CN110590683B - Preparation method of intermediate of targeting drug AZD3759 - Google Patents
Preparation method of intermediate of targeting drug AZD3759 Download PDFInfo
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- CN110590683B CN110590683B CN201910962926.1A CN201910962926A CN110590683B CN 110590683 B CN110590683 B CN 110590683B CN 201910962926 A CN201910962926 A CN 201910962926A CN 110590683 B CN110590683 B CN 110590683B
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- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
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Abstract
The invention discloses a preparation method of a targeting drug AZD3759 intermediate, which comprises the steps of hydrolyzing 6-nitroveratric acid under an alkaline condition to obtain 2-nitro-4-methoxyl group-5-hydroxybenzoic acid, reducing by hydrazine hydrate under the action of a catalyst ferric chloride hexahydrate and activated carbon mixture to obtain 2-amino-4-methoxy-5-hydroxybenzoic acid, reacting with formamidine acetate to obtain 4, 6-dihydroxy-7-methoxyquinazoline, reacting with acetyl chloride under alkaline conditions to obtain 4-hydroxy-6-acetoxy-7-methoxyquinazoline, and finally reacting with 3-chloro-2-fluoroaniline under the action of triphenylphosphine and azo reagent by Mitsunobu to obtain 4- [ (3-chloro-2-fluorophenyl) amino group]-6-acetoxy-7-methoxyquinazoline. The invention reduces the synthesis steps, reduces the use of harmful compounds, reduces the production cost and optimizes the production operation.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a targeting drug AZD3759 intermediate.
Background
AZD3759 is a lung cancer EGFR target developed by Aslicon and a targeted drug for targeting brain metastasis, and AZD3759 is mainly designed to effectively pass through a blood brain barrier so as to solve Central Nervous System (CNS) metastasis of EGFRM + non-small cell lung cancer patients. 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxy-7-methoxyquinazoline is an important intermediate for preparing AZD3759, and the structural formula is as follows:
at present, the synthetic route of 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxyl-7-methoxyquinazoline mainly adopts the synthetic route reported in CN105209456A, and the target product is prepared by using 6-nitroveratric acid as a raw material, hydrolyzing under an alkaline condition, carrying out palladium-carbon hydrogenation to reduce nitro, cyclizing, esterifying, chlorinating and reacting with 3-chloro-2-fluoroaniline, wherein the reaction equation is as follows:
the 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxyl-7-methoxyquinazoline prepared by the synthetic route is prepared by firstly chlorinating 4-hydroxy-6-acetoxyl-7-methoxyquinazoline by phosphorus oxychloride and then reacting the chlorinated 4-hydroxy-6-acetoxyl-7-methoxyquinazoline with 3-chloro-2-fluoroaniline to generate 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxyl-7-methoxyquinazoline, and the synthetic route is complex and is not easy to process, generates a large amount of acid water, and is unsafe due to the extreme toxicity of phosphorus oxychloride. The synthetic route also adopts palladium carbon to reduce the nitryl of the 3-hydroxyl-4-methoxyl-6-nitrobenzoic acid into amino by hydrogenation, the price of the palladium carbon is high, and the production cost is high; the high pressure reaction is dangerous.
Disclosure of Invention
The invention aims to overcome the defects and carries out process optimization on the basis of the patent CN 105209456A. Wherein the nitro reduction of the 2-nitro-4-methoxy-5-hydroxybenzoic acid is changed from palladium carbon catalytic reduction to hydrazine hydrate and ferric chloride hexahydrate activated carbon reduction; the 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxyl-7-methoxy quinazoline is prepared by removing one step of phosphorus oxychloride chlorination and directly carrying out Mitsunobu reaction. The invention reduces the synthesis steps, reduces the use of harmful compounds, reduces the production cost and optimizes the production operation.
