-1H-indole according to claim 4, wherein the substitution reaction temperature is 80 to 110 ℃.
6. The process for preparing 4-fluoro-5-hydroxy-2-methyl-1H-indole according to claim 1, wherein in step (2), one or more of the following conditions are included:
a. the mass ratio of the solvent B to the compound shown in the formula III is (3-15) to 1;
b. the catalyst 1 is zinc chloride, ferric chloride, aluminum chloride or cuprous chloride; the mass of the catalyst 1 is 0.5-10% of that of the compound shown in the formula III;
c. the orthoacetate is trimethyl orthoacetate or triethyl orthoacetate; the molar ratio of the orthoacetate triester to the compound of formula III is (1.0-6.0): 1.
7. The process for producing 4-fluoro-5-hydroxy-2-methyl-1H-indole according to claim 1, wherein the condensation reaction temperature in step (2) is 20 to 100 ℃.
8. The process for preparing 4-fluoro-5-hydroxy-2-methyl-1H-indole according to claim 7, wherein the condensation reaction temperature is 60 to 80 ℃.
9. The process for preparing 4-fluoro-5-hydroxy-2-methyl-1H-indole according to claim 1, wherein the mass ratio of the solvent C to the compound of formula IV in step (3) is (5-25): 1.
10. The method for preparing 4-fluoro-5-hydroxy-2-methyl-1H-indole according to claim 1, wherein the mass of palladium-carbon in step (3) is 0.5-10% of that of the compound of formula IV; the mass of the Raney nickel is 5-25% of that of the compound in the formula IV.
11. The method for preparing 4-fluoro-5-hydroxy-2-methyl-1H-indole as claimed in claim 10, wherein the mass of palladium carbon is 1-5% of the mass of the compound of formula IV, and the mass content of palladium in palladium carbon is 5%; the mass of the raney nickel is 10-15% of that of the compound shown in the formula IV, and the mass content of nickel in the raney nickel is 50%.
12. The method for preparing 4-fluoro-5-hydroxy-2-methyl-1H-indole according to claim 1, wherein the temperature of the reduction-cyclization reaction in step (3) is 20 to 100 ℃, the reducing agent used in the reduction reaction in the reduction-cyclization reaction is hydrogen, and the hydrogen pressure is 0.1 to 0.5 MPa.
13. The method for producing 4-fluoro-5-hydroxy-2-methyl-1H-indole according to claim 12, wherein the reduction-cyclization reaction temperature is 30 to 60 ℃ and the hydrogen pressure is 0.2 to 0.4 MPa.
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Denomination of invention: A preparation method of 4-fluoro-5-hydroxy-2-methyl-1H-indole Effective date of registration: 20221213 Granted publication date: 20200818 Pledgee: Guangdong Development Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2022980026441 |