CN113214249B - Synthesis method of pyrido [1,2-a ] pyrimidine-4-thioketone compound - Google Patents
Synthesis method of pyrido [1,2-a ] pyrimidine-4-thioketone compound Download PDFInfo
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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
Technical Field
The invention belongs to the technical field of medicine synthesis, relates to a synthesis method of a pyridopyrimidinone compound, and in particular relates to a synthesis method of a pyrido [1,2-a ] pyrimidine-4-thione compound.
Background
Sulfur-containing carbonyl heterocycles have long been of interest for their unique biological and pharmacological activity. Conventional synthesis methods typically use elemental sulfur, lawesson's reagent, isothiocyanate and phosphorus pentasulfide as sulfur sources for synthesis. However, these sulfur sources still suffer from disadvantages such as low atoms and low economy, difficulty in accessing the substrate, and/or low efficiency of the reaction. Therefore, finding an ideal carbonyl sulfide source is of great importance for efficient synthesis of valuable sulfur-containing carbonyl heterocycles.
Carbon disulfide (CS) 2 ) Not only is a chemical solvent commonly used in industry, but also has low cost, easy availability, good stability and is in organic solventIs an ideal carbonyl sulfide source. However, in the last decades, only few reports have proven CS 2 As a source of carbonyl sulfide, a sulfur-containing carbonyl heterocycle having biological activity is produced. Thus, CS 2 New applications in the construction of other important sulfur-containing carbonyl heterocycles are to be developed further.
Pyrido [1,2-a ] pyrimidine-4-thione is a key motif for many biological and pharmacological molecules, which plays a vital role as a bioisosteric substituted derivative in many pharmaceutical molecules, which has been widely studied in pharmaceutical chemistry and which also shows its great biomedical potential. However, the methods currently known for directly constructing pyrido [1,2-a ] pyrimidine-4-thione are extremely limited. As early as 1975, gilchrist et al reported the synthesis of pyrido [1,2-a ] pyrimidine-4-thione from sulfanilamide and diphenylcyclopropanethione, however, the substrate range of this reaction was limited and a multi-step synthesis of the substrate was required; in addition, the synthesis of diphenylcyclopropylthioketone relies on Lawesson's reagent or phosphorus pentasulfide, and the reaction lacks atomic economy. Over a long period of time, britsun and colleagues have not developed a new synthesis method for synthesizing pyrido [1,2-a ] pyrimidine-4-thione from 3-oxypropane-sulfamide and 2-aminopyridine with acetic acid until 2007, however, the selectivity of this reaction is completely determined by the structure of the substituents, and there are many condensation side reactions. In view of the limitations of the existing synthesis methods, how to find a simple method capable of efficiently constructing pyrido [1,2-a ] pyrimidine-4-thione compounds is a technical problem to be solved.
Disclosure of Invention
The invention aims to solve the technical problems and provides a synthesis method of a 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, easiness in expansion and the like, and has potential application prospects in organic synthesis and pharmaceutical industry.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a method for synthesizing a pyrido [1,2-a ] pyrimidine-4-thione compound (iii), comprising the following reaction step S1:
s1: reacting a compound of formula (II) with carbon disulphide under the action of a base to produce a compound of formula (III);
wherein each of R1, R2 and R3 is independently selected from the group consisting of: hydrogen, hydroxy, halogen; substituted or unsubstituted alkyl, ester, phenyl, alkoxy; amino and alkyl substituted amino, mercapto, acyl, nitrile, acyloxy, amide, aminoacyl, phosphine-containing group, ester, hydrocarbon, alkynyl, carboxyl, sulfonyl sulfonate;
the substituents refer to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 alkoxy, 3-to 10-membered heterocycle, and said heterocycle contains 1-3 heteroatoms selected from the group consisting of: n, O or S;
the R1 substituent position and each position on the pyridine ring comprise ortho, meta and para positions of N.
The invention provides a new synthetic pyrido [1,2-a ]]Pyrimidine-4-thione method using readily available ketimines and CS 2 By C (sp) 3 ) Thiocarbonylation of H-bonds to obtain the desired product. The following challenges are faced in the synthetic method of the present invention: first, with C (sp) 2 ) Thiocarbonylation of the-H bond with CS is of limited progress 2 Realization of C (sp) 3 ) Thiocarbonylation of the H bond has not been reported. Second, dearomatization of pyridine may occur during the reaction, making the process more subtle. Third, CS 2 Relatively low reactivity and requires proper activation. The inventor of the present invention has made extensive studies and has finally determined a new and effective method for directly using CS 2 With C (sp) in N- (2-pyridine) ketimines 3 ) Synthesis of pyrido [1,2-a ] by thiocarbonylation of the-H bond]Pyrimidine-4-thioketone has the characteristics of wide substrate range, good functional group tolerance, easy expansion and the like, and can efficiently reactThe target product is synthesized with higher yield.
