CN118084807A - Refining method of 3, 4-dihydro quinazoline compound - Google Patents

Refining method of 3, 4-dihydro quinazoline compound Download PDF

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Publication number
CN118084807A
CN118084807A CN202211498728.2A CN202211498728A CN118084807A CN 118084807 A CN118084807 A CN 118084807A CN 202211498728 A CN202211498728 A CN 202211498728A CN 118084807 A CN118084807 A CN 118084807A
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solvent
compound
refining
process according
ester
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Inventor
张二龙
郑军
候方园
葛李薇
武华周
廖娟
周旭
李莹
吴晶
柴雨柱
徐丹
朱春霞
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C267/00—Carbodiimides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/58—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a refining method of 3, 4-dihydro quinazoline compounds. The preparation method is simple and convenient to operate, can reduce the content of the impurity A to below 0.03%, has higher yield, and is suitable for industrial production.

Description

Refining method of 3, 4-dihydro quinazoline compound
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a refining method of a 3, 4-dihydro quinazoline compound.
Background
Compound VI is a cytomegalovirus inhibitor developed and developed by Ai Kuli s and the american moesaton pharmaceutical company, inhibiting viral replication by specifically targeting the viral-termination enzyme complex. The chemical name of the compound is (4S) - { 8-fluoro-2- [4- (3-methoxyphenyl) piperazin-1-yl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-quinazolin-4-yl } acetic acid, and the chemical structural formula is as follows:
Methods for synthesizing compound VI have been reported in various documents, such as patent CN101213180B, CN101863843B and CN104144678a.
The route disclosed in patent CN101213180B is as follows:
In this synthetic route, very difficult impurities to remove are produced. In the synthetic route, the chiral resolution of the compound VI is performed by ethyl acetate to remove impurities, but the residual amount of the impurities is still large by the method, so that development of a preparation method capable of removing the impurities is urgent.
Disclosure of Invention
In one aspect, the present invention provides a process for refining compound VI comprising: mixing the compound VI with a refining solvent, and performing crystallization, wherein the compound VI has the following structure
In some embodiments, the refining solvent of the refining step is selected from a mixed solvent of a C1-C6 ester solvent and an organic solvent A, wherein the organic solvent A is selected from a C2-C10 hydrocarbon solvent, a C2-C10 ether solvent, or a C3-C10 ketone solvent.
In some typical embodiments, the C1-C6 ester solvent is selected from methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, or isopropyl propionate. In some more typical embodiments, the C1-C6 ester solvent is methyl propionate.
In some typical embodiments, the organic solvent a is selected from methyl tertiary butyl ether, isopropyl ether, cyclohexanone, toluene, xylene, n-hexane, cyclohexane, n-heptane, isoheptane, n-octane, or isooctane. In some more typical embodiments, the organic solvent a is n-heptane.
In some typical embodiments, the solvent of the refining step is a mixed solvent of methyl propionate and n-heptane.
In some embodiments, the volume ratio of the C1-C6 ester solvent to the organic solvent A in the mixed solvent is 1.0:0-1.0:0.5.
In some typical embodiments, the volume ratio of the C1-C6 ester solvent to the organic solvent A in the mixed solvent is 1.0:0 to 1.0:0.4.
In some more typical embodiments, the volume ratio of the C1-C6 ester solvent to the organic solvent A in the mixed solvent is 1.0:0.4.
In some embodiments, the mass to volume ratio of compound VI to C1-C6 ester solvent is from 0.1 to 0.5.
In some typical embodiments, the volume to mass ratio of compound VI to the C1-C6 ester solvent is 0.4.
In some embodiments, the refining step is specifically:
(1) Adding the compound VI into a C1-C6 ester solvent, and heating to dissolve;
(2) Adding an organic solvent A, wherein the organic solvent A is selected from a C2-C10 hydrocarbon solvent, a C2-C10 ether solvent or a C3-C10 ketone solvent;
(3) Cooling, stirring and crystallizing.
In some typical embodiments, the C1-C6 ester solvent is selected from methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, or isopropyl propionate.
In some more typical embodiments, the C1-C6 ester solvent is methyl propionate.
