Method for in-situ preparation of 2-methylquinazolinone compound from calcium carbide and product thereof

Abstract

The invention relates to the field of medicines, pesticides and functional materials, in particular to a method for in-situ preparation of 2-methylquinazolinone compounds by using calcium carbide and a product of the 2-methylquinazolinone compounds. The preparation method comprises the following steps: taking an anthranilamide compound, a 2-aminothiophenecarboxamide compound, an anthranilic cyanophenyl compound or a 2-aminothiophenenitrile compound as a reaction substrate, and synthesizing the 2-methyl-2, 3-dihydroquinazolinone and the derivative thereof from the reaction substrate and calcium carbide under the regulation and control of inorganic metal sulfide and alkali; and further adding an oxidizing agent into the 2-methyl 2, 3-dihydroquinazolinone and the derivative thereof to synthesize the 2-methyl quinazolinone and the derivative thereof. The invention provides a novel synthetic route for 2-methyl 2, 3-dihydroquinazolinone, 2-methyl quinazolinone and derivatives thereof. The invention further provides a preparation method of the 2-methyl 2, 3-dihydroquinazolinone and 2-methyl quinazolinone. According to the invention, calcium carbide which is cheap and easy to obtain is used as a raw material for the first time, and efficient selective preparation of two target compounds is realized by using cheap reagents under relatively mild conditions.

Description

Technical Field

[0001] The present invention relates to the fields of medicine, pesticides and functional materials. Further, it relates to a method for in-situ preparing 2-methylquinazolinone compounds by using calcium carbide and the products thereof. Background Art

[0002] 2-Methyl-2,3-dihydroquinazolinone and 2-methylquinazolinone are important nitrogen-containing heterocyclic compounds. A variety of drug molecules and natural products containing quinazolinone compounds exhibit good biological activities in aspects such as anti-inflammatory, anti-tumor, sedative, antibacterial, antihypertensive and vasodilating. For example: methyprylon is clinically used as a sedative and hypnotic, febrifugine (a quinazolinone-type alkaloid) has antimalarial activity, and halofuginone (a drug containing a quinazolinone structure) is a broad-spectrum antiparasitic drug.

[0003] Currently, the synthesis methods of quinazolinone and its derivatives mainly include: 1. Prepared by the cyclization reaction of o-aminobenzamide and aldehyde under the action of a strong base; 2. Prepared by the in-situ oxidation of alcohol to aldehyde by o-aminobenzamide and alcohol under the catalysis of a transition metal and then the cyclization reaction; 3. Prepared by the cyano hydrolysis cyclization tandem reaction of o-aminobenzonitrile and aldehyde under the action of a strong base; 4. Prepared by o-aminobenzonitrile and alcohol under the co-regulation of a transition metal and a strong base. The existing synthesis methods of quinazolinone and its derivatives still have problems such as expensive raw materials, low atom utilization rate and metal residues. Summary of the Invention

[0004] The present invention provides a new synthesis route for 2-methyl-2,3-dihydroquinazolinone and 2-methylquinazolinone.

[0005] The present invention uses o-aminobenzamide, 2-aminothiophenecarboxamide, o-aminobenzonitrile or 2-aminothiophenecarbonitrile as reaction substrates. The reaction substrates and calcium carbide are synthesized into 2-methyl-2,3-dihydroquinazolinone under the regulation of an inorganic metal sulfide and a base; 2-Methyl-2,3-dihydroquinazolinone is further reacted with an oxidant to synthesize 2-methylquinazolinone.

[0006] One of the purposes of the present invention is to provide a method for in-situ preparing 2-methylquinazolinone compounds by using calcium carbide.

[0007] The method includes reacting the reaction substrate and calcium carbide in the presence of an inorganic metal sulfide, water, a strong base and an organic solvent.

[0008] The 2-methylquinazolinone compounds are selected from one of 2-methyl-2,3-dihydroquinazolinone and 2-methylquinazolinone.

[0009] The structural formula of the 2-methyl-2,3-dihydroquinazolinone is shown as formula (I) or formula (II): (I) (II).

[0010] In formula (I): X is selected from one of C and N; n is selected from 5, 6, 7, 8; R 1 is selected from one or two of H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 hydrocarbyl, C 1-8 hydroxy, or C 1-8 sulfonyl; R 2 is selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl, or C aryl with a derivative group, C 6-14 aryl, C 1-8 alkyl, or C alkyl with a derivative group, C 1-8 alkyl; R 3 is selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl, or C aryl with a derivative group, C 6-14 aryl, C 1-8 alkyl, or C alkyl with a derivative group, C 1-8 alkyl;

[0011] In formula (II): R 1 is selected from one or two of H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 hydrocarbyl, C 1-8 hydroxy, or C 1-8 sulfonyl; R 2 is selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl, or C aryl with a derivative group, C 6-14 aryl, C 1-8 alkyl, or C alkyl with a derivative group, C 1-8 alkyl; R 3 is selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl, or C aryl with a derivative group, C 6-14 aryl, C 1-8 alkyl, or C alkyl with a derivative group, C1-8 One of the aliphatic hydrocarbon groups.

