CN113214249B - Synthesis method of pyrido [1,2-a ] pyrimidine-4-thioketone compound - Google Patents

Abstract

The invention provides a pyrido [1,2-a ]]A method for synthesizing pyrimidine-4-thioketone compound, which belongs to the technical field of drug synthesis. The invention provides a synthesis method which utilizes N- (2-pyridine) ketimine and CS ₂ For starting materials, in the presence of a base and a solvent, by C (sp ³ ) Thiocarbonylation of the-H bond to give the desired pyrido [1,2-a ] product]The pyrimidine-4-thione has the characteristics of wide substrate range, good functional group tolerance, easy expansion and the like, can efficiently react and synthesize a target product, and has potential application prospects in organic synthesis and pharmaceutical industry.

Description

Synthesis method of pyrido[1,2-a]pyrimidine-4-thione compound

Technical field

The invention belongs to the technical field of drug synthesis and relates to a method for synthesizing pyridopyrimidinone compounds, specifically to a method for synthesizing pyrido[1,2-a]pyrimidine-4-thione compounds.

Background technique

Sulfur-containing carbonyl heterocyclic compounds have long attracted attention due to their unique biological and pharmacological activities. Traditional synthesis methods usually use elemental sulfur, Lawesson's reagent, isothiocyanate and phosphorus pentasulfide as sulfur sources. However, these sulfur sources still have some disadvantages, such as low atom and low economy, difficulty in intervening into the matrix and/or low reaction efficiency. Therefore, finding an ideal carbonyl sulfide source is of great significance for the efficient synthesis of valuable sulfur-containing carbonyl heterocycles.

Carbon disulfide (CS ₂ ) is not only a commonly used chemical solvent in industry, but also an ideal carbonyl sulfide source due to its low cost, easy availability, good stability, and good solubility in organic solvents. However, in the past few decades, there have been only few reports demonstrating _CS2 as a carbonyl sulfide source to produce biologically active sulfur-containing carbonyl heterocycles. Therefore, new applications of _CS2 in the construction of other important sulfur-containing carbonyl heterocyclic compounds are to be further developed.

Pyrido[1,2-a]pyrimidine-4-thione is a key motif in many biological and pharmacological molecules. It plays a vital role in many drug molecules as a bioisosteric substituted derivative. It has been widely studied in medicinal chemistry, which has also shown its great biomedical potential. However, currently known methods that can directly construct pyrido[1,2-a]pyrimidine-4-thiones are extremely limited. As early as 1975, Gilchrist et al. reported the synthesis of pyrido[1,2-a]pyrimidine-4-thione from sulfonamide and diphenylcyclopropenethione. However, the substrate range of this reaction was limited, and Multi-step synthesis of substrates is required; in addition, the synthesis of diphenylcyclopropanethione relies on Lawesson's reagent or phosphorus pentasulfide, and the reaction lacks atom economy. After a long period of time, until 2007, Britsun and colleagues developed a new synthesis method, which synthesized pyrido[1,2- a]pyrimidine-4-thione, however, the selectivity of this reaction is entirely determined by the structure of the substituent, and there are many condensation side reactions. In view of the limitations of the above-mentioned existing synthetic methods, how to find a simple method that can efficiently construct pyrido[1,2-a]pyrimidine-4-thione compounds has become an urgent technical problem to be solved.

Contents of the invention

The purpose of the present invention is to solve the above technical problems and provide a synthesis method of pyrido[1,2-a]pyrimidine-4-thione compound. The synthesis method provided by the invention has the characteristics of wide substrate range, good functional group tolerance, easy expansion, etc., and has potential application prospects in organic synthesis and pharmaceutical industry.

