CN114591251B - Chiral aminoquinazoline compound, and preparation method and application thereof - Google Patents
Chiral aminoquinazoline compound, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a chiral aminoquinazoline compound, and a preparation method and application thereof. The structural formula of the chiral aminoquinazoline compound is shown as formula I or II. The invention uses o-aminobenzamide, substituted benzaldehyde and CuCl 2 Reacting the obtained product with a chloro reagent, and reacting with chiral amine and an acid binding agent to obtain a chiral aminoquinazoline compound crude product; and dissolving and purifying by a salifying solvent to obtain the chiral aminoquinazoline compound. The preparation method is simple, the obtained chiral aminoquinazoline compound is easy to separate from acid salt formation crystals, and chiral acid with high optical purity can be obtained by taking the chiral aminoquinazoline compound as a resolving agent and efficiently separating the chiral aminoquinazoline compound. And the resolving agent and the chiral acid remained after resolution can be recycled, thus realizing the purposes of energy conservation, emission reduction and consumption reduction.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a chiral aminoquinazoline compound, and a preparation method and application thereof.
Background
The chemical substance having optical activity has wide application in the fields of medicine, pesticide and the like. Among the enantiomers of pharmaceutical and agricultural chemical molecules, the different configuration isomers generally have different biological activities, and enantiomers with low efficiency or invalid or toxic side effects can lead to reduced efficacy, aggravated pollution and extremely high possibility of causing phytotoxicity or drug resistance. Therefore, it is of great importance to obtain optically active chiral compounds efficiently.
The products of common chemical syntheses are mostly inactive racemates from which the single enantiomer must be resolved. The existing resolution methods include biological enzyme resolution, chromatographic resolution, extraction resolution, chemical resolution and the like. The diastereomer salt crystallization method in the chemical resolution method is the most widely used resolution technology in the industry at present because the operation is simple and easy to amplify, so that a novel resolution reagent still needs to be continuously developed.
Disclosure of Invention
The primary aim of the invention is to overcome the defects and shortcomings of the prior art and provide a chiral aminoquinazoline compound.
The invention also aims to provide a preparation method of the chiral aminoquinazoline compound.
It is a further object of the present invention to provide the use of the chiral aminoquinazolines described above.
The aim of the invention is achieved by the following technical scheme: a chiral aminoquinazoline compound has a structural formula shown in formula I or II:
wherein R is-H, -NO 2 -Cl, -Br, -I, alkyl with carbon chain length of C1-C4, -OCH 3 or-OEt.
The chiral amine is as follows:
the preparation method of the chiral aminoquinazoline compound comprises the following steps:
(1) Anthranilamide, substituted benzaldehyde and CuCl 2 Adding the mixture into an alcohol solvent, heating the mixture for the first time at 70 to 120 ℃, and detecting that the reaction of the anthranilamide is finished by TLC; then adding water, continuously heating for the second time at 70-120 ℃, filtering, and collecting solids; drying the obtained solid to obtain 2-substituted phenylquinazolin-4 (3H) -one;
(2) Mixing the product obtained in the step (1) with a chloro reagent and a solvent, heating to 70-110 ℃ for reaction, detecting the completion of the conversion reaction by TLC, removing the solvent, adding ice water, filtering, and drying a filter cake to obtain 4-chloro-2-substituted phenylquinazoline;
(3) Adding chiral amine, an acid binding agent and an organic solvent A into the 4-chloro-2-substituted phenylquinazoline obtained in the step (2), heating to react at 60-100 ℃, detecting the completion of the conversion reaction by TLC, evaporating the solvent under reduced pressure, adding water and the organic solvent B, extracting and stirring, separating liquid, washing with saturated saline water, drying with anhydrous sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, heating and evaporating the residual chiral amine under reduced pressure to obtain a crude product of the 4-amino-2-substituted phenylquinazoline;
(4) Adding a salt forming solvent into the crude 4-amino-2-substituted phenyl quinazoline product obtained in the step (3), maintaining the temperature at 0-5 ℃ in an ice bath, dropwise adding inorganic acid until the pH value of the solution is=2-5, maintaining the temperature for 8-24 h, and filtering and separating to obtain inorganic acid salt; and after dissolving inorganic acid salt in water, adding alkaline solution to adjust the pH to 11-13, extracting by using an extraction solvent, taking an organic phase, and evaporating the solvent to obtain a purified chiral aminoquinazoline product.
The anthranilamide, substituted benzaldehyde and CuCl described in step (1) 2 Preferably, the mixture ratio is 1:1-1.2:1.5-2; more preferably, the molar ratio is 1:1-1.03:1.7-2.
The substituent of the substituted benzaldehyde in the step (1) is-H, -NO 2 -Cl, -Br, -I, alkyl with carbon chain length of C1-C4, -OCH 3 or-OEt.
The alcohol in the step (1) is at least one of ethanol, isopropanol, n-butanol and tert-butanol.
The amount of alcohol described in step (1) is preferably the amount of alcohol: anthranilamide=1500-2000 mL, 1mol ratio.
The temperature of the first heating in step (1) is preferably 80 to 90 ℃.
The time for the first heating in the step (1) is preferably 10 to 18 hours.
The developing agent used in the TLC detection in the step (1) is obtained by mixing ethyl acetate and petroleum ether according to a volume ratio of 1:1.
