CN111808075B - Preparation method of pyridine quinazoline intermediate - Google Patents
Preparation method of pyridine quinazoline intermediate Download PDFInfo
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- CN111808075B CN111808075B CN202010925925.2A CN202010925925A CN111808075B CN 111808075 B CN111808075 B CN 111808075B CN 202010925925 A CN202010925925 A CN 202010925925A CN 111808075 B CN111808075 B CN 111808075B
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Abstract
The invention discloses a preparation method of a pyridine quinazoline intermediate, which adopts a synthetic route that: the 3- (hydrazinomethyl) pyridine and 2- (chloromethyl) aniline firstly undergo N-alkylation reaction, and then undergo benzene ring substitution reaction and cyclization reaction to obtain the 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazoline-2 (1H) -ketone. In the route, the side reactions of the benzyl chlorination reaction of the 2-methylaniline are more, the design is carried out in the previous step, the content of the 2- (chloromethyl) aniline after high vacuum rectification reaches 95.0-97.0%, and the impurities in the subsequent reaction are reduced. In addition, the expensive raw material 2-bromoheptafluoropropane is reacted in the next step, so that the raw material cost is reduced, and the total yield is 72.0-74.0% (calculated by the 2-bromoheptafluoropropane).
Description
Technical Field
The invention relates to the technical field of preparation of pesticide intermediates, in particular to a preparation method of a pyridine quinazoline intermediate 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazoline-2 (1H) -ketone.
Background
The pyridine quinazoline is a novel quinazoline insecticide which is effective on pests of the family of the stinkbug, and has excellent effects on aphids, whiteflies, mealybugs, leafhoppers and thrips. The molecular formula is as follows: c19H15F7N4O2The structural formula:
6- (perfluoropropan-2-yl) -3- ((pyridin-3-methylene) amino) -3, 4-dihydroquinazolin-2 (1H) -one is an important intermediate for the synthesis of pyridine quinazoline, 6- (perfluoropropan-2-yl) -3- ((pyridin-3-methylene) amino) -3, 4-dihydroquinazolin-2 (1H) -one accounts for 90.0% of the molar mass of the entire molecule of pyridine quinazoline, i.e., the cost of 6- (perfluoropropan-2-yl) -3- ((pyridin-3-methylene) amino) -3, 4-dihydroquinazolin-2 (1H) -one determines the raw material cost of the pyridine quinazoline.
The currently reported synthesis methods mainly include the following methods:
european patent EP1097932 discloses a method for synthesizing 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazolin-2 (1H) -one in five steps by using 2-nitro-5-heptafluoroisopropylbenzaldehyde, methyl hydrazinoformate, N-carbonyldiimidazole and 3-pyridineformaldehyde as raw materials. In the synthetic route, the synthetic difficulty of the starting material 2-nitro-5-heptafluoroisopropylbenzaldehyde is large, the industrial production is not realized for a while, and the price of the raw material N, N-carbonyl diimidazole is high. The raw material cost of the route is high, and industrialization is difficult to realize.
World patent WO2005123695 discloses ｃA method for synthesizing 3-amino-6- (perfluoropropane-2-yl) -3, 4-dihydroquinazolin-2 (1H) -one by five-step reaction using 2-methylaniline, 2-bromoheptafluoropropane, methyl chloroformate, chlorine gas, hydrazine hydrate and 3-pyridineformaldehyde as raw materials, which is similar to the synthetic methods disclosed in Japanese patent JP-A-8-325239 and JP 2001342186.
The yield of the final product, 3-amino-6- (perfluoropropan-2-yl) -3, 4-dihydroquinazolin-2 (1H) -one, was 63.3% calculated on 2-bromoheptafluoropropane. In the synthetic route, the benzyl chlorination reaction has a plurality of side reactions, the main impurity is 3-amino-8-chloro-6- (perfluoropropane-2-yl) -3, 4-dihydroquinazolin-2 (1H) -ketone (the content is about 8.0 percent), and the impurity has similar properties with the target intermediate and can generate adverse effects on subsequent reactions. In addition, the price of the raw material 2-bromoheptafluoropropane is high, which accounts for 80.0% of the material cost of the synthetic route, and the price of the 2-bromoheptafluoropropane determines the price of 3-amino-6- (perfluoropropane-2-yl) -3, 4-dihydroquinazolin-2 (1H) -one. In the synthetic route, expensive 2-bromoheptafluoropropane is used in the first step of reaction, so that the generation cost of 3-amino-6- (perfluoropropane-2-yl) -3, 4-dihydroquinazolin-2 (1H) -one is too high, and the industrial value of the 3-amino-6- (perfluoropropane-2-yl) -3, 4-dihydroquinazolin-2 (1H) -one is reduced.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and provides a synthetic method which has relatively low cost and simple and safe process operation and is prepared by adopting 3-pyridylaldehyde and 2-methylaniline as starting raw materials and performing N-alkylation reaction, free radical-initiated benzyl chlorination reaction, halogenated alkane substitution reaction, benzene ring substitution reaction and cyclization reaction to obtain 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazoline-2 (1H) -ketone.
