A method for in-situ preparation of 2-methylquinazolinone compounds using calcium carbide and its products

Abstract

The present invention relates to the fields of medicine, pesticides, and functional materials, and more particularly to a method for in-situ preparation of 2-methylquinazolinone compounds using calcium carbide and their products. The present invention uses o-aminobenzamide compounds, 2-aminothiophenecarboxamide compounds, o-aminobenzonitrile compounds, or 2-aminothiophenenitrile compounds as reaction substrates. The reaction substrates and calcium carbide are regulated by an inorganic metal sulfide and a base to synthesize 2-methyl-2,3-dihydroquinazolinone and its derivatives. An oxidant is further added to 2-methyl-2,3-dihydroquinazolinone and its derivatives to synthesize 2-methyl-2,3-dihydroquinazolinone and its derivatives. A new synthesis route is provided for 2-methyl-2,3-dihydroquinazolinone and 2-methyl-quinazolinone and their derivatives. The present invention utilizes inexpensive and readily available calcium carbide as a raw material for the first time, using inexpensive reagents to achieve efficient and selective preparation of two target compounds under relatively mild conditions.

Description

Technical Field

[0001] The present invention relates to the fields of medicine, pesticides and functional materials, and more particularly to a method for in-situ preparation of 2-methylquinazolinone compounds 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 quinazolinones exhibit promising biological activities in anti-inflammatory, anti-tumor, sedative, antibacterial, antihypertensive, and vasodilatory properties. For example, methazolone is clinically used as a sedative and hypnotic, febrifugine (a quinazolone-type alkaloid) exhibits antimalarial activity, and halofuginone (a drug containing a quinazolone structure) is a broad-spectrum antiparasitic drug.

[0003] Currently, the main synthetic methods for quinazolinone and its derivatives include: 1. Preparation by cyclization of o-aminobenzamide with aldehydes in the presence of a strong base; 2. Preparation by in situ oxidation of o-aminobenzamide with alcohols to aldehydes under transition metal catalysis, followed by cyclization; 3. Preparation by tandem cyanohydrolysis and cyclization of o-aminobenzonitrile with aldehydes in the presence of a strong base; and 4. Preparation by combining o-aminobenzonitrile with alcohols under the combined control of a transition metal and a strong base. Existing synthetic methods for quinazolinone and its derivatives still suffer from issues such as expensive raw materials, low atom utilization, and metal residues. Summary of the Invention

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

[0005] The present invention uses o-aminobenzamide, 2-aminothiophenecarboxamide, o-aminobenzonitrile or 2-aminothiophenenitrile as reaction substrates. The reaction substrates and calcium carbide are regulated by inorganic metal sulfide and base to synthesize 2-methyl 2, 3-dihydroquinazolinone. The 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 preparation of 2-methylquinazolinone compounds using calcium carbide.

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

[0008] The 2-methylquinazolinone compound is 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 in formula (I) or formula (II):

[0010] (I) (II).

[0011] In formula (I):

[0012] X is selected from one of C and N;

[0013] n is selected from 5, 6, 7, and 8;

[0014] R 1 Selected from H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 Hydrocarbon, C 1-8 Hydroxyl or C 1-8 one or two sulfonyl groups;

[0015] R 2 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 One of the aliphatic hydrocarbon groups;

[0016] R 3 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 A type of aliphatic hydrocarbon.

[0017] In formula (II):

[0018] R 1 Selected from H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 Hydrocarbon, C 1-8 Hydroxyl or C 1-8 one or two sulfonyl groups;

[0019] R 2 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 One of the aliphatic hydrocarbon groups;

[0020] R3 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 A type of aliphatic hydrocarbon.

[0021] The structural formula of the 2-methylquinazolinone is shown in formula (III) or formula (IV):

[0022] (III) (IV).