The amount of water used in step (1) is preferably as follows: anthranilamide=1200-1800 mL, 1mol ratio calculation; more preferably by water: anthranilamide=1400 to 1700ml:1mol ratio calculation.
The temperature of the second heating in step (1) is preferably 80 to 90 ℃.
The time of the second heating in the step (1) is preferably 0.5 to 1.5 hours; more preferably 1h.
The temperature of the drying in the step (1) is preferably 60-100 ℃; more preferably 90 ℃.
The chlorinating agent in the step (2) is at least one of thionyl chloride, phosphorus oxychloride and phosphorus pentachloride.
The amount of the chlorinating agent described in step (2) is preferably the amount of the chlorinating agent: the molar ratio of the 2-substituted phenyl quinazoline-4 (3H) -ketone is 1.5-4: 1 proportioning and calculating.
The solvent in the step (2) is at least one of chloroform and toluene.
The solvent used in step (2) is preferably used in an amount corresponding to 2-substituted phenylquinazolin-4 (3H) -one: solvent = 1mol: 400-1000 mL of the mixture ratio is calculated.
The alkaline solution in step (2) is preferably sodium hydroxide solution; more preferably, the concentration is 10 to 30% by mass of sodium hydroxide solution.
The temperature of the reaction in step (2) is preferably 70 to 80 ℃.
The reaction time in the step (2) is preferably 12 to 15 hours.
The developing agent used in the TLC detection in the step (2) is obtained by mixing methylene dichloride and petroleum ether according to the volume ratio of 1:1.
The means for removing the solvent described in step (2) is preferably evaporation.
The drying temperature in the step (2) is preferably 60-100 ℃; more preferably 80 ℃.
The acid-binding agent in step (3) is preferably K 2 CO 3 、Na 2 CO 3 At least one of triethylamine and pyridine.
The structural formula of the chiral amine in the step (3) is shown as follows:
the chiral amine in step (3) is preferably (S) -N ', N' -diethyl-1, 4-pentanediamine or (R) -N ', N' -diethyl-1, 4-pentanediamine.
The dosage of the reaction components in the step (3) is as follows: chiral amine: the mol ratio of the acid binding agent is 1:1-1.1: 1-2.
The organic solvent A in the step (3) is at least one of methanol, ethanol, isopropanol, n-butanol and acetonitrile.
The amount of the organic solvent A in the step (3) is as follows: 4-chloro-2-substituted phenylquinazoline = 1000-2500 mL:1mol ratio calculation.
The temperature of the reaction in step (3) is preferably 70 to 90 ℃; more preferably 80 ℃.
The reaction time in the step (3) is preferably 10 to 15 hours.
The developing agent used in the TLC detection in the step (3) is obtained by mixing ethyl acetate, petroleum ether and triethylamine according to a volume ratio of 20:30:1.
The organic solvent B in the step (3) is preferably at least one of dichloromethane, chloroform and ethyl acetate.
The amount of the organic solvent B in the step (3) is as follows: 4-amino-2-substituted phenylquinazoline=500 to 1500ml:1mol ratio calculation.
The water in the step (3) is used in an amount corresponding to the amount of the organic solvent B: water volume ratio=1:0.8-1.3; more preferably in organic solvent B: water volume ratio = 1:1 ratio calculation.
The specific flow of step (4) is preferably as follows: adding a salifying solvent to dissolve a chiral aminoquinazoline crude product, maintaining the temperature at 0-5 ℃ in an ice bath, dropwise adding inorganic acid until the pH value is=2-4, continuously maintaining the temperature for 5-15 h to obtain inorganic acid salt, filtering, repeatedly washing a filter cake with an alcohol solvent of ice, drying, dissolving with water, adding an alkaline solution to adjust the pH value to 11-13, adding an extraction solvent for extraction, washing an obtained organic phase with saturated saline water, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and obtaining the purified chiral aminoquinazoline.
The salifying solvent in the step (4) is at least one of methanol, ethanol, isopropanol, n-butanol and water.
The salt-forming solvent is preferably used in the step (4) in an amount of: crude 4-amino-2-substituted phenylquinazoline = 400-1000 mL:1mol ratio calculation.
The inorganic acid in the step (4) is at least one of hydrochloric acid, sulfuric acid and phosphoric acid.
The hydrochloric acid is preferably concentrated hydrochloric acid with the concentration of 36 mass percent.
The sulfuric acid is preferably concentrated sulfuric acid with the concentration of 98% by mass.
The phosphoric acid is preferably phosphoric acid with a concentration of 83% by mass.
The amount of water used in step (4) is such that the filter cake is completely dissolved, preferably by the extraction solvent: water volume ratio=1:0.8-1.3; more preferably as an extraction solvent: water volume ratio = 1:1 ratio calculation.
The extraction solvent in the step (4) is preferably at least one of dichloromethane, chloroform and ethyl acetate.
The amount of the extraction solvent in the step (4) is as follows: 4-amino-2-substituted phenylquinazoline = 400-1500 ml:1mol ratio.
The alkaline solution in the step (4) is NaOH, KOH and Na 2 CO 3 At least one of the solutions.
The concentration of the alkaline solution is preferably 10-30% by mass.
