Thiazolopyrimidine compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a thiazolopyrimidine compound as well as a preparation method and application thereof. The thiazolopyrimidine compound is efficiently prepared at room temperature and in an air atmosphere by taking pyrimidinethione and alpha-bromocinnamyl aldehyde as raw materials under the condition of no photocatalyst or additive. Compared with a previously reported preparation method, the method has the advantages of being green, environmentally friendly, safe, efficient and energy-saving, the substrate application range is wide, the compatibility of product functional groups is good, raw materials are easy to obtain, transition metal, a photocatalyst and an external oxidizing agent are not needed, and the medical intermediates and the medical molecules can be simply, conveniently and efficiently synthesized through the method.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a thiazolopyrimidine compound, a preparation method and application. BACKGROUND

[0002] Thiazolopyrimidine compounds (mainly including thiazolo[3,2-a]pyrimidine, thiazolo[4,5-d]pyrimidine and thiazolo[5,4-d]pyrimidine) are important analogues of purine and have important applications in the fields of medicine and pesticide. Under traditional conditions, although remarkable achievements have been made in the construction of thiazolopyrimidine skeleton, these methods still have some deficiencies. Most of the methods need heating and transition metal catalysts, and some of the methods need stoichiometric oxidants to promote the reaction, which is contrary to the concept of green chemistry. In addition, due to the strong coordination ability between transition metals and heteroatoms, it is difficult to remove trace transition metals from heteroaryl compounds, which is not conducive to drug research.

[0003] In recent years, with the development of visible light catalysis, photo-oxidation and reduction catalysis has been widely used in the construction of nitrogen-containing heterocycles. However, compared with this, a method for preparing thiazolopyrimidine from pyrimidinone under visible light conditions has not been reported.

[0004] Therefore, it is a technical problem to be solved by those skilled in the art to develop a green and efficient method for cyclizing pyrimidine thione and bromocinnamaldehyde into thiazolopyrimidine compounds under visible light conditions without using photocatalysts and metal catalysts under mild and neutral reaction conditions. SUMMARY

[0005] Therefore, in order to solve the problem, the application provides a thiazolopyrimidine compound, a preparation method and application.

[0006] It should be noted that the application provides a method which is efficient, green, environmentally friendly and easy to scale up. A series of thiazolopyrimidine compounds are efficiently synthesized under room temperature conditions by irradiating simple and readily available pyrimidine thione and alpha-bromocinnamaldehyde as raw materials. The application not only has simple reaction operation and environmental friendliness, but also is carried out at room temperature. In addition, the application does not need transition metal catalysts, photosensitizers and additives. The method of the application can be used to simply and efficiently synthesize pharmaceutical intermediates and pharmaceutical molecules.

[0007] In order to achieve the above purpose, the application adopts the following technical solutions:

[0008] A first technical purpose of the application is to provide a thiazolopyrimidine compound, and the structure of the thiazolopyrimidine compound is as follows:

[0009]

[0010] Wherein, R1 is alkyl or alkenyl; R2 is alkyl, phenyl, or p-methoxy-substituted phenyl or p-fluorine-substituted phenyl; R3 is phenyl, naphthyl, or p-hydroxy-substituted phenyl or p-methoxy-substituted phenyl; R4 is phenyl or p-chloro-substituted phenyl or p-methoxy-substituted phenyl.

[0011] The second technical objective of this invention is to provide a method for preparing the thiazopyrimidine compounds as described above, the synthetic route of which is as follows:

[0012]

[0013] R1, R2, R3, and R4 are defined as previously given.

[0014] Specifically, pyrimidinethione is used as a raw material and reacted with α-bromocinnamaldehyde under visible light irradiation to generate thiazopyrimidine compounds.

[0015] Optionally, the molar ratio of pyrimidinethione to α-bromocinnamaldehyde is 1:1 to 5:8.

[0016] Optionally, the visible light irradiation is selected from one or more light sources selected from 5000-5500K white light, 395-400nm violet light, and 460-465nm blue light, and the power of the irradiation light source is 6-10W, specifically one of 6W, 7W, 8W, 9W, and 10W.

[0017] Optionally, the reaction time is 1-24 hours, the reaction temperature is room temperature, and the reaction atmosphere is air.

[0018] Optionally, the reaction solvent is one or more of dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylacetamide.

[0019] Furthermore, in the method described in this invention, after the reaction is completed, the product is separated and characterized using conventional separation and purification methods to obtain the corresponding product.

[0020] A third technical objective of this invention is to provide the application of the thiazopyrimidine compound as described above in pharmaceutical formulations.

[0021] Furthermore, the thiazopyrimidine compounds can be used as pharmaceutical intermediates or pharmaceutical molecules.

[0022] It should be noted that thiazopyrimidine compounds (mainly including thiazo[3,2-a]pyrimidine, thiazo[4,5-d]pyrimidine, and thiazo[5,4-d]pyrimidine) are important purine analogs with significant applications in the pharmaceutical and pesticide fields. Among them, thiazo[3,2-a]pyrimidine ketones and their derivatives possess diverse biological activities and can be used as anti-inflammatory agents, antioxidants, antibacterial agents, anticancer drugs, antitumor drugs, anticonvulsants, anti-Parkinson's disease drugs, and antiviral drugs. Based on this, the thiazopyrimidine compounds synthesized / prepared by the method of this invention can also be used as pharmaceutical intermediates and pharmaceutical molecules.