[0023] In formula (III):

[0024] X is selected from one of C and N;

[0025] n is selected from 5, 6, 7, and 8;

[0026] R 1 Selected from H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 Hydrocarbon, C 1-8 Hydroxyl or C 1-8 one or two sulfonyl groups;

[0027] R 2 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 A type of aliphatic hydrocarbon.

[0028] In formula (IV):

[0029] R 1 Selected from H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 Hydrocarbon, C 1-8 Hydroxyl or C 1-8 one or two sulfonyl groups;

[0030] R 2 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 A type of aliphatic hydrocarbon.

[0031] The reaction substrate is selected from one of reaction substrate 1 and reaction substrate 2.

[0032] The reaction substrate 1 is selected from one of o-aminobenzamide and 2-aminothiophenecarboxamide.

[0033] The structural formula of the o-aminobenzamide is shown in formula (V):

[0034] (V);

[0035] In formula (V):

[0036] X is selected from one of C and N;

[0037] n is selected from 5, 6, 7 or 8;

[0038] R 1 Selected from H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 Hydrocarbon, C 1-8 Hydroxyl or C 1-8 one or two sulfonyl groups;

[0039] R 2 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 One of the aliphatic hydrocarbon groups;

[0040] R 3 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 A type of aliphatic hydrocarbon.

[0041] The structural formula of the 2-aminothiophenecarboxamide is shown in formula (VI):

[0042] (VI);

[0043] In formula (VI):

[0044] R 1 Selected from H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 Hydrocarbon, C 1-8 Hydroxyl or C 1-8 one or two sulfonyl groups;

[0045] R 2 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 One of the aliphatic hydrocarbon groups;

[0046] R 3 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 A type of aliphatic hydrocarbon.

[0047] The reaction substrate 2 is selected from one of o-aminobenzonitrile and 2-aminothiophenecarbonitrile.

[0048] The structural formula of the o-aminobenzonitrile is shown in formula (VII):

[0049] (VII);

[0050] In formula (VII):

[0051] X is selected from one of C and N;

[0052] n is selected from 5, 6, 7 or 8;

[0053] R 1 Selected from H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 Hydrocarbon, C 1-8 Hydroxyl or C 1-8 one or two sulfonyl groups;

[0054] R 3 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 A type of aliphatic hydrocarbon.

[0055] The structural formula of the 2-aminothiophenecarbonitrile is shown in formula (VIII):

[0056] (VIII);

[0057] In formula (VIII):

[0058] R1 Selected from H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 Hydrocarbon, C 1-8 Hydroxyl or C 1-8 one or two sulfonyl groups;

[0059] R 3 Selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 6-14 Aromatic hydrocarbon group or C with derivative group 6-14 Aromatic hydrocarbon group, C 1-8 Aliphatic hydrocarbon group or C with derivative group 1-8 A type of aliphatic hydrocarbon.

[0060] In formula (I) to formula (VIII):

[0061] The C 1-15 Hydrocarbyl groups include but are not limited to C 1-15 Alkyl, phenyl, phenyl having alkyl substitution, etc.; preferably methyl, naphthyl ring, 2-methylphenyl;

[0062] The C 1-8 Alkyloxy includes but is not limited to C 1-8 Alkoxy, C 6-8 Aromatic alkyloxy; preferably methoxy;

[0063] The C 1-8 Sulfonyl groups include but are not limited to C 1-8 Alkylsulfonyl, C 6-8 Aromatic hydrocarbon sulfonyl group;

[0064] R 1 The substitution positions on the benzene ring and the thiophene ring are any feasible positions and are not particularly limited in the present invention;

[0065] The C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 C involved in alkylsulfonyl 1-8 The alkyl group may be an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and may be a linear alkyl group or a branched alkyl group, and the present invention has no particular limitation.

[0066] In the present invention,

[0067] The product corresponding to the reaction substrate of formula (V) is formula (I) or formula (III);

[0068] The product corresponding to the reaction substrate of formula (VII) is of formula (I) or formula (III),

[0069] The product corresponding to the reaction substrate of formula (VI) is formula (II) or formula (IV);

[0070] The product corresponding to the reaction substrate of formula (VIII) is formula (II) or formula (IV).

