CN112480124A - Trifluoromethyl substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-diketone and preparation method thereof - Google Patents
Trifluoromethyl substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-diketone and preparation method thereof Download PDFInfo
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Abstract
The invention discloses trifluoromethyl-substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-diketone, which belongs to the field of organic synthesis, and the preparation method of the compound comprises the steps of dissolving a chiral organic catalyst and alkenyl succinimide (I) in an organic solvent, then adding cyclic trifluoromethyl ketimine (II) and an additive, reacting and stirring for 0.5-2 days at a certain temperature, and after the reaction is finished, separating and purifying to obtain the compound; the invention realizes the preparation of trifluoromethyl substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-diketone through continuous asymmetric Mannich addition reaction/intramolecular transamidation reaction; the quinazolinone with a core skeleton structure of the compound is widely present in bioactive compounds, and the skeleton structure of the compound can be greatly enriched by the preparation method; the preparation method has the advantages of mild reaction conditions, simple and convenient operation, wide substrate application range, high stereoselectivity and the like.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to trifluoromethyl-substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-diketone and a preparation method thereof.
Background
Trifluoromethyl-substituted quinazolinones exist as important benzo-heterocyclic skeletons in a number of compounds with typical biological activities, such as weight loss, phosphodiesterase 7 inhibition, Na+/Ca2+Exchange inhibition activity and HIV-1 non-nucleoside reverse transcriptase inhibition activity. In a plurality of literature reports for synthesizing chiral quinazolinone containing trifluoromethyl, cyclic trifluoromethyl ketimine is mostly selected as an electrophilic receptor to construct chiral quinazolinone with a simple structure through one-step addition reaction. However, the construction of chiral polycyclic compounds with trifluoromethyl substituted quinazolinone core backbone by asymmetric tandem cyclization is rare and is currently being investigated for tetrahydropyrrole [1,2-c]Asymmetric synthesis of quinazoline-3, 5-diones has not been reported. Thus, efficient and synthetic methods have been developed to construct chiral compounds having such backbones, in particular chiral tetrahydropyrrole [1,2-c ] containing trifluoromethyl substitutions]Quinazoline-3, 5-diones are highly desirable.
Disclosure of Invention
One of the objectives of the present invention is to provide a trifluoromethyl-substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-dione and a preparation method thereof, so as to achieve the above objective.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a trifluoromethyl substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-dione having a structure represented by the following structural formula (III):
in the above structural formula (III), R1The radicals are selected from aryl, heteroaryl, fused aryl, alkyl, R2The radicals being selected from various types of protecting groups, R3Radicals selected from alkyl radicals, halogen atoms, R4The radicals are selected from alkyl radicals.
As a preferred technical scheme: the R is1The group is selected from one of phenyl, o-methylphenyl, o-methoxyphenyl, o-fluorophenyl, o-chlorophenyl, o-bromophenyl, m-methylphenyl, m-chlorophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, 3, 4-dimethoxyphenyl, 2-naphthyl, 2-thiophene, 2-furan and n-propyl; the R is2One selected from methyl, phenyl, tert-butyloxycarbonyl, acetyl, benzoyl, benzenesulfonyl and p-toluenesulfonyl; the R is3One selected from methyl, trifluoromethyl, p-methoxybenzyl, fluorine and chlorine; the R is4Is selected from one of benzyl, p-methoxybenzyl and o-bromobenzyl.
The invention provides a brand-new chiral pyrrolidine [1,2-c ] quinazoline-3, 5-diketone substituted by trifluoromethyl, wherein trifluoromethyl, valerolactam and quinazolinone skeletons of the compounds are widely existed in bioactive molecules and candidate drug molecules, and the compounds further enrich molecular libraries of fluorine-containing compounds and quinazolinone compounds and establish chemical bases for screening related drug candidate molecules.
The second objective of the present invention is to provide a preparation method of the trifluoromethyl-substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-dione, so as to solve the problems that no related report and system research exist in the skeleton of the compound;
by the method, a series of chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-diketone compounds containing trifluoromethyl can be quickly, simply and conveniently synthesized.