The application of the chiral aminoquinazoline compound in chiral acid resolution; preferably comprises the following steps: resolving chiral acid in an alcohol solvent by using the chiral aminoquinazoline to obtain diastereomeric salt formed by the chiral acid and the chiral aminoquinazoline, dissociating the chiral acid in an acidic aqueous solution, and extracting to obtain chiral acid with a single configuration; more preferably, the method comprises the following specific steps:
A. dissolving the chiral aminoquinazoline in alcohol or alcohol water solution, refluxing at 60-80 ℃, adding racemized chiral acid, refluxing for 1-3 h, cooling to room temperature, cooling to 0-5 ℃ in an ice bath, and keeping the cooling temperature for 10-30 h; filtering, reserving filtrate, and drying filter cake to obtain diastereomeric amine salt;
B. dissolving diastereomeric amine salt in water, adding inorganic acid to make chiral acid free, adding extraction solvent to make extraction and concentration so as to obtain the invented chiral acid with single configuration.
The application of the chiral aminoquinazoline compound in chiral acid resolution further comprises the following specific steps:
C. removing solvent from the filtrate, adding water, adjusting pH to 1-2, extracting with extraction solvent, heating the separated organic phase to optical rotation of 0, and removing solvent to obtain racemized chiral acid;
D. removing water from the water phase obtained after the extraction in the step B and the step C, dissolving the water phase by alcohol, dropwise adding inorganic acid until the pH value of the solution is=2-5, maintaining the temperature for 8-24 h, and filtering and separating to obtain inorganic acid salt; after inorganic acid salt is dissolved in water, alkaline solution is added to adjust the pH value to 11-13, extraction solvent extraction is carried out, organic phase is taken, anhydrous sodium sulfate is dried, filtration and filtrate concentration are carried out, and recovered purified chiral aminoquinazoline is obtained.
The alcohol is preferably isopropanol.
The alcohol water solution is preferably alcohol and water according to the volume ratio of 2-4: 1, mixing the obtained alcohol aqueous solution; more preferably alcohol and water in a volume ratio of 3:1, mixing the obtained alcohol aqueous solution.
The inorganic acid is hydrochloric acid preferably; more preferably hydrochloric acid with a concentration of 36.5% by mass.
The solvent is preferably methylene chloride.
The chiral aminoquinazoline is preferably S- (+) -chiral aminoquinazoline.
The chiral acid is preferably 2-chloropropionic acid.
The single configuration chiral acid is preferably (S) -2-chloropropionic acid.
Compared with the prior art, the invention has the following advantages and effects:
the chiral aminoquinazoline compound synthesized by the method has a simple synthesis route, is easy to separate from acid salt formation crystals, and can be used as a resolving agent to efficiently separate chiral acid with high optical purity. And the resolving agent and the chiral acid remained after resolution can be recycled, thus realizing the purposes of energy conservation, emission reduction and consumption reduction.
Drawings
FIG. 1 is a schematic representation of the synthetic route to chiral 4-amino-2-substituted phenylquinazoline derivatives.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto.
Example 1 preparation of chiral amines
600g S-mandelic acid is dissolved in 1800ml of ethanol, 600g of 2-amino-5-diethylaminopentane is added, the mixture is stirred and heated to room temperature, a large amount of solid is separated out, the solid is filtered by suction, the filtrate is left to be a white solid, and the white solid is dried at 75 ℃ to obtain 520g of S-mandelate. The mandelate was washed with 1200mL of water, neutralized to ph=11 with 15% (w/v) sodium hydroxide solution, extracted twice with 1000mL of dichloromethane with stirring, the filtrates were combined after separation, and dried over anhydrous Na 2 SO 4 Drying, filtering and spin-drying to obtain (S) -2-amino-5-diethylaminopentane (namely (S) -N ', N' -diethyl-1, 4-pentanediamine), and weighing 260g.
The filtrate obtained in the previous step is dried by spin-drying, 1200mL of water is added, the solution is neutralized to pH=11 by sodium hydroxide solution with the concentration of 15% (w/v), 1200mL of dichloromethane is stirred and extracted, and the organic phase is separated by anhydrous Na 2 Drying SO4, filtering, spin-drying to obtain 300g of (R) -2-amino-5-diethylaminopentane, adding 600g of R-mandelic acid dissolved in 1800mL of ethanol, stirring to release heat to room temperature, precipitating a large amount of solid, filtering, reserving filtrate to obtain white solid, dissolving the white solid with 1200mL of water, neutralizing with 15% sodium hydroxide to pH=11, stirring and extracting with 1000mL of dichloromethane twice, separating liquid, and combining filtrate anhydrous Na 2 Drying SO4, filtering and spin-drying to obtain (R) -2-amino-5-diethylaminopentane (i.e., (R) -N ', N' -diethyl)-1, 4-pentanediamine) 220g.
Example 2 preparation of (S) -4-amino-2-phenylquinazoline
(1) Synthesis of 2-phenylquinazolin-4 (3H) -one:
50.0g of anthranilamide, 40.0g of benzaldehyde and 85g of CuCl are taken 2 Adding 600mL of ethanol, stirring at 80 ℃ for reaction for 16H, adding 500mL of water after the completion of the reaction of the anthranilamide by TLC detection (the developing agent is obtained by mixing ethyl acetate and petroleum ether according to the volume ratio of 1:1), continuously heating and stirring for 1H, filtering, and drying a filter cake at 90 ℃ to obtain 67.2g of white solid, wherein the solid is 2-phenylquinazoline-4 (3H) -ketone, and the yield is 82.3%.