[0071] The inorganic metal sulfide can be selected from a wide range. Preferably, the inorganic metal sulfide is selected from at least one of an alkali metal sulfide and an alkali metal hydrosulfide, more preferably at least one of K2S, Na2S, NaHS, KHS, Na2Sx, and K2Sx, and even more preferably at least one of K2S, Na2S, KHS, and NaHS; wherein x in Na2Sx and K2Sx is selected from 2, 3, 4, 5, or 6.

[0072] The strong base can be selected from a wide range. As a preferred embodiment, the strong base is selected from alkali metal hydroxides, alkaline earth metal hydroxides, C 1-6 The at least one metal alkoxide is more preferably selected from an alkali metal hydroxide or a metal salt of tert-butoxide.

[0073] The organic solvent is a type of solvent that uses organic matter as a medium. There is no particular limitation and it can be selected from a 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, it is selected from N-methylpyrrolidone (NMP), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA), acetonitrile, C 1-8 At least one of alcohols; further preferably selected from NMP, C 2-6 At least one of alcohol, DMF, and DMA.

[0074] The amount of the organic solvent can be selected within a wide range. As a preferred embodiment, the amount of the organic solvent is 1-5 mL relative to 1 mmol of the reaction substrate; that is, the ratio of the reaction substrate to the organic solvent is 1 mmol: (1 mL-5 mL).

[0075] The molar ratio of the reaction substrate to calcium carbide, water, inorganic metal sulfide, and strong base can be selected within a wide range. As a preferred embodiment, the molar ratio of 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 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).

[0076] The method for in-situ preparation of 2-methylquinazolinone compounds using calcium carbide comprises the following steps:

[0077] (1) Mix the reaction substrate, water, strong base and organic solvent, add inorganic metal sulfide and calcium carbide, and react under closed stirring conditions; collect the organic phase after the reaction is completed;

[0078] (2-1) The organic phase is purified to obtain the 2-methyl 2, 3-dihydroquinazolinone; or,

[0079] (2-2) Adding an oxidant to the organic phase, carrying out an oxidation reaction under stirring, removing the solvent after the reaction, and purifying to obtain the 2-methylquinazolinone.

[0080] The method includes a method for preparing 2-methyl 2, 3-dihydroquinazolinone or a method for preparing 2-methylquinazolinone.

[0081] The method for preparing 2-methyl 2, 3-dihydroquinazolinone comprises: mixing a reaction substrate, water, a strong base and an organic solvent, adding an inorganic metal sulfide and calcium carbide, and reacting under closed stirring conditions; after the reaction is completed, collecting an organic phase; and purifying the organic phase to obtain the 2-methyl 2, 3-dihydroquinazolinone.

[0082] The method for preparing 2-methylquinazolinone comprises: mixing a reaction substrate, water, a strong base and an organic solvent, adding an inorganic metal sulfide and calcium carbide, and reacting under closed stirring conditions; collecting an organic phase after the reaction is completed; adding an oxidant to the organic phase, carrying out an oxidation reaction under stirring conditions, removing the solvent after the reaction is completed, and purifying to obtain the 2-methylquinazolinone.

[0083] As can be seen, both the method for preparing 2-methyl-2,3-dihydroquinazolinone and the method for preparing 2-methylquinazolinone comprise the following steps: mixing a reaction substrate, water, a strong base, and an organic solvent, adding an inorganic metal sulfide and calcium carbide, and reacting under closed stirring conditions; and 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 and the reaction continues, the 2-methylquinazolinone is obtained.

[0084] In the method, the reaction temperature and reaction time of step (1) can be selected within a wide range. Depending on the reaction substrate, the reaction temperature and reaction time in step (1) may vary.

[0085] When the reaction substrate is selected from reaction substrate 1; as a preferred embodiment, the reaction temperature of step (1) is 70-130°C, more preferably 110-120°C; the reaction time of step (1) is 1-24 h, more preferably 2-6 h.