[0023] Compared with the prior art, the beneficial effects of the present invention are:

[0024] This invention provides a highly efficient method for preparing thiazopyrimidine compounds at room temperature and in air atmosphere using pyrimidine thione and α-bromocinnamaldehyde as raw materials without photocatalysts or additives. Compared to previously reported methods, this invention offers advantages such as being green, environmentally friendly, safe, and energy-efficient. It also boasts a wide range of applicable substrates, good functional group compatibility of the products, readily available raw materials, and eliminates the need for transition metals, photocatalysts, and external oxidants. Furthermore, this method allows for the simple and efficient synthesis of pharmaceutical intermediates and molecules. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0026] Figure 1 These are the hydrogen spectrum (a) and carbon spectrum (b) of compound 4 of the present invention.

[0027] Figure 2 These are the proton spectrum (a) and carbon spectrum (b) of compound 6 of the present invention.

[0028] Figure 3 These are the proton spectrum (a) and carbon spectrum (b) of compound 8 of the present invention.

[0029] Figure 4 These are the proton spectrum (a) and carbon spectrum (b) of compound 10 of the present invention.

[0030] Figure 5 These are the hydrogen spectrum (a), carbon spectrum (b), and fluorine spectrum (c) of compound 12 of the present invention. Detailed Implementation

[0031] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0032] The term "embodiment" used herein, as an example, is not necessarily to be construed as superior to or better than other embodiments. Performance testing in the embodiments of this application, unless otherwise specified, employs conventional testing methods in the art. It should be understood that the terminology used in this application is merely for describing particular implementations and is not intended to limit the scope of this disclosure.

[0033] Unless otherwise stated, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains; other experimental methods and technical means not specifically mentioned herein refer to experimental methods and technical means commonly used by one of ordinary skill in the art.

[0034] To better illustrate the content of this application, numerous specific details are provided in the following detailed embodiments. Those skilled in the art should understand that this application can be implemented even without certain specific details. In the embodiments, some methods, means, instruments, and devices well-known to those skilled in the art are not described in detail in order to highlight the main points of this application.

[0035] Without conflict, the technical features disclosed in the embodiments of this application can be combined arbitrarily, and the resulting technical solution belongs to the content disclosed in the embodiments of this application.

[0036] This invention discloses a method for synthesizing thiazopyrimidine compounds.

[0037] To better understand the present invention, the following embodiments are provided for further detailed description of the present invention, but they should not be construed as limiting the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above-described invention are also considered to fall within the protection scope of the present invention.

[0038] It should be noted that the reactants and solvents described below are all conventional substances, and the CAS number for α-bromocinnamaldehyde is 5443-49-2, and the CAS number for pyrimidinethione is 33458-26-3.

[0039] Example 1

[0040]

[0041] In a 10 mL quartz tube, pyrimidine thione 3 (69.1 mg, 0.25 mmol), α-bromocinnamaldehyde (63.3 mg, 0.30 mmol), and a 1 mL mixed solution of dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylacetamide in a ratio of 4:3:3 were added sequentially. The reaction tube was stirred for 2 h under 10 W blue light (460-465 nm) at room temperature (25 °C). After the reaction was completed, the organic phase was extracted with 50 mL of saturated brine, collected, and then the volatile components were removed under reduced pressure. The mixture was then separated by thin-layer chromatography (elution was petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1) to obtain the pale yellow solid target product 4 (88.3 mg, yield 87%).

[0042] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0043] Example 2

[0044]

[0045] The reaction steps and operations were the same as in Example 1, except that the starting material added to the reaction system was ethyl 6-methyl-2-thio-4-(m-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate 5 (113697-58-8, 72.6 mg, 0.25 mmol). The reaction was stopped, and after post-treatment, the target product 6 (84.1 mg, yield 80%) was obtained as a pale yellow solid.

[0046] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0047] Example 3

[0048]

[0049] The reaction steps and operations were the same as in Example 1, except that ethyl 4-(4-methoxyphenyl)-6-methyl-2-thio-1,2,3,4-tetrahydropyrimidine-5-carboxylate 7 (113697-57-7, 76.6 mg, 0.25 mmol) was added to the reaction system, and after post-treatment, the target product 8 (79.9 mg, yield 73%) was obtained as a pale yellow solid.

[0050] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0051] Example 4

[0052]

[0053] The reaction steps and operations were the same as in Example 1, except that ethyl 4-(4-hydroxyphenyl)-6-methyl-2-thio-1,2,3,4-tetrahydropyrimidine-5-carboxylate 9 (203118-28-9, 73.1 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 10 (82.4 mg, yield 78%) was obtained after post-treatment.

[0054] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0055] Example 5

[0056]

[0057] The reaction steps and operations were the same as in Example 1, except that ethyl 4-(4-fluorophenyl)-6-methyl-2-thio-1,2,3,4-tetrahydropyrimidine-5-carboxylate 11 (201287-93-6, 73.6 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 12 (93.9 mg, yield 89%) was obtained after post-treatment.

[0058] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0059] Example 6

[0060]

[0061] The reaction steps and operations were the same as in Example 1, except that ethyl 4-(4-bromophenyl)-6-methyl-2-thio-1,2,3,4-tetrahydropyrimidine-5-carboxylate 13 (123629-46-9, 88.8 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 14 (91.4 mg, yield 75%) was obtained after post-treatment.

[0062] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0063] Example 7

[0064]

[0065] The reaction steps and operations were the same as in Example 1, except that ethyl 4-(4-chlorophenyl)-6-methyl-2-thio-1,2,3,4-tetrahydropyrimidine-5-carboxylate 15 (154866-92-9, 77.7 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 16 (82.9 mg, yield 75%) was obtained after post-treatment.

[0066] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0067] Example 8

[0068]

[0069] The reaction steps and operations were the same as in Example 1, except that ethyl 6-methyl-4-(4-methylthiophenyl)-2-thio-1,2,3,4-tetrahydropyrimidine-5-carboxylate 17 (292871-44-4, 80.6 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 18 (98.3 mg, yield 87%) was obtained after post-treatment.