[0012] The structural formula of the 2-methylquinazolinone is shown in Formula (III) or Formula (IV): (III) (IV).

[0013] In Formula (III): X is selected from one of C and N; n is selected from 5, 6, 7, 8; R 1 is selected from one or two of H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 hydrocarbon group, C 1-8 hydroxy group or C 1-8 sulfonyl group; R 2 is selected from one of H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl group or C with a derivative group 6-14 aryl group, C 1-8 aliphatic hydrocarbon group or C with a derivative group 1-8 aliphatic hydrocarbon group.

[0014] In Formula (IV): R 1 is selected from one or two of H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 hydrocarbon group, C 1-8 hydroxy group or C 1-8 sulfonyl group; R 2 is selected from one of H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl group or C with a derivative group 6-14 aryl group, C 1-8 aliphatic hydrocarbon group or C with a derivative group 1-8 aliphatic hydrocarbon group.

[0015] The reaction substrate is selected from one of reaction substrate 1 and reaction substrate 2.

[0016] The reaction substrate 1 is selected from one of o-aminobenzamide and 2-aminothiophenecarboxamide.

[0017] The structural formula of the o-aminobenzamide is shown in Formula (V): (V); In Formula (V): X is selected from one of C and N; n is selected from 5, 6, 7 or 8; R 1 is selected from one or two of H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 hydrocarbyl, C 1-8 hydroxy or C 1-8 sulfonyl; R 2 is selected from one of H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl or aryl having a derived group, C 6-14 aryl, C 1-8 alkyl or alkyl having a derived group, C 1-8 alkyl; R 3 is selected from one of H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl or aryl having a derived group, C 6-14 aryl, C 1-8 alkyl or alkyl having a derived group, C 1-8 alkyl;

[0018] The structural formula of the 2-aminothiophenecarboxamide is shown in formula (VI): (VI); In formula (VI): R 1 is selected from one or two of H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 hydrocarbyl, C 1-8 hydroxy or C 1-8 sulfonyl; R 2 is selected from one of H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl or aryl having a derived group, C 6-14 aryl, C 1-8 alkyl or alkyl having a derived group, C 1-8 alkyl; R 3 is selected from one of H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl or aryl having a derived group, C 6-14 aryl, C 1-8 alkyl or alkyl having a derived group, C 1-8 alkyl;

[0019] The reaction substrate 2 is selected from one of o-aminobenzonitrile and 2-aminothiophenecarbonitrile.

[0020] The structural formula of the o-aminobenzonitrile is as shown in formula (VII): (VII); In formula (VII): X is selected from one of C and N; n is selected from 5, 6, 7 or 8; R 1 is selected from one or two of H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 hydrocarbyl, C 1-8 hydrocarbyloxy or C 1-8 sulfonyl; R 3 is selected from one of H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl, or C 6-14 aryl with a derivative group, C 1-8 alkyl, or C 1-8 alkyl with a derivative group;

[0021] The structural formula of the 2-aminothiophenecarbonitrile is as shown in formula (VIII): (VIII); In formula (VIII): R 1 is selected from one or two of H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 hydrocarbyl, C 1-8 hydrocarbyloxy or C 1-8 sulfonyl; R 3 is selected from one of H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl, or C 6-14 aryl with a derivative group, C 1-8 alkyl, or C 1-8 alkyl with a derivative group;

[0022] In formulas (I) to (VIII): The C 1-15 hydrocarbyl includes but is not limited to C 1-15 alkyl, biphenyl, biphenyl with alkyl substitution, etc.; preferably selected from methyl, naphthalene ring, 2-methylphenyl; The C 1-8 hydrocarbyloxy includes but is not limited to C 1-8 alkoxy, C 6-8 aryloxy; preferably selected from methoxy; The C 1-8 sulfonyl includes but is not limited to C1-8 alkylsulfonyl, C 6-8 arylsulfonyl; R 1 The substitution positions on the benzene ring and the thiophene ring are any feasible positions, and the present invention has no particular limitation; The C 1-8 alkyl, C 1-8 alkoxy, C 1-8 The C involved in alkylsulfonyl 1-8 alkyl can be an alkyl with 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, which can be a straight-chain alkyl or a branched-chain alkyl, and the present invention has no particular limitation.

[0023] In the present invention, The product corresponding to the reaction substrate of formula (V) is formula (I) or formula (III); The product corresponding to the reaction substrate of formula (VII) is formula (I) or formula (III), The product corresponding to the reaction substrate of formula (VI) is formula (II) or formula (IV); The product corresponding to the reaction substrate of formula (VIII) is formula (II) or formula (IV).