(2) Synthesis of 4-chloro-2-phenylquinazoline:
200mL of chloroform, 115.0g of SOCl was added to the solid obtained in step (1) 2 The reaction was carried out at 70℃for 12h, and the tail gas was taken up in 30% (w/w) NaOH solution. TLC detection (developing agent is obtained by mixing dichloromethane and petroleum ether according to the volume ratio of 1:1) is carried out, the solvent is distilled off after the conversion reaction is finished, ice water is added, stirring and filtering are carried out, the filter cake is dried at 80 ℃, 64.5g of light yellow solid 4-chloro-2-phenylquinazoline is obtained, and the yield is 88.6%.
(3) Synthesis of (S) -4-amino-2-phenylquinazoline:
adding 43.0g of (S) -N ', N' -diethyl-1, 4-pentanediamine, 64.5g of 4-chloro-2-phenylquinazoline and 35.0g of potassium carbonate into 500mL of isopropanol, refluxing for 13h at 80 ℃, detecting (the developing agent is obtained by mixing ethyl acetate, petroleum ether and triethylamine according to the volume ratio of 20:30:1) by TLC, removing solvent by decompression after the reaction, adding 200mL of water and 200mL of dichloromethane, stirring, extracting and separating liquid, drying the organic phase by anhydrous sodium sulfate, filtering, removing the solvent by decompression, heating and decompressing, removing residual chiral amine by decompression, and obtaining 80.3g of (S) -4-amino-2-phenylquinazoline crude product with the yield of 81.4 percent.
(4) Purification of (S) -4-amino-2-phenylquinazoline:
150mL of ethanol is used for dissolving the product obtained in the step (3), the ice bath is maintained at 0-5 ℃, hydrochloric acid is slowly added dropwise until the pH=2, the temperature is continuously maintained for 8 hours, hydrochloride precipitation is obtained, the filtering is carried out, a filter cake is washed by a small amount of ice ethanol, and 79.3g of hydrochloride wet product is obtained after drying at 70 ℃. 100mL of water was added to dissolve the hydrochloride, 30% (w/w) NaOH solution was added to adjust the pH to 13, 150mL of methylene chloride was added to extract, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure from the filtrate to obtain 56.0g of purified (S) -4-amino-2-phenylquinazoline in 69.7% yield.
The detection data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.54-8.47(m,2H),8.40-8.31(m,1H),7.92 (d,J＝8.0Hz,1H),7.78-7.74(m,2H),7.47(ddt,J＝8.2,5.4,2.4Hz,4H),4.75-4.61(m,1H),2.43–2.31(m,6H),1.79-1.70(m,1H),1.61(m,J＝13.3,7.5,4.7Hz,1H), 1.49(m,J＝10.3,6.7,2.4Hz,2H),1.31(d,J＝6.6Hz,3H),0.85(t,J＝7.1Hz, 6H).[α]2D1＝+59.2(c＝1，CH 2 Cl 2 )。
example 3 preparation of (S) -4-amino-2- (4-chlorophenyl) -quinazoline
(1) Synthesis of 2- (4-chlorophenyl) -quinazolin-4 (3H) -one:
45.0g of anthranilamide, 48.0g of 4-chlorobenzaldehyde and 80.0g of CuCl are taken respectively 2 After 500mL of isopropanol is added and stirred for 16H at 82 ℃, TLC detection (the developing agent is obtained by mixing ethyl acetate and petroleum ether according to the volume ratio of 1:1) is finished, 400mL of water is added and is continuously heated and stirred for 1H, filtration and filter cake drying at 90 ℃ are carried out, and 66.8g of pale yellow solid 2- (4-chlorophenyl) -quinazolin-4 (3H) -one is obtained, and the yield is 81.5%.
(2) Synthesis of 4-chloro-2- (4-chlorophenyl) -quinazoline:
adding 200mL of chloroform and 105g of SOCl into the solid obtained in the step (1) 2 The reaction was carried out at 80℃for 12h, the tail gas being taken up in 30% (w/w) NaOH solution. TLC detection (developing agent is obtained by mixing dichloromethane and petroleum ether according to the volume ratio of 1:1) is finished, solvent is evaporated, ice water is added for stirring, filtering is carried out, filter cake is dried at 80 ℃, and 60.6g of light yellow solid 4-chloro-2- (4-chlorophenyl) quinazoline is obtained, and the yield is 85.7%.
(3) Synthesis of (S) -4-amino-2- (4-chlorophenyl) -quinazoline:
taking 37.0g of (S) -N ', N' -diethyl-1, 4-pentanediamine, 63.0g of 4-chloro-2- (4-chlorophenyl) -quinazoline and 35.0g of potassium carbonate, adding into 500mL of ethanol, refluxing for 12h at 80 ℃, after TLC detection (the developing agent is obtained by mixing ethyl acetate, petroleum ether and triethylamine according to the volume ratio of 20:30:1), after the reaction is finished, evaporating solvent under reduced pressure, adding 200mL of water and 200mL of ethyl acetate, extracting and separating liquid, drying the organic phase by anhydrous sodium sulfate, filtering, evaporating solvent under reduced pressure from filtrate, heating and evaporating residual chiral amine under reduced pressure to obtain 73.3g of (S) -4-amino-2- (4-chlorophenyl) -quinazoline crude product, and the yield is 79.3%.
