CN112538073A - Preparation method of pazopanib intermediate - Google Patents
Preparation method of pazopanib intermediate Download PDFInfo
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Abstract
The invention provides a preparation method of a pazopanib key intermediate 2, 3-dimethyl-N- (2-chloropyrimidin-4-yl) -N-methyl-2H-indazole-6-amine. The method comprises the following steps of (1) reacting 6-halogenated-2, 3-dimethyl-2H-indazole serving as a raw material to obtain N,2, 3-trimethyl-2H-indazole-6-amine; and further reacting to obtain 2, 3-dimethyl-N- (2-chloropyrimidin-4-yl) -N-methyl-2H-indazol-6-amine. The method has the advantages of short synthetic route, easily available raw materials, low cost, mild reaction conditions, high safety and high yield, and is suitable for industrial mass production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a pazopanib key intermediate N,2, 3-trimethyl-2H-indazole-6-amine and 2, 3-dimethyl N- (2-chloropyrimidin-4-yl) -N-methyl-2H-indazole-6-amine.
Background
Pazopanib hydrochloride, chemically known as 5- [ [4- [ (2, 3-dimethyl-2H-indazol-6-yl) methylamino ] pyrimidin-2-yl ] amino ] -2-methylbenzenesulfonamide hydrochloride, is a second generation of multi-target tyrosinase inhibitor. Developed by GlaxoSmithKline, uk, 10 months in 2009, was approved by the FDA for marketing and was used clinically for the treatment of advanced kidney cancer. The 2, 3-dimethyl N- (2-chloropyrimidin-4-yl) -N-methyl-2H-indazole-6-amine is a key intermediate for preparing pazopanib hydrochloride, and is condensed and salified with 2-methyl-5-aminobenzenesulfonamide to obtain the pazopanib hydrochloride.
The method described in patent W002059110 is as follows:
in the second reaction step, methyl iodide or dimethyl sulfate is used as the N methylating agent, and in mass production, methyl iodide and dimethyl sulfate are toxic, dangerous and low in operability, and expensive cesium carbonate is used.
In the method disclosed in CN201210131002.5, the route is as follows:
in the route, the synthesis route is long, metal potassium or metal sodium is required to participate in the reaction to reduce the nitrogen-carbon double bond, and the safety is low.
Therefore, a preparation method of 2, 3-dimethyl-N- (2-chloropyrimidin-4-yl) -N-methyl-2H-indazol-6-amine, which has the advantages of short synthetic route, readily available raw materials, mild reaction conditions, high safety and high yield, is needed.
Disclosure of Invention
The invention provides a preparation method of pazopanib intermediate N,2, 3-trimethyl-2H-indazole-6-amine, which has the advantages of short synthetic route, easily obtained raw materials, low cost, mild reaction conditions, low toxicity and high yield.
In another aspect, the invention provides a preparation method of a pazopanib intermediate 2, 3-dimethyl-N- (2-chloropyrimidin-4-yl) -N-methyl-2H-indazole-6-amine.
In a first aspect of the present invention, there is provided a process for the preparation of a compound of formula II, comprising the steps of:
(v) reacting a compound shown in a formula III with a compound shown in a formula IV in an inert solvent to obtain a compound shown in a formula II;
wherein, X in the compound of the formula III and the compound of the formula IV is independently halogen.
In another preferred embodiment, the compound of formula IV wherein X is bromo, chloro or iodo; preferably, bromine or chlorine, more preferably, chlorine.
In another preferred embodiment, X in the compound of formula III is bromo, chloro or iodo, preferably bromo or chloro, more preferably bromo.
In another preferred embodiment, the reaction is an ammonolysis reaction.
In another preferred embodiment, the reaction in step (v) has one or more of the following characteristics:
the inert solvent is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, isopropanol, pyridine, or combinations thereof; preferably, ethanol;
the reaction temperature is 20-100 ℃, preferably 60-80 ℃, more preferably 70-80 ℃;
the reaction time is 0.5 to 12 hours, preferably 0.5 to 8 hours, more preferably 2 to 6 hours, and still more preferably 3 to 5 hours.