[0024] The inorganic metal sulfide can be selected within a relatively wide range. As a preferred embodiment, the inorganic metal sulfide is selected from at least one of alkali metal sulfides and alkali metal hydrosulfides, more preferably from at least one of K2S, Na2S, NaHS, KHS, Na2Sx, and K2Sx, and further preferably from at least one of K2S, Na2S, KHS, and NaHS; x in Na2Sx and K2Sx is selected from 2, 3, 4, 5, or 6.

[0025] The strong base can be selected within a relatively wide range. As a preferred embodiment, the strong base is selected from at least one of alkali metal hydroxides, alkaline earth metal hydroxides, and 1-6 alkoxide salts, more preferably from alkali metal hydroxides or metal salts of tert-butanol.

[0026] The organic solvent is a type of solvent with an organic substance as the medium, without particular limitation, and can be selected within a relatively wide range. As a preferred embodiment, the organic solvent is a polar solvent, such as a polar aprotic solvent and / or a polar protic solvent; more preferably from at least one of N-methylpyrrolidone (NMP), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA), acetonitrile, and 1-8 alcohol; further preferably from at least one of NMP, 2-6 alcohol, DMF, and DMA.

[0027] The amount of the organic solvent can be selected within a relatively wide range. As a preferred embodiment, relative to 1 mmol of the reaction substrate, the amount of the organic solvent is 1 - 5 mL; that is, the ratio of the amount of the reaction substrate to the organic solvent is 1 mmol : (1 mL - 5 mL).

[0028] The molar ratios of the reaction substrate to calcium carbide, water, inorganic metal sulfide, and strong base can be selected within a relatively wide range. As a preferred embodiment, the molar ratio of the reaction substrate 1 to calcium carbide, water, inorganic metal sulfide, and strong base is 1 : (1 - 6) : (1 - 24) : (1 - 10) : (0.2 - 3), more preferably 1 : (2 - 4) : (4 - 10) : (1 - 4) : (0.5 - 2). As a preferred embodiment, the molar ratio of the reaction substrate 2 to calcium carbide, water, inorganic metal sulfide, and strong base is 1 : (1 - 6) : (3 - 48) : (0.5 - 10) : (0.5 - 4), more preferably 1 : (2 - 4) : (4 - 32) : (1 - 4) : (1 - 3).

[0029] The method for in-situ preparing 2-methylquinazolinone compounds by using calcium carbide includes the following steps: (1) Mix the reaction substrate, water, strong base, and organic solvent, add inorganic metal sulfide and calcium carbide, and carry out the reaction under sealed stirring conditions; after the reaction is completed, collect the organic phase; (2-1) Purify the organic phase to obtain the 2-methyl-2,3-dihydroquinazolinone; or, (2-2) Add an oxidizing agent to the organic phase, carry out an oxidation reaction under stirring conditions, remove the solvent after the reaction is completed, and purify to obtain the 2-methylquinazolinone.

[0030] The method includes a method for preparing 2-methyl-2,3-dihydroquinazolinone or a method for preparing 2-methylquinazolinone.

[0031] The method for preparing 2-methyl-2,3-dihydroquinazolinone includes: mixing the reaction substrate, water, strong base, and organic solvent, adding inorganic metal sulfide and calcium carbide, and carrying out the reaction under sealed stirring conditions; after the reaction is completed, collect the organic phase; purify the organic phase to obtain the 2-methyl-2,3-dihydroquinazolinone.

[0032] The method for preparing 2-methylquinazolinone includes: mixing the reaction substrate, water, strong base, and organic solvent, adding inorganic metal sulfide and calcium carbide, and carrying out the reaction under sealed stirring conditions; after the reaction is completed, collect the organic phase; add an oxidizing agent to the organic phase, carry out an oxidation reaction under stirring conditions, remove the solvent after the reaction is completed, and purify to obtain the 2-methylquinazolinone.

[0033] It can be seen that the methods for preparing 2-methyl-2,3-dihydroquinazolinone and 2-methylquinazolinone both include the following steps: mixing the reaction substrate, water, strong base and organic solvent, adding inorganic metal sulfide and calcium carbide, and carrying out the reaction under sealed stirring conditions; collecting the organic phase after the reaction. If the organic phase is directly separated and purified, the 2-methyl-2,3-dihydroquinazolinone is obtained; if an oxidant is added to the organic phase to continue the reaction, the 2-methylquinazolinone is obtained.

[0034] In the said method, the reaction temperature and reaction time conditions in step (1) can be selected within a relatively wide range. Different reaction substrates will cause changes in the reaction temperature and reaction time in step (1).

[0035] When the reaction substrate is selected from reaction substrate 1; as a preferred option, the reaction temperature in step (1) is 70 - 130 °C, more preferably 110 - 120 °C; the reaction time in step (1) is 1 - 24 h, more preferably 2 - 6 h.