[0070] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0071] Example 9

[0072]

[0073] The reaction steps and operations were the same as in Example 1, except that ethyl 4-(2,4-dimethylphenyl)-6-methyl-2-thio-1,2,3,4-tetrahydropyrimidine-5-carboxylate 19 (696652-50-3, 76.1 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 20 (90.3 mg, yield 83%) was obtained after post-treatment.

[0074] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0075] Example 10

[0076]

[0077] The reaction steps and operations were the same as in Example 1, except that ethyl 4-(3,4-dimethylphenyl)-6-methyl-2-thio-1,2,3,4-tetrahydropyrimidine-5-carboxylate 21 (1506560-57-1, 76.1 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 22 (81.2 mg, yield 75%) was obtained after post-treatment.

[0078] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0079] Example 11

[0080]

[0081] The reaction steps and operations were the same as in Example 1, except that ethyl 4-cyclohexyl-6-methyl-2-thio-1,2,3,4-tetrahydropyrimidine-5-carboxylate 23 (112080-25-8, 70.5 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 24 (69.5 mg, yield 68%) was obtained after post-treatment.

[0082] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0083] Example 12

[0084]

[0085] The reaction steps and operations were the same as in Example 1, except that 25 ethyl 6-methyl-4-(1-naphthyl)-2-thio-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ester (81.6 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 26 (97.7 mg, yield 86%) was obtained after post-treatment.

[0086] An aromatic aldehyde (10 mmol, 1.0 equivalent), a 1,3-dicarbonyl compound (10 mmol, 1.0 equivalent), a thiourea (15 mmol, 1.5 equivalent), and LaCl7HO (5 mmol, 0.5 equivalent) were added to a 50 mL reaction tube equipped with a magnetic stir bar. 1-2 drops of concentrated hydrochloric acid were slowly added as a Lewis acid, using ethanol as the solvent. The mixture was refluxed for 5 hours. After the reaction was complete, the mixture was allowed to cool naturally to room temperature. 5-10 g of crushed ice was added and the mixture was stirred vigorously to precipitate the target product. The product was collected by filtration through a Buchner funnel, washed with an ice-water mixture, and dried to give a solid product, namely ethyl 6-methyl-4-(1-naphthyl)-2-thio-1,2,3,4-tetrahydropyrimidine-5-carboxylate.

[0087] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0088] Example 13

[0089]

[0090] The reaction procedure and operation were the same as in Example 1, except that ethyl 4-(furan-2-yl)-6-methyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 27 (123629-45-8, 66.6 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and after post-treatment, the target product 28 (44.5 mg, yield 45%) was obtained as a pale yellow solid.

[0091] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0092] Example 14

[0093]

[0094] The reaction steps and operations were the same as in Example 1, except that 29 ethyl 5-(isothiazo-5-yl)-6-methyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ester (70.8 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 30 (71.7 mg, yield 69%) was obtained after post-treatment.

[0095] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0096] Example 15

[0097]

[0098] The reaction steps and operations were the same as in Example 1, except that methyl 6-methyl-4-phenyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ester 31 (126827-25-6, 65.6 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 32 (81.3 mg, yield 83%) was obtained after post-treatment.

[0099] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0100] Example 16

[0101]

[0102] The reaction steps and operations were the same as in Example 1, except that methyl 6-ethyl-4-phenyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid 33 (916078-09-6, 69.1 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 34 (89.4 mg, yield 88%) was obtained after post-treatment.

[0103] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0104] Example 17

[0105]

[0106] The reaction steps and operations were the same as in Example 1, except that methyl 4-phenyl-6-propyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid 35 (923104-14-7, 72.6 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 36 (81.8 mg, yield 78%) was obtained after post-treatment.

[0107] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0108] Example 18

[0109]

[0110] The reaction steps and operations were the same as in Example 1, except that ethyl 6-(methoxymethyl)-4-phenyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 37 (76.6 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 38 (75.9 mg, yield 70%) was obtained after post-treatment.

[0111] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0112] Example 19

[0113]

[0114] The reaction steps and operations were the same as in Example 1, except that 39 propyl 6-methyl-4-phenyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (321691-00-3, 72.6 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 40 (66.8 mg, yield 64%) was obtained after post-treatment.

[0115] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0116] Example 20

[0117]

[0118] The reaction steps and operations were the same as in Example 1, except that 6-methyl-4-phenyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid isobutyl ester 41 (76.1 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 42 (80.6 mg, yield 74%) was obtained after post-treatment.

[0119] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0120] Example 21

[0121]

[0122] The reaction steps and operations were the same as in Example 1, except that 6-methyl-4-phenyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid tert-butyl ester 43 (356773-73-4, 76.1 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 44 (68.9 mg, yield 63%) was obtained after post-treatment.

[0123] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0124] Example 22

[0125]

[0126] The reaction steps and operations were the same as in Example 1, except that 6-methyl-4-phenyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid allyl ester 45 (440088-19-7, 72.1 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 46 (77.5 mg, yield 74%) was obtained after post-treatment.

[0127] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0128] Example 23

[0129]

[0130] The reaction steps and operations were the same as in Example 1, except that ethyl 6-(4-methoxyphenyl)-4-phenyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 47 (92.1 mg, 0.25 mmol) was added to the reaction system, the reaction was stopped, and the target product 48 (88.2 mg, yield 80%) was obtained after post-treatment.

[0131] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0132] Example 24

[0133]

[0134] The reaction steps and operations were the same as in Example 1, except that 49 (89.1 mg, 0.25 mmol) of 6-(4-fluorophenyl)-4-phenyl-2-thiooxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester was added to the reaction system, the reaction was stopped, and the target product 50 (79.5 mg, yield 65%) was obtained after post-treatment.