The technical scheme for realizing the invention is as follows:
the method comprises the following steps of reacting 3-pyridylaldehyde with hydrazine hydrate to generate 3- (hydrazino methylene) pyridine, using hydrazine hydrate as a reaction solvent while using the hydrazine hydrate as a reaction raw material, reducing the use of the solvent, recovering the hydrazine hydrate under negative pressure after the reaction is completed, reducing the consumption of the hydrazine hydrate, and ensuring the product content to be 95.0-97.0%;
secondly, under the initiation of a free radical initiator azobisisobutyronitrile, 2-methylaniline and chlorine gas are subjected to free radical substitution reaction to prepare a 2- (chloromethyl) aniline crude product, and then the 2- (chloromethyl) aniline crude product is rectified in high vacuum to finally obtain the 2- (chloromethyl) aniline with the purity of 95.0-97.0%, wherein the content of dichloro byproducts is lower than 0.5%, so that the impurity content of subsequent reaction can be effectively reduced;
preparing 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline from 3- (hydrazinomethylene) pyridine and 2- (chloromethyl) aniline through an N-alkylation reaction, wherein the product content is 95.0-97.0%;
performing benzene ring substitution reaction on 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, 2-bromoheptafluoropropane, sodium hydrosulfite, sodium carbonate and tetrabutylammonium hydrogen sulfate to obtain 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, wherein the product content is 94.0-96.0%;
preparing 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazolin-2 (1H) -one from 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline and bis (trichloromethyl) carbonate through cyclization, wherein the product content is 95.0-97.0%;
the reaction formula is as follows:
the molar ratio of the 3-pyridylaldehyde to the hydrazine hydrate is 1: 4.5-5.5, the 3-pyridylaldehyde is dripped into the hydrazine hydrate within 30 minutes at the temperature of 45-50 ℃, the stirring reaction is continued for 1-2 hours, and the liquid chromatography tracking analysis is adopted. After the reaction is finished, removing hydrazine hydrate at the temperature of 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain oily 3- (hydrazinomethylene) pyridine;
the molar ratio of the 2-methylaniline to the chlorine gas is 1: 1.0-1.5, the dosage of the azodiisobutyronitrile is 5.0-8.0% of the mass of the 2-methylaniline, the dosage of the solvent dichloroethane is 5-8 times of the mass of the 2-methylaniline, the chlorine gas is introduced within 10 hours at the temperature of 60-65 ℃, the stirring is continued for 2 hours, and the liquid chromatography tracking analysis is carried out. After the reaction is finished, washing an organic phase by using a saturated sodium carbonate aqueous solution, desolventizing at 40-45 ℃ under the vacuum degree of-0.07 to-0.09 MPa to obtain a 2- (chloromethyl) aniline crude product, and rectifying at 60-65 ℃ under the vacuum degree of-0.098 to-0.10 MPa to obtain 2- (chloromethyl) aniline with the content of 95.0-97.0%;
and step three, the molar ratio of the 3- (hydrazino methylene) pyridine to the 2- (chloromethyl) aniline is 1:1, the using amount of the solvent ethanol is 5-8 times of the mass of the 3- (hydrazino methylene) pyridine, the stirring reaction is carried out for 2-3 hours at the temperature of 40-45 ℃, and the liquid chromatography tracking analysis is carried out. After the reaction is finished, removing the solvent at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa, washing with a saturated sodium bicarbonate solution, extracting with toluene, and removing the toluene under negative pressure to obtain 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the product content of 95.0-97.0%;
the mol ratio of the 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline to the 2-bromoheptafluoropropane, sodium hydrosulfite, sodium carbonate and tetrabutylammonium hydrogen sulfate is 1:1.2: 0.6-1.4: 1.2:0.05, the using amount of solvent methyl tert-butyl ether is 5-8 times of the mass of the 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, the 2-bromoheptafluoropropane is added within 6 hours at the temperature of 20-25 ℃, the reaction is continued for 2 hours, and the liquid chromatography tracking analysis is carried out. After the reaction is finished, washing an organic phase to be neutral, and desolventizing at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the product content of 94.0-96.0%;
the mol ratio of the 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline to the bis (trichloromethyl) carbonate is 2.5-3: 1, the dosage of the solvent toluene is 5-8 times of the mass of the 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, the bis (trichloromethyl) carbonate is added at the temperature of 40-50 ℃, the reaction is carried out for 6 hours, and the liquid chromatography tracking analysis is carried out. And after the reaction is finished, washing with water to be neutral, and desolventizing at 60-65 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazoline-2 (1H) -ketone, wherein the product content is 95.0-97.0 percent, and the yield is 72.0-74.0 percent (calculated by 2-bromoheptafluoropropane).