[0036] When the reaction substrate is selected from reaction substrate 2; as a preferred option, the reaction temperature in step (1) is 80 - 140 °C, more preferably 100 - 130 °C; the reaction time in step (1) is 5 - 24 h, more preferably 8 - 12 h.

[0037] In step (1) of the said method, the organic phase can be collected by conventional methods. As a specific option, the collection of the organic phase includes: cooling the organic phase to room temperature, extracting with ethyl acetate, and washing with saturated brine.

[0038] In step (2-1) of the said method, the purification can be carried out by conventional purification methods. As a specific option, the purification includes: drying the organic phase and then removing the solvent under reduced pressure to obtain a crude product, and separating the 2-methyl-2,3-dihydroquinazolinone from the crude product by recrystallization or column chromatography.

[0039] In step (2-2) of the said method, the oxidant can be selected within a relatively wide range. As a preferred option, the oxidant is at least one of H2O2, KMnO4, K2Cr2O7, Dess-Martin periodinane (DMP), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

[0040] In step (2-2) of the said method, the dosage of the oxidant can be selected within a relatively wide range. As a preferred option, the molar ratio of the oxidant to the reaction substrate is (1 - 10):1, more preferably (1 - 6):1.

[0041] In the said method, the temperature and time conditions of the reaction in step (2-2) can be selected within a relatively wide range. As a preferred embodiment, the reaction temperature in step (2-2) is 5-50 °C, more preferably 10-30 °C; the reaction time in step (2-2) is 0.1-2 h, more preferably 0.5-1 h.

[0042] In step (2-2) of the said method, the organic solvent can be removed by a conventional method. As a specific embodiment, the organic solvent can be removed by vacuum distillation.

[0043] In step (2-2) of the said method, the purification can be carried out by a conventional purification method. As a specific embodiment, the purification includes: recrystallization or column chromatography separation.

[0044] The said method can selectively synthesize 2,3-dihydroquinazolinone and 2-methylquinazolinone derivatives by regulating specific reaction conditions. The said method can achieve the efficient and selective preparation of two target compounds under relatively mild conditions.

[0045] As a specific embodiment, the method for synthesizing the compound shown in formula (I) includes: In a reaction kettle, successively add the compound shown in formula (V) or formula (VII), water, a strong base and a solvent, stir for 10 minutes, successively add an inorganic metal sulfide and ground calcium carbide to the reaction kettle, seal the reaction kettle, control the reaction temperature at 110-120 °C, after the reaction is completed, cool to room temperature, extract with ethyl acetate and wash with saturated brine, dry the organic phase and remove the solvent under reduced pressure to obtain a crude product, and the crude product is separated by recrystallization or column chromatography to obtain the compound shown in formula (I).

[0046] As a specific embodiment, the method for synthesizing the compound shown in formula (III) includes: In a reaction kettle, successively add the compound shown in formula (V) or formula (VII), water, a strong base and a solvent, stir for 10 minutes, successively add an inorganic metal sulfide and ground calcium carbide to the reaction kettle, seal the reaction kettle, control the reaction temperature at 110-120 °C, after the reaction is completed, cool to room temperature, extract with ethyl acetate and wash with saturated brine, dry the organic phase and remove the solvent under reduced pressure to obtain a crude product, then add an oxidant in a molar amount 2-6 times that of the compound shown in formula (V) or formula (VII), stir at room temperature for 20-60 min, and the crude product is separated by recrystallization or column chromatography to obtain the compound shown in formula (III).

[0047] As a specific embodiment, the method for synthesizing the compound shown in formula (II) includes: In a reaction kettle, sequentially add the compound shown in formula (VI) or formula (VIII), water, a strong base, and a solvent, stir for 10 minutes, sequentially add an inorganic metal sulfide and ground calcium carbide to the reaction kettle, seal the reaction kettle, control the reaction temperature at 110 - 120 °C, after the reaction is completed, cool to room temperature, extract with ethyl acetate and wash with saturated brine, dry the organic phase and remove the solvent under reduced pressure to obtain a crude product, and separate the compound shown in formula (II) from the crude product by recrystallization or column chromatography.

[0048] As a specific embodiment, the method for synthesizing the compound shown in formula (IV) includes: In a reaction kettle, sequentially add the compound shown in formula (VI) or formula (VIII), water, a strong base, and a solvent, stir for 10 minutes, sequentially add an inorganic metal sulfide and ground calcium carbide to the reaction kettle, seal the reaction kettle, control the reaction temperature at 110 - 120 °C, after the reaction is completed, cool to room temperature, extract with ethyl acetate and wash with saturated brine, dry the organic phase and remove the solvent under reduced pressure to obtain a crude product, then add an oxidant with a molar amount 2 - 6 times that of the compound shown in formula (VI) or formula (VIII), stir at room temperature for 20 - 60 min, and separate the compound shown in formula (IV) from the crude product by recrystallization or column chromatography.

[0049] The second object of the present invention is to provide a new 2 - methyl - 2,3 - dihydroquinazolinone compound synthesized by the above - mentioned method.