In order to achieve the above objects, the technical solutions adopted by the present invention are as follows:

A synthesis method of pyrido[1,2-a]pyrimidine-4-thione compound (III), which includes the following reaction steps S1:

S1: Use the compound of formula (II) to react with carbon disulfide under the action of a base to generate the compound of formula (III);

Wherein, R1, R2 and R3 are each independently selected from the following groups: hydrogen, hydroxyl, halogen; substituted or unsubstituted alkyl, ester group, phenyl, alkoxy; amino and alkyl-substituted amino, mercapto , acyl group, nitrile group, acyloxy group, amide group, amine acyl group, phosphine-containing group, ester group, hydrocarbyl group, alkynyl group, carboxyl group, sulfonate sulfonyl group;

The substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the following group: halogen, C1-C4 alkyl, C1-C4 alkoxy, 3-10 membered heterocycle, and The heterocyclic ring contains 1-3 heteroatoms selected from the following group: N, O or S;

The position of the R1 substituent and each position on the pyridine ring include the ortho, meta and para positions of N.

The present invention provides a new method for synthesizing pyrido[1,2-a]pyrimidine-4-thione, which utilizes readily available ketimines and CS ₂ through C(sp ³ )-H bonds. thiocarbonylation to obtain the target product. The following challenges were faced in the synthetic method of the present invention: First, compared with the limited progress in thiocarbonylation of C(sp ² )-H bonds, the utilization of CS ₂ to achieve thiocarbonylation of C(sp ³ )-H bonds No reports yet. Second, dearomatization of pyridine may occur during the reaction, making the process more subtle. Third, the reactivity of CS ₂ is relatively low and requires appropriate activation. After a lot of exploration and research, the inventor of the present invention finally determined a new and effective method to directly use CS ₂ and the C(sp ³ )-H bond in N-(2-pyridine)ketimine to carry out sulfide synthesis. The carbonylation reaction synthesizes pyrido[1,2-a]pyrimidine-4-thione, which has the characteristics of wide substrate range, good functional group tolerance, and easy expansion. It can react efficiently to synthesize the target product, and its yield is relatively high. high.

Further, the C1-C4 alkoxy group is a methoxy group or an ethoxy group, and the C1-C4 alkyl group is a methyl group or an ethyl group.

Furthermore, the 3-10 membered heterocyclic ring is a monocyclic ring, a bicyclic ring, a spiro ring or a bridged ring.

Further, the halogen includes F, Cl, and Br.

Further, the molar ratio of the compound (II) to carbon disulfide is 1:1-3.

Further, the base is lithium tert-butoxide, and the amount of the base is 1 to 5 molar equivalents of compound (II).

Further, the reaction step S1 also includes adding a solvent, and the solvent includes diethyl ether, tetrahydrofuran, 1,4-dioxane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, methyl tert. Butyl ether, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, isopropyl ether, propyl ether, tert-butyl ether, n-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide , DMSO, acetonitrile, toluene, xylene, trimethylbenzene, n-hexane, cyclohexane, n-pentane, ethyl acetate, dichloromethane, chloroform or chloroform; preferably, the added amount of the solvent is every 0.1 mol compound (Ⅱ) was added to 1L solvent.

Furthermore, the reaction step S1 is performed during heating, and the reaction temperature after heating is 20-150°C, preferably 130°C.

Furthermore, the reaction time of the reaction step S1 is 5-30h, preferably 24h.

Further, the preparation method includes reacting 1 molar equivalent of the compound of formula (II) with 1.5 molar equivalent of carbon disulfide in tetrahydrofuran at 100°C and adding 2.5 molar equivalent of lithium tert-butoxide for 10 hours to obtain the compound of formula (III).

The beneficial effects of the present invention are as follows:

The present invention provides a new method for synthesizing pyrido[1,2-a]pyrimidine-4-thione, which utilizes N-(2-pyridine)ketimine and CS ₂ through C(sp ³ )- The target product pyrido[1,2-a]pyrimidine-4-thione is obtained through thiocarbonylation of H bonds. Compared with existing synthesis methods, this synthesis method has a wide substrate range, good functional group tolerance, and ease of use. Expansion and other characteristics, it has great application prospects in organic synthesis and pharmaceutical industry.