In some typical embodiments, the organic solvent a is selected from methyl tertiary butyl ether, isopropyl ether, cyclohexanone, toluene, xylene, n-hexane, cyclohexane, n-heptane, isoheptane, n-octane, or isooctane. In some more typical embodiments, the organic solvent a is n-heptane.
In some typical embodiments, the temperature of the warmed solution of step (1) is 40 to 80 ℃, preferably 55 to 65 ℃.
In some typical embodiments, after the step (1) is warmed to dissolve, the reaction is stirred for 0.1 to 1h, preferably 0.5h.
In some typical embodiments, the organic solvent a of step (2) may be added dropwise.
In some typical embodiments, the temperature of the step (3) is reduced to a temperature of 0 to 25 ℃, preferably 10 to 20 ℃.
In some typical embodiments, the step (3) is stirred crystallization for 1 to 2 hours, preferably 1.5 hours.
Further, the preparation method of the compound VI comprises the following specific steps:
1) Reacting a compound V under the action of a C1-C6 ester solvent and (R, R) -N, N' -bis (trifluoromethanesulfonyl) -1, 2-diphenylethylenediamine;
2) D- (+) -di-p-methylbenzoyl tartaric acid is added into the reaction solution of the 1) to react to obtain a compound VI.
In some embodiments, the C1-C6 ester solvent is selected from methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, or isopropyl propionate, preferably the C1-C6 ester solvent is methyl propionate.
In some embodiments, the molar ratio of D- (+) -di-p-methylbenzoyl tartaric acid to compound V is 0.8 to 1.2, preferably 1.1.
In some typical embodiments, the mass to volume ratio of the compound V to the C1-C6 ester solvent is from 0.3 to 0.7, preferably 0.5.
In some typical embodiments, the molar ratio of (R, R) -N, N' -bis (trifluoromethanesulfonyl) -1, 2-diphenylethylenediamine to compound V is from 0.01:1 to 0.03:1, preferably 0.02:1.
Further, the preparation method of the compound V comprises the following specific steps:
In an organic solvent, the compound III reacts with phosphoryl chloride, phosphorus trichloride or phosphorus pentachloride in the presence of alkali I, a solution containing a compound IV is obtained after post treatment, and water, 1- (3-methoxyphenyl) piperazine or salt thereof and alkali II are added into the solution to react to obtain a compound V.
In some typical embodiments, the compound III is reacted with phosphorus pentachloride in the presence of a base in an organic solvent.
In some typical embodiments, the organic solvent is selected from xylenes or toluene, preferably toluene.
In some typical embodiments, the base I is pyridine or 2-picoline, preferably 2-picoline.
In some typical embodiments, the base II is DIPEA or triethylamine, preferably triethylamine.
In some typical embodiments, the molar ratio of base I to compound III is from 2:1 to 3:1, preferably 2.5:1.
In some typical embodiments, the mass to volume ratio of compound III to organic solvent is from 0.3 to 0.6, preferably 0.45g/ml.
In some typical embodiments, the molar ratio of phosphorus pentachloride to compound III is from 0.9:1 to 1.1:1, preferably 1.0:1.
In some typical embodiments, the molar ratio of base II to compound III is from 3:1 to 4:1, preferably 3.5:1.
In some typical embodiments, the mass to volume ratio of compound III to water is from 0.125 to 0.25, preferably 0.17.
In some typical embodiments, the molar ratio of 1- (3-methoxyphenyl) piperazine to compound III is 0.8:1 to 1.2:1, preferably 1:1.
Further, the preparation method of the compound III comprises the following specific steps:
the compound II reacts with 2-methoxy-5-trifluoromethyl aniline in an organic solvent in the presence of alkali.
In some typical embodiments, the organic solvent is selected from ethyl acetate or isopropyl acetate, preferably isopropyl acetate.
In some typical embodiments, the organic base is selected from imidazole or DMAP, preferably DMAP.
In some typical embodiments, the molar ratio of organic base to compound II is from 0.01:1 to 0.03:1, preferably 0.02:1.
In some typical embodiments, the mass to volume ratio of compound II to organic solvent is from 0.1 to 0.5, preferably 0.3.