[0050] The new 2 - methyl - 2,3 - dihydroquinazolinone compound is selected from 2,5 - dimethyl - 2,3 - dihydroquinazolinone; 5 - chloro - 2 - methyl - 2,3 - dihydroquinazolinone; 5 - bromo - 2 - methyl - 2,3 - dihydroquinazolinone; 6 - methoxy - 2 - methyl - 2,3 - dihydroquinazolinone; 6 - cyano - 2 - methyl - 2,3 - dihydroquinazolinone; 2,7 - dimethyl - 2,3 - dihydroquinazolinone; 7 - methoxy - 2 - methyl - 2,3 - dihydroquinazolinone; 7 - chloro - 2 - methyl - 2,3 - dihydroquinazolinone; 7 - bromo - 2 - methyl - 2,3 - dihydroquinazolinone; 8 - amino - 2 - methyl - 2,3 - dihydroquinazolinone; 6,7 - dimethoxy - 2 - methyl - 2,3 - dihydroquinazolinone; 6,7 - dichloro - 2 - methyl - 2,3 - dihydroquinazolinone; 2 - methyl - 2,3 - dihydropyrido[3,2 - d]pyrimidin - 4(1H) - one; 2-Methyl-2,3-dihydrobenzo[h]quinazolin-4(1H)-one.

[0051] Compared with the prior art, the beneficial effects of the present invention are as follows: For the first time, the present invention uses easily available calcium carbide as a raw material and uses inexpensive reagents to achieve the highly selective preparation of two target compounds under relatively mild conditions.

[0052] For the first time, the present invention uses safe and easily available inorganic metal sulfides as activators for regulating reactions, and under relatively mild conditions, selectively converts calcium carbide with o-aminobenzamide and / or o-aminobenzonitrile into 2-methyl-2,3-dihydroquinazolinone or 2-methylquinazolinone. Compared with the prior art, the method of the present invention has the advantages that the raw materials are safe, easily available, and have higher atom utilization rate. It does not require expensive metal catalysts with complex post-treatment, is environmentally friendly, has fewer by-products, and has low costs, and has high popularization and application value. Specifically: 1. Safe, inexpensive, and easily available calcium carbide is used as a reaction raw material; 2. High-pressure-resistant equipment is not required, and the explosion risk is low; 3. Safe and easily available inorganic metal sulfides are used as regulating reagents for selective synthesis, avoiding the problem of metal residues caused by the use of metal catalysts; 4. By simply regulating the reaction conditions, the highly selective synthesis of two different quinazolinone compounds is achieved, with high atom economy; 5. This method has strong substrate applicability for the synthesis of both 2,3-dihydroquinazolinone and 2-methylquinazolinone, and the yields are relatively high.

[0053] In summary, the method of the present invention for selectively synthesizing 2,3-dihydroquinazolinone and 2-methylquinazolinone by using inorganic sulfides to regulate calcium carbide with o-aminobenzamide and / or o-aminobenzonitrile uses safe, stable, and easily available calcium carbide as a raw material, does not require transition metal catalysis and high-pressure-resistant equipment. Compared with the above methods, this method has more prominent advantages in "atom economy" and "green chemistry". BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 1H NMR spectrum of the product prepared in Examples 1-15; Figure 2 13C NMR spectrum of the product prepared in Examples 1-15; Figure 3 1H NMR spectrum of the product prepared in Example 16; Figure 4 13C NMR spectrum of the product prepared in Example 16. DETAILED DESCRIPTION OF THE INVENTION

[0055] The present invention will be specifically described below in conjunction with specific drawings and embodiments. It is necessary to point out here that the following embodiments are only for further illustration of the present invention and should not be construed as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made by those skilled in the art to the present invention based on the content of the present invention still fall within the protection scope of the present invention.

[0056] The reaction reagents involved in the embodiments are all common commercially available products.

[0057] The nuclear magnetic resonance spectrometer used in the embodiments is of the model Agilent 500 MHz DD2.

[0058] Examples 1-15 Synthesis of 2-methyl-2,3-dihydroquinazolinone by reacting o-aminobenzamide with calcium carbide 1 mmol of o-aminobenzamide, 3 mmol of water, a certain amount of potassium hydroxide and 2 mL of solvent were successively added to the reaction kettle, and stirred at room temperature for 10 minutes. A certain amount of inorganic metal sulfide and 2 mmol of calcium carbide were weighed and added to the reaction kettle. The reaction kettle was closed and placed in a constant temperature sand bath at T °C, and stirred for t h. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate and washed with saturated brine. The organic phase was dried and the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (200-300 mesh silica gel) to obtain a solid compound with a purity greater than 99%.

[0059] Table 1 shows the yields of synthesizing 2,3-dihydroquinazolinone from o-aminobenzamide and calcium carbide by using different types of inorganic metal sulfides, different feeding ratios, different reaction temperatures, different reaction times, and different solvents in Examples 1-15. The feeding ratio refers to the molar ratio of o-aminobenzamide:CaC2:KOH:K2S:H2O.