(4) Purification of (S) -4-amino-2- (4-chlorophenyl) -quinazoline:
150mL of isopropyl alcohol is dissolved, after the (S) -4-amino-2- (4-chlorphenyl) -quinazoline obtained in the step (3) is maintained at the temperature of 0-5 ℃, sulfuric acid is slowly added dropwise until the pH value is=2, the temperature is continuously maintained for 10 hours, sulfate precipitation is obtained, filtration is carried out, and a filter cake is washed by a small amount of icy isopropyl alcohol, so that 70.3g of wet sulfate product is obtained. 100mL of water was added to dissolve the sulfate, 20% (w/w) NaOH solution was added to adjust the pH to 13, 150mL of methylene chloride was added to extract, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure from the filtrate to obtain 50.1g of purified (S) -4-amino-2- (4-chlorophenyl) -quinazoline in a yield of 68.3%.
The detection data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.54(d,J＝7.6Hz,1H),8.49(dd,J＝8.8, 2.7Hz,3H),7.74(d,J＝4.0Hz,2H),7.54(d,J＝8.4Hz,2H),7.46(dq,J＝8.3,4.5Hz,1H),4.61(h,J＝6.9Hz,1H),3.24–2.87(m,6H),1.89–1.59(m,4H),1.32(d,J ＝6.5Hz,3H),1.03(dt,J＝14.8,7.1Hz,6H).[α]2D1＝+48.6(c＝1，CH 2 Cl 2 )。
example 4 preparation of (R) -4-amino-2- (4-methoxyphenyl) -quinazoline
(1) Synthesis of 2- (4-methoxyphenyl) -quinazolin-4 (3H) -one:
respectively weighing 50.0g of anthranilamide, 50.0g of 4-methoxybenzaldehyde and 100.0g of CuCl 2 Adding into 700mL of tertiary butanol, stirring for 15H at 90 ℃, after TLC detection (developing agent is obtained by mixing ethyl acetate and petroleum ether according to volume ratio of 1:1) is finished, adding 500mL of water, continuously heating and stirring for 1H, filtering, drying filter cake at 90 ℃ to obtain 73.1g of white solid 2- (4-methoxyphenyl) -quinazoline-4 (3H) -ketone,the yield thereof was found to be 78.8%.
(2) Synthesis of 4-chloro-2- (4-methoxyphenyl) -quinazoline:
240ml of toluene and 120.0g of SOCl were added to the 2- (4-methoxyphenyl) -quinazolin-4 (3H) -one obtained in step (1) 2 The reaction is carried out for 13h at 80 ℃, the tail gas is absorbed by 30% (w/w) NaOH alkali liquor, TLC detection (the developing agent is obtained by methylene dichloride and petroleum ether according to the volume ratio of 1:1) is carried out, the solvent is distilled off after the conversion reaction is completed, ice water is added, stirring and filtering are carried out, the filter cake is dried at 80 ℃, and 68.1g of light yellow solid 4-chloro-2- (4-methoxyphenyl) quinazoline is obtained, and the yield is 86.8%.
(3) Synthesis of (R) -4-amino-2- (4-methoxyphenyl) -quinazoline:
(R) -N ', N' -diethyl-1, 4-pentanediamine 40g, 4-chloro-2- (4-methoxyphenyl) -quinazoline 68.1g and potassium carbonate 35.0g are added into 500mL of acetonitrile, reflux is carried out for 14h at 80 ℃, after TLC detection (the developing agent is obtained by mixing ethyl acetate, petroleum ether and triethylamine according to the volume ratio of 20:30:1) solvent evaporation, 200mL of water and 200mL of dichloromethane are added for stirring, liquid separation, the organic phase is dried by anhydrous sodium sulfate, filtration and filtrate reduced pressure evaporation are carried out on the solvent, residual chiral amine is obtained by heating and reduced pressure evaporation, and the chiral (R) -4-amino-2- (4-methoxyphenyl) quinazoline crude product 80.4g is obtained, and the yield is 80.3%.
(4) Purification of (R) -4-amino-2- (4-methoxyphenyl) -quinazoline:
after (R) -4-amino-2- (4-methoxyphenyl) -quinazoline is dissolved in 90mL of ethanol, hydrochloric acid is slowly added dropwise to the solution until the pH value is=2 after the temperature is maintained at 0-5 ℃ in an ice bath, hydrochloride precipitation is obtained after the solution is continuously kept at the temperature and is left overnight, the solution is filtered, a filter cake is repeatedly washed with the ice ethanol for several times to obtain 78.3g of hydrochloride wet product, 80mL of water is dissolved, 20% (w/w) NaOH solution is added to adjust the pH value to 13, 90mL of ethyl acetate is added for extraction, an organic phase is washed with saturated saline solution, anhydrous sodium sulfate is dried, the solution is filtered, the solvent is distilled off from the filtrate under reduced pressure, and 53.2g of purified (R) -4-amino-2- (4-methoxyphenyl) -quinazoline is obtained, and the yield is 66.2%.