Further, the preparation method of the compound VI provided by the invention comprises the following steps:
1) The compound II reacts with 2-methoxy-5-trifluoromethyl aniline under the action of DMAP by taking isopropyl acetate as a solvent to obtain a compound III;
2) The compound III reacts with toluene as a solvent under the action of 2-methylpyridine and phosphorus pentachloride, and a solution of the compound IV is obtained after post treatment; 1- (3-methoxyphenyl) piperazine or hydrochloride, water and 2-methylpyridine are added into the solution to react to obtain the compound V.
4) Reacting a compound V under the action of a C1-C6 ester solvent and (R, R) -N, N' -bis (trifluoromethanesulfonyl) -1, 2-diphenylethylenediamine;
5) D- (+) -di-p-methylbenzoyl tartaric acid is added into the reaction solution of the 4) to react to obtain a compound VI.
Further, the preparation method of the compound VI provided by the invention comprises the following steps:
1) 2-bromo-6-fluoroaniline reacts with ethyl acrylate in the presence of a palladium catalyst, a phosphine ligand and alkali in an organic solvent, and then is treated to obtain a solution containing a compound I; adding phenyl chloroformate, water and disodium hydrogen phosphate into the solution, and reacting to obtain a compound II;
2) The compound II reacts with 2-methoxy-5-trifluoromethyl aniline under the action of DMAP by taking isopropyl acetate as a solvent to obtain a compound III;
3) The compound III is reacted under the action of 2-methylpyridine and phosphorus pentachloride by taking toluene as a solvent to obtain a compound IV;
4) The compound IV and 1- (3-methoxyphenyl) piperazine dihydrochloride react under the action of toluene, water and 2-methylpyridine to obtain a compound V.
5) Reacting a compound V under the action of a C1-C6 ester solvent and (R, R) -N, N' -bis (trifluoromethanesulfonyl) -1, 2-diphenylethylenediamine;
6) Adding D- (+) -di-p-methylbenzoyl tartaric acid into the reaction solution of the 5) to react to obtain a compound VI.
In another aspect, the present invention provides a compound II,
In another aspect, the present invention provides a compound III,
In another aspect, the present invention provides a compound IV,
In another aspect, the present invention provides a compound V,
The invention has the following beneficial effects through the preparation process: the preparation method of the compound VI is simple and convenient to operate, is suitable for industrial use, and can reduce the content of the impurity A to below 0.03 percent.
Correlation definition:
in the invention, "D-DTTA" is D- (+) -di-p-methylbenzoyl tartaric acid;
In the present invention, "DIPEA" is N, N-diisopropylethylamine;
In the present invention, "DMAP" is 4-dimethylaminopyridine;
in the present invention, "DMF" is;
In the present invention, "h" means hour, "min" means minute, "ml" means milliliter.
Detailed Description
For a better understanding of the invention, the invention is further described below in connection with specific examples.
The reagents and raw materials used in the invention are all commercially available products.
Example 1
DMF (21 g), 2-bromo-6-fluoroaniline (7 g), ethyl acrylate (7.4 g) and DIPEA (5.7 g) were added to a 100mL reaction flask, and tris (o-methylphenyl) phosphine (0.7 g) and palladium acetate (0.07 g) were added in this order, followed by nitrogen substitution. Heating to 85-95 deg.c and reaction for 2-3 hr.
The temperature is reduced to 20-30 ℃ and filtered. Isopropyl acetate (60 g) and purified water (35 g) were added, extracted, and the organic phase was collected. The organic phase was washed 3 times with purified water (30 g), the aqueous phase was separated, purified water (23 g) and disodium hydrogen phosphate (19.8 g) were added to the organic phase containing Compound I, phenyl chloroformate (7.2 g) was added, and the temperature was controlled at 35℃to 45℃and reacted for 4 hours.
Standing for separating liquid, and collecting organic phase. N-heptane (67 g) was added to the obtained organic phase, the temperature was controlled at 20℃to 30℃and stirred for crystallization for 1h. And (5) carrying out suction filtration and drying to obtain a solid, namely 9.7g of the compound II.
Example 2
Isopropyl acetate (30 ml), compound II (9 g), 2-methoxy-5-trifluoromethylaniline (6.0 g) and DMAP (0.07 g) were added to a 50ml reaction flask. Controlling the temperature to be 70-80 ℃ for reaction for 4h.
Cooling to 10-20 deg.c, stirring and crystallizing. And (5) carrying out suction filtration and drying. And (3) collecting the materials to obtain 11.2g of solid compound III.