[0060] Table 1

[0061] In Examples 1-15, the structural formula of o-aminobenzamide is: .

[0062] The 1H nuclear magnetic resonance spectra of the solid compounds prepared in Examples 1-15 are as Figure 1 shown; The 13C nuclear magnetic resonance spectra of the solid compounds prepared in Examples 1-15 are as Figure 2 shown; The nuclear magnetic characterization data of the solid compounds prepared in Examples 1-15: 1 H NMR (500 MHz, DMSO- d 6) δ7.89 (s, 1H), 7.59 (d,J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.71 – 6.65 (m,2H), 6.60 (s, 1H), 4.82 (q, J = 5.7 Hz, 1H), 1.31 (d, J = 5.8 Hz, 3H). 13 C NMR (126MHz, DMSO- d 6) δ 164.1, 148.8, 133.1, 127.5, 117.2, 115.2, 114.3, 60.9, 21.3。

[0063] The solid compounds prepared in Examples 1 to 15 are 2-methyl-2,3-dihydroquinazolinone, and its structural formula is 。

[0064] The synthetic route of 2-methyl-2,3-dihydroquinazolinone is: 。

[0065] Example 16 Synthesis of 2-methylquinazolinone from o-aminobenzamide and calcium carbide Add 1 mmol of o-aminobenzamide, 3 mmol of water, 1 mmol of potassium hydroxide and 2 mL of solvent to the reaction kettle in sequence, stir at room temperature for 10 minutes, weigh 3 mmol of potassium sulfide and 2 mmol of calcium carbide and add them to the reaction kettle, close the reaction kettle, place it in a sand bath at 110 °C, and stir and react for 5 h. After the reaction is completed, cool to room temperature, extract with ethyl acetate and wash with saturated brine. Add 1 mmol of KMnO4 to the organic phase, stir for 60 min, filter and distill off the solvent under reduced pressure to obtain the crude product. The crude product is separated by column chromatography (200-300 mesh silica gel) to obtain a solid compound with a purity greater than 99%.

[0066] The nuclear magnetic resonance hydrogen spectrum of the solid compound prepared in Example 16 is as Figure 3 shown.

[0067] The nuclear magnetic resonance carbon spectrum of the solid compound prepared in Example 16 is as Figure 4 shown.

[0068] Nuclear magnetic characterization data of the solid compound prepared in Example 16: 1 H NMR (500 MHz, DMSO- d 6, TMS)δ 8.05 (d, J= 7.7 Hz, 1H), 7.71 (t, J = 6.9 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H),7.39 (t, J = 6.9 Hz, 1H), 4.76 (s, 1H), 2.33 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6,TMS) δ 162.9, 155.7, 149.2, 133.7, 126.3, 125.7, 125.3, 120.7, 22.0。

[0069] In Example 16, the structural formula of o-aminobenzamide is: 。

[0070] The solid compound prepared in Example 16 is 2-methylquinazolinone, and its structural formula is 。

[0071] The synthetic route of 2-methylquinazolinone is: 。

[0072] Examples 17 to 26 Synthesis of 2-methyl-2,3-dihydroquinazolinone from different o-aminobenzamide substrates Refer to the synthesis method of Example 5 to synthesize 2-methyl-2,3-dihydroquinazolinone. The substrate structures, product structures, product yields and NMR characterization data of the products are listed in Table 2.

[0073] The synthetic route of 2-methyl-2,3-dihydroquinazolinone is as follows: 。

[0074] Table 2

[0075] Examples 27 to 49 Synthesis of 2-methyl-2,3-dihydroquinazolinone from o-aminobenzonitrile and calcium carbide Add 1 mmol of o-aminobenzonitrile, 6 mmol of water, 2.5 mmol of base, and 2 mL of solvent to the reaction kettle in sequence, stir at room temperature for 10 minutes, weigh K2S and calcium carbide and add them to the reaction kettle, close the reaction kettle, place it in a constant temperature sand bath at T °C, and stir and react for t h. After the reaction is completed, cool to room temperature, remove the solvent by vacuum distillation to obtain a crude product, and separate the crude product by column chromatography (200-300 mesh silica gel) to obtain a solid compound with a purity greater than 99%.

[0076] Table 3 shows the yields of synthesizing 2,3-dihydroquinazolinone from o-aminobenzamide and calcium carbide by using different types of bases, different feed ratios, different reaction temperatures, different reaction times, and different solvents in Examples 27-49. The feed ratio refers to the molar ratio of o-aminobenzamide:CaC2:base:K2S:H2O.

[0077] Table 3

[0078] The structural formula of o-aminobenzonitrile in Examples 27-49 is: .