The detection data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.53–8.37(m,2H),8.37–8.27(m,1H),7.86 (d,J＝7.9Hz,1H),7.79–7.67(m,2H),7.42(ddd,J＝8.2,5.4,2.8Hz,1H),7.12–6.96(m,2H),4.66(hept,J＝6.7Hz,1H),3.83(s,3H),2.43–2.33(m,6H),1.81– 1.68(m,1H),1.68–1.54(m,1H),1.49(tdd,J＝13.5,7.8,3.8Hz,2H),1.31(d,J＝6.6Hz,3H),0.86(t,J＝7.1Hz,6H).[α]2D1＝-39.6(c＝1，CH 2 Cl 2 )。
example 5 preparation of (R) -4-amino-2- (3-methylphenyl) quinazoline
(1) Synthesis of 2- (3-methylphenyl) -quinazolin-4 (3H) -one:
55g of anthranilamide, 50.0g of 3-methylbenzaldehyde and 95g of CuCl are taken 2 Adding the mixture into 800mL of ethanol, stirring and refluxing for 18H at 80 ℃, after TLC detection (the developing agent is obtained by mixing ethyl acetate and petroleum ether according to the volume ratio of 1:1) is finished, adding 700mL of water, continuously heating and stirring for 1H, filtering, and drying a filter cake at 90 ℃ to obtain 79.3g of white solid, wherein the solid is 2- (3-methylphenyl) -quinazoline-4 (3H) -ketone, and the yield is 83.1%.
(2) Synthesis of 4-chloro-2- (3-methylphenyl) quinazoline:
the solid obtained in the step (1) was added with 250mL of chloroform, 160.0g of POCl 3 The reaction was carried out at 70℃for 15h, and the tail gas was taken up in 30% (w/w) NaOH solution. TLC detection (developing agent is obtained by mixing dichloromethane and petroleum ether according to the volume ratio of 1:1) is carried out, solvent is removed after the conversion reaction, ice water is added, stirring and filtering are carried out, filter cake is dried at 80 ℃, 74.4g of light yellow solid 4-chloro-2- (3-methylphenyl) quinazoline is obtained, and the yield is 86.9%.
(3) Synthesis of (R) -4-amino-2- (3-methylphenyl) quinazoline:
taking 52.0g of (R) -N ', N' -diethyl-1, 4-pentanediamine, 74.4g of 4-chloro-2- (3-methylphenyl) quinazoline and 41.0g of potassium carbonate, adding into 700mL of ethanol, refluxing for 15h at 80 ℃, after the TLC detection (the developing agent is obtained by mixing ethyl acetate, petroleum ether and triethylamine according to the volume ratio of 20:30:1), evaporating solvent under reduced pressure by an oil pump, adding 200mL of water and 200mL of dichloromethane, stirring, extracting and separating liquid, drying an organic phase by anhydrous sodium sulfate, filtering, evaporating solvent under reduced pressure by filtrate, heating and evaporating residual chiral amine under reduced pressure to obtain 81.8g of (R) -4-amino-2- (3-methylphenyl) quinazoline crude product, and the yield is 74.4%.
(4) Purification of (R) -4-amino-2- (3-methylphenyl) quinazoline:
150mL of ethanol is used for dissolving the product obtained in the step (3), the ice bath is maintained at the temperature of 0-5 ℃, hydrochloric acid is slowly added dropwise until the pH=2, the temperature is continuously maintained for 8 hours, hydrochloride precipitation is obtained, the filtering is carried out, a filter cake is washed by a small amount of ice ethanol, and 74.9g of hydrochloride wet product is obtained after drying at 70 ℃. The hydrochloride was dissolved in 100mL of water, the pH was adjusted to 13 with 30% (w/w) NaOH solution, 150mL of methylene chloride was added to extract, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure to give 56.4g of purified (R) -4-amino-2- (3-methylphenyl) quinazoline in a yield of 68.9%.
The detection data are as follows:
1 H NMR(500MHz,Chloroform-d)δ8.47–8.06(m,2H),7.98–7.83(m,1H), 7.77–7.58(m,2H),7.37(td,J＝7.8,4.2Hz,2H),7.26(d,J＝8.0Hz,1H),6.00(d,J＝7.5Hz,1H),4.67(hept,J＝6.6Hz,1H),2.57–2.40(m,9H),1.86–1.57(m,4H), 1.37(d,J＝6.5Hz,3H),0.99(t,J＝7.2Hz,6H).[α]2D1＝-43.1(c＝1，CH 2 Cl 2 )。
EXAMPLE 6 use of (S) -4-amino-2- (4-chlorophenyl) -quinazoline
(1) Formation of (S) -2-chloropropionic acid amine salt:
50.0g of (S) -4-amino-2- (4-chlorophenyl) -quinazoline was dissolved in 70mL of aqueous isopropanol (alcohol: water volume ratio=3:1), refluxed at 70 ℃ while 13.5g of racemic 2-chloropropionic acid was slowly added dropwise, the temperature was maintained for 1 hour, cooled to room temperature and kept at 0-5 ℃ in an ice bath, and after standing overnight, (S) -2-chloropropionic acid- (S) -4-amino-2- (4-chlorophenyl) -quinazoline salt appeared, filtered, the filtrate rich in R- (+) -2-chloropropionic acid was left, the filter cake was rinsed with a small amount of icy isopropanol, and the filter cake was dried at 22.3g, and the yield was 31.3% (the racemate was denominator).