Example 3
Toluene (25 ml), compound III (11.2 g) and 2-methylpyridine (6.1 g) were added to a 100ml reaction flask. . Phosphorus pentachloride (5.5 g) was added. After the addition, controlling the temperature to be between 35 and 45 ℃ for reaction for 4 hours.
And (3) dropwise adding a potassium hydroxide aqueous solution into the reaction solution, quenching, and regulating the pH value to 6-8. Stirring, standing, separating liquid and collecting an organic phase;
The organic phase was washed with aqueous citric acid (10 ml) and purified water (20 ml) in this order, and the organic phase was collected. The organic phase obtained is toluene solution of compound IV. Purified water (65.9 g) was added to the solution. 1- (3-methoxyphenyl) piperazine (5.1 g) and triethylamine (9.3 g) were added in this order. Controlling the temperature to be 20-30 ℃ for reaction for 1h.
Controlling the temperature to be 20-30 ℃, separating the water phase, and collecting the organic phase; washing the organic phase with aqueous citric acid solution and purified water (20 ml) at 20-30 ℃ to obtain an aqueous phase, and collecting the organic phase; the organic phase was concentrated to dryness. Methyl tertiary butyl ether (67 ml, temperature controlled to 0-10 ℃, stirring and pulping for 1h, suction filtration, drying and material collection) is added to obtain a solid, namely the compound V12.7g.
Example 4
Methyl propionate (147 ml) was added to a glass reaction vessel, and compound V (14.7 g) and (R, R) -N, N' -bis (trifluoromethanesulfonyl) -1, 2-diphenylethylenediamine (0.23 g) were added with stirring. Controlling the temperature to be 70-80 ℃ for reaction for 30h.
The temperature of the reaction solution is controlled to be 20-30 ℃, and D- (+) -di-p-methylbenzoyl tartaric acid (10.4 g) is added under stirring. Controlling the temperature to be between 0 and 10 ℃, and stirring and crystallizing for 1 hour. Suction filtration and drying are carried out to obtain 19.1g of compound VI.
Example 5
Methyl propionate, n-heptane and compound VI (1 g) prepared in example 4 were added to a glass reaction flask. Controlling the temperature to be 55-65 ℃ and stirring for 0.5h. Cooling to 10-20 deg.c, stirring and crystallizing for 16 hr. And (5) centrifuging and spin-drying. And heating the obtained filter cake to 40-50 ℃, and vacuum drying until the drying weight loss is less than or equal to 3.0%.
The inventors adjusted the volume ratio of methyl propionate to n-heptane, the results are shown in table 1,
Examples 6-9 process scale-up was performed based on the results of table 1.
Example 6
Methyl propionate (865 g), n-heptane (265 g) and compound VI (189 g) prepared as described in example 4 were added to a glass reactor. Controlling the temperature to be 55-65 ℃ and stirring for 0.5h. Cooling to 10-20 deg.c, stirring and crystallizing for 1 hr. And (5) centrifuging and spin-drying. The obtained filter cake is heated to 40-50 ℃ and dried in vacuum until the drying weight loss is less than or equal to 2.0%, and the yield is 80%. Impurity a was not detected.
Example 7
Methyl propionate (804 g), n-heptane (321.3 g) and compound VI (176 g) prepared as in example 4 were added to a glass reactor. Controlling the temperature to be 55-65 ℃ and stirring for 0.5h. Cooling to 10-20 deg.c, stirring and crystallizing for 1.5 hr. And (5) centrifuging and spin-drying. The obtained filter cake is heated to 40-50 ℃ and dried in vacuum until the drying weight loss is less than or equal to 2.0%, and the yield is 84%. The impurity A was 0.01%.
Example 8
Methyl propionate (797 g), n-heptane (318 g) and compound VI (174 g) prepared as described in example 4 were added to a glass reaction flask. Controlling the temperature to be 55-65 ℃ and stirring for 0.5h. Cooling to 10-20 deg.c, stirring and crystallizing for 1.5 hr. And (5) centrifuging and spin-drying. The obtained filter cake is heated to 40-50 ℃ and dried in vacuum until the drying weight loss is less than or equal to 2.0%, and the yield is 86%. Impurity A was 0.02%.