[0135] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0136] Example 25

[0137]

[0138] The reaction steps and operations were the same as in Example 1, except that (Z)-2-bromo-3-(4-fluorophenyl)propenal 51 (1464895-88-2, 80.2 mg, 0.35 mmol) was added to the reaction system, the reaction was stopped, and the target product 52 (85.3 mg, yield 80%) was obtained after post-treatment.

[0139] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0140] Example 26

[0141]

[0142] The reaction steps and operations were the same as in Example 1, except that (Z)-2-bromo-3-(4-chlorophenyl)propenal 53 (900506-05-0, 85.9 mg, 0.35 mmol) was added to the reaction system, the reaction was stopped, and the target product 54 (87.2 mg, yield 79%) was obtained after post-treatment.

[0143] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0144] Example 27

[0145]

[0146] The reaction steps and operations were the same as in Example 1, except that (Z)-2-bromo-3-(4-methoxyphenyl)propenal 55 (900506-04-9, 84.4 mg, 0.35 mmol) was added to the reaction system, the reaction was stopped, and after post-treatment, the pale yellow solid target product 56 (82.8 mg, yield 76%) was obtained.

[0147] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0148] Example 28

[0149]

[0150] The reaction steps and operations were the same as in Example 1, except that (Z)-2-bromo-3-(3-chlorophenyl)propenal 57 (1352755-79-3, 86.0 mg, 0.35 mmol) was added to the reaction system, the reaction was stopped, and the target product 58 (35.6 mg, yield 32%) was obtained after post-treatment.

[0151] The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0152] The characterization data of the above compounds are as follows:

[0153] (E)-2-benzyl-3-hydroxy-7-methyl-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (4): TLC (petroleum ether / ethyl acetate = 3:1, v / v), Rf = 0.3; pale yellow solid (88.3 mg, 87%); mp 161.3–161.9 °C. 1 H NMR (600MHz, CDCl3) δ7.41 (d, J = 7.4Hz, 2H), 7.35-7.28 (m, 5H), 7.25-7.22 (m, 3H), 6.80 (s, 1H) ,6.35(s,1H),5.95(s,1H),5.46(s,1H),3.90-3.79(m,2H),2.13(s,3H),0.95(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.3,162.5,152.7,141.1,134.7,128.9,128.9,128.6,128.4, 128.4,128.3,128.0,127.1,105.5,88.7,60.0,56.9,22.7,13.9.HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 23 N2O3S + 407.1424; Found 407.1424.

[0154] (E)-2-benzylidene-3-hydroxy-7-methyl-5-(m-tolyl)-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (6):TLC (petroleum ether / ethyl acetate = 3:1, v / v), Rf = 0.3; pale yellow solid (84.1 mg, 80%); mp 173.6–173.8 °C. 1H NMR (600MHz, CDCl3) δ7.34-7.32(m,2H),7.25-7.20(m,6H),7.09(d,J=7.0Hz,1H),6.80(s,1H),6.15( s,1H),5.90(s,1H),5.47(s,1H),3.91-3.80(m,2H),2.33(s,3H),2.14(s,3H),0.97(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.4,162.4,152.7,141.1,138.5,134.8,129.4,129.1,128.9,128.7,128 .4,128.3,128.1,127.1,125.6,105.5,88.7,60.0,56.9,22.8,21.6,14.0.HRMS(ESI)m / z:[M+H] + Calcd forC 24 H 25 N2O3S + 421.1580; Found 421.1578.

[0155] (E)-2-benzyl-3-hydroxy-5-(4-methoxyphenyl)-7-methyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (8):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.2; pale yellow solid (79.9 mg, 73%); mp 171.3-171.7℃. 1 H NMR (600MHz, CDCl3) δ7.33-7.30(m,4H),7.25-7.22(m,3H),6.85(d,J=8.6Hz,2H),6.80(s,1H),6.30( s,1H),5.89(s,1H),5.48(s,1H),3.90-3.80(m,2H),3.78(s,3H),2.13(s,3H),0.98(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.5,162.3,159.8,152.4,134.8,133.5,129.6,128.9,128.3,128 .3,128.2,127.0,114.1,105.7,88.7,60.0,56.3,55.4,22.7,14.0.HRMS(ESI)m / z:[M+H] + Calcd for C 24 H25 N2O4S + 437.1530; Found 437.1535.

[0156] (E)-2-benzyl-3-hydroxy-5-(4-hydroxyphenyl)-7-methyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (10):TLC (petroleum ether / ethyl acetate = 1:1, v / v), R f =0.5; pale yellow solid (82.4 mg, 78%); mp 20 4.0-241.1℃. 1 H NMR (600MHz, DMSO) δ9.54 (s, 1H), 7.44-7.41 (m, 3H), 7.32-7.29 (m, 3H), 7.12 (d, J = 8.5Hz, 2H), 6.93 (s, 1H), 6. 75(d,J=8.5Hz,2H),5.59(s,1H),5.54(d,J=8.0Hz,1H),4.03-3.93(m,2H),2.26(s,3H),1.09(t,J=7.1Hz,3H). 13 C NMR (150MHz, DMSO) δ165.8,160.4,157.5,153.8,134.9,131.7,129.4,128.9,128. 7,128.0,125.1,115.4,104.5,87.0,59.4,54.7,22.7,14.0.HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 23 N2O4S + 423.1373; Found 423.1368.