Compared with other synthesis methods, the invention has the following advantages:
1) the benzyl chlorination reaction with more side reactions and low yield is carried out in the first step, the consumption of raw materials is reduced, the boiling point of the 2- (chloromethyl) aniline is lower and has larger difference with that of other impurities, and the dichloro by-product can be controlled at lower concentration by high vacuum rectification purification, so that the content of impurities in the subsequent reaction is reduced;
2) the 2-bromoheptafluoropropane with the highest raw material cost is reacted in the next step, so that the consumption of the 2-bromoheptafluoropropane is effectively reduced, and the raw material cost is reduced;
3) the product has high purity, and the content is 95.0-97.0% (liquid chromatography, external standard);
4) the total yield is high and is 72.0-74.0% (calculated by 2-bromoheptafluoropropane).
Detailed Description
The invention is further described in the following description and specific preferred embodiments, without thereby limiting the scope of protection of the invention.
Example 1
281.5g (4.5mol) of 80.0% hydrazine hydrate was charged into a 1000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel at constant pressure, and 107.1g (1.0mol) of 3-pyridinecarboxaldehyde was added dropwise at 45 ℃ over 30 minutes, and the reaction was continued for 2 hours. After the liquid chromatography tracking reaction is finished, removing hydrazine hydrate at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain oily 3- (hydrazinomethylene) pyridine for later use.
107.2g (1.0mol) of 2-methylaniline, 5.4g (5.0%) of azobisisobutyronitrile and 550g of dichloroethane were charged in a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and an aeration device, and 70.9g (1.0mol) of chlorine gas was passed through at 60 ℃ for 10 hours, followed by further reaction for 2 hours. After the liquid chromatography tracking reaction is finished, washing an organic phase by using a saturated sodium carbonate aqueous solution, desolventizing at 40-45 ℃ under the vacuum degree of-0.07 to-0.09 MPa to obtain a 2- (chloromethyl) aniline crude product, and rectifying and purifying at 60-65 ℃ under the vacuum degree of-0.098 to-0.10 MPa to obtain 139.4g of 2- (chloromethyl) aniline, wherein the content: 96.1% (liquid chromatography, external standard) for use.
The product of the above two steps and 850g of ethanol were charged into a 2000mL three-necked flask equipped with a mechanical stirrer, condenser, and thermometer, and the reaction was stirred at 40 ℃ for 2 hours. After the liquid chromatography tracking reaction is finished, removing the solvent at 40-45 ℃ and under the vacuum degree of-0.07-0.09 MPa, washing by using a saturated sodium bicarbonate solution, extracting by using toluene, and removing methylbenzene at 60-65 ℃ and under the vacuum degree of-0.07-0.09 MPa to obtain 215.9g of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, wherein the content: 95.4% (liquid chromatography, external standard), and a total yield of 91.0% (based on 2-methylaniline) in three steps.
113.1g (0.5mol) of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, 52.2g (0.3mol) of sodium dithionite, 63.6g (0.6mol) of sodium carbonate, 17.0g (0.05mol) of tetrabutylammonium hydrogensulfate and 570g of methyl tert-butyl ether were charged into a 2000mL four-necked flask equipped with mechanical stirring, condenser, thermometer and aeration device, and 124.5g (0.5mol) of 2-bromoheptafluoropropane was passed through for 6 hours at 20 ℃ and the reaction was continued for 2 hours. After the reaction is finished, washing an organic phase to be neutral, and desolventizing at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 150.8g of 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the content: 94.2% (liquid chromatography, external standard) with a yield of 81.2% (calculated on 2-bromoheptafluoropropane).