(2) Preparation of (S) -2-chloropropionic acid:
dissolving diastereomer salt of the (S) -2-chloropropionic acid- (S) -4-amino-2- (4-chlorophenyl) quinazoline system obtained in the previous step in 25mL of water, adding concentrated hydrochloric acid with the mass fraction of 36.5% for 5mL, extracting with 50mL of dichloromethane four times, separating liquid, drying an organic phase with anhydrous sodium sulfate, filtering, and decompressing filtrateAfter evaporation of the solvent, 4.7g of (S) -2-chloropropionic acid was obtained in a yield of 95.4% (based on the non-corresponding salt). [ alpha ]]2D5＝-13.8(c＝1，CHCl 3 ) (S) - (-) 2 Chloropropionic acid [ alpha ]]2D5＝-15.1(c＝1，CHCl 3 )。
(3) Recovery of chiral acids
And (3) decompressing the filtrate rich in R- (+) -2-chloropropionic acid in the step (1) to remove the solvent, adding 30mL of water, adjusting the pH to 1-2 by hydrochloric acid, adding 60mL of dichloromethane to extract and separate liquid for multiple times, heating the organic phase to 110 ℃, enabling the optical rotation to be 0 after 20h, and distilling and recovering the solvent to obtain the racemized 2-chloropropionic acid. The high-temperature racemized 2-chloropropionic acid can be used for cyclic resolution.
(4) Recovery of resolving agent
After the water in the water phase in the steps (2) and (3) is distilled off under reduced pressure, 40mL of ethanol is added for dissolution, hydrochloric acid is added dropwise to the solution until the pH value is=2-4 at the temperature of 0-5 ℃ in an ice bath, the temperature is maintained overnight, hydrochloride (38.3 g of wet product) is obtained by filtration, 50mL of water is added for dissolution, 6g of sodium hydroxide and 50mL of dichloromethane are added for extraction, the organic phase is dried over anhydrous sodium sulfate and filtered, and the filtrate is distilled off under reduced pressure to obtain 27.5g of (S) -4-amino-2- (4-chlorophenyl) -quinazoline. The recovered (S) -4-amino-2- (4-chlorophenyl) quinazoline can be recycled.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1. A chiral aminoquinazoline compound, which is characterized in that: the structural formula of the chiral aminoquinazoline compound is shown as formula I or II:
wherein R is-NO 2 -Cl, -Br, -I, carbon chain length is C1-C4 alkyl or-OEt.
2. The method for preparing chiral aminoquinazoline compounds according to claim 1, which is characterized by comprising the following steps:
(1) Anthranilamide, substituted benzaldehyde and CuCl 2 Adding the mixture into an alcohol solvent, heating the mixture for the first time at 70 to 120 ℃, and detecting that the reaction of the anthranilamide is finished by TLC; then adding water, continuously heating for the second time at 70-120 ℃, filtering, and collecting solids; drying the obtained solid to obtain 2-substituted phenylquinazolin-4 (3H) -one;
(2) Mixing the product obtained in the step (1) with a chloro reagent and a solvent, heating to 70-110 ℃ for reaction, detecting the completion of the conversion reaction by TLC, removing the solvent, adding ice water, filtering, and drying a filter cake to obtain 4-chloro-2-substituted phenylquinazoline;
(3) Adding chiral amine, an acid binding agent and an organic solvent A into the 4-chloro-2-substituted phenylquinazoline obtained in the step (2), heating to react at 60-100 ℃, detecting the completion of the conversion reaction by TLC, evaporating the solvent under reduced pressure, adding water and the organic solvent B, extracting and stirring, separating liquid, washing with saturated saline water, drying with anhydrous sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, heating and evaporating the residual chiral amine under reduced pressure to obtain a crude product of the 4-amino-2-substituted phenylquinazoline;
(4) Adding a salt forming solvent into the crude 4-amino-2-substituted phenyl quinazoline product obtained in the step (3), maintaining the temperature at 0-5 ℃ in an ice bath, dropwise adding inorganic acid until the pH value of the solution is=2-5, maintaining the temperature for 8-24 h, and filtering and separating to obtain inorganic acid salt; dissolving inorganic acid salt in water, adding alkaline solution to adjust pH to 11-13, extracting with extraction solvent, taking organic phase, evaporating solvent to obtain purified chiral aminoquinazoline product;
the substituent of the substituted benzaldehyde in the step (1) is-NO 2 -Cl, -Br, -I, alkyl with carbon chain length C1-C4 or-OEt;
the structural formula of the chiral amine in the step (3) is shown as follows:
3. the method for preparing chiral aminoquinazoline compounds according to claim 2, wherein:
the specific flow of the step (4) is as follows: adding a salifying solvent to dissolve a chiral aminoquinazoline crude product, maintaining the temperature at 0-5 ℃ in an ice bath, dropwise adding inorganic acid until the pH value is=2-4, continuously maintaining the temperature for 8-24 hours to obtain inorganic acid salt, filtering, repeatedly washing a filter cake with an alcohol solvent of ice, drying, dissolving with water, adding an alkaline solution to adjust the pH value to 11-13, adding an extraction solvent for extraction, washing an obtained organic phase with saturated saline water, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and obtaining the purified chiral aminoquinazoline.