[0157] (E)-2-benzyl-5-(4-fluorophenyl)-3-hydroxy-7-methyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidin-6-carboxylic acid ethyl ester (12):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.3; pale yellow solid (93.9 mg, 89%); mp 150.3-150.5℃. 1H NMR(600MHz, CDCl3)δ7.38(dd,J=8.5,5.3Hz,2H),7.34-7.32(m,2H),7.27-7.22(m,3H),7.04-7.01(m,2H), 6.82(s,1H),6.15(s,1H),5.94(s,1H),5.44(s,1H),3.90-3.80(m,2H),2.13(s,3H),0.97(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.2,163.8(d,J=246.0),162.4,152.8,137.1(d,J=3.0),134.6,130.1(d,J =9.0),129.0,128.5,128.3,127.8,127.3,115.8(d,J=21.0),105.4,88.7,60.1,56.2,22.8,14.0. 19 F NMR(565MHz,CDCl3)δ-35.20(s).HRMS(ESI)m / z:[M+H] + Calcd forC 23 H 22 FN2O3S + 425.1330; Found 425.1330.

[0158] (E)-2-benzyl-5-(4-bromophenyl)-3-hydroxy-7-methyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (14):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.3; pale yellow solid (91.4 mg, 75%); mp 173.6-173.8℃. 1 H NMR (600MHz, CDCl3) δ7.48-7.46(m,2H),7.35-7.22(m,8H),6.82(s,1H),6.01(s,1H) ),5.91(s,1H),5.43(s,1H),3.90-3.82(m,2H),2.13(s,3H),0.99(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.2,162.5,153.1,140.1,134.6,132.1,130.1,129.0,128.5, 128.3,127.6,127.4,122.8,105.1,88.6,60.2,56.3,22.9,14.0.HRMS(ESI)m / z:[M+H]+ Calcd for C 23 H 22 BrN2O3S + 485.0529; Found 485.0527.

[0159] (E)-2-benzyl-5-(4-chlorophenyl)-3-hydroxy-7-methyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (16):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.2; pale yellow solid (82.9 mg, 75%); mp 161.1-161.5℃. 1 H NMR (600MHz, CDCl3) δ7.35-7.31(m,6H),7.27-7.22(m,3H),6.82(s,1H),6.08(s,1H) ),5.92(s,1H),5.43(s,1H),3.90-3.82(m,2H),2.13(s,3H),0.98(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.2,162.5,153.0,139.6,134.6,134.6,129.8,129.1,129.0, 128.5,128.3,127.6,127.4,105.2,88.6,60.2,56.2,22.9,14.0.HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 22 ClN2O3S + 441.1034; Found 441.1039.

[0160] (E)-2-benzyl-3-hydroxy-7-methyl-5-[4-(methylthio)phenyl]-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (18):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.2; pale yellow solid (98.3 mg, 87%); mp 180.4-180.7℃. 1H NMR (600MHz, CDCl3) δ7.32-7.29(m,4H),7.25-7.19(m,5H),6.80(s,1H),6.58(s,1H),5.9 0(s,1H),5.47(s,1H),3.90-3.81(m,2H),2.45(s,3H),2.12(s,3H),0.98(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.3,162.5,152.7,139.2,137.9,134.7,128.9,128.8,128.4,128 .3,128.0,127.1,126.5,105.3,88.6,60.1,56.4,22.7,15.6,14.0.HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 25 N2O3S2 + 453.1301; Found 453.1297.

[0161] (E)-2-benzyl-5-(2,4-dimethylphenyl)-3-hydroxy-7-methyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (20):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.3; pale yellow solid (90.3 mg, 83%); mp 210.2-210.3℃. 1 H NMR (600MHz, CDCl3) δ7.31(t,J=7.6Hz,2H),7.25-7.20(m,4H),6.99-6.94(m,2H),6.78(s,1H),6.62(s,1H),6.16(s,1 H),5.34(s,1H),3.86-3.77(m,2H),2.57(s,3H),2.27(s,3H),2.10(s,3H),0.93(t,J=7.1Hz,3H).HRMS(ESI)m / z:[M+H] + Calcd for C 25 H 27 N2O3S + 435.1737; Found 435.1730.

[0162] (E)-2-benzyl-5-(3,4-dimethylphenyl)-3-hydroxy-7-methyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (22):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.3; pale yellow solid (81.2 mg, 75%); mp 163.6-163.9℃. 1 H NMR (600MHz, CDCl3) δ7.32-7.29(m,2H),7.24-7.21(m,3H),7.14-7.12(m,2H),7.08(d,J=7.7Hz,1H),6.79(s,1H),6 .72(s,1H),5.89(s,1H),5.50(s,1H),3.90-3.81(m,2H),2.23(d,J=6.4Hz,6H),2.14(s,3H),0.98(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.5,162.5,152.4,138.6,137.0,137.0,134.8,130.0,129.5,128.9 ,128.2,126.9,125.8,105.5,88.7,60.0,56.6,22.7,19.9,19.6,13.9.HRMS(ESI)m / z:[M+H] + Calcd for C 25 H 27 N2O3S + 435.1737; Found 435.1732.

[0163] (E)-2-benzyl-5-cyclohexyl-3-hydroxy-7-methyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (24):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.3; pale yellow solid (69.7 mg, 68%); mp 162.6-162.8℃. 1H NMR(600MHz,DMSO)δ7.46(t,J=7.6Hz,2H),7.38(d,J=7.5Hz,2H),7.35-7.3 2(m,1H),7.29(d,J=8.6Hz,1H),7.02(s,1H),6.08(d,J=8.2Hz,1H),4.79(d ,J=3.2Hz,1H),4.18-4.06(m,2H),2.18(s,3H),1.67(d,J=12.3Hz,2H),1.6 0-1.52(m,4H),1.23(t,J=7.1Hz,3H),1.15-1.01(m,4H),0.84-0.80(m,1H). 13 C NMR(150MHz,DMSO)δ166.8,161.8,155.4,134.9,130.1,129.0,128.0,128.0,124.9,1 01.4,87.9,59.4,55.0,44.4,27.9,26.9,25.8,25.7,22.5,14.2.HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 29 N2O3S + 413.1893; Found 413.1889.