The technical scheme of the invention is as follows: a preparation method of an intermediate of a targeting drug AZD3759 comprises the following steps:
1) hydrolyzing 6-nitro veratric acid under alkaline condition to obtain 2-nitro-4-methoxy-5-hydroxybenzoic acid;
2) 2-nitro-4-methoxyl-5-hydroxybenzoic acid is reduced by nitryl to obtain 2-amino-4-methoxyl-5-hydroxybenzoic acid;
3) reacting 2-amino-4-methoxy-5-hydroxybenzoic acid with formamidine acetate for cyclization to obtain 4, 6-dihydroxy-7-methoxyquinazoline;
4) reacting 4, 6-dihydroxy-7-methoxy quinazoline with acetyl chloride under an alkaline condition to obtain 4-hydroxy-6-acetoxyl-7-methoxy quinazoline;
5) 4-hydroxy-6-acetoxyl-7-methoxy quinazoline reacts with 3-chloro-2-fluoroaniline to obtain 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxyl-7-methoxy quinazoline;
it is characterized in that the utility model is characterized in that,
the 2-nitro-4-methoxyl-5-hydroxybenzoic acid in the step 2) is reduced by hydrazine hydrate under the action of a mixture of ferric chloride hexahydrate and activated carbon serving as a catalyst to obtain 2-amino-4-methoxyl-5-hydroxybenzoic acid;
the 4-hydroxy-6-acetoxy-7-methoxyquinazoline and the 3-chloro-2-fluoroaniline are subjected to Mitsunobu reaction under the action of triphenylphosphine and an azo reagent (diethyl azodicarboxylate DEAD, diisopropyl azodicarboxylate DIAD) to obtain the 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxy-7-methoxyquinazoline.
Further, in the step 2), the mass ratio of ferric trichloride hexahydrate to activated carbon is 1:10 to 20 parts; the dosage of the mixture of ferric trichloride hexahydrate and activated carbon is 5-20% of the weight of 3-hydroxy-4-methoxy-6-nitrobenzoic acid.
Further, the molar ratio of the 2-nitro-4-methoxy-5-hydroxybenzoic acid to the hydrazine hydrate in the step 2) is 1: 2-5; the solvent is at least one of water, methanol, ethanol and isopropanol; the reaction temperature is 60-100 ℃, and the reaction time is 2-8 h.
Further, the molar ratio of the 4-hydroxy-6-acetoxy-7-methoxyquinazoline to the 3-chloro-2-fluoroaniline in the step 5) is 1: 1-2; the molar ratio of the 4-hydroxy-6-acetoxyl-7-methoxyquinazoline to the triphenylphosphine and the azo reagent is 1: 1-2: 1 to 2. The solvent is at least one of tetrahydrofuran, dichloromethane and toluene; the reaction temperature is 0-30 ℃, and the reaction time is 2-6 h.
In the step 1), alkali is added to catalyze the hydrolysis of the 6-nitroveratric acid, and the molar ratio of the alkali to the 6-nitroveratric acid is 1: 2-5; the solvent is water; the alkali is at least one of sodium hydroxide and potassium hydroxide; the reaction temperature is 80-100 ℃, and the reaction time is 2-6 h.
In the step 3), the molar ratio of 2-amino-4-methoxy-5-hydroxybenzoic acid to formamidine acetate is 1: 1.5-3, and the solvent is at least one of DMF, DMA and ethylene glycol monomethyl ether; the reaction temperature is 80-130 ℃, and the reaction time is 4-8 h.
In the step 4), the base is organic base or inorganic base, the organic base is at least one of triethylamine, pyridine and N, N-diisopropylethylamine, and the inorganic base is at least one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. In the step 4), the molar ratio of the 4, 6-dihydroxy-7-methoxyquinazoline to acetyl chloride is 1: 1.5-3, and the solvent is at least one of tetrahydrofuran, dichloromethane and toluene; the reaction temperature is-5 ℃ to 25 ℃, and the reaction time is 2 to 6 hours.