In another preferred embodiment, the molar ratio of the compound of formula III to the compound of formula IV is 1:0.8-2, preferably 1:0.9-1.8, more preferably 1: 1.2-1.6.
In another preferred embodiment, said step (v) is carried out in the presence of a base, preferably said base is selected from the group consisting of: sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N-diisopropylethylamine, or a combination thereof; preferably, sodium bicarbonate.
In another preferred embodiment, the molar ratio of the base to the compound of formula III is from 0.5 to 4: 1, preferably, 2-4: 1, more preferably, 2.5-3.5: 1.
in another preferred embodiment, the compound of formula III is prepared by the following process:
(iv) reacting the compound of formula VI with a methylating agent in an inert solvent to obtain a compound of formula III;
in another preferred embodiment, the reaction in step (iv) has one or more of the following characteristics:
the inert solvent is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, toluene, ethanol, methanol, isopropanol, pyridine, or combinations thereof; preferably, toluene;
the methylating agent is selected from the group consisting of: methyl iodide, dimethyl sulfate, methyl chloride, methyl bromide, or combinations thereof;
the reaction temperature is 60-120 ℃, preferably 80-115 ℃;
the reaction time is 0.5-12h, preferably 4-10h, more preferably 6-10 h.
In another preferred embodiment, the compound of formula VI is prepared by the following process:
(iii) reacting a compound of formula VII with nitrite in an acidic solvent to obtain a compound of formula VI;
in another preferred embodiment, the reaction in step (iii) has one or more of the following characteristics:
the acidic solvent is selected from the group consisting of: hydrochloric acid, acetic acid, hydrobromic acid;
the nitrite reagent is selected from the group consisting of: potassium nitrite, sodium nitrite, or a combination thereof;
the reaction temperature is 0-40 ℃, preferably 10-30 ℃, more preferably 15-25 ℃;
the reaction time is 0.1 to 5 hours, preferably 0.2 to 3 hours, more preferably 0.5 to 2.5 hours.
In another preferred embodiment, the compound of formula VII is prepared by the following process:
(ii) reacting the compound shown in the formula VIII with iron powder in the presence of concentrated hydrochloric acid to obtain a compound shown in the formula VII;
in another preferred embodiment, the reaction in step (ii) has one or more of the following characteristics:
the reaction temperature is 20-70 ℃, preferably 30-60 ℃, and more preferably 40-55 ℃;
the reaction time is 0.5-12h, preferably 1-8h, more preferably 2-6 h.
In another preferred embodiment, the compound of formula VIII is prepared by the following process:
(i) reacting a compound of formula IX with a halogenating agent in an inert solvent to provide a compound of formula VIII;
in another preferred embodiment, the reaction in step (i) has one or more of the following characteristics:
the inert solvent is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, ethanol, methanol, isopropanol, pyridine, or combinations thereof; preferably, dichloromethane;
the halogenating agent is selected from the group consisting of: n-bromosuccinimide, N-chlorosuccinimide, or a combination thereof;
the reaction temperature is 20-60 ℃, preferably 30-50 ℃;
the reaction time is 0.5-6h, preferably 1-4h, more preferably 1-3 h.
In another preferred embodiment, X is bromine, chlorine or iodine, preferably, bromine or chlorine, more preferably, bromine.
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I, said process comprising the steps of:
(v) reacting a compound of formula III with a compound of formula IV in an inert solvent to obtain a compound of formula II;
(vi) reacting a compound of formula II with a compound of formula V in an inert solvent to obtain a compound of formula I;
wherein, X in the compound of the formula III, the compound of the formula IV and the compound of the formula V is independently halogen.
In another preferred embodiment, the compound of formula IV wherein X is bromo, chloro or iodo; preferably, bromine or chlorine, more preferably, chlorine.
In another preferred embodiment, X in the compound of formula III is bromo, chloro or iodo, preferably bromo or chloro, more preferably bromo.
In another preferred embodiment, the compound of formula V wherein X is bromo, chloro or iodo; preferably, bromine or chlorine, more preferably, chlorine.