98.6g (0.25mol) of 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline, 29.7g (0.10mol) of bis (trichloromethyl) carbonate and 500g of toluene were charged into a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel at constant pressure, and reacted at 40 ℃ for 6 hours. After the reaction is finished, washing the organic phase to be neutral, and desolventizing at 60-65 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 100.1g of 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazoline-2 (1H) -ketone, wherein the content: 95.8% (liquid chromatography, external standard), a yield of 91.3% (calculated as 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline) and an overall yield of 74.1% (calculated as 2-bromoheptafluoropropane).
Example 2
313.0g (5.0mol) of 80.0% hydrazine hydrate was charged into a 1000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel at constant pressure, 107.1g (1mol) of 3-pyridinecarboxaldehyde was added dropwise at 45 ℃ over 30 minutes, and the reaction was continued for 2 hours. After the liquid chromatography tracking reaction is finished, removing hydrazine hydrate at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain oily 3- (hydrazinomethylene) pyridine for later use.
107.2g (1.0mol) of 2-methylaniline, 8.6g (8%) of azobisisobutyronitrile and 550g of dichloroethane were charged in a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and an aeration device, and 92.2g (1.3mol) of chlorine gas was added at 65 ℃ over 10 hours, followed by further reaction for 2 hours. After the liquid chromatography tracking reaction is finished, washing an organic phase by using a saturated sodium carbonate aqueous solution, desolventizing at 40-45 ℃ under the vacuum degree of-0.07 to-0.09 MPa to obtain a 2- (chloromethyl) aniline crude product, and rectifying at 60-65 ℃ under the vacuum degree of-0.098 to-0.10 MPa to obtain 140.1g of 2- (chloromethyl) aniline, wherein the content: 96.4% (liquid chromatography, external standard) for use.
The product of the above two steps and 850g of ethanol were charged into a 2000mL three-necked flask equipped with a mechanical stirrer, condenser, and thermometer, and stirred at 40 ℃ for 3 hours. After the liquid chromatography tracking reaction is finished, desolventizing at 40-45 ℃ and under the vacuum degree of-0.07-0.09 MPa to remove the solvent, washing by using a saturated sodium bicarbonate solution, extracting by using toluene, and removing the toluene at 60-65 ℃ and under the vacuum degree of-0.07-0.09 MPa to obtain 216.9g of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the content: 95.8% (liquid chromatography, external standard), and a total yield of 91.8% (based on 2-methylaniline) in three steps.
113.1g (0.5mol) of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, 87.1g (0.5mol) of sodium dithionite, 63.6g (0.6mol) of sodium carbonate, 17.0g (0.05mol) of tetrabutylammonium hydrogensulfate and 700g of methyl tert-butyl ether were charged into a 2000mL four-necked flask equipped with mechanical stirring, condenser, thermometer and aeration device, and 124.5g (0.5mol) of 2-bromoheptafluoropropane was passed through for 6 hours at 25 ℃ and the reaction was continued for 2 hours. After the reaction is finished, washing an organic phase to be neutral, and desolventizing at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 149.0g of 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the content: 94.1% (liquid chromatography, external standard) and a yield of 80.3% (based on 2-bromoheptafluoropropane).
98.6g (0.25mol) of 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline, 29.7g (0.10mol) of bis (trichloromethyl) carbonate and 620g of toluene were charged into a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel at constant pressure, and reacted at 45 ℃ for 6 hours. After the reaction is finished, washing the organic phase to be neutral, and desolventizing at 60-65 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 99.2g of 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazoline-2 (1H) -ketone, wherein the content: 96.6% (liquid chromatography, external standard), a yield of 91.2% (based on 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline) and an overall yield of 73.2% (based on 2-bromoheptafluoropropane).
Example 3
344.3g (5.5mol) of 80.0% hydrazine hydrate was charged into a 1000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel at constant pressure, 107.1g (1mol) of 3-pyridinecarboxaldehyde was added dropwise at 45 ℃ over 30 minutes, and the reaction was continued for 2 hours. After the liquid chromatography tracking reaction is finished, removing hydrazine hydrate at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain oily 3- (hydrazinomethylene) pyridine for later use.