[0164] (E)-2-benzyl-3-hydroxy-7-methyl-5-(naphthyl-1-yl)-2,3-dihydro-5H-thiazo[3,2-a]pyrimidin-6-carboxylic acid ethyl ester (26):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.3; pale yellow solid (97.7 mg, 86%); mp 186.9-187.1℃. 1 H NMR (600MHz, DMSO) δ7.97(d,J=8.1Hz,1H),7.92(d,J=7.9Hz,1H),7.66(s,1H),7.60-7.54(m,3H),7.42-7.38(m,3H),7.27(dd, J=18.7,7.4Hz,3H),6.84(s,1H),6.57(s,1H),5.25(d,J=9.3Hz,1H),3.78-3.75(m,2H),3.34(s,1H),2.35(s,3H),0.72(s,3H). 13C NMR(150MHz,DMSO)δ165.6,160.4,134.8,130.8,129.0,128.9,128.0,127.9,1 26.9,126.0,125.4,122.7,104.6,87.3,59.2,22.6,13.6.HRMS(ESI)m / z:[M+H] + Calcd for C 27 H 25 N2O3S + 457.1580; Found 457.1585.

[0165] (E)-2-benzyl-5-(furan-2-yl)-3-hydroxy-7-methyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidin-6-carboxylic acid ethyl ester (28):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.25; pale yellow solid (44.5 mg, 45%); mp 185.8-186.0℃. 1 H NMR (600MHz, CDCl3) δ7.35-7.33(m,3H),7.28-7.25(m,3H),6.90(s,1H),6.32-6.30(m,2H),6 .01(s,1H),5.91(s,1H),5.71(s,1H),4.04-3.92(m,2H),2.21(s,3H),1.07(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.3,162.4,154.5,153.1,142.9,134.8,129.0,128.4,128 .3,126.8,110.7,109.1,102.5,88.9,60.2,49.7,22.8,14.2.HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 21 N2O4S + 397.1217; Found 397.1217.

[0166] (E)-2-benzyl-3-hydroxy-5-(isothiazo-5-yl)-7-methyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (30):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.3; pale yellow solid (71.7 mg, 69%); mp 185.2-185.7℃. 1H NMR (600MHz, DMSO) δ7.81(d,J=3.2Hz,1H),7.75(d,J=3.2Hz,1H),7.59(d,J=8.6Hz,1H),7.46-7.44(m,2H),7.36-7 .31(m,3H),7.02(s,1H),6.11(s,1H),6.01(d,J=7.6Hz,1H),4.14-4.08(m,2H),2.30(s,3H),1.16(t,J=7.1Hz,3H). 13 CNMR(150MHz,DMSO)δ169.1,165.2,161.8,156.9,142.9,134.8,129.1,129.0,128 .1,128.0,125.5,121.8,102.3,87.8,59.9,51.7,22.8,14.1.HRMS(ESI)m / z:[M+H] + Calcd forC 20 H 20 N3O3S2 + 414.0941; Found 414.0938.

[0167] (E)-2-benzyl-3-hydroxy-7-methyl-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid methyl ester (32):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.2; pale yellow solid (81.3 mg, 83%); mp 174.9-175.0℃. 1 H NMR(600MHz, CDCl3)δ7.40(d,J=7.3Hz,2H),7.35-7.27(m,6H),7.23(d,J=7.4Hz,2 H),6.80(s,1H),6.08(s,1H),5.94(s,1H),5.46(s,1H),3.40(s,3H),2.13(s,3H). 13 C NMR (150MHz, CDCl3) δ166.8,162.6,152.8,141.1,134.7,129.0,128.9,128.7,128. 4,128.3,128.3,128.0,127.1,105.5,88.7,56.8,51.0,22.8.HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 21 N2O3S +393.1267; Found 393.1270.

[0168] (E)-2-benzyl-7-ethyl-3-hydroxy-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidin-6-carboxylic acid methyl ester (34):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.4; pale yellow solid (89.4 mg, 88%); mp 181.3-181.5℃. 1 H NMR (600MHz, CDCl3) δ7.39 (d, J = 7.1Hz, 2H), 7.36-7.28 (m, 5H), 7.25-7.23 (m, 3H), 6.78 (s, 1H), 6.03 (s, 1H),5.94(s,1H),5.45(s,1H),3.40(s,3H),2.69-2.64(m,1H),2.22-2.16(m,1H),1.12(t,J=7.4Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.5,162.8,158.0,141.1,134.8,129.0,128.9,128.6,128.3, 128.3,128.2,128.1,126.9,104.8,88.6,56.7,51.0,28.8,13.0.HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 23 N2O3S + 407.1424; Found 407.1423.

[0169] (E)-2-benzyl-3-hydroxy-5-phenyl-7-propyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidin-6-carboxylic acid methyl ester (36):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.5; pale yellow solid (81.8 mg, 78%); mp 17919-180.0℃. 1 H NMR (600MHz, CDCl3) δ7.39 (d, J = 7.1Hz, 2H), 7.35-7.28 (m, 5H), 7.25-7.22 (m, 3H), 6.78 (s, 1H), 6.35 (s, 1H), 5.95 (s,1H),5.45(s,1H),3.39(s,3H),2.68-2.64(m,1H),2.16-2.11(m,1H),1.64-1.54(m,2H),0.91(t,J=7.4Hz,3H).13 C NMR (150MHz, CDCl3) δ166.5,162.7,156.7,141.2,134.8,128.9,128.9,128.6,128.3,12 8.2,128.1,126.9,105.3,88.5,60.0,56.8,51.0,37.1,22.1,14.2.HRMS(ESI)m / z:[M+H] + Calcd forC 24 H 25 N2O3S + 421.1580; Found 421.1578.