The synthesis reaction of the invention specifically comprises the following steps:
1) preparation of 2-nitro-4-methoxy-5-hydroxybenzoic acid
Adding sodium hydroxide into water, stirring to dissolve completely, adding 6-nitroveratric acid, heating to 80-100 ℃, reacting for 2-6 h, pouring the reaction solution into cold dilute hydrochloric acid to separate out a product, filtering, and drying to obtain a yellow solid 2-nitro-4-methoxy-5-hydroxybenzoic acid;
2) preparation of 2-amino-4-methoxy-5-hydroxybenzoic acid
Adding 2-nitro-4-methoxy-5-hydroxybenzoic acid into methanol, adding a mixture of ferric trichloride hexahydrate and activated carbon, heating to the reaction temperature of 60-100 ℃, dropwise adding hydrazine hydrate, keeping the temperature for 2-8 h after dropwise adding, filtering, and concentrating to dryness to obtain 2-amino-4-methoxy-5-hydroxybenzoic acid;
3) preparation of 4, 6-dihydroxy-7-methoxyquinazoline
Adding 2-amino-4-methoxy-5-hydroxybenzoic acid and formamidine acetate into ethylene glycol monomethyl ether, reacting for 4-8 h at 80-130 ℃, concentrating to dryness, adding water for dissolving, adjusting the alkalinity with ammonia water to separate out a product, filtering and drying to obtain 4, 6-dihydroxy-7-methoxy quinazoline;
4) preparation of 4-hydroxy-6-acetoxy-7-methoxyquinazoline
Adding 4, 6-dihydroxy-7-methoxy quinazoline and triethylamine into DCM, cooling to-5 ℃, dropwise adding acetyl chloride, reacting at normal temperature for 2-6 h after completing dropwise adding, adding water, separating, washing and drying an organic phase with brine, and concentrating to dryness to obtain 4-hydroxy-6-acetoxyl-7-methoxy quinazoline;
5) preparation of 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxy-7-methoxyquinazoline
Adding 4-hydroxy-6-acetoxyl-7-methoxy quinazoline, triphenylphosphine and 3-chloro-2-fluoroaniline into tetrahydrofuran, dripping DIAD at 0-30 ℃, reacting for 2-6 h after dripping, adding dilute hydrochloric acid to adjust the pH value to 2-3, extracting with dichloromethane to remove impurities, retaining a water phase, adjusting the water phase to be alkaline with sodium hydroxide water solution, filtering and drying to obtain 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxyl-7-methoxy quinazoline.
The invention has the beneficial effects that: in the invention, the nitro reduction of the 2-nitro-4-methoxy-5-hydroxybenzoic acid is changed from palladium carbon catalytic reduction to hydrazine hydrate and ferric chloride hexahydrate activated carbon reduction; the 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxyl-7-methoxy quinazoline is prepared by removing one step of phosphorus oxychloride chlorination and directly carrying out Mitsunobu reaction. The process has the advantages of simple steps, convenient operation, easily obtained raw materials, less generated acidic wastewater and easy industrial production.
Drawings
FIG. 1 is a mass spectrum of 2-nitro-4-methoxy-5-hydroxybenzoic acid prepared in example 1 of the present invention;
FIG. 2 is a mass spectrum of 4, 6-dihydroxy-7-methoxyquinazoline prepared in example 3 of the present invention;
FIG. 3 is a mass spectrum of 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxy-7-methoxyquinazoline prepared in example 5 of the present invention;
FIG. 4 is an HPLC chromatogram of 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxy-7-methoxyquinazoline prepared in example 5 of the present invention.
Detailed Description
Example 1: preparation of 2-nitro-4-methoxy-5-hydroxybenzoic acid
Dissolving 118g of sodium hydroxide in 400g of water, adding 118g of 6-nitroveratric acid, heating to 100 ℃, preserving heat for reaction for 6h, pouring the system into 1160g of dilute hydrochloric acid, reducing the pH value to be less than 2, cooling to room temperature, filtering, washing with water, and drying to obtain 108g of yellow solid, namely the 2-nitro-4-methoxy-5-hydroxybenzoic acid, wherein the molar yield is 97.6%, and the purity is 99%.
ESI-MS:m/z([M-H] - ) 212.0 as shown in FIG. 1.
Example 2: preparation of 2-amino-4-methoxy-5-hydroxybenzoic acid
Adding 100g of 2-nitro-4-methoxy-5-hydroxybenzoic acid into 500g of methanol, and adding ferric trichloride hexahydrate in a mass ratio: 20g of a mixture of 1:10 of activated carbon, heating to reflux, dropwise adding 115g of 40% hydrazine hydrate, keeping refluxing for 4h after dropwise adding, cooling to room temperature after the reaction is finished, filtering to remove the catalyst, and concentrating the solution to dryness to obtain 80g of an off-white solid, namely the 2-amino-4-methoxy-5-hydroxybenzoic acid, wherein the molar yield is 93.1% and the purity is 99%.
Example 3: preparation of 4, 6-dihydroxy-7-methoxyquinazoline
Adding 80g of 2-amino-4-methoxy-5-hydroxybenzoic acid and 90g of formamidine acetate into 450g of ethylene glycol monomethyl ether, heating to 110 ℃, preserving the temperature for 6h, after the reaction is finished, concentrating under reduced pressure to dryness, adding 450g of water and 50g of ammonia water, stirring at room temperature for 2h, filtering, and drying at 50 ℃ for 6h to obtain 71g of brown solid, namely 4, 6-dihydroxy-7-methoxyquinazoline, wherein the molar yield is 84.6% and the purity is 99.2%.