107.2g (1.0mol) of 2-methylaniline, 5.4g (5%) of azobisisobutyronitrile and 550g of dichloroethane were charged in a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and an aeration device, and 106.4g (1.5mol) of chlorine gas was introduced at 60 ℃ for 10 hours, followed by further reaction for 2 hours. After the liquid chromatography tracking reaction is finished, washing an organic phase by using a saturated sodium carbonate aqueous solution, desolventizing at 40-45 ℃ under the vacuum degree of-0.07 to-0.09 MPa to obtain a 2- (chloromethyl) aniline crude product, and rectifying and purifying at 60-65 ℃ under the vacuum degree of-0.098 to-0.10 MPa to obtain 138.8g of 2- (chloromethyl) aniline, wherein the content: 96.6% (liquid chromatography, external standard) for use.
The product of the above two steps and 850g of ethanol were charged into a 2000mL three-necked flask equipped with a mechanical stirrer, condenser, and thermometer, and stirred at 40 ℃ for 2 hours. After the liquid chromatography tracking reaction is finished, removing the solvent at 40-45 ℃ under the vacuum degree of-0.07-0.09 MPa, washing with a saturated sodium bicarbonate solution, extracting with toluene, and removing the toluene at 60-65 ℃ under the vacuum degree of-0.07-0.09 MPa to obtain 214.3g of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the content: 96.7% (liquid chromatography, external standard), and a total yield of 91.6% (based on 2-methylaniline) in three steps.
113.1g (0.5mol) of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, 121.9g (0.7mol) of sodium dithionite, 63.6g (0.6mol) of sodium carbonate, 17.0g (0.05mol) of tetrabutylammonium hydrogensulfate and 900g of methyl tert-butyl ether were charged into a 2000mL four-necked flask equipped with mechanical stirring, condenser, thermometer and aeration device, and 124.5g (0.5mol) of 2-bromoheptafluoropropane was passed through for 6 hours at 20 ℃ and the reaction was continued for 2 hours. After the reaction is finished, washing an organic phase to be neutral, and desolventizing at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 150.9g of 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the content: 95.1% (liquid chromatography, external standard) and a yield of 80.5% (based on 2-bromoheptafluoropropane).
98.6g (0.25mol) of 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline, 29.7g (0.10mol) of bis (trichloromethyl) carbonate and 750g of toluene were charged into a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel at constant pressure, and reacted at 50 ℃ for 6 hours. After the reaction is finished, washing the organic phase to be neutral, and desolventizing at 60-65 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 101.0g of 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazoline-2 (1H) -ketone, wherein the content: 96.1% (liquid chromatography, external standard), a yield of 92.4% (based on 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline) and an overall yield of 74.4% (based on 2-bromoheptafluoropropane).
Example 4
281.5g (4.5mol) of 80.0% hydrazine hydrate was charged into a 1000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel at constant pressure, and 107.1g (1.0mol) of 3-pyridinecarboxaldehyde was added dropwise at 50 ℃ over 30 minutes, and the reaction was continued for 2 hours. After the liquid chromatography tracking reaction is finished, removing hydrazine hydrate at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain oily 3- (hydrazinomethylene) pyridine for later use.
107.2g (1.0mol) of 2-methylaniline, 8.6g (8%) of azobisisobutyronitrile and 850g of dichloroethane were charged in a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and an aeration device, and 70.9g (1.0mol) of chlorine gas was introduced at 65 ℃ for 10 hours, followed by further reaction for 2 hours. After the liquid chromatography tracking reaction is finished, washing an organic phase by using a saturated sodium carbonate aqueous solution, desolventizing at 40-45 ℃ under the vacuum degree of-0.07 to-0.09 MPa to obtain a 2- (chloromethyl) aniline crude product, and rectifying and purifying at 60-65 ℃ under the vacuum degree of-0.098 to-0.10 MPa to obtain 139.2g of 2- (chloromethyl) aniline, wherein the content: 95.7% (liquid chromatography, external standard) for use.
The product of the above two steps and 850g of ethanol were charged into a 2000mL three-necked flask equipped with a mechanical stirrer, condenser, and thermometer, and the reaction was stirred at 45 ℃ for 2 hours. After the liquid chromatography tracking reaction is finished, removing the solvent at 40-45 ℃ under the vacuum degree of-0.07 to-0.09 MPa, washing with a saturated sodium bicarbonate solution, extracting with toluene, and removing the toluene at 60-65 ℃ under the vacuum degree of-0.07 to-0.09 MPa to obtain 216.9g of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the content: 95.3% (liquid chromatography, external standard), and a total yield of 91.3% (based on 2-methylaniline) in three steps.