[0170] (E)-2-benzyl-3-hydroxy-7-(methoxymethyl)-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (38):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.1; pale yellow solid (75.9 mg, 70%); mp 169.0-169.6℃. 1 H NMR (600MHz, CDCl3) δ7.41(d,J=7.1Hz,2H),7.34-7.31(m,4H),7.29-7.27(m,1H),7.24(d,J=8.3Hz,3H),6.81(s,1H),5.94 (s,1H),5.53(s,1H),4.40(d,J=13.3Hz,1H),4.25(d,J=13.3Hz,1H),3.95-3.85(m,2H),3.36(s,3H),1.01(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ165.7,163.4,152.5,140.74,134.8,128.9,128.9,128.7,12 8.5,128.3,126.5,106.2,88.4,71.9,60.4,58.9,56.6,13.9.HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 25 N2O4S + 437.1530; Found 437.1532.

[0171] (E)-2-benzyl-3-hydroxy-7-methyl-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidin-6-carboxylic acid isopropyl ester (40):TLC (petroleum ether / ethyl acetate = 3:1, v / v), Rf =0.3; pale yellow solid (66.8 mg, 64%); mp 185.5-186.3℃. 1 H NMR (600MHz, CDCl3) δ7.41 (d, J = 7.3Hz, 2H), 7.35-7.28 (m, 5H), 7.25-7.21 (m, 3H), 6.81 (s, 1H), 6.29 (s, 1H ),5.93(s,1H),5.47(s,1H),4.75-4.71(m,1H),2.16(s,3H),1.11(d,J=6.3Hz,3H),0.74(d,J=6.2Hz,3H). 13 C NMR (150MHz, CDCl3) δ165.8,162.3,141.2,134.7,129.0,128.8,128.6,128.5,128.4, 128.3,128.1,127.1,105.7,88.7,67.5,56.9,22.6,22.1,21.2.HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 25 N2O3S + 421.1580; Found 421.1580.

[0172] (E)-2-benzyl-3-hydroxy-7-methyl-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidin-6-carboxylic acid isobutyl ester (42):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.4; pale yellow solid (80.6 mg, 74%); mp 174.3-174.5℃. 1 H NMR (600MHz, CDCl3) δ7.41 (d, J = 7.3Hz, 2H), 7.35-7.27 (m, 5H), 7.25-7.20 (m, 3H), 6.81 (s, 1H), 6.48 (s, 1H), 5.94 (s ,1H),5.51(s,1H),3.63-3.58(m,2H),2.19(s,3H),1.66-1.60(m,1H),0.72(d,J=6.7Hz,3H),0.66(d,J=6.7Hz,3H). 13C NMR (150MHz, CDCl3) δ166.6,162.4,153.1,140.9,134.7,129.0,128.9,128.7,128.3,12 8.3,128.2,127.0,105.3,88.6,70.6,56.8,27.6,22.9,19.3,19.2.HRMS(ESI)m / z:[M+H] + Calcdfor C 25 H 27 N2O3S + 435.1737; Found 435.1733.

[0173] (E)-2-benzyl-3-hydroxy-7-methyl-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidin-6-carboxylic acid tert-butyl ester (44):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.4; pale yellow solid (68.9 mg, 63%); mp 179.1-179.4℃. 1 H NMR (600MHz, CDCl3) δ7.41 (d, J = 7.2Hz, 2H), 7.37-7.29 (m, 5H), 7.24-7.22 (m, 3H) ),6.80(s,1H),6.04(s,1H),5.85(s,1H),5.47(s,1H),2.16(s,3H),1.15(s,9H). 13 C NMR (150MHz, CDCl3) δ165.9,161.9,151.8,141.1,134.8,129.0,128.8,128.6,128 .3,128.3,128.3,126.9,106.7,88.6,80.5,57.0,28.1,22.4.HRMS(ESI)m / z:[M+H] + Calcd for C 25 H 27 N2O3S + 435.1737; Found 435.1739.

[0174] (E)-2-benzyl-3-hydroxy-7-methyl-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidin-6-carboxylic acid allyl ester (46):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.35; pale yellow solid (77.5 mg, 74%); mp 167.2-167.7℃. 1H NMR (600MHz, CDCl3) δ7.41 (d, J = 7.2Hz, 2H), 7.35-7.28 (m, 5H), 7.25-7.21 (m, 3H), 6.80 (s, 1H), 6.63 (s ,1H),5.98(s,1H),5.61-5.55(m,1H),5.47(s,1H),5.06-5.00(m,2H),4.32-4.26(m,2H),2.13(s,3H). 13 C NMR (150MHz, CDCl3) δ165.9,162.6,141.0,134.6,132.2,129.0,128.9,128.7,128.4,128 .4,128.3,127.9,127.2,117.9,105.2,88.7,64.9,56.8,22.7,13.9.HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 23 N2O3S + 419.1424; Found 419.1424.

[0175] (E)-2-benzyl-3-hydroxy-7-(4-methoxyphenyl)-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (48):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.3; pale yellow solid (88.2 mg, 80%); mp 178.7-179.3℃. 1 H NMR (600MHz, CDCl3) δ7.50(d,J=7.3Hz,2H),7.41-7.33(m,6H),7.28-7.27(m,2H),7.17(d,J=8.6Hz,2H),6.75(d,J=8 .7Hz,2H),6.59(s,1H),6.25(s,1H),6.01(s,1H),5.26(s,1H),3.81-3.75(m,2H),3.74(s,3H),0.75(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ167.6,162.8,160.1,153.0,140.8,135.0,131.8,130.0,129.1,128.9,128 .8,128.3,128.2,128.1,126.5,113.1,105.2,88.0,60.4,56.8,55.4,13.6.HRMS(ESI)m / z:[M+H]+ Calcd for C 29 H 27 N2O4S + 499.1686; Found 499.1684.