[0086] When the reaction substrate is selected from reaction substrate 2; as a preferred embodiment, the reaction temperature of step (1) is 80-140°C, more preferably 100-130°C; the reaction time of step (1) is 5-24 h, more preferably 8-12 h.

[0087] In step (1) of the method, the organic phase can be collected by conventional methods. As a specific solution, collecting the organic phase includes: cooling the organic phase to room temperature, extracting with ethyl acetate, and washing with saturated brine.

[0088] In step (2-1) of the method, the purification can be performed using conventional purification methods. As a specific embodiment, the purification includes drying the organic phase and then removing the solvent under reduced pressure to obtain a crude product, and then recrystallizing or separating the crude product by column chromatography to obtain the 2-methyl-2,3-dihydroquinazolinone.

[0089] In step (2-2) of the method, the oxidant can be selected from a wide range. As a preferred embodiment, the oxidant is at least one of H2O2, KMnO4, K2Cr2O7, Dess-Martin periodinane (DMP), and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).

[0090] In step (2-2) of the method, the amount of the oxidant can be selected within a wide range. As a preferred embodiment, the molar ratio of the oxidant to the reaction substrate is (1-10):1, more preferably (1-6):1.

[0091] In the method, the reaction temperature and time conditions of step (2-2) can be selected within a wide range. As a preferred embodiment, the reaction temperature of step (2-2) is 5-50°C, more preferably 10-30°C; and the reaction time of step (2-2) is 0.1-2 h, more preferably 0.5-1 h.

[0092] In step (2-2) of the method, the organic solvent can be removed by conventional means. As a specific solution, the organic solvent can be removed by vacuum distillation.

[0093] In step (2-2) of the method, the purification can adopt a conventional purification method. As a specific scheme, the purification includes: recrystallization or column chromatography separation.

[0094] The method can selectively synthesize 2,3-dihydroquinazolinone and 2-methylquinazolinone derivatives by regulating specific reaction conditions. The method can achieve efficient and selective preparation of the two target compounds under relatively mild conditions.

[0095] As a specific scheme, the method for synthesizing the compound represented by formula (I) comprises:

[0096] The compound represented by formula (V) or formula (VII), water, a strong base and a solvent are added to the reaction kettle in sequence and stirred for 10 minutes. The inorganic metal sulfide and the ground calcium carbide are added to the reaction kettle in sequence. The reaction kettle is sealed and the reaction temperature is controlled to be 110-120°C. After the reaction is completed, it is cooled to room temperature, extracted with ethyl acetate, washed with saturated brine, and the organic phase is dried and the solvent is removed under reduced pressure to obtain a crude product. The crude product is recrystallized or separated by column chromatography to obtain a compound represented by formula (I).

[0097] As a specific scheme, the method for synthesizing the compound represented by formula (III) includes:

[0098] The compound represented by formula (V) or formula (VII), water, a strong base and a solvent are added to the reaction kettle in sequence and stirred for 10 minutes. The inorganic metal sulfide and the ground calcium carbide are added to the reaction kettle in sequence. The reaction kettle is sealed and the reaction temperature is controlled to be 110-120°C. After the reaction is completed, it is cooled to room temperature, extracted with ethyl acetate, washed with saturated brine, and the organic phase is dried and the solvent is removed under reduced pressure to obtain a crude product. An oxidant in an amount 2-6 times the molar amount of the compound represented by formula (V) or formula (VII) is added, and the mixture is stirred at room temperature for 20-60 minutes. The crude product is recrystallized or separated by column chromatography to obtain a compound represented by formula (III).