Characterised in that the reaction in step (v) has one or more of the following characteristics:
the inert solvent is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, isopropanol, pyridine, or combinations thereof; preferably, ethanol;
the reaction temperature is 20-100 ℃, preferably 60-80 ℃, more preferably 70-80 ℃;
the reaction time is 0.5 to 12 hours, preferably 0.5 to 8 hours, more preferably 2 to 6 hours, and still more preferably 3 to 5 hours.
In another preferred embodiment, the molar ratio of the compound of formula III to the compound of formula IV is 1:0.8-2, preferably 1:0.9-1.8, more preferably 1: 1.2-1.6.
In another preferred embodiment, said step (v) is carried out in the presence of a base, preferably said base is selected from the group consisting of: sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N-diisopropylethylamine, or a combination thereof; preferably, sodium bicarbonate.
In another preferred embodiment, the molar ratio of the base to the compound of formula III is from 0.5 to 4: 1, preferably, 2-4: 1, more preferably, 2.5-3.5: 1.
in another preferred embodiment, the compound of formula II and the compound of formula V are used in a molar ratio of 1: 1-3, preferably, 1: 1-2; more preferably, 1: 1.2-1.5.
In another preferred embodiment, the reaction in step (vi) has one or more of the following characteristics:
the inert solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, isopropanol, or a combination thereof;
the reaction temperature is 50-90 ℃, preferably 60-80 ℃, and more preferably 65-75 ℃;
the reaction time is 10-24h, preferably 12-24h, more preferably 16-20 h.
In another preferred embodiment, step (vi) is reacted in the presence of a base, preferably selected from the group consisting of: sodium hydroxide, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, or a combination thereof.
In another preferred embodiment, in step (vi), the molar ratio of the base to the amount of the compound of formula II used is 1.2 to 2: 1, preferably, 1.4-1.8:1, more preferably, 1.4-1.6: 1.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor develops a new method for preparing 2, 3-dimethyl-N- (2-chloropyrimidin-4-yl) -N-methyl-2H-indazol-6-amine by taking 6-halo-2, 3-dimethyl-2H-indazole as a starting raw material through two-step ammonolysis reaction through extensive and intensive research and a large number of screens and tests. The present invention has been completed based on this finding.
Term(s) for
Preparation of 6-halo-2, 3-dimethyl-2H-indazole (III)
Can be synthesized by the following route:
in another preferred embodiment, the compound of formula III is prepared by the following process:
(iv) reacting the compound of formula VI with a methylating agent in an inert solvent to obtain a compound of formula III;
in another preferred embodiment, the reaction in step (iv) has one or more of the following characteristics:
the inert solvent is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, toluene, ethanol, methanol, isopropanol, pyridine, or combinations thereof; preferably, toluene;
the methylating agent is selected from the group consisting of: methyl iodide, dimethyl sulfate, methyl chloride, methyl bromide, or combinations thereof;
the reaction temperature is 60-120 ℃, preferably 80-115 ℃;
the reaction time is 0.5-12h, preferably 4-10h, more preferably 6-10 h.
In another preferred embodiment, the compound of formula VI is prepared by the following process:
(iii) reacting a compound of formula VII with nitrite in an acidic solvent to obtain a compound of formula VI;
in another preferred embodiment, the reaction in step (iii) has one or more of the following characteristics:
the acidic solvent is selected from the group consisting of: hydrochloric acid, acetic acid, hydrobromic acid;
the nitrite reagent is selected from the group consisting of: potassium nitrite, sodium nitrite, or a combination thereof;
the reaction temperature is 0-40 ℃, preferably 10-30 ℃, more preferably 15-25 ℃;
the reaction time is 0.1 to 5 hours, preferably 0.2 to 3 hours, more preferably 0.5 to 2.5 hours.
In another preferred embodiment, the compound of formula VII is prepared by the following process:
(ii) reacting the compound shown in the formula VIII with iron powder in the presence of concentrated hydrochloric acid to obtain a compound shown in the formula VII;
in another preferred embodiment, the reaction in step (ii) has one or more of the following characteristics:
the reaction temperature is 20-70 ℃, preferably 30-60 ℃, and more preferably 40-55 ℃;
the reaction time is 0.5-12h, preferably 1-8h, more preferably 2-6 h.