The adopted technical scheme is that alkenyl succinimide and chiral organic catalyst of the following formula (I) are respectively weighed and dissolved in an organic solvent, cyclic trifluoromethyl ketimine and additive of the following formula (II) are added under stirring, the stirring is continued, and separation and purification are carried out after the reaction is completed, so as to obtain the compound;
the reaction formula is as follows:
the chiral organic catalyst in the reaction formula is a quinine derived thiourea or aromatic amide catalyst; "chiral organic catalyst" in the following examples also refers to cyclohexanediamine-derived thiourea or squaramide catalysts; it should be noted that "chiral catalyst a", "chiral catalyst B", "chiral catalyst C" and "chiral catalyst D" described in the examples refer to substituted compounds corresponding to A, B, C, D in the box of the above formula.
In addition, as will be understood by those skilled in the art, the chiral catalyst used in the present application is not limited to the above four catalysts, and the present invention can be implemented by using cinchona alkaloid thiourea or squaramide as a parent and performing similar transformation on the Ar substituent.
The 2-arylalkenyl succinimide (I) has the following structure:
wherein R is1The group is selected from aryl, heteroaryl, fused aryl and alkyl; r2The groups are selected from various types of protecting groups, mainly including aryl, alkyl, acyl, sulfonyl.
The cyclic trifluoromethyl ketimine (II) has the following structure:
wherein R is3The radicals are selected from alkyl radicals, halogen atoms; r4The radicals are selected from alkyl radicals.
The invention realizes the preparation of trifluoromethyl substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-diketone by continuous asymmetric Mannich addition reaction/intramolecular transamidation reaction.
As a preferred technical scheme: the organic solvent is selected from one or more of methyl tert-butyl ether, 1, 2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran and toluene; further preferably dichloromethane; because the reaction takes the shortest time to complete in the solvent, the reaction yield is the highest and the stereoselectivity is the best.
As a preferred technical scheme: the dosage of the chiral catalyst is 5 mol% at the lowest. On the premise of ensuring the reaction yield and stereoselectivity, the dosage of the chiral catalyst can be saved.
As a preferred technical scheme: the molar ratio of the alkenyl succinimide of the formula (I) to the cyclic trifluoromethyl ketimine of the formula (II) is 1: 1-1: 4, preferably 1: 1.2; because the test proves that: at a molar ratio of 1:1.2, the reaction gave the best results, with no corresponding increase in yield and stereoselectivity either with increasing or decreasing reaction molar ratio.
As a preferred technical scheme: the concentration of the alkenylsuccinimide compound of formula (II) is 0.05 to 0.4mol/L, and more preferably 0.10mol/L, and the reaction at this concentration has the highest yield while ensuring a precursor having a small amount of solvent.
As a preferred technical scheme: the reaction temperature is 0-50 ℃, and the reaction temperature is preferably 25 ℃, because the reaction energy consumption is lower at the reaction temperature on the premise of ensuring the best reaction yield and stereoselectivity.
As a preferred technical scheme: the additive is anhydrous magnesium sulfate and the additive is sodium sulfate,
a molecular sieve is used for the molecular sieve,
a molecular sieve is used for the molecular sieve,
molecular sieves, further preferred
The molecular sieve can reduce the hydrolysis of the annular trifluoromethyl ketimine (II) to the maximum extent and ensure the yield of the reaction.
As a preferred technical scheme: the reaction time is 0.5-3 days.
The invention has the advantages that: the invention realizes the preparation of trifluoromethyl substituted chiral pyrrolidine [1,2-c ] quinazoline-3, 5-diketone by asymmetric Mannich addition reaction/intramolecular transamidation reaction catalyzed by an organic small molecule catalyst for the first time; the quinazolinone with a core skeleton structure of the compound is widely present in bioactive compounds, and the skeleton structure of the compound can be greatly enriched by the preparation method; the preparation method has the advantages of mild reaction conditions, simple and convenient operation, wide substrate application range, high stereoselectivity and the like, and the method only needs to add a catalyst and an additive for removing water, does not need to additionally add a metal catalyst or an oxidant, thereby reducing the synthesis cost and simplifying the process flow for recycling the solvent.
Drawings
FIG. 1 is a hydrogen spectrum of III-a obtained in example 1;
FIG. 2 is a carbon spectrum of III-a obtained in example 1;
FIG. 3 is a hydrogen spectrum of III-f obtained in example 6;
FIG. 4 shows a hydrogen spectrum of III-f obtained in example 6.
Detailed Description
The invention will be further explained with reference to the drawings.