[0099] As a specific scheme, the method for synthesizing the compound represented by formula (II) includes:

[0100] Add the compound represented by formula (VI) or formula (VIII), water, strong base and solvent to the reaction kettle in sequence, stir for 10 minutes, add inorganic metal sulfide and ground calcium carbide to the reaction kettle in sequence, seal the reaction kettle, control the reaction temperature to 110-120°C, and after the reaction is completed, cool to room temperature, extract with ethyl acetate, wash with saturated brine, dry the organic phase, and remove the solvent under reduced pressure to obtain a crude product. The crude product is recrystallized or separated by column chromatography to obtain a compound represented by formula (II).

[0101] As a specific scheme, the method for synthesizing the compound represented by formula (IV) includes:

[0102] The compound represented by formula (VI) or formula (VIII), water, a strong base and a solvent are added to the reaction kettle in sequence and stirred for 10 minutes. The inorganic metal sulfide and the ground calcium carbide are added to the reaction kettle in sequence. The reaction kettle is sealed and the reaction temperature is controlled to be 110-120°C. After the reaction is completed, it is cooled to room temperature, extracted with ethyl acetate, washed with saturated brine, and the organic phase is dried and the solvent is removed under reduced pressure to obtain a crude product. An oxidant in an amount 2-6 times the molar amount of the compound represented by formula (VI) or formula (VIII) is added, and the mixture is stirred at room temperature for 20-60 minutes. The crude product is recrystallized or separated by column chromatography to obtain a compound represented by formula (IV).

[0103] A second object of the present invention is to provide a novel 2-methyl-2,3-dihydroquinazolinone compound synthesized by the method.

[0104] 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-Nitrilo-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.

[0105] Compared with the prior art, the present invention has the following beneficial effects:

[0106] The present invention utilizes cheap and readily available calcium carbide as a raw material for the first time and uses inexpensive reagents to achieve efficient and selective preparation of two target compounds under relatively mild conditions.

[0107] This invention, for the first time, utilizes safe and readily available inorganic metal sulfides as activators to control the reaction, achieving highly selective conversion of calcium carbide with o-aminobenzamide and / or o-aminobenzonitrile into 2-methyl-2,3-dihydroquinazolinone or 2-methylquinazolinone under relatively mild conditions. Compared to existing technologies, the present method utilizes safe and readily available raw materials, achieves higher atomic utilization, and eliminates the need for expensive and complex post-processing metal catalysts. It offers advantages such as environmental friendliness, minimal byproducts, and low cost, making it highly valuable for widespread application. Specifically:

[0108] 1. Safe, cheap and readily available calcium carbide is used as the reaction raw material;

[0109] 2. No high-pressure resistant equipment is required, and the risk of explosion is low;

[0110] 3. Using safe and readily available inorganic metal sulfides as regulating reagents for selective synthesis avoids the metal residue problem caused by the use of metal catalysts;

[0111] 4. By simply adjusting the reaction conditions, a highly selective synthesis of two different quinazolinone compounds was achieved with high atom economy;

[0112] 5. This method has strong substrate applicability for the synthesis of 2, 3-dihydroquinazolinone and 2-methylquinazolinone with high yield.

[0113] In summary, the present method for selectively synthesizing 2,3-dihydroquinazolinone and 2-methylquinazolinone by regulating calcium carbide with o-aminobenzamide and / or o-aminobenzonitrile using inorganic sulfide uses safe, stable, and readily available calcium carbide as a raw material, does not require transition metal catalysts and high-pressure equipment, and, compared with the above methods, has more prominent advantages in "atom economy" and "green chemistry." BRIEF DESCRIPTION OF THE DRAWINGS

[0114] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the product prepared in Example 1-15;

[0115] Figure 2 is the carbon NMR spectrum of the product prepared in Example 1-15;

[0116] Figure 3 is the H NMR spectrum of the product prepared in Example 16;

[0117] Figure 4 This is the carbon NMR spectrum of the product prepared in Example 16. DETAILED DESCRIPTION

[0118] The present invention will be described in detail below with reference to specific drawings and embodiments. It is necessary to point out that the following embodiments are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art to the present invention based on the contents of the present invention still fall within the scope of protection of the present invention.

[0119] The reaction reagents involved in the examples are all commonly used commercially available products.

