CN115433134A - Catalytic enantioselective synthesis method of dihydro quinazolinone - Google Patents
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- CN115433134A CN115433134A CN202211126936.XA CN202211126936A CN115433134A CN 115433134 A CN115433134 A CN 115433134A CN 202211126936 A CN202211126936 A CN 202211126936A CN 115433134 A CN115433134 A CN 115433134A
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- 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
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
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Abstract
A catalytic enantioselective synthesis method of dihydro quinazolinone comprises the following steps: (1) The catalyst, 2-aminobenzamide and
the molecular sieve is arranged in a dry reaction tube; (2) The reaction tube is vacuumized and then filled with N 2 (ii) a Repeating the reaction for three times to ensure that the reaction tube is in an inert atmosphere condition; (3) Under the condition of inert atmosphere, adding an organic solvent into a reaction tube, and then dropwise adding an aryl aldehyde compound; (4) Reacting the materials in the reaction tube for 24-48 h under the stirring condition, and then removing the solvent to obtain a crude product of the dihydroquinazolinone product; purifying by column chromatography to obtain dihydro-quinazolinone. The chiral phosphoric acid catalyst is used for the catalytic enantioselective synthesis of the dihydroquinazolinone, so that good yield and ee value can be obtained.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a catalytic enantioselective synthesis method of dihydro quinazolinone.
Background
Dihydroquinazolinones are important heterocyclic compounds that affect many cellular processes. They have a wide range of biological, pharmaceutical and pharmaceutic properties and are components of anti-tumour, antibiotic, anti-hypertonic, antipyretic, analgesic, diuretic, anti-histamine, antidepressant and vasodilators. Furthermore, 2, 3-dihydroquinazolinones have been shown to be potent tubulin inhibitors with significant antiproliferative activity against several human cancer cell lines. As potent inhibitors of tubulin polymerization, they act similarly to the antimitotic agent colchicine. In general, racemic mixtures of 2, 3-dihydroquinazolinones have been determined, however, recent studies have shown that the enantiomer (S) -2, 3-dihydroquinazolinone has significantly higher activity in inhibiting choline binding and tubulin assembly. The 2, 3-dihydroquinazolinone racemate and the (S) -2, 3-dihydroquinazolinone have the following molecular formulas:
bis-naphthyl chiral Phosphoric Acids (PAs) have been shown to be multifunctional and highly efficient catalysts useful in a variety of enantioselective transformations. Chiral phosphoric acid catalysts have been reported to have been successful in a number of carbon-carbon and carbon-heteroatom bonding processes as well as in various redox reactions.
The dihydroquinazolinone compound is prepared by adopting a lower-cost preparation method at present, and is a problem which needs to be solved urgently.
Disclosure of Invention
The invention aims to provide a catalytic enantioselective synthesis method of dihydro quinazolinone, which utilizes a catalyst, 2-aminobenzamide and an aryl aldehyde compound to react to generate the dihydro quinazolinone product.
The method of the invention is carried out according to the following steps:
(1) The catalyst, 2-aminobenzamide and
the molecular sieve is arranged in a dry reaction tube;
(2) The reaction tube is vacuumized and then filled with N 2 (ii) a Repeating the reaction for three times to ensure that the reaction tube is in an inert atmosphere condition;
(3) Under the condition of inert atmosphere, adding an organic solvent into a reaction tube, and then dropwise adding an aryl aldehyde compound;
(4) And (3) reacting the materials in the reaction tube for 24-48 h under the stirring condition, and then removing the solvent to obtain a crude product of the dihydroquinazolinone product.
In the method, the catalyst is a chiral phosphoric acid catalyst or diphenyl phosphate; the chiral phosphoric acid catalyst is a self-supported chiral phosphoric acid catalyst, which is described in chinese patent 202211113737.5, and a specific preparation method is given in the following specific examples.
In the method, a chiral phosphoric acid catalyst is used as a catalyst to obtain a dihydroquinazolinone isomer; the diphenyl phosphate is used as a catalyst to obtain the dihydro quinazolinone racemate.
In the above method, the aryl aldehyde compound is benzaldehyde, 3, 4-dimethoxybenzaldehyde, 3-methylbenzaldehyde, 4-benzaldehyde, 3-bromobenzaldehyde or 3-fluorobenzaldehyde.
In the above process, the molar ratio of the 2-aminobenzamide to the aryl aldehyde compound is 1: 1 (1 to 1.2).
In the above process, the catalyst is used in an amount of 10% by mole based on the 2-aminobenzamide.
In the above-mentioned method, the first step,
the dosage of the molecular sieve is 1-10% of the mass of the 2-aminobenzamide.
In the method, the organic solvent is chloroform, and the dosage of the organic solvent is 10-50% of the mass of the 2-aminobenzamide.