Example 1: synthesis of Compound (III-a)
The method comprises the following steps: in a reaction tube, catalyst B (0.005mmol) and 2-arylalkenylsuccinimide I-a (0.1mmol, reactant concentration 0.1mol/L) were dissolved in 1.0mL of dichloromethane; cyclic trifluoromethylketimine II-a (0.12mmol) was then added and the reaction mixture was stirred at 0 ℃ for 12 hours and then at 25 ℃ for 12 hours (TLC monitoring). Separating and purifying by column chromatography (dichloromethane: petroleum ether: ethyl acetate: 8:1: 0.5-5: 1:1) to obtain compound III-a with yield of 95% and >20:1dr 94% ee;
the method 2 comprises the following steps: in a reaction tube, catalyst C (0.02mmol) and 2-arylalkenylsuccinimide I-a (0.1mmol, reactant concentration 0.1mol/L) were dissolved in 1.0mL of methyl tert-butyl ether; then, anhydrous magnesium sulfate (50mg) and cyclic trifluoromethylketimine II-a (0.12mmol) were added to the reaction mixture, and the reaction mixture was stirred at 0 ℃ for 12 hours, followed by stirring at 25 ℃ for 12 hours (TLC monitoring). Separating and purifying by column chromatography (dichloromethane: petroleum ether: ethyl acetate: 8:1: 0.5-5: 1:1) to obtain compound III-a with yield of 80%, >20:1dr and 89% ee;
the method 3 comprises the following steps: in a round-bottom flask, chiral organic catalyst A (0.1mmol) and 2-phenylalkenyl succinimide I-a (2.0mmol reactant concentration of 0.1mol/L) were dissolved in 20mL of dichloromethane; then add into
Molecular sieves (1.0g) and beta-trifluoromethylenone II-a (2.4mmol) were added, and the reaction mixture was stirred at 0 ℃ for 12 hours and then stirred at 25 ℃ for 12 hours (TLC monitoring). Separating and purifying by column chromatography (dichloromethane: petroleum ether: ethyl acetate: 8:1: 0.5-5: 1:1) to obtain compound III-a with yield of 96%;>20:1dr，97％ee.；[α]D 20＝+148.7(c 1.00,CH2Cl2) (ii) a m.p.163.5-166.2 ℃; the ee value was determined by HPLC (Chiralpak AD-H column) (mobile phase: n-hexane/isopropanol-75/25; flow rate: 1.0 mL/min; lambda-254 nm; t;)minor＝7.00min,tmajor＝9.71min)；1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.57(dd,J＝6.7,3.0Hz,2H),7.49(d,J＝14.7Hz,2H),7.44-7.35(m,3H),7.22-7.15(m,3H),6.87(d,J＝8.9Hz,1H),6.83(d,J＝8.7Hz,2H),6.49(s,1H),5.23(d,J＝16.3Hz,1H),5.07(d,J＝16.3Hz,1H),3.75(s,3H),1.58(s,9H)；13C NMR(101MHz,CDCl3)δ166.3,159.1,150.9,146.8,137.3,136.6,133.3,131.6,131.0,130.4,129.7,129.1,128.3,128.0,127.3,126.9,126.3,124.5(q,J＝289.6Hz,1C),118.0,117.2,114.4,84.8,67.3(q,J＝30.0Hz,1C),55.3,46.2,45.1,28.1；HRMS(ESI)Calcd.for C33H30ClF3N3O6[M+H]+656.1775; 656.1771 the hydrogen and carbon spectra are shown in FIGS. 1-2.