113.1g (0.5mol) of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, 52.2g (0.3mol) of sodium dithionite, 63.6g (0.6mol) of sodium carbonate, 10.2g (0.03mol) of tetrabutylammonium hydrogensulfate and 570g of methyl tert-butyl ether were charged into a 2000mL four-necked flask equipped with mechanical stirring, condenser, thermometer and aeration device, and 124.5g (0.5mol) of 2-bromoheptafluoropropane was passed through for 6 hours at 25 ℃ and the reaction was continued for 2 hours. After the reaction is finished, washing an organic phase to be neutral, and desolventizing at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 153.5g of 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the content: 95.3% (liquid chromatography, external standard) and a yield of 81.7% (based on 2-bromoheptafluoropropane).
98.6g (0.25mol) of 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline, 24.7g (0.083mol) of bis (trichloromethyl) carbonate and 500g of toluene were charged into a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel at constant pressure, and reacted at 40 ℃ for 6 hours. After the reaction is finished, washing the organic phase to be neutral, and desolventizing at 60-65 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 100.3g of 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazoline-2 (1H) -ketone, wherein the content: 96.2% (liquid chromatography, external standard), a yield of 91.8% (based on 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline) and an overall yield of 75.0% (based on 2-bromoheptafluoropropane).
Example 5
313.0g (5.0mol) of 80.0% hydrazine hydrate was charged into a 1000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel at constant pressure, 107.1g (1mol) of 3-pyridinecarboxaldehyde was added dropwise at 50 ℃ over 30 minutes, and the reaction was continued for 2 hours. After the liquid chromatography tracking reaction is finished, removing hydrazine hydrate at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain oily 3- (hydrazinomethylene) pyridine for later use.
107.2g (1.0mol) of 2-methylaniline, 5.4g (5%) of azobisisobutyronitrile and 850g of dichloroethane were charged in a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and an aeration device, and 92.2g (1.3mol) of chlorine gas was introduced at 60 ℃ for 10 hours, followed by further reaction for 2 hours. After the liquid chromatography tracking reaction is finished, washing an organic phase by using a saturated sodium carbonate aqueous solution, desolventizing at 40-45 ℃ under the vacuum degree of-0.07 to-0.09 MPa to obtain a 2- (chloromethyl) aniline crude product, and rectifying and purifying at 60-65 ℃ under the vacuum degree of-0.098 to-0.10 MPa to obtain 140.6g of 2- (chloromethyl) aniline, wherein the content: 96.8% (liquid chromatography, external standard) for use.
The product of the above two steps and 850g of ethanol were charged into a 2000mL three-necked flask equipped with a mechanical stirrer, condenser, and thermometer, and the reaction was stirred at 45 ℃ for 3 hours. After the liquid chromatography tracking reaction is finished, removing the solvent at 40-45 ℃ under the vacuum degree of-0.07-0.09 MPa, washing with a saturated sodium bicarbonate solution, extracting with toluene, and removing the toluene at 60-65 ℃ under the vacuum degree of-0.07-0.09 MPa to obtain 216.1g of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the content: 96.4% (liquid chromatography, external standard), and 92.1% (calculated on 2-methylaniline) of the total three-step yield.
113.1g (0.5mol) of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, 87.1g (0.5mol) of sodium dithionite, 63.6g (0.6mol) of sodium carbonate, 10.2g (0.03mol) of tetrabutylammonium hydrogensulfate and 700g of methyl tert-butyl ether were charged into a 2000mL four-necked flask equipped with mechanical stirring, condenser, thermometer and aeration device, and 124.5g (0.5mol) of 2-bromoheptafluoropropane was passed through for 6 hours at 20 ℃ and the reaction was continued for 2 hours. After the reaction is finished, washing an organic phase to be neutral, and desolventizing at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 151.6g of 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the content: 94.8% (liquid chromatography, external standard) and a yield of 81.1% (based on 2-bromoheptafluoropropane).
98.6g (0.25mol) of 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline, 24.7g (0.083mol) of bis (trichloromethyl) carbonate and 620g of toluene were charged into a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and an isobaric dropping funnel and reacted at 45 ℃ for 6 hours. After the reaction is finished, washing the organic phase to be neutral, and desolventizing at 60-65 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 100.7g of 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazoline-2 (1H) -ketone, wherein the content: 95.8% (liquid chromatography, external standard), a yield of 91.8% (calculated as 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline) and an overall yield of 74.5% (calculated as 2-bromoheptafluoropropane).