In another preferred embodiment, the compound of formula VIII is prepared by the following process:
(i) reacting a compound of formula IX with a halogenating agent in an inert solvent to provide a compound of formula VIII;
in another preferred embodiment, the reaction in step (i) has one or more of the following characteristics:
the inert solvent is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, ethanol, methanol, isopropanol, pyridine, or combinations thereof; preferably, dichloromethane;
the halogenating agent is selected from the group consisting of: n-bromosuccinimide, N-chlorosuccinimide, or a combination thereof;
the reaction temperature is 20-60 ℃, preferably 30-50 ℃;
the reaction time is 0.5-6h, preferably 1-4h, more preferably 1-3 h.
In another preferred embodiment, X is bromine, chlorine or iodine, preferably, bromine or chlorine, more preferably, bromine.
Preparation of N,2, 3-trimethyl-2H-indazol-6-amine (II)
A process for preparing a compound of formula II, comprising the steps of:
(v) reacting a compound shown in a formula III with a compound shown in a formula IV in an inert solvent to obtain a compound shown in a formula II;
wherein, X in the compound of the formula III and the compound of the formula IV is independently halogen.
In another preferred embodiment, the compound of formula IV wherein X is bromo, chloro or iodo; preferably, bromine or chlorine, more preferably, chlorine.
In another preferred embodiment, X in the compound of formula III is bromo, chloro or iodo, preferably bromo or chloro, more preferably bromo.
In another preferred embodiment, the reaction is an ammonolysis reaction.
In another preferred embodiment, the reaction in step (v) has one or more of the following characteristics:
the inert solvent is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, isopropanol, pyridine, or combinations thereof; preferably, ethanol;
the reaction temperature is 20-100 ℃, preferably 60-80 ℃, more preferably 70-80 ℃;
the reaction time is 0.5 to 12 hours, preferably 0.5 to 8 hours, more preferably 2 to 6 hours, and still more preferably 3 to 5 hours.
In another preferred embodiment, the molar ratio of the compound of formula III to the compound of formula IV is 1:0.8-2, preferably 1:0.9-1.8, more preferably 1: 1.2-1.6.
In another preferred embodiment, said step (v) is carried out in the presence of a base, preferably said base is selected from the group consisting of: sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N-diisopropylethylamine, or a combination thereof; preferably, sodium bicarbonate.
In another preferred embodiment, the molar ratio of the base to the compound of formula III is from 0.5 to 4: 1, preferably, 2-4: 1, more preferably, 2.5-3.5: 1.
preparation of 2, 3-dimethyl-N- (2-chloropyrimidin-4-yl) -N-methyl-2H-indazol-6-amine (I)
A process for the preparation of a compound of formula I comprising the steps of:
(v) reacting a compound shown in a formula III with a compound shown in a formula IV in an inert solvent to obtain a compound shown in a formula II;
(vi) reacting a compound of formula II with a compound of formula V in an inert solvent to obtain a compound of formula I;
wherein, X in the compound of the formula III, the compound of the formula IV and the compound of the formula V is independently halogen.
In another preferred embodiment, the compound of formula IV wherein X is bromo, chloro or iodo; preferably, bromine or chlorine, more preferably, chlorine.
In another preferred embodiment, X in the compound of formula III is bromo, chloro or iodo, preferably bromo or chloro, more preferably bromo.
In another preferred embodiment, the compound of formula V wherein X is bromo, chloro or iodo; preferably, bromine or chlorine, more preferably, chlorine.
In another preferred embodiment, the reaction in step (vi) has one or more of the following characteristics:
the inert solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, isopropanol, or a combination thereof;
the reaction temperature is 50-90 ℃, preferably 60-80 ℃, and more preferably 65-75 ℃;
the reaction time is 10-24h, preferably 12-24h, more preferably 16-20 h.
In another preferred embodiment, step (vi) is reacted in the presence of a base, preferably selected from the group consisting of: sodium hydroxide, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, or a combination thereof.