[0120] The nuclear magnetic resonance spectrometer used in the examples is Agilent 500 MHz DD2.

[0121] Examples 1 to 15

[0122] Synthesis of 2-Methyl-2, 3-Dihydroquinazolinone by Reaction of o-aminobenzamide with Calcium Carbide

[0123] To a reaction kettle, add 1 mmol of o-aminobenzamide, 3 mmol of water, a certain amount of potassium hydroxide, and 2 mL of solvent, sequentially. Stir at room temperature for 10 minutes. Weigh a certain amount of inorganic metal sulfide and 2 mmol of calcium carbide and add them to the reaction kettle. Close the reactor and place it in a constant-temperature sand bath at T°C, stirring for 3 hours. After the reaction is complete, cool to room temperature, extract with ethyl acetate, and wash with saturated brine. The organic phase is dried, and the solvent is removed under reduced pressure to obtain a 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%.

[0124] Table 1 shows the yields of 2,3-dihydroquinazolinone synthesized from o-aminobenzamide and calcium carbide using different inorganic metal sulfides, feed ratios, reaction temperatures, reaction times, and solvents, respectively, in Examples 1-15. The feed ratio refers to the molar ratio of o-aminobenzamide: CaC₂: KOH: K₂S: H₂O.

[0125] Table 1

[0126]

[0127] In Examples 1 to 15, the structural formula of o-aminobenzamide is: .

[0128] The H NMR spectra of the solid compounds prepared in Examples 1 to 15 are as follows: Figure 1 As shown;

[0129] The carbon NMR spectra of the solid compounds prepared in Examples 1 to 15 are as follows: Figure 2 As shown;

[0130] The NMR characterization data of the solid compounds prepared in Examples 1 to 15 are as follows: 1H 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 (126 MHz, DMSO- d 6) δ 164.1, 148.8, 133.1, 127.5, 117.2, 115.2, 114.3, 60.9, 21.3.

[0131] The solid compound prepared in Examples 1 to 15 is 2-methyl-2, 3-dihydroquinazolinone, and its structural formula is .

[0132] The synthetic route of 2-methyl 2, 3-dihydroquinazolinone is:

[0133] .

[0134] Example 16

[0135] Synthesis of 2-Methylquinazolinone from o-aminobenzamide and calcium carbide

[0136] To a reaction kettle, add 1 mmol of o-aminobenzamide, 3 mmol of water, 1 mmol of potassium hydroxide, and 2 mL of solvent, sequentially. Stir at room temperature for 10 minutes. Then, weigh 3 mmol of potassium sulfide and 2 mmol of calcium carbide and add them to the reaction kettle. The reaction kettle is closed and placed in a sand bath at 110°C, where it is stirred for 5 hours. After the reaction is complete, 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 minutes, filter, and remove the solvent by vacuum distillation to obtain a crude product. This crude product is then separated by column chromatography (200-300 mesh silica gel) to obtain a solid compound with a purity greater than 99%.

[0137] The H NMR spectrum of the solid compound prepared in Example 16 is as follows: Figure 3 shown.

[0138] The carbon NMR spectrum of the solid compound prepared in Example 16 is as follows: Figure 4 shown.

[0139] The NMR 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.

[0140] In Example 16, the structural formula of o-aminobenzamide is: .

[0141] The solid compound prepared in Example 16 is 2-methylquinazolinone, and its structural formula is .

[0142] The synthetic route of 2-methylquinazolinone is:

[0143] .

[0144] Examples 17 to 26

[0145] Synthesis of 2-Methyl 2, 3-Dihydroquinazolinone Using Different Anthranilamide Substrates

[0146] 2-Methyl-2,3-dihydroquinazolinone was synthesized according to the synthesis method of Example 5. The substrate structure, product structure, product yield, and NMR characterization data of the product are listed in Table 2.

[0147] The synthetic route of 2-methyl 2, 3-dihydroquinazolinone is as follows:

[0148] .