4. A process for the preparation of chiral aminoquinazolines according to claim 2 or 3, characterized in that:
the anthranilamide, substituted benzaldehyde and CuCl described in step (1) 2 The molar ratio is 1:1-1.2:1.5-2;
the amount of alcohol used in step (1) is as follows: anthranilamide=1500-2000 mL, 1mol ratio calculation;
the water used in the step (1) is as follows: anthranilamide=1200-1800 mL, 1mol ratio calculation;
the amount of the chlorinating agent in the step (2) is as follows: the molar ratio of the 2-substituted phenyl quinazoline-4 (3H) -ketone is 1.5-4: 1, proportioning and calculating;
the solvent used in step (2) was used in an amount of 2-substituted phenylquinazolin-4 (3H) -one: solvent = 1mol, 400-1000 mL proportioning calculation;
the dosage of the reaction components in the step (3) is calculated according to the weight ratio of 4-chloro-2-substituted phenyl quinazoline: chiral amine: the mol ratio of the acid binding agent is 1:1-1.1: 1-2, calculating;
the amount of the organic solvent A in the step (3) is as follows: 4-chloro-2-substituted phenylquinazoline = 1000-2500 mL:1mol ratio calculation;
the amount of the organic solvent B in the step (3) is as follows: 4-amino-2-substituted phenylquinazoline=500-1500 ml:1mol ratio calculation;
the water in the step (3) is used in an amount corresponding to the amount of the organic solvent B: water volume ratio=1:0.8-1.3;
the salt-forming solvent is used in the step (4) according to the amount of the salt-forming solvent: crude 4-amino-2-substituted phenylquinazoline = 400-1000 mL:1mol ratio calculation;
the amount of the extraction solvent in the step (4) is as follows: 4-amino-2-substituted phenylquinazoline = 400-1500 ml:1mol ratio.
5. A process for the preparation of chiral aminoquinazolines according to claim 2 or 3, characterized in that:
the alcohol in the step (1) is at least one of ethanol, isopropanol, n-butanol and tert-butanol;
the chlorinating agent in the step (2) is at least one of thionyl chloride, phosphorus oxychloride and phosphorus pentachloride;
the solvent in the step (2) is at least one of chloroform and toluene;
the acid binding agent in the step (3) is K 2 CO 3 、Na 2 CO 3 At least one of triethylamine and pyridine;
the organic solvent A in the step (3) is at least one of methanol, ethanol, isopropanol, n-butanol and acetonitrile;
the organic solvent B in the step (3) is at least one of dichloromethane, chloroform and ethyl acetate;
the salifying solvent in the step (4) is at least one of methanol, ethanol, isopropanol, n-butanol and water;
the inorganic acid in the step (4) is at least one of hydrochloric acid, sulfuric acid and phosphoric acid;
the extraction solvent in the step (4) is at least one of dichloromethane, chloroform and ethyl acetate;
the alkaline solution in the step (4) is NaOH, KOH and Na 2 CO 3 At least one of the solutions.
6. A process for the preparation of chiral aminoquinazolines according to claim 2 or 3, characterized in that:
the temperature of the first heating in the step (1) is 80-90 ℃;
the time of the first heating in the step (1) is 10-18 hours;
the temperature of the second heating in the step (1) is 80-90 ℃;
the second heating time in the step (1) is 0.5-1.5 h;
the temperature of the drying in the step (1) is 60-100 ℃;
the temperature of the reaction in the step (2) is 70-80 ℃;
the reaction time in the step (2) is 12-15 h;
the temperature of the reaction in the step (3) is 70-90 ℃;
the reaction time in the step (3) is 10-15 h.
7. A process for the preparation of chiral aminoquinazolines according to claim 2 or 3, characterized in that:
the developing agent used in the TLC detection in the step (1) is obtained by mixing ethyl acetate and petroleum ether according to the volume ratio of 1:1;
the developing agent used in the TLC detection in the step (2) is obtained by mixing dichloromethane and petroleum ether according to the volume ratio of 1:1;
the developing agent used in the TLC detection in the step (3) is obtained by mixing ethyl acetate, petroleum ether and triethylamine according to the volume ratio of 20:30:1.
8. The use of a chiral aminoquinazoline compound of claim 1 in chiral acid resolution.
9. The use of chiral aminoquinazolines according to claim 8 in chiral acid resolution, characterized in that it comprises the steps of: resolving chiral acid in an alcohol solvent by using the chiral aminoquinazoline of claim 8 to obtain diastereomeric salt formed by the chiral acid and the chiral aminoquinazoline, dissociating the chiral acid in an acidic aqueous solution, and extracting to obtain the chiral acid with single configuration.
10. The application of chiral aminoquinazoline compounds in chiral acid resolution according to claim 9, which is characterized by comprising the following specific steps:
A. dissolving the chiral aminoquinazoline in alcohol or alcohol water solution, refluxing at 60-80 ℃, adding racemized chiral acid, refluxing for 1-3 h, cooling to room temperature, cooling to 0-5 ℃ in an ice bath, and keeping the cooling temperature for 10-30 h; filtering, reserving filtrate, and drying filter cake to obtain diastereomeric amine salt;
B. dissolving diastereomeric amine salt in water, adding inorganic acid to make chiral acid free, adding extraction solvent to make extraction and concentration so as to obtain the invented chiral acid with single configuration.
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