Example 2: synthesis of Compound (III-b)
In a reaction tube, catalyst B (0.005mmol) and 2-arylalkenylsuccinimide I-a (0.1mmol, reactant concentration 0.1mol/L) were dissolved in 1.0mL of dichloromethane; then, anhydrous magnesium sulfate (50mg) and cyclic trifluoromethylketimine II-b (0.12mmol) were added to the reaction mixture, and the reaction mixture was stirred at 0 ℃ for 12 hours, followed by stirring at 25 ℃ for 12 hours (TLC monitoring). Separating and purifying by column chromatography (dichloromethane: petroleum ether: ethyl acetate: 9:1: 0.5-5: 1:1) to obtain compound III-b as white solid; the yield thereof is 94%,>20:1dr,92％ee；[α]D 20＝+183.2(c 1.00,CH2Cl2) (ii) a m.p.133.7-134.4 ℃ determination of the ee value by HPLC (Chiralpak AD-H column) (mobile phase: n-hexane/isopropanol 80/20; flow rate: 1.0 mL/min; lambda 254 nm; t ℃. (t;)minor＝7.71min,tmajor＝9.26min)；1H NMR(300MHz,DMSO-d6)δ11.39(s,1H),8.04(s,1H),7.84(d,J＝8.7Hz,1H),7.80-7.63(m,3H),7.62-7.48(m,3H),7.39(d,J＝8.9Hz,1H),7.20(d,J＝8.3Hz,2H),6.92(d,J＝8.3Hz,2H),5.37(s,1H),5.30(d,J＝16.3Hz,1H),5.19(d,J＝16.3Hz,1H),3.71(s,3H),1.35(s,9H)；13C NMR(151MHz,DMSO-d6)δ165.6,158.7,153.9,148.1,145.8,144.7(q,J＝25.1Hz,1C),140.3,136.5(q,J＝5.3Hz,1C),132.5,131.0,130.2(q,J＝9.5Hz,1C),129.3(2C),128.7,127.9,127.2,124.3(q,J＝289.4Hz,1C),123.3(q,J＝307.6Hz,1C),116.8(qJ＝5.6Hz,1C),114.3,81.7,66.4(q,J＝30.2Hz,1C),55.1,47.5,45.0,27.4；HRMS(ESI)Calcd.for C34H30F6N3O6[M+H]+:690.2039；found:690.2043。
Example 3: synthesis of Compound (III-c)
In a reaction tube, catalyst D (0.005mmol) and 2-arylalkenylsuccinimide I-a (0.1mmol, reactant concentration 0.1mol/L) were dissolved in 1.0mL of dichloromethane; then add into
Molecular sieves (50mg) and cyclic trifluoromethylketimine II-c (0.12mmol) were added and the reaction mixture was stirred at 0 ℃ for 12 hours and then at 25 ℃ for 12 hours (TLC monitoring). Separating and purifying by column chromatography (dichloromethane: petroleum ether: ethyl acetate: 7:1:0.5) to obtain compound III-c as white solid; the yield is 95%;>20:1dr,94％ee.；[α]D 20＝+147.5(c 1.00,CH2Cl2) (ii) a m.p.153.4-154.4 ℃ determination of the ee value by HPLC (Chiralpak AD-H column) (mobile phase: n-hexane/isopropanol 75/25; flow rate: 1.0 mL/min; lambda. 254 nm; t ℃. (t;)minor＝4.56min,tmajor＝6.44min)；1H NMR(300MHz,CDCl3)δ7.77(s,1H),7.65-7.52(m,4H),7.52-7.28(m,4H),7.20(t,J＝7.2Hz,2H),7.12(t,J＝7.0Hz,1H),7.02(d,J＝7.5Hz,1H),6.62(d,J＝8.9Hz,1H),6.51(s,1H),5.34(d,J＝17.4Hz,1H),5.16(d,J＝17.4Hz,1H),1.59(s,9H).13C NMR(151MHz,CDCl3)δ166.3,150.9,146.7,137.6,136.4,133.9,133.2,133.1,131.6,131.3,130.6,129.7,129.2,129.1,128.7,128.2,127.4,127.2,126.1,124.4(q,J＝289.2Hz,1C),122.4,117.8,117.0,85.0,67.4(q,J＝29.6Hz,1C),47.3,45.1,28.1；HRMS(ESI)Calcd.for C32H27BrClF3N3O5[M+H]+:704.0775；found:704.0773。
Example 4: synthesis of Compound (III-d)
In a reaction tube, catalyst B (0.005mmol) and 2-arylalkenylsuccinimide I-B (0.1mmol, reactant concentration 0.1mol/L) were dissolved in 1.0mL of dichloromethane; then add into