Detailed ways

In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is described in detail below with reference to the examples. It is necessary to point out that the following examples are only used to explain and illustrate the present invention and are not intended to limit the present invention. . Some non-essential improvements and adjustments made by those skilled in the art based on the above-mentioned content of the invention still belong to the protection scope of the present invention.

Example 1

A method for synthesizing pyrido[1,2-a]pyrimidine-4-thione compounds, the reaction formula of which is as follows (1):

Thiocarbonylation reaction was carried out with N-(2-pyridyl)ketimine (compound 1a) and CS _2. After screening different bases and solvents, the bases included: sodium tert-butoxide, potassium tert-butoxide, tert-butoxide Lithium butoxide, magnesium tert-butoxide, cesium carbonate, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide; solvents include: diethyl ether, tetrahydrofuran, 1,4-dioxane, diethyl Glyme, glycol dimethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, isopropyl ether, propyl ether, tert-butyl ether, n-butyl ether, N,N -Dimethylformamide, N,N-dimethylacetamide, DMSO, acetonitrile, toluene, xylene, trimethylbenzene, n-hexane, cyclohexane, n-pentane, ethyl acetate, dichloromethane, chloroform, Trichloromethane, combine the above bases and solvents in pairs, and the screening results show that lithium tert-butoxide (LiO ^t Bu) is the best base and tetrahydrofuran (THF) is the best solvent, so the formula determined in reaction formula (1) The base was LiO ^t Bu, the solvent was THF, and the amount of CS ₂ was 1.5 molar equivalents of compound 1a. The above reaction conditions were optimized, and the optimization results are shown in Table 1.

Table 1

Note: Reaction conditions: 1a (0.2mmol), CS ₂ (0.3mmol), THF (2mL); b is the isolation yield; c is the addition of water (0.2mmol); d is the yield calculated on a 0.4mmol scale.

It can be seen from Table 1 that by adding 4.5 molar equivalents of LiO ^t Bu to THF at 130°C and reacting for 24 hours, the highest yield of the target product can be obtained at 99% (entry 1). In order to realize the reaction under milder reaction conditions, the amount of base, reaction temperature and reaction time were further screened. The screening results of the dosage of LiO ^t Bu show that 2.5 molar equivalent is the optimal dosage (entries 1-5). It is worth noting that when no base is added, essentially no product is formed, indicating the importance of base to the above reaction (entry 5).

It was further found that choosing the reaction temperature of 100°C is better (entries 3, 6, 7), and the reaction time can be compressed from 24h to 10h (entries 6, 8, 12). In addition, the above reaction also afforded compound 2a in 66% yield at room temperature (entry 11).

Example 2

Examination of substrate scope:

Under the optimal reaction conditions of Example 1 (entry 12), the substrate range of N-(2-pyridyl)ketimine was expanded (see Table 2). The structural formula of reaction substrate 1 is as follows: 1a～1u , the structural formula of the obtained product 2 is as 2a~2u, and the yields of the obtained target products are listed in Table 2.

As can be seen from Table 2, under optimal reaction conditions, a series of (E)-1-aryl-N-(pyridin-2-yl)ethyl-1-imine (1a, 1c-1i) Excellent yields are converted into corresponding products, including electron-withdrawing groups (EWGs) or electron-donating groups (EDGs) in the para position on the benzene ring, such as methyl, halogen groups (-F, -Cl, -Br) , trifluoromethyl, trifluoromethoxy (-OCF ₃ ). In addition, substrates with substituents at the ortho (1j) or meta (1k, 1l) position of the benzene ring also performed well. In addition to monosubstituents, substrates containing two (1m) or three substituents (1n) on the benzene ring can also undergo this transformation to obtain good to excellent yields. Pleasantly, the alkyl-substituted N-(2-pyridyl)ketimine substrate 1o is reactive in this reaction. Substrates with different substituents on the pyridine ring (1p-1s) were also studied, and it was found that substrates with EDGs on the pyridine ring performed better than substrates with EWGs. In addition to monosubstituted pyrimidines, disubstituted pyrimidines (2t) can also be generated well. In addition, the yield of 2u, an important motif in synthetic biomedicine, also reached 58%.