Example 6
344.3g (5.5mol) of 80.0% hydrazine hydrate was charged into a 1000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel at constant pressure, 107.1g (1mol) of 3-pyridinecarboxaldehyde was added dropwise at 50 ℃ over 30 minutes, and the reaction was continued for 2 hours. After the liquid chromatography tracking reaction is finished, removing hydrazine hydrate at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain oily 3- (hydrazinomethylene) pyridine for later use.
107.2g (1.0mol) of 2-methylaniline, 8.6g (8%) of azobisisobutyronitrile and 850g of dichloroethane were charged into a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and an aeration device, and 106.4g (1.5mol) of chlorine gas was added at 65 ℃ over 10 hours, followed by further reaction for 2 hours. After the liquid chromatography tracking reaction is finished, washing an organic phase by using a saturated sodium carbonate aqueous solution, desolventizing at 40-45 ℃ under the vacuum degree of-0.07 to-0.09 MPa to obtain a 2- (chloromethyl) aniline crude product, and rectifying at 60-65 ℃ under the vacuum degree of-0.098 to-0.10 MPa to obtain 140.5g of 2- (chloromethyl) aniline, wherein the content: 97.0% (liquid chromatography, external standard) for use.
The product of the above two steps and 850g of ethanol were charged into a 2000mL three-necked flask equipped with a mechanical stirrer, condenser, and thermometer, and stirred at 45 ℃ for 2 hours. After the liquid chromatography tracking reaction is finished, desolventizing at 40-45 ℃ and under the vacuum degree of-0.07-0.09 MPa to remove the solvent, washing with a saturated sodium bicarbonate solution, extracting with toluene, and removing the toluene at 40-45 ℃ and under the vacuum degree of-0.07-0.09 MPa to obtain 218.7g of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the content: 95.1% (liquid chromatography, external standard), and a total yield of 91.9% (based on 2-methylaniline) in three steps.
113.1g (0.5mol) of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, 121.9g (0.7mol) of sodium dithionite, 63.6g (0.6mol) of sodium carbonate, 10.2g (0.03mol) of tetrabutylammonium hydrogensulfate and 900g of methyl tert-butyl ether were charged into a 2000mL four-necked flask equipped with mechanical stirring, condenser, thermometer and aeration device, and 124.5g (0.5mol) of 2-bromoheptafluoropropane was passed through for 6 hours at 25 ℃ to continue the reaction for 2 hours. After the reaction is finished, washing the reaction product to be neutral, and desolventizing the reaction product at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 149.1g of 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the content: 94.4% (liquid chromatography, external standard) and a yield of 80.1% (based on 2-bromoheptafluoropropane).
98.6g (0.25mol) of 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline, 24.7g (0.083mol) of bis (trichloromethyl) carbonate and 750g of toluene were charged into a 2000mL four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel at constant pressure, and reacted at 50 ℃ for 6 hours. After the reaction is finished, washing with water to be neutral, and desolventizing at 60-65 ℃ and under the vacuum degree of-0.07-0.09 MPa to obtain 102.0g of 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazoline-2 (1H) -ketone, wherein the content is as follows: 95.1% (liquid chromatography, external standard), a yield of 92.3% (calculated as 4- (perfluoropropan-2-yl) -2- ((2- (pyridin-3-methylene) hydrazino) methyl) aniline) and an overall yield of 73.9% (calculated as 2-bromoheptafluoropropane).
The foregoing is considered as illustrative of the preferred embodiments of the invention and is not to be construed as limiting the invention in any way. Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Therefore, any simple modification, equivalent change and modification made to the above embodiments according to the technical spirit of the present invention should fall within the protection scope of the technical scheme of the present invention, unless the technical spirit of the present invention departs from the content of the technical scheme of the present invention.