[0149] Table 2

[0150]

[0151] Examples 27 to 49

[0152] Synthesis of 2-Methyl 2, 3-Dihydroquinazolinone from o-Aminobenzonitrile and Calcium Carbide

[0153] To a reaction kettle, add 1 mmol of o-aminobenzonitrile, 6 mmol of water, 2.5 mmol of a base, and 2 mL of a solvent, sequentially. Stir at room temperature for 10 minutes. Weigh K2S and calcium carbide and add them to the reaction kettle. Close the reactor and place it in a constant-temperature sand bath at T°C, stirring for 3 h. After the reaction is complete, cool to room temperature and remove the solvent by vacuum distillation to obtain a crude product. This crude product is then separated by column chromatography (200-300 mesh silica gel) to obtain a solid compound with a purity greater than 99%.

[0154] Table 3 shows the yields of 2,3-dihydroquinazolinone synthesized from o-aminobenzamide and calcium carbide using different base types, feed ratios, reaction temperatures, reaction times, and solvents in Examples 27-49. The feed ratio refers to the molar ratio of o-aminobenzamide: CaC₂: base: K₂S: H₂O.

[0155] Table 3

[0156]

[0157] The structural formula of o-aminobenzonitrile in Examples 27 to 49 is: .

[0158] The NMR characterization data of the solid compounds prepared in Examples 27 to 49 are as follows: 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.

[0159] The solid compound prepared in Examples 27 to 49 is 2-methyl-2, 3-dihydroquinazolinone, and its structural formula is .

[0160] The synthetic route of 2-methyl 2, 3-dihydroquinazolinone is:

[0161] .

[0162] Example 50

[0163] Synthesis of 2-Methylquinazolinone from o-Aminobenzonitrile and Calcium Carbide

[0164] To the reactor, 1 mmol of o-aminobenzonitrile, 5 mmol of water, 2.5 mmol of sodium hydroxide, and 2 mL of solvent were added in sequence and stirred at room temperature for 10 minutes. 3 mmol of potassium sulfide and 2 mmol of calcium carbide were weighed and added to the reactor. The reactor was closed and placed in a sand bath at 120°C. The reaction was stirred for 8 hours. After the reaction was completed, the mixture was cooled to room temperature and the solvent was removed by distillation under reduced pressure to obtain crude product 1.

[0165] To the crude product 1, 1 mL of ethyl acetate and 1 mmol of KMnO4 were added, and the mixture was stirred for 60 min. After filtration, the solvent was removed by distillation under reduced pressure to obtain the crude product 2. The crude product 2 was separated by column chromatography (200-300 mesh silica gel) to obtain a solid compound with a purity greater than 99%.

[0166] In Example 50, the structural formula of o-aminobenzonitrile is: ;

[0167] The NMR 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.

[0168] The solid compound prepared in Example 50 is 2-methylquinazolinone, and its structural formula is .

[0169] The synthetic route of 2-methylquinazolinone is:

[0170] .

[0171] Examples 51 to 65

[0172] Synthesis of 2-Methyl 2, 3-Dihydroquinazolinone from Different o-Aminobenzonitrile Substrates and Calcium Carbide

[0173] 2-Methyl-2,3-dihydroquinazolinone was synthesized according 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.

[0174] The synthetic route of 2-methyl 2, 3-dihydroquinazolinone derivatives is as follows:

[0175] .

[0176] Table 4

[0177]

[0178] Examples 66-67

[0179] Synthesis of 2-Methylthieno[2,3-D]pyrimidin-4-one Compounds from Different 2-Amino-3-cyanothiophene Substrates and Calcium Carbide

[0180] 2-Methylthieno[2,3-D]pyrimidin-4-one was synthesized by referring 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.

[0181] The synthetic route of 2-methylthieno[2,3-D]pyrimidin-4-one compound is as follows:

[0182] .