To further demonstrate the application of this transformation in organic chemistry, a gram-scale reaction of 1a was performed, and the results showed that the target product 2a was obtained in 87% yield.

To sum up, the above-mentioned synthesis reaction of the present invention has the characteristics of wide substrate range, good functional group tolerance, easy expansion, etc., and can well obtain the corresponding target product with good yield.

Table 2

Note: Reaction conditions are: substrate 1 (0.4mmol), CS ₂ (0.6mmol), LiO ^t Bu (1.0mmol), THF (4mL), 100°C, 10h. The amplification reaction conditions are: substrate 1 (5mmol), CS ₂ (7.5mmol), LiO ^t Bu (12.5mmol), THF (50mL), 100°C, 10h.

Claims (11)

1. A method for synthesizing pyrido[1,2-a]pyrimidine-4-thione compound (III), which is characterized in that it includes the following reaction step S1: S1: Use the compound of formula (II) and carbon disulfide to react under the action of lithium tert-butoxide and a solvent at 20-150°C to generate the compound of formula (III); wherein the amount of lithium tert-butoxide is 1 to 5 molar equivalents Compound (II); the solvent includes diethyl ether, tetrahydrofuran, 1,4-dioxane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran , 3-methyltetrahydrofuran, isopropyl ether, propyl ether, tert-butyl ether, n-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, DMSO, acetonitrile, toluene, xylene , trimethylbenzene, n-hexane, cyclohexane, n-pentane, ethyl acetate, methylene chloride, chloroform or chloroform; Wherein, the R1 is selected from any one of the following groups: hydrogen, hydroxyl, halogen; substituted or unsubstituted alkyl, ester group, phenyl, alkoxy; amino and alkyl substituted amino, mercapto, acyl , nitrile group, acyloxy group, amide group, amide acyl group, alkynyl group, carboxyl group; the R2 is selected from any one of the following groups: hydrogen, substituted or unsubstituted alkyl, phenyl; the R3 is selected from From any of the following groups: hydrogen, substituted or unsubstituted alkyl; The substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the following group: halogen, C1-C4 alkyl, C1-C4 alkoxy, 3-10 membered heterocycle, and The heterocyclic ring contains 1-3 heteroatoms selected from the following group: N, O or S; The R1 substituent is located at the ortho, meta or para position of N. 2. The synthesis method according to claim 1, characterized in that the C1-C4 alkoxy group is a methoxy group or an ethoxy group, and the C1-C4 alkyl group is a methyl group or an ethyl group. 3. The synthesis method according to claim 1, characterized in that the 3-10 membered heterocyclic ring is a monocyclic ring or a bicyclic ring. 4. The synthesis method according to claim 1, characterized in that the 3-10 membered heterocyclic ring is a spiro ring or a bridged ring. 5. The synthesis method according to claim 1, characterized in that the halogen is F, Cl, or Br. 6. The synthesis method according to claim 1, characterized in that the molar ratio of compound (II) to carbon disulfide is 1:1-3. 7. The synthesis method according to claim 1, characterized in that the added amount of the solvent is 1 L of solvent for every 0.1 mol of compound (II). 8. The synthesis method according to claim 1, characterized in that the reaction temperature is 130°C. 9. The synthesis method according to claim 1, characterized in that the reaction time is 5-30 h. 10. The synthesis method according to claim 8, characterized in that the reaction time is 24 hours. 11. The synthetic method according to claim 1, characterized in that the synthetic method includes adding 1 molar equivalent of the compound of formula (II) and 1.5 molar equivalents of carbon disulfide to tetrahydrofuran at 100° C. and adding 2.5 molar equivalents of tert-butyl. The lithium alkoxide was reacted for 10 hours to obtain the compound of formula (III).