In another preferred embodiment, in step (vi), the molar ratio of the base to the amount of the compound of formula II used is 1.2 to 2: 1, preferably, 1.4-1.8:1, more preferably, 1.4-1.6: 1.
The main advantages of the invention include:
(1) the preparation method has the advantages of short synthetic route, easily available raw materials and low cost, and compared with the raw material 6-amino-2, 3-dimethyl-2H-indazole used in the prior art, the compound of the formula III is easier to prepare.
(2) The preparation method has the advantages of simple operation, mild reaction conditions, short time, good safety and high yield, and is suitable for industrial production.
(3) The method avoids using highly toxic methylating agent and alkali metal which is difficult to store and use, and improves the process safety on the whole.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
Reagent
Monomethylamine hydrochloride (98%) is available from Saien chemical technology, Inc. (Shanghai)
2, 4-dichloropyrimidine (98%) was available from Sahn's chemical technology (Shanghai) Co., Ltd
Example 1
Synthesis of 2-ethyl-5-bromonitrobenzene
A3L reaction flask was charged with 1.1L of methylene chloride and 212g of o-ethylnitrobenzene (1.4mol) and heated to reflux, and 250g of N-bromosuccinimide (1.4mol) was added in portions under reflux for reflux reaction for 2 hours. After the reaction, controlling the temperature to be 25 +/-5 ℃, dropwise adding 1.27kg of saturated sodium sulfite into the reaction system to terminate the reaction, standing for layering, concentrating the organic phase, adding 0.72kg of n-heptane to recrystallize to obtain 290.3g of 2-ethyl-5-bromonitrobenzene, wherein the molar yield is 90%.
Example 2
Synthesis of 2-ethyl-5-bromoaniline
Adding 600g of concentrated hydrochloric acid and 100g of 2-ethyl-5-bromonitrobenzene (0.434mol) into a 2L reaction bottle, heating to 50 +/-5 ℃, adding 49g of reduced iron powder (0.875mol) in batches, reacting for 5 hours after the addition is finished, cooling to 25 +/-5 ℃, adding a saturated aqueous solution of sodium carbonate to adjust the pH to 7-8, performing suction filtration, washing a filter cake with 330g of methyl tert-ether, separating filtrate, extracting an aqueous phase with 220g of methyl tert-ether, combining organic phases, washing the organic phases with 330g of an aqueous solution of sodium bicarbonate, and concentrating to obtain 80g of a product, wherein the molar yield is 92%.
Example 3
Synthesis of 3-methyl-6-bromo-2H-indole
Adding 2.1kg of glacial acetic acid and 200g of 2-ethyl-5-bromoaniline (1mol) into a 5L reaction bottle, uniformly stirring, controlling the temperature to be 20 +/-5 ℃, dropwise adding 85g of potassium nitrite aqueous solution (1mol), stirring for 0.5 hour after dropwise adding, adding the reaction solution into 1kg of ice water, stirring for 2 hours, centrifuging, washing by 520g of toluene to obtain 175g of 3-methyl-6-bromo-1H-indole, wherein the molar yield is 82.9%.
Example 4
2, 3-dimethyl-6-bromo-2H-indoles
1.31kg of toluene and 300g of 3-methyl-6-bromo-1H-indole (1.52mol) are added into a 5L reaction bottle, the temperature is increased to reflux, 202g of methyl iodide (1.42mol) is added into the reaction system dropwise for reaction for 8 hours, then the temperature is reduced to 25 +/-5 ℃, 1.65kg of saturated sodium bicarbonate solution is added dropwise for quenching, the centrifugation is carried out, 1.2kg of dichloromethane is added for recrystallization, 270g of 2, 3-dimethyl-6-bromo-2H-indole is obtained, and the molar yield is 84.5%.
Example 5
Preparation of N,2, 3-trimethyl-2H-indazol-6-amine (II)
A1L reaction flask was charged with 22.5g (0.1mol) of 6-bromo-2, 3-dimethyl-2H-indazole and 400mL of ethanol, stirred with 10.1g (0.15mol) of monomethylamine hydrochloride, added with 38.8g (0.3mol) of N, N-diisopropylethylamine, and allowed to warm to 75-78 ℃ for 4 hours. Cooling to room temperature, filtering the obtained reaction solution, concentrating the mother solution to dryness, adding 200mL of ethyl acetate and 200mL of water, stirring, separating the liquid, extracting the water layer twice with 200mL of ethyl acetate, each time with 100mL, combining ethyl acetate layers, and concentrating under reduced pressure to dryness. The residue was recrystallized from 120mL of ethyl acetate to give 14.0g of an off-white solid in 80% molar yield.