ESI-MS: M/z ([ M-H ] -) was 191.0, as shown in FIG. 2.
Example 4: preparation of 4-hydroxy-6-acetoxy-7-methoxyquinazoline
Adding 60g of 4, 6-dihydroxy-7-methoxyquinazoline into 800g of DCM, adding 63.2g of triethylamine, dropwise adding 49g of acetyl chloride, controlling the internal temperature to be less than 0 ℃, after the dropwise addition is finished, heating to the normal temperature, stirring for 6h, after the reaction is finished, adding 800g of water, stirring for 0.5h, separating, washing the organic phase once by 400g of saturated saline, drying by anhydrous sodium sulfate, filtering, concentrating to dryness to obtain 72g of 4-hydroxy-6-acetoxyl-7-methoxyquinazoline, and directly carrying out the next reaction without purification.
Example 5: preparation of 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxy-7-methoxyquinazoline
72g of 4-hydroxy-6-acetoxy-7-methoxyquinazoline, 80.6g of triphenylphosphine and 56.7g of 3-chloro-2-fluoroaniline were added to 720g of tetrahydrofuran, and then, at 20 ℃, 62.2g of DIAD was added dropwise, after completion of the dropwise addition, the mixture was reacted for 4 hours, 500g of 5% hydrochloric acid was added thereto, the pH was adjusted to 2-3, the mixture was stirred for 0.5 hour, impurities were removed by extraction with 720g of dichloromethane, the aqueous phase was retained, the aqueous phase was made basic with 20% aqueous sodium hydroxide solution, filtered, the filter cake was washed with water to neutrality, and dried to obtain 94.5g of 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxy-7-methoxyquinazoline, a total molar yield of the two steps of 83.7% and a HPLC purity of 99.13% (as shown in FIG. 4).
ESI-MS: M/z ([ M-H ] -) was 360.0, as shown in FIG. 3.
Claims (7)
1. A preparation method of an intermediate of a targeting drug AZD3759 comprises the following steps:
1) hydrolyzing 6-nitro veratric acid under alkaline condition to obtain 2-nitro-4-methoxy-5-hydroxybenzoic acid;
2) 2-nitro-4-methoxy-5-hydroxybenzoic acid is reduced by nitro to obtain 2-amino-4-methoxy-5-hydroxybenzoic acid;
3) reacting 2-amino-4-methoxy-5-hydroxybenzoic acid with formamidine acetate for cyclization to obtain 4, 6-dihydroxy-7-methoxyquinazoline;
4) reacting 4, 6-dihydroxy-7-methoxy quinazoline with acetyl chloride under an alkaline condition to obtain 4-hydroxy-6-acetoxyl-7-methoxy quinazoline;
5) 4-hydroxy-6-acetoxyl-7-methoxyl quinazoline reacts with 3-chloro-2-fluoroaniline to obtain 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxyl-7-methoxyl quinazoline;
it is characterized in that the utility model is characterized in that,
the 2-nitro-4-methoxyl-5-hydroxybenzoic acid in the step 2) is reduced by hydrazine hydrate under the action of a mixture of ferric chloride hexahydrate and activated carbon serving as a catalyst to obtain 2-amino-4-methoxyl-5-hydroxybenzoic acid; the adopted solvent is at least one of water, methanol, ethanol and isopropanol;
the 4-hydroxy-6-acetoxyl-7-methoxyquinazoline and the 3-chloro-2-fluoroaniline react by Mitsunobu under the action of triphenylphosphine and an azo reagent to obtain 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxyl-7-methoxyquinazoline; the azo reagent is diethyl azodicarboxylate or diisopropyl azodicarboxylate; the solvent is at least one of tetrahydrofuran, dichloromethane and toluene.
2. The method for preparing the AZD3759 intermediate as the targeted drug according to claim 1, wherein in the mixture of ferric trichloride hexahydrate and activated carbon in the step 2), the mass ratio of ferric trichloride hexahydrate to activated carbon is 1: 10-20; the dosage of the mixture of ferric trichloride hexahydrate and activated carbon is 5-20% of the weight of 2-nitro-4-methoxy-5-hydroxybenzoic acid.
3. The preparation method of the AZD3759 intermediate as the targeted drug as claimed in claim 1, wherein the molar ratio of 2-nitro-4-methoxy-5-hydroxybenzoic acid to hydrazine hydrate in the step 2) is 1: 2 to 5.