Example 9
Methyl propionate (775 g), n-heptane (318 g) and compound VI (169 g) prepared as in example 4 were charged to a glass reactor. Controlling the temperature to be 55-65 ℃ and stirring for 0.5h. Cooling to 10-20 deg.c, stirring and crystallizing for 1.5 hr. And (5) centrifuging and spin-drying. The obtained filter cake is heated to 40-50 ℃ and dried in vacuum until the drying weight loss is less than or equal to 2.0%, and the yield is 82%. Impurity A was 0.02%.
Example 10 method for detecting impurity A content
The structure of impurity a is as follows:
Preparation of impurity A:
9.99g of compound V and 50ml of toluene are weighed into a reaction bottle, 0.3g of (S, S) -N, N' -bis (trifluoromethanesulfonyl) -1, 2-diphenylethylenediamine is added, the temperature is raised to 60-70 ℃ for reaction for 13 hours, and the mixture is concentrated to dryness after the reaction is finished. Column chromatography gave 9.22g of impurity A.
1.15G of impurity A and 10ml of ethyl acetate were added to the reaction flask and stirred, and sodium hydrogencarbonate solution (0.50 g of sodium hydrogencarbonate and 5ml of water) was added thereto and stirred at 20℃to 30℃for 1 hour. The filter cake was washed with 10ml of water. The layers were allowed to stand and the organic phase was washed with 10ml of water. The organic layer was concentrated, the concentrated oily substance was dissolved with 10ml of acetone, a lithium hydroxide solution (0.45 g of LiOH and 10ml of water) was added to the reaction system, and the reaction was stirred at 30 ℃. After the completion of the reaction, 70ml of water was added, and the pH was adjusted to 4 to5 with a 1N hydrochloric acid solution (solid precipitation). And (5) suction filtration and forced air drying. The dried sample was dissolved in 30ml of dichloromethane, filtered, concentrated, and n-heptane was added to pulp the obtained solid, which was air-dried to obtain 0.70g of impurity A.
Method for detecting content of impurity A
Chromatographic conditions:
The elution mode is isocratic elution.

Claims (10)

1. A process for refining compound VI comprising: mixing the compound VI with a refining solvent, and performing crystallization, wherein the compound VI has the following structure
2. The refining process according to claim 1, wherein the refining solvent is selected from a mixed solvent of a C1-C6 ester solvent and an organic solvent A selected from a C2-C10 hydrocarbon solvent, a C2-C10 ether solvent or a C3-C10 ketone solvent.
3. The refining process according to claim 2, wherein the C1-C6 ester solvent is selected from methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate or isopropyl propionate; preferably, the C1-C6 ester solvent is methyl propionate.
4. The refining process according to claim 2, wherein the organic solvent a is selected from methyl tert-butyl ether, isopropyl ether, cyclohexanone, toluene, xylene, n-hexane, cyclohexane, n-heptane, isoheptane, n-octane or isooctane; preferably, the organic solvent a is n-heptane.
5. The refining process according to claim 2, wherein the volume ratio of the C1-C6 ester solvent to the organic solvent A in the mixed solvent is 1.0:0-1.0:0.5; preferably, the volume ratio of the C1-C6 ester solvent to the organic solvent A in the mixed solvent is 1.0:0-1.0:0.4; more preferably, the volume ratio of the C1-C6 ester solvent to the organic solvent A in the mixed solvent is 1.0:0.4.
6. The refining process according to claim 2, wherein the mass-volume ratio of the compound VI to the C1-C6 ester solvent is 0.1-0.5.
7. The refining process according to claim 2, wherein the volume to mass ratio of the compound VI to the C1-C6 ester solvent is 0.4.
8. The refining process according to claim 1, further comprising a preparation method of the compound VI, comprising the following specific steps:
1) Reacting a compound V under the action of a C1-C6 ester solvent and (R, R) -N, N' -bis (trifluoromethanesulfonyl) -1, 2-diphenylethylenediamine;
2) D- (+) -di-p-methylbenzoyl tartaric acid is added into the reaction solution of the 1) to react to obtain a compound VI.
9. A process for the preparation of compound VI comprising:
10. compounds of formula (I)
CN202211498728.2A 2022-11-28 2022-11-28 Refining method of 3, 4-dihydro quinazoline compound Pending CN118084807A (en)

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