Further, the C1-C4 alkoxy is methoxy or ethoxy, and the C1-C4 alkyl is methyl or ethyl.
Further, the 3-10 membered heterocyclic ring is a single ring, a bicyclic ring, a spiro ring or a bridged ring.
Further, the halogen comprises F, cl and Br.
Further, the molar ratio of the compound (II) to the carbon disulfide is 1:1-3.
Further, the alkali is lithium t-butoxide, and the amount of the alkali is 1 to 5 molar equivalents of the compound (II).
Further, the reaction step S1 further comprises adding a solvent, wherein the solvent comprises diethyl ether, tetrahydrofuran, 1, 4-dioxane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, methyl tertiary butyl ether, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, isopropyl ether, propyl ether, tertiary butyl ether, N-butyl ether, N-dimethylformamide, N-dimethylacetamide, DMSO, acetonitrile, toluene, xylene, trimethylbenzene, N-hexane, cyclohexane, N-pentane, ethyl acetate, methylene chloride, chloroform or chloroform; preferably, the solvent is added in an amount of 1L per 0.1mol of the compound (II).
Further, the reaction step S1 is performed during heating, and the reaction temperature after heating is 20 to 150 ℃, preferably 130 ℃.
Further, the reaction time of the reaction step S1 is 5 to 30 hours, preferably 24 hours.
Further, the preparation method comprises the step of adding 2.5 molar equivalents of lithium tert-butoxide to 1 molar equivalent of the compound of the formula (II) and 1.5 molar equivalents of carbon disulfide in tetrahydrofuran at 100 ℃ for reaction for 10 hours to obtain the compound of the formula (III).
The beneficial effects of the invention are as follows:
the invention provides a new synthetic pyrido [1,2-a ]]Pyrimidine-4-thione method utilizing N- (2-pyridine) ketimine and CS 2 By C (sp) 3 ) Thiocarbonylation of the-H bond to obtain the desired productPyrido [1,2-a ]]Compared with the existing synthesis method, the pyrimidine-4-thione has the characteristics of wide substrate range, good functional group tolerance, easy expansion and the like, and has a large application prospect in organic synthesis and pharmaceutical industry.
Detailed Description
In order that the objects, technical solutions and advantages of the present invention will become more apparent, the following detailed description of the present invention will be made with reference to the examples, which are given by way of illustration and explanation only, and are not intended to limit the present invention. Some non-essential modifications and adaptations of the invention according to the foregoing summary will still fall within the scope of the invention.
Example 1
A synthesis method of a pyrido [1,2-a ] pyrimidine-4-thioketone compound, which has a reaction formula (I):
with N- (2-pyridyl) ketimine (compound 1 a) and CS 2 The thiocarbonylation reaction is carried out, and different bases and solvents are screened, wherein the bases comprise: sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, magnesium tert-butoxide, cesium carbonate, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide; the solvent comprises: diethyl ether, tetrahydrofuran, 1, 4-dioxane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, methyl tertiary butyl ether, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, isopropyl ether, propyl ether, tertiary butyl ether, N-butyl ether, N-dimethylformamide, N-dimethylacetamide, DMSO, acetonitrile, toluene, xylene, trimethylbenzene, N-hexane, cyclohexane, N-pentane, ethyl acetate, dichloromethane, chloroform and chloroform, combining the above alkali and solvents two by two, and obtaining lithium tert-butoxide (LiO) from the screening result t Bu) is the optimal base and Tetrahydrofuran (THF) is the optimal solvent, so the base identified in equation (one) is LiO t Bu, solvent THF, CS 2 Is used in an amount of 1.5 molar equivalents of compound 1a. On the pair ofThe reaction conditions were optimized and the optimized results are shown in table 1.
TABLE 1
Note that: reaction conditions: 1a (0.2 mmol), CS 2 (0.3 mmol), THF (2 mL); b is the isolated yield; c is the addition of water (0.2 mmol); d is the yield calculated on a 0.4mmol scale.
As can be seen from Table 1, 4.5 molar equivalents of LiO are added to THF at 130 ℃ t Bu, 24h, gave the highest yield of the desired product of 99% (entry 1). In order to achieve this reaction under milder reaction conditions, the amount of base used, the reaction temperature and the reaction time were further selected. LiO (LiO) t The Bu dose screening results indicated that 2.5 molar equivalents were the optimal dose (entries 1-5). Notably, when no base was added, substantially no product was formed, indicating the importance of the base to the reaction described above (entry 5).
It was further found that it is preferable to select a reaction temperature of 100 ℃ (entries 3, 6, 7), and that the reaction time can be compressed from 24h to 10h (entries 6, 8, 12). In addition, the above reaction also gave compound 2a at room temperature to a yield of 66% (item 11).