Claims (6)
1. A preparation method of a pyridine quinazoline intermediate is characterized by comprising the following steps: 3- (hydrazinomethylene) pyridine is obtained by the reaction of 3-pyridine formaldehyde and hydrazine hydrate; carrying out benzyl chlorination reaction on o-toluidine and chlorine to obtain 2- (chloromethyl) aniline; performing N-alkylation reaction on 3- (hydrazinomethylene) pyridine and 2- (chloromethyl) aniline to obtain 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, performing benzene ring substitution reaction on the 2- (bromoheptafluoropropane to obtain 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline and 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, and finally performing cyclization reaction on the 4- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3 with bis (trichloromethyl) carbonate, 4-dihydroquinazolin-2 (1H) -one of the formula:
2. the preparation method of the pyridine quinazoline intermediate according to claim 1, characterized in that in the reaction of the 3-pyridinecarboxaldehyde and the hydrazine hydrate, the molar ratio of the 3-pyridinecarboxaldehyde to the hydrazine hydrate is 1: 4.5-5.5, the 3-pyridinecarboxaldehyde is dripped into the hydrazine hydrate within 30 minutes at 45-50 ℃, the reaction is continued to be stirred for 1-2 hours, and the liquid chromatography tracking analysis is performed; and removing hydrazine hydrate under negative pressure after the reaction is finished to obtain oily 3- (hydrazinomethylene) pyridine with the product content of 95.0-97.0%.
3. The preparation method of the pyridine quinazoline intermediate according to claim 1, characterized in that the 2-methylaniline is subjected to benzyl chlorination reaction under the initiation of free radicals, the free radical initiator is azobisisobutyronitrile, the dosage of the azodiisobutyronitrile is 5.0-8.0% of the mass of the 2-methylaniline, the molar ratio of the 2-methylaniline to chlorine gas is 1: 1.0-1.5, the dosage of dichloroethane as a solvent is 5-8 times of the mass of the 2-methylaniline, the chlorine gas is completely introduced within 10 hours at 60-65 ℃, the stirring is continued for 2 hours, and the liquid chromatography tracking analysis is performed; after the reaction is finished, washing an organic phase by using a saturated sodium carbonate aqueous solution, desolventizing at 40-45 ℃ under the vacuum degree of-0.07 to-0.09 MPa to obtain a 2- (chloromethyl) aniline crude product, and rectifying at 60-65 ℃ under the vacuum degree of-0.098 to-0.10 MPa to obtain the 2- (chloromethyl) aniline with the content of 95.0-97.0%.
4. The preparation method of the pyridine quinazoline intermediate according to claim 1, characterized in that in the N-alkylation reaction, the molar ratio of 3- (hydrazinomethylene) pyridine to 2- (chloromethyl) aniline is 1:1, the amount of solvent ethanol is 5-8 times of the mass of 3- (hydrazinomethylene) pyridine, the mixture is stirred for 2-3 hours at 40-45 ℃, and the mixture is subjected to liquid chromatography tracking analysis; after the reaction is finished, removing the solvent at 40-45 ℃ under the vacuum degree of-0.07 to-0.09 MPa, washing an organic phase by using a saturated sodium bicarbonate solution, and desolventizing and removing toluene at 40-45 ℃ under the vacuum degree of-0.07 to-0.09 MPa to obtain the 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the product content of 95.0-97.0%.
5. The preparation method of a pyridine quinazoline intermediate according to claim 1, characterized in that in the benzene ring substitution reaction, the molar ratio of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline to 2-bromoheptafluoropropane, sodium hydrosulfite, sodium carbonate and tetrabutylammonium hydrogen sulfate is 1:1.2: 0.6-1.4: 1.2:0.05, the amount of solvent methyl tert-butyl ether is 5-8 times of the mass of 2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, 2-bromoheptafluoropropane is added within 6 hours at 20-25 ℃, the reaction is continued for 2 hours, and the liquid chromatography tracking analysis is carried out; after the reaction is finished, washing the organic phase to be neutral, and desolventizing at 40-45 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain the 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline with the product content of 94.0-96.0%.
6. The preparation method of the pyridine quinazoline intermediate according to claim 1, characterized in that in the cyclization reaction, the molar ratio of 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline to bis (trichloromethyl) carbonate is 2.5-3: 1, the amount of solvent toluene is 5-8 times of the mass of 4- (perfluoropropane-2-yl) -2- ((2- (pyridine-3-methylene) hydrazino) methyl) aniline, bis (trichloromethyl) carbonate is added at 40-50 ℃, the reaction is carried out for 6 hours, and the liquid chromatography tracking analysis is carried out; after the reaction is finished, washing the organic phase to be neutral, and desolventizing at 60-65 ℃ and under the vacuum degree of-0.07 to-0.09 MPa to obtain 6- (perfluoropropane-2-yl) -3- ((pyridine-3-methylene) amino) -3, 4-dihydroquinazoline-2 (1H) -ketone, wherein the content of the product is 95.0-97.0%, and the total yield is 72.0-74.0% by taking 2-bromoheptafluoropropane as a raw material.
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