[0079] The NMR characterization data of the solid compounds prepared in Examples 27-49: 1 H NMR (500 MHz, DMSO- d 6,TMS) δ 7.89 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.71 –6.65 (m, 2H), 6.60 (s, 1H), 4.82 (q, J = 5.7 Hz, 1H), 1.31 (d, J = 5.8 Hz, 3H). 13 CNMR (126 MHz, DMSO- d 6, TMS) δ 164.1, 148.8, 133.1, 127.5, 117.2, 115.2,114.3, 60.9, 21.3.

[0080] The solid compounds prepared in Examples 27-49 are 2-methyl-2,3-dihydroquinazolinone, and its structural formula is .

[0081] The synthetic route of 2-methyl-2,3-dihydroquinazolinone is: .

[0082] Example 50 Synthesis of 2-methylquinazolinone from o-aminobenzonitrile and calcium carbide Add 1 mmol of o-aminobenzonitrile, 5 mmol of water, 2.5 mmol of sodium hydroxide and 2 mL of solvent to the reaction kettle in sequence, stir at room temperature for 10 minutes, weigh 3 mmol of potassium sulfide and 2 mmol of calcium carbide and add them to the reaction kettle, close the reaction kettle, place it in a sand bath at 120 °C, stir and react for 8 h. After the reaction is completed, cool to room temperature, and remove the solvent by vacuum distillation to obtain crude product 1; Add 1 mL of ethyl acetate and 1 mmol of KMnO4 to crude product 1, stir for 60 min, filter and then remove the solvent by vacuum distillation to obtain crude product 2. Crude product 2 is separated by column chromatography (200 - 300 mesh silica gel) to obtain a solid compound with a purity greater than 99%.

[0083] In Example 50, the structural formula of o-aminobenzonitrile is: ; Nuclear magnetic characterization data of the solid compound prepared in Example 50: 1 H NMR (500 MHz, DMSO- d 6, TMS)δ 8.05 (d, J = 7.7 Hz, 1H), 7.71 (t, J = 6.9 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H),7.39 (t, J = 6.9 Hz, 1H), 4.76 (s, 1H), 2.33 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6,TMS) δ 162.9, 155.7, 149.2, 133.7, 126.3, 125.7, 125.3, 120.7, 22.0。

[0084] The solid compound prepared in Example 50 is 2-methylquinazolinone, and its structural formula is 。

[0085] The synthesis route of 2-methylquinazolinone is: 。

[0086] Examples 51 - 65 Synthesis of 2-methyl-2,3-dihydroquinazolinone from different o-aminobenzonitrile substrates and calcium carbide 2-Methyl-2,3-dihydroquinazolinone was synthesized with reference to the synthesis method of Example 48. The substrate structure, product structure, product yield and NMR characterization data of the product are listed in Table 4.

[0087] The synthetic route of 2-methyl-2,3-dihydroquinazolinone derivatives is as follows: 。

[0088] Table 4

[0089] Examples 66 - 67 Synthesis of 2-methylthieno[2,3-d]pyrimidin-4-one compounds from different 2-amino-3-cyanothiophene substrates and calcium carbide 2-Methylthieno[2,3-d]pyrimidin-4-one compounds were synthesized with reference to the synthesis method of Example 48. The substrate structure, product structure, product yield and NMR characterization data of the product are listed in Table 5.

[0090] The synthetic route of 2-methylthieno[2,3-d]pyrimidin-4-one compounds is as follows: 。

[0091] Table 5

Claims

1. A method for in-situ preparing 2-methylquinazolinone compounds using calcium carbide, which includes reacting reaction substrates and calcium carbide in the presence of inorganic metal sulfides, water, strong base, and organic solvents; The 2-methylquinazolinone compounds are selected from one of 2-methyl-2,3-dihydroquinazolinone and 2-methylquinazolinone; The reaction substrates are selected from one of reaction substrate 1 and reaction substrate 2; The reaction substrate 1 is selected from one of o-aminobenzamide and 2-aminothiophenecarboxamide; The reaction substrate 2 is selected from one of o-aminobenzonitrile and 2-aminothiophenecarbonitrile.

2. The method according to claim 1, wherein, The structural formula of the 2-methyl-2,3-dihydroquinazolinone is shown as formula (Ⅰ) or formula (Ⅱ): （Ⅰ） （Ⅱ）； The structural formula of the 2-methylquinazolinone is shown as formula (Ⅲ) or formula (Ⅳ): （Ⅲ） （Ⅳ）； The structural formula of the o-aminobenzamide is shown as formula (Ⅴ): （Ⅴ）； The structural formula of the 2-aminothiophenecarboxamide is shown as formula (Ⅵ): （Ⅵ）； The structural formula of the o-aminobenzonitrile is shown as formula (Ⅶ): （Ⅶ）； The structural formula of the 2-aminothiophenecarbonitrile is shown as formula (Ⅷ): （Ⅷ）； X in formula (Ⅰ), formula (Ⅲ), formula (Ⅴ), and formula (Ⅶ) independently selects from C and N; n in formula (Ⅰ), formula (Ⅲ), formula (Ⅴ), and formula (Ⅶ) independently selects from 5, 6, 7, and 8; R in Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), and Formula (VIII) 1 is independently selected from one or two of H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 hydrocarbyl, C 1-8 hydroxy, or C 1-8 sulfonyl R in formula (I), formula (II), formula (III), formula (IV), formula (V), and formula (VI) 2 independently selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl or C with a derivative group 6-14 aryl, C 1-8 alkyl or C with a derivative group 1-8 alkyl; R in formula (I), formula (II), formula (V), formula (VI), formula (VII), and formula (VIII) 3 is independently selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 aryl or C 6-14 aryl having a derivative group, C 1-8 alkyl or C 1-8 alkyl having a derivative group, one of them.