[0183] Table 5

[0184]

Claims

1. A method for in-situ preparation of 2-methylquinazolinone compounds using calcium carbide, comprising: (1) Mix the reaction substrate, water, strong base and organic solvent, add inorganic metal sulfide and calcium carbide, and react under closed stirring conditions; collect the organic phase after the reaction is completed; (2-1) The organic phase is purified to obtain the 2-methyl 2, 3-dihydroquinazolinone; or, (2-2) adding an oxidizing agent to the organic phase, carrying out an oxidation reaction under stirring, removing the solvent after the reaction, and purifying to obtain the 2-methylquinazolinone; The reaction substrate is 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; The structural formula of the 2-methyl 2, 3-dihydroquinazolinone is shown in formula (I) or formula (II): Formula (I), (II); The structural formula of the 2-methylquinazolinone is shown in formula (III) or formula (IV): （Ⅲ） （Ⅳ）； The structural formula of the o-aminobenzamide is shown in formula (V): （Ⅴ）； The structural formula of the 2-aminothiophenecarboxamide is shown in formula (VI): （Ⅵ）； The structural formula of the o-aminobenzonitrile is shown in formula (VII): （Ⅶ）； The structural formula of the 2-aminothiophenecarbonitrile is shown in formula (VIII): （Ⅷ）； R in formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII) 1 Independently selected from H, F, Cl, Br, I, CF3, OCF3, NO2, CN, C 1-15 Hydrocarbon, C 1-8 One or two of the alkoxy groups; 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 Aromatic hydrocarbon group, C 1-8 One of the aliphatic hydrocarbon groups; R in formula (I), formula (II), formula (V), formula (VI), formula (VII), and formula (VIII) 3 Independently selected from H, NH2, F, Cl, Br, I, CF3, OCF3, C 1-8 A type of aliphatic hydrocarbon.

2. The method according to claim 1, wherein The inorganic metal sulfide is selected from at least one of alkali metal sulfides and alkali metal hydrosulfides; or / and, The strong base is selected from alkali metal hydroxides, alkaline earth metal hydroxides, C 1-6 At least one of alkoxide metal salts; or / and, The organic solvent is a polar solvent; or / and, The reaction substrate and the organic solvent are used in a ratio of 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).

3. The method according to claim 1, wherein The inorganic metal sulfide is selected from at least one of K2S, Na2S, NaHS, KHS, Na2Sx, and K2Sx; wherein x in Na2Sx and K2Sx is selected from 2, 3, 4, 5, or 6; or / and The strong base is selected from at least one of an alkali metal hydroxide and a metal salt of tert-butoxide; or / and, The organic solvent is selected from N-methylpyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric triamide, acetonitrile, C 1-8 at least one of 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).

4. The method according to claim 1, 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, 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.

5. The method according to claim 1, 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, 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.

6. The method according to claim 1, wherein In step (2-2), The oxidant is at least one of H2O2, KMnO4, K2Cr2O7, Dess-Martin periodinane, and 2,3-dichloro-5,6-dicyano-p-benzoquinone; or / and, The molar ratio of the oxidant 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.

7. The method according to claim 1, wherein In step (2-2), The molar ratio of the oxidant 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.

8. A method for in-situ preparation of 2-methylquinazolinone compounds using calcium carbide, comprising: 1 mmol of o-aminobenzonitrile, water, sodium hydroxide, and 2 mL of n-butanol were added to a reaction kettle in sequence, and the mixture was stirred at room temperature for 10 minutes. K2S and calcium carbide were weighed and added to the reaction kettle. The reaction kettle was closed and placed in a constant temperature sand bath at 120°C, and the reaction was stirred for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was separated by column chromatography on 200-300 mesh silica gel to obtain the 2-methyl-2,3-dihydroquinazolinone. The structural formula of the o-aminobenzonitrile is ; The structural formula of the 2-methyl 2,3-dihydroquinazolinone is ; The molar ratio of o-aminobenzonitrile: CaC2: sodium hydroxide: K2S: H2O is 1:2:2.5:3:5.

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