MS(m/z)：176(M+H)。1HNMR(400MHz CDCl3)δ：2.51(s，3H),2.89(s,3H),3.75(s,1H),3.99(s,3H),6.47(dd,J＝8.8、2.0Hz,1H),6.55(d，J＝2.2Hz,1H),7.31(d，J＝8.8Hz,1H)
Example 6
Preparation of N,2, 3-trimethyl-2H-indazol-6-amine (II)
A1L reaction flask was charged with 22.5g (0.1mol) of 6-bromo-2, 3-dimethyl-2H-indazole and 400mL of ethanol, stirred with 10.1g (0.15mol) of monomethylamine hydrochloride, charged with 25.2g (0.3mol) of sodium hydrogencarbonate, and allowed to warm to 40-50 ℃ for 4 hours. Cooling to room temperature, filtering the obtained reaction solution, concentrating the mother solution to dryness, adding 200mL of ethyl acetate and 200mL of water, stirring, separating the liquid, extracting the water layer twice with 200mL of ethyl acetate, each time with 100mL, combining ethyl acetate layers, and concentrating under reduced pressure to dryness. The residue was recrystallized from 120mL of ethyl acetate to give 11.02g of an off-white solid in 63% molar yield.
MS(m/z)：176(M+H)。1HNMR(400MHz CDCl3)δ：2.51(s，3H),2.89(s,3H),3.75(s,1H),3.99(s,3H),6.47(dd,J＝8.8、2.0Hz,1H),6.55(d，J＝2.2Hz,1H),7.31(d，J＝8.8Hz,1H)
Example 7
N,2, 3-trimethyl-2H-indazol-6-amine (II)) Preparation of
A1L reaction flask was charged with 22.5g (0.1mol) of 6-bromo-2, 3-dimethyl-2H-indazole and 400ml of ethanol, stirred with 10.1g (0.15mol) of monomethylamine hydrochloride, charged with 25.2g (0.3mol) of sodium hydrogencarbonate, and allowed to warm to 75 to 78 ℃ for 4 hours. Cooling to room temperature, filtering the obtained reaction solution, concentrating the mother solution to dryness, adding 200mL of ethyl acetate and 200mL of water, stirring, separating the liquid, extracting the water layer twice with 200mL of ethyl acetate, each time with 100mL, combining ethyl acetate layers, and concentrating under reduced pressure to dryness. The residue was recrystallized from 120mL of ethyl acetate to give 15.8g of an off-white solid in 90% molar yield.
MS(m/z)：176(M+H)。1HNMR(400MHz CDCl3)δ：2.51(s，3H),2.89(s,3H),3.75(s,1H),3.99(s,3H),6.47(dd,J＝8.8、2.0Hz,1H),6.55(d，J＝2.2Hz,1H),7.31(d，J＝8.8Hz,1H)
Example 8
Preparation of 2, 3-dimethyl-N- (2-chloropyrimidin-4-yl) -N-methyl-2H-indazol-6-amine (I)
A500 mL reaction flask was charged with 17.5g (0.1mol) of the compound of formula II N,2, 3-trimethyl-2H-indazol-6-amine, 160mL of ethanol, 35mL of tetrahydrofuran, stirred, charged with 12.6g (0.15mol) of sodium bicarbonate and 19.4g (0.13mol) of 2, 4-dichloropyrimidine, warmed to 70-75 deg.C for 16H, freed of most of the solvent under reduced pressure, cooled to room temperature, charged with 100mL of water, stirred, filtered, and the filter cake was washed once more with 100mL of water. Drying gave 24.4g of off-white product in 85% molar yield.