In the step (2), the reaction tube is vacuumized until the pressure in the reaction tube is lower than 0.001MPa.
In the above step (2), N is charged 2 Until the pressure in the reaction tube is normal pressure.
In the step (4), the stirring conditions are magnetic stirring.
In the step (4), the solvent removal means removal of the organic solvent anhydrous chloroform.
In the step (4), after the reaction is carried out for 24 to 48 hours under the stirring condition, the completion of the reaction is confirmed by NMR, and the stirring is stopped.
In the step (4), after the crude product of the dihydroquinazolinone product is obtained, the crude product is purified by column chromatography to obtain the dihydroquinazolinone product, wherein the purity of the dihydroquinazolinone product is more than 90%, and the purity of the dihydroquinazolinone product refers to enantioselectivity.
In the above process, when the product is 2-phenyl-2, 3-dihydroquinazolin-4 (1H) -one, the equation for the reaction is:
the chiral phosphoric acid catalyst is used for the catalytic enantioselective synthesis of the dihydroquinazolinone, so that good yield and ee value can be obtained; if raceme is required to be obtained, diphenyl phosphate is used as the catalyst, and higher yield can be obtained as well; after determining the conditions for the catalytic enantioselective synthesis of dihydroquinazolinones, the potential applications of this synthesis method were evaluated; the aldehyde with different substituents has no obvious change on the yield and the enantioselectivity of the product, and the higher yield and the enantioselectivity are obtained, the yield is up to 93 percent, and the enantioselectivity can reach 94 percent (ee value).
Drawings
FIG. 1 is a NMR chart of 2-phenyl-2, 3-dihydroquinazolin-4 (1H) -one obtained in example 1 of the present invention;
FIG. 2 is a carbon nuclear magnetic resonance image of 2-phenyl-2, 3-dihydroquinazolin-4 (1H) -one of example 1 of the present invention.
Detailed Description
The yield of 2-phenyl-2, 3-dihydroquinazolin-4 (1H) -one in the examples of the invention is 90-93%.
The ee value of 2-phenyl-2, 3-dihydroquinazolin-4 (1H) -one in the examples of the invention is 91 to 94%.
In the embodiment of the invention, the racemate catalyst is diphenyl phosphate.
In the examples of the present invention, the chiral column of HPLC was ODH.
In the embodiment of the invention, the stirring time at room temperature is 24-48 h.
In the embodiment of the invention, the preparation method of the chiral phosphoric acid catalyst is already described in Chinese patent 202211113737.5, and the structural formula is as follows:
n is more than or equal to 2. The preparation method comprises the following steps:
s1, 1mmol of compound-1 and 10mmol of poly (4-vinylpyridine) were taken up and added to a dry Schlenk tube, followed by drying under vacuum for 1h to give a mixture. The structure of compound-1 is:
s2, under the nitrogen atmosphere, 5mLCH 2 Cl 2 And 3mmol of POCl 3 Adding to the mixture obtained in step S1, reacting at 30 ℃ for 40h, filtering the mixture through cotton to remove poly (4-vinylpyridine); the solvent was then evaporated to give a pale yellow intermediate; the intermediate was used as crude without further purification;
wherein the structural formula of the generated intermediate is as follows:
s3, taking 160mg AlCl in nitrogen atmosphere 3 77mg of the intermediate formed in step S2, 1mL of CHCl was added 3 In the solution, under the condition of 58 ℃, magnetically stirring for 48 hours, standing, and taking a crude precipitate;
and S4, washing the precipitate crude product obtained in the step S3 with ethanol once, washing the precipitate crude product with 6mol/L HCl solution twice and washing the precipitate crude product with ethanol three times in sequence, performing Soxhlet extraction on the precipitate crude product with ethanol for 24 hours, and drying the precipitate crude product in a vacuum oven at 75 ℃ for 24 hours to obtain a black solid which is a self-supported chiral phosphoric acid catalyst, wherein the yield of the catalyst is 99%.