Molecular sieves (50mg) and cyclic trifluoromethylketimine II-a (0.12mmol) were added, and the reaction mixture was stirred at 0 ℃ for 12 hours, and then stirred at 25 ℃ for 12 hours (TLC monitoring). Separating and purifying by column chromatography (dichloromethane: petroleum ether: ethyl acetate: 8:1:0.5) to obtain compound III-d as white solid; the yield thereof was found to be 81%,>20:1dr,99％ee；[α]D 20＝+167.5(c 1.00,CH2Cl2) (ii) a m.p.139.2-141.8 ℃ determination of the ee value by HPLC (Chiralpak AD-H column) (mobile phase: n-hexane/isopropanol 80/20; flow rate: 1.0 mL/min; lambda. 254 nm; t ℃. (t;)minor＝11.03min,tmajor＝16.32min)；1H NMR(400MHz,CDCl3)δ7.70(s,1H),7.51(s,1H),7.33-7.25(m,1H),7.19(dd,J＝11.5,8.7Hz,4H),7.02(s,1H),6.87(dd,J＝8.7,2.9Hz,2H),6.83(d,J＝8.7Hz,2H),6.47(s,1H),5.24(d,J＝16.4Hz,1H),5.07(d,J＝16.4Hz,1H),3.93(s,3H),3.90(s,3H),3.75(s,3H),1.56(s,9H)；13C NMR(101MHz,CDCl3)δ168.8,166.6,159.1,151.1,149.3,146.9,139.0,137.6,136.6,136.2,131.0,128.4,128.0,127.9,127.3,126.9,126.1,124.5(q,J＝289.5Hz,1C),118.0,117.2,114.4,114.1,111.2,84.7,67.20(q,J＝29.8Hz,1C),56.2,56.0,55.3,46.2,31.3,28.0；HRMS(ESI)Calcd.for C35H34ClF3N3O8[M+H]+:716.1987；found:716.2018。
Example 5: synthesis of Compound (III-e)
In the reactionIn a tube, catalyst D (0.005mmol) and 2-arylalkenylsuccinimide I-c (0.1mmol, reactant concentration 0.1mol/L) were dissolved in 1.0mL of dichloromethane; then add into
Molecular sieves (50mg) and cyclic trifluoromethylketimine II-a (0.12mmol) were added, and the reaction mixture was stirred at 0 ℃ for 12 hours, and then stirred at 25 ℃ for 12 hours (TLC monitoring). Separating and purifying by column chromatography (dichloromethane: petroleum ether: ethyl acetate: 8:1:0.5) to obtain compound III-e as white solid; the yield thereof was found to be 87%,>20:1dr,91％ee；[α]D 20＝+131.2(c 1.00,CH2Cl2) (ii) a m.p.175-6-176.9 ℃ determination of the ee value by HPLC (Chiralpak AD-H column) (mobile phase: n-hexane/isopropanol 75/25; flow rate: 1.0 mL/min; lambda. 254 nm; t ℃. (t;)minorr＝7.64min,tmajor＝10.72min)；1H NMR(400MHz,CDCl3)δ7.80-7.76(m,1H),7.73(s,1H),7.54(s,1H),7.49-7.39(m,2H),7.36(dd,J＝5.1,2.9Hz,1H),7.23-7.14(m,3H),6.87(d,J＝8.9Hz,1H),6.84(d,J＝8.7Hz,2H),6.40(s,1H),5.23(d,J＝16.3Hz,1H),5.09(d,J＝16.3Hz,1H),3.76(s,3H),1.62(s,9H)；13C NMR(151MHz,CDCl3)δ166.6,159.1,151.4,146.9,136.7,135.2,131.0,130.3,128.9,128.4,128.0,127.6,127.4,127.2,127.0,125.4,124.4(q,J＝278.5Hz,1C),124.1,118.0,117.3,114.5,85.1,67.4(q,J＝30.6Hz,1C),55.4,46.3,45.4,28.1；HRMS(ESI)Calcd.for C31H28ClF3N3O6S[M+H]+:662.1339；found:662.1346。
Example 6: synthesis of Compound (III-f)
In a reaction tube, catalyst B (0.005mmol) and 2-arylalkenylsuccinimide I-c (0.1mmol, reactant concentration 0.1mol/L) were dissolved in 1.0mL of dichloromethane; then add into
Molecular sieves (50mg) and cyclic trifluoromethylketimine II-a (0.12mmol) were added, and the reaction mixture was stirred at 0 ℃ for 12 hours, and then stirred at 25 ℃ for 12 hours (TLC monitoring). Separating and purifying by column chromatography (dichloromethane: petroleum ether: ethyl acetate: 8:1:0.5) to obtain compound III-f as light yellow solid; the yield thereof is 95%,>20:1dr,97％ee；[α]D 20＝+204.5(c 1.00,CH2Cl2) (ii) a m.p.176.8-177.2 ℃ determination of the ee value by HPLC (Chiralpak AD-H column) (mobile phase: n-hexane/isopropanol 75/25; flow rate: 1.0 mL/min; lambda. 254 nm; t ℃. (t;)minor＝8.44min,tmajor＝13.4min)；1H NMR(300MHz,DMSO-d6)δ11.40(s,1H),8.27(s,1H),8.04(dd,J＝12.4,7.9Hz,3H),7.92-7.70(m,3H),7.70-7.60(m,2H),7.54(dd,J＝8.9,2.4Hz,1H),7.21(dd,J＝8.9Hz,3H),6.91(d,J＝8.3Hz,2H),5.35(s,1H),5.25(d,J＝16.2Hz,1H),5.13(d,J＝16.2Hz,1H),3.71(s,3H),1.34(s,9H)；13C NMR(151MHz,DMSO-d6)δ165.6,158.6,151.4,145.9,136.5,136.0,133.6,132.7,131.9,131.6,131.3,130.9,130.2,129.7,128.8,128.6,128.2,128.1,128.0,127.8,127.6,127.4,127.1,126.6,124.4(q,J＝289.0Hz,1C),118.0,114.2,81.8,66.3(q,J＝31.2Hz,1C),55.1,48.2,44.9,27.5；HRMS(ESI)Calcd.for C37H32ClF3N3O6[M+H]+706.1932; the found:706.1940. hydrogen and carbon spectra are shown in FIGS. 3-4.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A trifluoromethyl-substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-dione, characterized by having a structure represented by the following structural formula (III):