Example 2
Examination of substrate range:
under the optimal reaction conditions of example 1 (item 12), the substrate range of N- (2-pyridyl) ketimine was enlarged (see Table 2), the structural formulae of reaction substrate 1 were shown as 1a to 1u, the structural formulae of the obtained product 2 were shown as 2a to 2u, and the yields of the obtained target products were shown in Table 2.
As can be seen from Table 2, under the optimal reaction conditions, a series of (E) -1-aryl-N- (pyridin-2-yl) ethyl-1-imine (1 a,1c-1 i) are converted in excellent yields to the corresponding products, including Electron Withdrawing Groups (EWGs) or Electron Donating Groups (EDGs) para to the benzene ring, such as methyl, halogen groups (-F, -Cl, -Br), trifluoromethyl, trifluoromethoxy (-OCF) 3 ). In addition, the benzene ring is ortho (1 j) or meta (1 k,1 l)Substrates with substituents also perform well. In addition to mono-substituents, substrates containing di (1 m) or tri-substituents (1 n) on the benzene ring can also be subjected to such conversions to obtain good to good yields. It is desirable that the alkyl-substituted N- (2-pyridyl) ketimine substrate 1o be reactive in this reaction. Substrates with different substituents on the pyridine ring (1 p-1 s) were also studied and found to perform better with EDGs than with EWGs. In addition to mono-substituted pyrimidines, di-substituted pyrimidines (2 t) can be produced well. In addition, the yield of the important motif 2u of the synthetic biomedicine reaches 58%.
To further demonstrate the use of this conversion in organic chemistry, gram-scale reactions of 1a were performed, which showed that the target product 2a was obtained in 87% yield.
In conclusion, the synthesis reaction has the characteristics of wide substrate range, good functional group tolerance, easy expansion and the like, can well obtain corresponding target products, and has good yield.
TABLE 2
Note that: the reaction conditions are as follows: substrate 1 (0.4 mmol), CS 2 (0.6mmol)，LiO t Bu (1.0 mmol), THF (4 mL), 100deg.C, for 10h. The amplification reaction conditions are as follows: substrate 1 (5 mmol), CS 2 (7.5mmol)，LiO t Bu(12.5mmol)，THF(50mL)，100℃，10h。
Claims (11)
1. A method for synthesizing a pyrido [1,2-a ] pyrimidine-4-thione compound (iii), comprising the following reaction step S1:
s1: reacting a compound of formula (II) with carbon disulfide under the action of lithium tert-butoxide and a solvent at 20-150 ℃ to generate a compound of formula (III); wherein the dosage of the lithium tert-butoxide is 1-5 molar equivalents of the compound (II); the solvent comprises diethyl ether, tetrahydrofuran, 1, 4-dioxane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, methyl tertiary butyl ether, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, isopropyl ether, propyl ether, tertiary butyl ether, N-butyl ether, N-dimethylformamide, N-dimethylacetamide, DMSO, acetonitrile, toluene, xylene, trimethylbenzene, N-hexane, cyclohexane, N-pentane, ethyl acetate, dichloromethane, chloroform or chloroform;
wherein, R1 is selected from any one of the following groups: hydrogen, hydroxy, halogen; substituted or unsubstituted alkyl, ester, phenyl, alkoxy; amino and alkyl substituted amino, mercapto, acyl, nitrile, acyloxy, amido, aminoacyl, alkynyl and carboxyl; the R2 is selected from any one of the following groups: hydrogen, substituted or unsubstituted alkyl, phenyl; the R3 is selected from any one of the following groups: hydrogen, substituted or unsubstituted alkyl;
the substituents refer to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 alkoxy, 3-to 10-membered heterocycle, and said heterocycle contains 1-3 heteroatoms selected from the group consisting of: n, O or S;
the R1 substituent is positioned at the ortho position, the meta position or the para position of N.
2. The method of claim 1, wherein the C1-C4 alkoxy is methoxy or ethoxy and the C1-C4 alkyl is methyl or ethyl.
3. The method of claim 1, wherein the 3-10 membered heterocycle is monocyclic or bicyclic.
4. The method of claim 1, wherein the 3-10 membered heterocycle is a spiro or bridged ring.
5. The method of claim 1, wherein the halogen is F, cl, br.
6. The synthetic method according to claim 1, wherein the molar ratio of the compound (ii) to carbon disulphide is 1:1-3.
7. The synthesis method according to claim 1, wherein the solvent is added in an amount of 1L per 0.1mol of the compound (II).
8. The synthetic method of claim 1 wherein the temperature of the reaction is 130 ℃.
9. The synthetic method of claim 1 wherein the reaction time is from 5 to 30 hours.
10. The synthetic method of claim 8 wherein the reaction time is 24 hours.
11. The synthesis according to claim 1, comprising reacting 1 molar equivalent of the compound of formula (ii) with 1.5 molar equivalents of carbon disulphide in tetrahydrofuran at 100 ℃ with the addition of 2.5 molar equivalents of lithium tert-butoxide for 10h to obtain the compound of formula (iii).
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