In order to make the technical problems, technical solutions and advantageous effects solved by the present invention more apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
Chiral phosphoric acid catalyst (10 mol%), 2-aminobenzamide (0.1mmol, 1eq) and 1.36mg
Molecular sieve, adding into a dry reaction tube; pumping and charging N to the reaction tube 2 Thirdly; under an inert atmosphere, 6.8mg of anhydrous chloroform is added; benzaldehyde (0.11mmol, 1.1eq) was then added dropwise and the reaction mixture stirred at room temperature; NMR confirmed the reaction was complete, stirring was stopped, and after removal of the solvent, the crude product was obtained; the crude product is purified by column chromatography to give pure 2, 3-dihydroquinazolinones (2-phenyl-2, 3-dihydroquinazolin-4 (1H) -one) in good yield; yield 91%, enantioselectivity 94% (ee);
the nuclear magnetic resonance result is 1 H NMR(400MHz,DMSO-d 6 ) δ 8.30 (d, J =2.3hz, 1h), 7.62 (dd, J =7.8,1.5hz, 1h), 7.54-7.47 (m, 2H), 7.45-7.33 (m, 3H), 7.25 (ddd, J =8.5,7.3,1.6hz, 1h), 7.12 (s, 1H), 6.76 (d, J =8.1hz, 1h), 6.72-6.64 (m, 1H), 5.77 (d, J = 2.21h); the result of carbon resonance is 13 C NMR(101MHz,DMSO-d 6 )δ163.62,147.88,141.64,133.34,128.48,128.35,127.37,126.88,117.13,114.96,114.42,66.56；
The results of nuclear magnetic resonance are shown in FIG. 1, and the results of carbon resonance are shown in FIG. 2; the molecular formula of 2-phenyl-2, 3-dihydroquinazolin-4 (1H) -one is:
example 2
The method is the same as example 1, except that:
(1) 3, 4-dimethoxy benzaldehyde is dropwise added;
(2) To obtain 2- (3, 4-dimethoxyphenyl) -2, 3-dihydroquinazolin-4 (1H) -one with a yield of 91%; the result of the nuclear magnetic resonance is 1 H NMR(400MHz,DMSO-d 6 ) δ =8.17 (bs, 1H), 7.62 (dd, J =7.8and1, 5hz, 1h), 7.30-7.19 (m, 1H), 7.13 (d, J =1,8hz, 1h), 7.06-6.89 (m, 3H), 6.76 (d, J =7.8hz, 1h), 6.72-6.63 (m, 1H), 5.70 (bs, 1H), 3.80-3.71 (2xs, 6H); the result of carbon resonance is 13 C NMR(101MHz,DMSO-d 6 )δ＝163.59,148.89,148.49,147.92,133.51,133.08,127.20,119.09,117.00,114.94,114.31,111.22,110.57,66.42,55.49,55.38；
Enantioselectivity was 92%; the molecular formula of 2- (3, 4-dimethoxyphenyl) -2, 3-dihydroquinazolin-4 (1H) -one is:
example 3
The method is the same as example 1, except that:
(1) 3-methyl benzaldehyde is dripped;
(2) The 2- (3-methylphenyl) -2, 3-dihydroquinazolin-4 (1H) -one was prepared in 92% yield and 94% enantioselectivity; the result of nuclear magnetic resonance is 1 H NMR(400MHz,DMSO-d 6 ) δ =8.41 (bs, 1H), 7.81 (dd, J =7.8and1.5hz, 1h), 7.57-7.31 (m, 5H), 7.25 (bs, 1H), 6.94 (d, J =7.5hz, 1h), 6.90-6.81 (m, 1H), 5.90 (bs, 1H), 2.28 (s, 3H); the result of carbon resonance is 13 C NMR(101MHz,DMSO-d 6 )δ＝163.46,147.77,141.40,137.29,133.14,128.93,128.10,127.36,127.21,123.88,116.94,114.80,114.25,66.52,20.95；
The molecular formula of 2- (3-methylphenyl) -2, 3-dihydroquinazolin-4 (1H) -one is:
example 4
The method is the same as example 1, except that:
(1) 4-phenyl benzaldehyde is dripped;
(2) The yield of the prepared 2- (4-biphenyl) -2, 3-dihydroquinazolin-4 (1H) -one is 90 percent, and the enantioselectivity is 91 percent; the result of the nuclear magnetic resonance is 1 H NMR(400MHz,DMSO-d 6 ) δ =8.35 (bs, 1H), 7.74-7.54 (m, 7H), 7.51-7.42 (m, 2H), 7.41-7.32 (m, 1H), 7.30-7.21 (m, 1H), 7.17 (bs, 1H), 6.77 (d, J =7.8hz, 1h), 6.73-6.64 (m, 1H), 5.81 (bs, 1H); the result of carbon resonance is 13 C NMR(101MHz,DMSO-d 6 )δ＝163.45,147.68,140.74,140.20,139.60,133.20,128.81,127.42,127.30,127.25,126.56,126.51,117.01,114.87,114.31,66.09,；
The molecular formula of 2- (4-biphenyl) -2, 3-dihydroquinazolin-4 (1H) -one is:
example 5
The method is the same as example 1, except that:
(1) 3-bromobenzaldehyde is dropwise added;
(2) The yield of the prepared 2- (3-bromophenyl) -2, 3-dihydroquinazolin-4 (1H) -one is 93%, and the enantioselectivity is 94%; the result of the nuclear magnetic resonance is 1 H NMR(400MHz,DMSO-d 6 ) 8.40 (bs, 1H), 7.69 (t, J =1.8hz, 1h), 7.62 (dd, J =7.8and1.5hz, 1h), 7.58-7.46 (m, 2H), 7.41-7.17 (m, 3H), 6.77 (d, J =7.8hz, 1h), 6.74-6.64 (m, 1H), 5.79 (bs, 1H); the result of carbon resonance is 13 C NMR(101MHz,DMSO-d 6 )δ＝163.26,147.35,144.51,133.33,131.03,130.45,129.51,127.24,125.65,121.46,117.19,114.770,114.34,65.41；
The molecular formula of 2- (3-bromophenyl) -2, 3-dihydroquinazolin-4 (1H) -one is:
example 6
The method is the same as example 1, except that:
(1) 3-fluorobenzaldehyde is dropwise added;
(2) The yield of the prepared 2- (3-fluorophenyl) -2, 3-dihydroquinazolin-4 (1H) -one is 93 percent, and the enantioselectivity is 91 percent; the result of nuclear magnetic resonance is 1 H NMR(400MHz,DMSO-d 6 ) δ =8.39 (bs, 1H), 7.61 (dd, J =7.5and1.5hz, 1h), 7.49-7.38 (m, 1H), 7.37-7.11 (m, 5H), 6.76 (dd, J =8.1and 0.6hz, 1h), 6.72-6.64 (m, 1H), 5.78 (t, J =1.8hz, 1h); the result of carbon resonance is 13 C NMR(101MHz,DMSO-d 6 )δ＝163.27,161.92,147.40,144.72,133.28,130.25,127.22,122.64,117.16,115.12,114.84,114.34,113.44,65.48；
The molecular formula of 2- (3-fluorophenyl) -2, 3-dihydroquinazolin-4 (1H) -one is:
example 7
The method is the same as example 1, except that: using diphenyl phosphate as a catalyst, the dihydroquinazolinone racemate was finally obtained in the same manner as in example 1.
While the foregoing specification illustrates and describes the preferred embodiments of the present invention, it is to be understood that the invention is not limited to the precise forms disclosed herein and that it is not to be considered as excluding other embodiments and from consideration of the specification, which may be used in other combinations, modifications, and environments and which may be modified within the scope of the concepts described herein, as indicated by the above teachings or as may be learned by the practice of the relevant art. And that modifications or variations may be effected by those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (9)
1. A catalytic enantioselective synthesis method of dihydro quinazolinone is characterized by comprising the following steps:
(1) The catalyst, 2-aminobenzamide and
the molecular sieve is arranged in a dry reaction tube;
(2) The reaction tube was evacuated and then charged with N 2 (ii) a Repeating the reaction for three times to ensure that the reaction tube is in an inert atmosphere condition;
(3) Under the condition of inert atmosphere, adding an organic solvent into a reaction tube, and then dropwise adding an aryl aldehyde compound;
(4) And (3) reacting the materials in the reaction tube for 24-48 h under the stirring condition, and then removing the solvent to obtain a crude product of the dihydroquinazolinone product.
2. The catalytic enantioselective synthesis process of dihydro quinazolinone according to claim 1, characterized in that the catalyst is chiral phosphoric acid catalyst or diphenyl phosphate.
3. The catalytic enantioselective synthesis process of dihydroquinazolinone according to claim 1, characterized in that said chiral phosphoric acid catalyst is used as catalyst to obtain dihydroquinazolinone isomers; the diphenyl phosphate is used as a catalyst, and then the dihydro quinazolinone racemate is obtained.
4. The catalytic enantioselective synthesis process of dihydro quinazolinone according to claim 1, characterized in that the aryl aldehyde compound is benzaldehyde, 3, 4-dimethoxybenzaldehyde, 3-methylbenzaldehyde, 4-phenylbenzaldehyde, 3-bromobenzaldehyde or 3-fluorobenzaldehyde.
5. The process for the catalytic enantioselective synthesis of dihydroquinazolinones according to claim 1, characterized in that the molar ratio of 2-aminobenzamide to aryl aldehydes is between 1: 1and 1.2.
6. The method for the catalytic enantioselective synthesis of dihydroquinazolinones according to claim 1, characterized in that the amount of catalyst used is 10% of the moles of 2-aminobenzamide.
7. The process for the catalytic enantioselective synthesis of dihydroquinazolinones according to claim 1, characterized in that said process
The dosage of the molecular sieve is 1-10% of the mass of the 2-aminobenzamide.
8. The catalytic enantioselective synthesis process of dihydro quinazolinone according to claim 1, characterized in that the organic solvent is chloroform, the amount of which is 10-50% of the mass of 2-aminobenzamide.
9. The catalytic enantioselective synthesis method of dihydroquinazolinone according to claim 1, characterized in that in step (4), after obtaining crude dihydroquinazolinone product, the crude dihydroquinazolinone product is purified by column chromatography to obtain dihydroquinazolinone product with purity of more than 90%.
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- 2022-09-16 CN CN202211126936.XA patent/CN115433134A/en active Pending
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