4. The preparation method of the intermediate of the targeted drug AZD3759 as claimed in claim 1, wherein the reaction temperature in the step 2) is 60-100 ℃, and the reaction time is 2-8 h.
5. The preparation method of the AZD3759 intermediate of the targeted drug according to claim 1, wherein the molar ratio of the 4-hydroxy-6-acetoxy-7-methoxyquinazoline to the 3-chloro-2-fluoroaniline in the step 5) is 1: 1-2; the molar ratio of the 4-hydroxy-6-acetoxyl-7-methoxyquinazoline to the triphenylphosphine and the azo reagent is 1: 1-2: 1 to 2.
6. The preparation method of the intermediate of the targeted drug AZD3759 as claimed in claim 1, wherein the reaction temperature in the step 5) is 0-30 ℃, and the reaction time is 2-6 h.
7. The preparation method of the intermediate of the targeting drug AZD3759 as claimed in any one of claims 1 to 6,
1) preparation of 2-nitro-4-methoxy-5-hydroxybenzoic acid
Adding sodium hydroxide into water, stirring to dissolve completely, adding 6-nitroveratric acid, raising the temperature to 80-100 ℃, reacting for 2-6 h, pouring the reaction liquid into cold dilute hydrochloric acid to separate out a product, filtering and drying to obtain 2-nitro-4-methoxy-5-hydroxybenzoic acid;
2) preparation of 2-amino-4-methoxy-5-hydroxybenzoic acid
Adding 2-nitro-4-methoxy-5-hydroxybenzoic acid into methanol, adding a mixture of ferric trichloride hexahydrate and activated carbon, heating to the reaction temperature of 60-100 ℃, dropwise adding hydrazine hydrate, keeping the temperature to react for 2-8 h after dropwise adding, filtering, and concentrating the filtrate to dryness to obtain 2-amino-4-methoxy-5-hydroxybenzoic acid;
3) preparation of 4, 6-dihydroxy-7-methoxy quinazoline
Adding 2-amino-4-methoxy-5-hydroxybenzoic acid and formamidine acetate into ethylene glycol monomethyl ether, reacting for 4-8 h at 80-130 ℃, concentrating to dryness, adding water for dissolving, adjusting to alkalinity with ammonia water to precipitate a product, filtering, and drying to obtain 4, 6-dihydroxy-7-methoxy quinazoline;
4) preparation of 4-hydroxy-6-acetoxy-7-methoxyquinazoline
Adding 4, 6-dihydroxy-7-methoxy quinazoline and triethylamine into dichloromethane, cooling to-5 ℃, dropwise adding acetyl chloride, reacting at normal temperature for 2-6 h after dropwise adding, adding water, separating liquid, washing an organic phase with brine, drying, and concentrating to dryness to obtain 4-hydroxy-6-acetoxyl-7-methoxy quinazoline;
5) preparation of 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxy-7-methoxyquinazoline
Adding 4-hydroxy-6-acetoxyl-7-methoxy quinazoline, triphenylphosphine and 3-chloro-2-fluoroaniline into tetrahydrofuran, dripping diisopropyl azodicarboxylate at 0-30 ℃, reacting for 2-6 h after dripping, adding acid to adjust the pH value to 2-3, extracting with dichloromethane to remove impurities, retaining a water phase, adjusting the water phase to be alkaline with sodium hydroxide aqueous solution, filtering and drying to obtain 4- [ (3-chloro-2-fluorophenyl) amino ] -6-acetoxyl-7-methoxy quinazoline.
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CN103275072A (en) * | 2013-05-22 | 2013-09-04 | 苏州明锐医药科技有限公司 | Preparation method of saracatinib |
CN105209456A (en) * | 2013-03-06 | 2015-12-30 | 阿斯利康(瑞典)有限公司 | Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor |
WO2017096997A1 (en) * | 2015-12-09 | 2017-06-15 | 苏州明锐医药科技有限公司 | Preparation method for cariprazine |
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CN105209456A (en) * | 2013-03-06 | 2015-12-30 | 阿斯利康(瑞典)有限公司 | Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor |
CN103275072A (en) * | 2013-05-22 | 2013-09-04 | 苏州明锐医药科技有限公司 | Preparation method of saracatinib |
WO2017096997A1 (en) * | 2015-12-09 | 2017-06-15 | 苏州明锐医药科技有限公司 | Preparation method for cariprazine |
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