MS(m/z)：288(M+H)。1HNMR(400MHz，DMSO-d6)δ：2.62(s，3H)，3.43(s，3H)，4.06(s，3H)，6.24(d，J＝6.0Hz，1H)，6.87(dd，J＝8.8、2.0Hz，1H)，7.49(d，J＝0.8Hz，1H)，7.31(dd，J＝8.8Hz、0.8Hz 1H)，7.93(d，J＝6.0Hz，1H)。
Comparative example 1
Preparation of 2, 3-dimethyl-6-amino-2H-indole
Preparation of o-ethylaniline
Adding 100g of o-ethyl nitrobenzene and 800ml of anhydrous methanol into a 1L reaction bottle, stirring, adding 5% palladium carbon 5g, replacing with hydrogen for three times, filling hydrogen for normal pressure reaction, reacting for 4 hours, sampling and detecting, completely removing the raw materials, filtering the palladium carbon, concentrating and drying the mother liquor to obtain 115.1g of o-ethylaniline, wherein the molar yield is 95.0%.
Preparation of 2-ethyl-5-nitroaniline
121g (1mol) of o-ethylaniline and 500ml of concentrated sulfuric acid are added into a 1L reaction bottle, the reaction bottle is cooled to 0-5 ℃, 93g (1.5mol) of concentrated nitric acid is slowly dripped, and the reaction is kept for 0.5 hour after dripping. The reaction solution was poured into 5000ml of ice water, the pH was adjusted to 7 to 8 with an aqueous solution of sodium hydroxide under cooling, a solid was precipitated, and the cake was dried and recrystallized from cyclohexane to give 123g of a yellow solid with a molar yield of 74.1%.
Preparation of 3-methyl-6-nitro-1H-indole
3.75L of glacial acetic acid and 125g of 2-ethyl-5-nitroaniline (0.75mol) were added to a 5L reaction flask, tert-butyl nitrite (0.75mol) was added dropwise at room temperature, and stirring was continued for 0.5 hour after the dropwise addition. The reaction was concentrated to dryness, and the resulting yellow solid was dissolved in 1.5L of ethyl acetate and washed three times with aqueous sodium bicarbonate solution, dried, filtered, and concentrated to dryness to give 120g of yellow solid in 90.5 mol yield.
Preparation of 2, 3-dimethyl-6-nitro-2H-indole
1400ml of isopropanol were added to a 3L reaction flask and heated to reflux, 32g of sodium (1.4mol) were added in portions, stirred until completely dissolved, 130g of 3-methyl-6-nitro-1H-indole (0.73mol) were added and reflux was continued for 3 hours after the addition was complete. A solution of 300g (2.1mol) of methyl iodide and 450ml of isopropanol was added dropwise and refluxed for 5 hours. Cooled, left to stand overnight and filtered to give 121g of a pale yellow solid in 88.3% molar yield.
Synthesis of 2, 3-dimethyl-6-amino-2H-indole
1200ml of anhydrous methanol and 120g (0.6mol) of 2, 3-dimethyl-6-nitro-2H-indole are added into a 3L reaction bottle, stirred and dissolved, 12g of 5% palladium carbon is added, after three times of hydrogen replacement, hydrogen is filled in, and the reaction is carried out at normal temperature for 6 hours, sampling detection shows that the raw material completely disappears, the palladium carbon is removed by filtration, the filtrate is concentrated to be dry, and water is recrystallized to obtain 110.7g of product, wherein the molar yield is 93%.
In conclusion, the method for synthesizing 2, 3-dimethyl-N- (2-chloropyrimidin-4-yl) -N-methyl-2H-indazole-6-amine by using 6-halo-2, 3-dimethyl-2H-indazole has the advantages of short synthetic route, mild reaction conditions, simplicity and convenience in operation, easiness in purification of products, good safety and high yield (the total yield can reach 76.5%), and is suitable for industrial production. Compared with the raw material 2, 3-dimethyl-6-amino-2H-indole in the prior art, the 6-halo-2, 3-dimethyl-2H-indazole used in the synthetic route has the advantages of shorter synthetic route, milder preparation conditions (hydrogenation step is reduced), no need of expensive palladium reagent, greenness, environmental protection and high yield, so that the raw material cost can be further reduced, the operation safety is improved by using the 6-bromo-2, 3-dimethyl-2H-indazole as the raw material, and the 6-halo-2, 3-dimethyl-2H-indazole is more suitable for industrial production.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A process for preparing a compound of formula II, comprising the steps of:
(v) reacting a compound shown in a formula III with a compound shown in a formula IV in an inert solvent to obtain a compound shown in a formula II;
wherein, X in the compound of the formula III and the compound of the formula IV is independently halogen.