3. The method according to claim 1, wherein, The inorganic metal sulfides are selected from at least one of alkali metal sulfides and alkali metal hydrosulfides; or / and, The strong base is selected from at least one of alkali metal hydroxides, alkaline earth metal hydroxides, and C 1-6 alkoxide salts; or / and, The organic solvent is a polar solvent; or / and, The dosage ratio of the reaction substrate to the organic solvent is 1 mmol:(1 mL - 5 mL); or / and, The molar ratio of the reaction substrate 1 to calcium carbide, water, inorganic metal sulfide, and strong base is 1:(1 - 6):(1 - 24):(1 - 10):(0.2 - 3); or / and, The molar ratio of the reaction substrate 2 to calcium carbide, water, inorganic metal sulfide, and strong base is 1:(1 - 6):(3 - 48):(0.5 - 10):(0.5 - 4).

4. The method according to claim 1, wherein, The inorganic metal sulfides are selected from at least one of K2S, Na2S, NaHS, KHS, Na2Sx, and K2Sx; x in Na2Sx and K2Sx selects from 2, 3, 4, 5, or 6; or / and, The strong base is selected from at least one of alkali metal hydroxides and metal tert-butoxides; or / and, The organic solvent is selected from at least one of N-methylpyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoramide, acetonitrile, C 1-8 alcohols; or / and, The molar ratio of the reaction substrate 1 to calcium carbide, water, inorganic metal sulfide, and strong base is 1:(2 - 4):(4 - 10):(1 - 4):(0.5 - 2); or / and, The molar ratio of the reaction substrate 2 to calcium carbide, water, inorganic metal sulfide, and strong base is 1:(2 - 4):(4 - 32):(1 - 4):(1 - 3).

5. The method according to claim 1, characterized in that, It includes the following steps: (1) Mix the reaction substrate, water, strong base, and organic solvent, add inorganic metal sulfide and calcium carbide, and react under sealed stirring conditions; after the reaction ends, collect the organic phase; The organic phase is purified to obtain the 2-methyl-2,3-dihydroquinazolinone; or, An oxidizing agent is added to the organic phase, and an oxidation reaction is carried out under stirring conditions. After the reaction is completed, the solvent is removed and purified to obtain the 2-methylquinazolinone.

6. The method according to claim 5, wherein In step (1), The reaction substrate is selected from reaction substrate 1, and the reaction temperature is 70 - 130 °C; or / and, The reaction substrate is selected from reaction substrate 1, and the reaction time is 1 - 24 h; or / and, The reaction substrate is selected from reaction substrate 2, and the reaction temperature is 80 - 140 °C; or / and, The reaction substrate is selected from reaction substrate 2, and the reaction time is 5 - 24 h.

7. The method according to claim 5, wherein In step (1), The reaction substrate is selected from reaction substrate 1, and the reaction temperature is 110 - 120 °C; or / and, The reaction substrate is selected from reaction substrate 1, and the reaction time is 2 - 6 h; or / and, The reaction substrate is selected from reaction substrate 2, and the reaction temperature is 100 - 130 °C; or / and, The reaction substrate is selected from reaction substrate 2, and the reaction time is 8 - 12 h.

8. The method according to claim 5, wherein In step (2-2), The oxidizing agent is at least one of H2O2, KMnO4, K2Cr2O7, Dess-Martin periodinane, 2,3-dichloro-5,6-dicyano-p-benzoquinone; or / and, The molar ratio of the oxidizing agent to the reaction substrate is (1 - 10):1; or / and, The reaction temperature is 5 - 50 °C; and / or, The reaction time is 0.1 - 2 h.

9. The method according to claim 5, characterized in that, In step (2-2), The molar ratio of the oxidizing agent to the reaction substrate is (1 - 5):1; or / and, The reaction temperature is 10 - 30 °C; and / or, The reaction time is 0.5 - 1 h.

10. A 2-methyl-2,3-dihydroquinazolinone compound obtained by the method according to any one of claims 1 - 9; The 2-methyl-2,3-dihydroquinazolinone compounds are selected from , , , , , , , , , , , , , .

Images