in the above structural formula (III), R1The group is selected from aryl, heteroaryl, fused aryl and alkyl; r2The group is selected from various protective agents, including one of aryl, alkyl, acyl and sulfonyl; r3The radical is selected from one of alkyl and halogen atoms; r4The radicals are selected from alkyl radicals.
2. Trifluoromethyl-substituted chiral tetrahydropyrrole [1,2-c according to claim 1]A quinazoline-3, 5-dione characterized by: the R is1The group is selected from one of phenyl, o-methylphenyl, o-methoxyphenyl, o-fluorophenyl, o-chlorophenyl, o-bromophenyl, m-methylphenyl, m-chlorophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, 3, 4-dimethoxyphenyl, 2-naphthyl, 2-thiophene, 2-furan and n-propyl; the R is2One selected from methyl, phenyl, tert-butyloxycarbonyl, acetyl, benzoyl, benzenesulfonyl and p-toluenesulfonyl; the R is3One selected from methyl, trifluoromethyl, p-methoxybenzyl, fluorine and chlorine; the R is4Is selected from one of benzyl, p-methoxybenzyl and o-bromobenzyl.
3. The preparation method of trifluoromethyl-substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-dione as claimed in claim 1 or 2, characterized in that, respectively weighing alkenyl succinimide of the following formula (I) and chiral organic catalyst, dissolving them in organic solvent, adding additive and cyclic trifluoromethyl ketimine of the following formula (II) under stirring, continuing stirring, after reaction, separating and purifying to obtain the compound;
the 2-arylalkenyl succinimide (I) has the following structure:
wherein R is1The group is selected from aryl, heteroaryl, fused aryl and alkyl; r2The radicals being selected from various types of protecting groups, main packageIncluding aryl, alkyl, acyl, sulfonyl.
The cyclic trifluoromethyl ketimine (II) has the following structure:
wherein R is3The radicals are selected from alkyl radicals, halogen atoms; r4The radicals are selected from alkyl radicals.
4. The preparation method according to claim 3, wherein the organic solvent is one or more selected from methyl tert-butyl ether, 1, 2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran and toluene, preferably dichloromethane.
5. The process according to claim 3, wherein the chiral catalyst is used in an amount of 1mol to 30 mol%, preferably 5 mol%.
6. The method according to claim 3, wherein the molar ratio of the alkenyl succinimide of formula (I) to the cyclic trifluoromethyl ketimine of formula (II) is 1:1 to 1:4, preferably 1: 1.2.
7. The method according to claim 3, wherein the concentration of the alkenylsuccinimide compound of formula (II) is 0.05 to 0.4mol/L, preferably 0.10 mol/L.
8. The method according to claim 3, wherein the reaction temperature is 0 to 50 ℃.
9. The production method according to claim 3, wherein the additive is anhydrous magnesium sulfate,
a molecular sieve is used for the molecular sieve,
a molecular sieve is used for the molecular sieve,
one of the molecular sieves, preferably
And (3) a molecular sieve.
10. The method according to claim 3, wherein the reaction time is 0.5 to 3 days.
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