2. The method of claim 1, wherein the reaction in step (v) has one or more of the following characteristics:
the inert solvent is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, isopropanol, pyridine, or combinations thereof; preferably, ethanol;
the reaction temperature is 20-100 ℃, preferably 60-80 ℃, more preferably 70-80 ℃;
the reaction time is 0.5 to 12 hours, preferably 0.5 to 8 hours, more preferably 2 to 6 hours, and still more preferably 3 to 5 hours.
3. The process according to claim 1, wherein the molar ratio of the compound of formula III to the compound of formula IV is 1:0.8 to 2, preferably 1:0.9 to 1.8, more preferably 1:1.2 to 1.6.
4. The process of claim 1, wherein step (v) is carried out in the presence of a base, preferably selected from the group consisting of: sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N-diisopropylethylamine, or a combination thereof; preferably, sodium bicarbonate.
5. The process of claim 4, wherein the molar ratio of base to compound of formula III is from 0.5 to 4: 1, preferably, 2-4: 1, more preferably, 2.5-3.5: 1.
6. the process of claim 1, wherein the compound of formula III is prepared by:
(iv) reacting the compound of formula VI with a methylating agent in an inert solvent to obtain a compound of formula III;
7. the process of claim 6, wherein the compound of formula VI is prepared by:
(iii) reacting a compound of formula VII with nitrite in an acidic solvent to obtain a compound of formula VI;
8. the process of claim 7, wherein the compound of formula VII is prepared by:
(ii) reacting the compound shown in the formula VIII with iron powder in the presence of concentrated hydrochloric acid to obtain a compound shown in the formula VII;
9. a process for the preparation of a compound of formula I, said process comprising the steps of:
(v) reacting a compound of formula III with a compound of formula IV in an inert solvent to obtain a compound of formula II;
(vi) reacting a compound of formula II with a compound of formula V in an inert solvent to obtain a compound of formula I;
wherein, X in the compound of the formula III, the compound of the formula IV and the compound of the formula V is independently halogen.
10. The process of claim 9, wherein step (v) is carried out in the presence of a base, preferably selected from the group consisting of: sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N-diisopropylethylamine, or a combination thereof; preferably, sodium bicarbonate.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373963A (en) * | 2012-04-28 | 2013-10-30 | 上海医药工业研究院 | Intermediate of pazopanib hydrochloride and preparation method of intermediate of pazopanib hydrochloride |
| CN103373989A (en) * | 2012-04-28 | 2013-10-30 | 上海医药工业研究院 | Preparation method of intermediate of pazopanib hydrochloride |
| CN103450085A (en) * | 2013-08-15 | 2013-12-18 | 凯莱英医药集团（天津）股份有限公司 | Preparation method of pazopanib hydrochloride key intermediate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373963A (en) * | 2012-04-28 | 2013-10-30 | 上海医药工业研究院 | Intermediate of pazopanib hydrochloride and preparation method of intermediate of pazopanib hydrochloride |
| CN103373989A (en) * | 2012-04-28 | 2013-10-30 | 上海医药工业研究院 | Preparation method of intermediate of pazopanib hydrochloride |
| CN103450085A (en) * | 2013-08-15 | 2013-12-18 | 凯莱英医药集团（天津）股份有限公司 | Preparation method of pazopanib hydrochloride key intermediate |
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| YICHENG MEI, ET AL: "A Novel Practical Synthesis of Pazopanib: An Anticancer Drug", LETTERS IN ORGANIC CHEMISTRY, vol. 9, no. 4, pages 276 - 279, XP009176620, DOI: 10.2174/157017812800233714 * |
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