[0176] (E)-2-benzyl-7-(4-fluorophenyl)-3-hydroxy-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidin-6-carboxylic acid ethyl ester (50):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.4; pale yellow solid (79.5 mg, 65%); mp 176.2-176.9℃. 1 H NMR (600MHz, CDCl3) δ7.49 (d, J = 7.3Hz, 2H), 7.42-7.34 (m, 5H), 7.30-7.26 (m, 3H), 7.19-7.17 (m, 2H), 6.92 (t ,J=8.7Hz,2H),6.61(s,1H),6.07(s,1H),6.01(s,1H),5.27(s,1H),3.80-3.72(m,2H),0.73(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ167.0,163.8,162.9,162.2,140.5,134.8,130.3,130.3,129.2,1 29.0,129.0,128.4,128.4,128.0,126.7,114.8,114.7,106.2,88.1,60.5,56.8,13.5. 19 F NMR(565MHz,CDCl3)δ-34.89(s).HRMS(ESI)m / z:[M+H] + Calcd for C 28 H 24 FN2O3S + 487.1486; Found 499.1486.

[0177] (E)-2-(4-fluorobenzyl)-3-hydroxy-7-methyl-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (52):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.3; pale yellow solid (85.3 mg, 80%); mp 190.7-190.9℃. 1H NMR (600MHz, CDCl3) δ7.40(d,J=7.1Hz,2H),7.35-7.33(m,2H),7.30(t,J=7.2Hz,1H),7.21(dd,J=8.6,5.2Hz,2H),7.01(t ,J=8.6Hz,2H),6.76(s,1H),6.16(s,1H),5.92(s,1H),5.44(s,1H),3.93-3.81(m,2H),2.13(s,3H),0.96(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.28(s),163.18(s),162.16(s),161.53(s),130.99(s),130.07(d,J=8.1Hz),128.91(s),128.81(d,J=30 .6Hz),128.41(s),127.87(s),116.17(s),116.08(d,J=21.8Hz),105.55(s),88.63(s),60.09(s),56.89(s),22.72(s),13.96(s). 19 F NMR(565MHz,CDCl3)δ-34.00(s).HRMS(ESI)m / z:[M+H] + Calcd forC 23 H 22 FN2O3S + 425.1330; Found 425.1321.

[0178] (E)-2-(4-chlorobenzyl)-3-hydroxy-7-methyl-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (54):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.33; pale yellow solid (87.2 mg, 79%); mp 192.4-192.5℃. 1 H NMR(600MHz, CDCl3)δ7.40(d,J=7.3Hz,2H),7.36-7.33(m,2H),7.31-7.29(m,3H),7.17(d,J=8.5Hz,2H),6 .75(s,1H),6.00,(s,1H),5.91(s,1H),5.45(s,1H),3.92-3.81(m,2H),2.13(s,3H),0.97(t,J=7.1Hz,3H). 13C NMR (150MHz, CDCl3) δ166.2,161.9,140.9,134.2,133.2,129.5,129.2,128.9,128 .7,128.4,125.7,105.7,88.7,77.4,60.2,56.9,22.7,14.0.HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 22 ClN2O3S + 441.1034; Found 441.1028.

[0179] (E)-3-hydroxy-2-(4-methoxybenzyl)-7-methyl-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (56):TLC (petroleum ether / ethyl acetate = 3:1, v / v), R f =0.2; pale yellow solid (82.8 mg, 76%); mp 176.7-177.7℃. 1 H NMR (600MHz, CDCl3) δ7.41(d,J=7.3Hz,2H),7.35-7.32(m,2H),7.28(d,J=7.3Hz,1H),7.15(d,J=8.7Hz,2H),6.83(d,J=8.8Hz ,2H),6.73(s,1H),6.52(s,1H),5.95(s,1H),5.43(s,1H),3.90-3.81(m,2H),3.78(s,3H),2.12(s,3H),0.95(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.4,162.7,159.5,141.3,129.8,128.8,128.5,128.4,127.4, 126.8,125.2,114.4,105.3,88.7,59.9,56.9,55.4,22.7,13.9.HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 25 N2O4S + 437.1530; Found 441.1524.

[0180] (E)-2-(3-chlorobenzyl)-3-hydroxy-7-methyl-5-phenyl-2,3-dihydro-5H-thiazo[3,2-a]pyrimidin-6-carboxylic acid ethyl ester (58):TLC (petroleum ether / ethyl acetate = 3:1, v / v), Rf =0.33; pale yellow solid (35.6 mg, 32%); mp 196.2-196.4℃. 1 H NMR (600MHz, CDCl3) δ7.40(d,J=7.3Hz,2H),7.35(t,J=7.4Hz,2H),7.30(dd,J=14.2,7.5Hz,2H),7.25(d,J=1.8Hz,2H) ,7.15(d,J=7.6Hz,1H),6.78(s,1H),5.85(s,1H),5.51(s,1H),4.02-3.90(m,2H),2.28(s,3H),1.06(t,J=7.1Hz,3H). 13 C NMR (150MHz, DMSO) δ165.6,160.3,154.3,141.0,137.0,133.6,131.2,130.8,128.9,128.5,1 27.9,127.8,127.4,126.0,123.9,104.3,87.0,59.5,55.2,22.7,14.0.HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 22 ClN2O3S + 441.1034; Found 441.1028.

[0181] To further demonstrate the beneficial effects of the present invention and to better understand it, the technical features disclosed in the present invention are further illustrated by the following comparative examples, but these should not be construed as limiting the present invention. Other improvements made by those skilled in the art based on the above description of the invention, without inventive effort, are also considered to fall within the protection scope of the present invention.

[0182] Comparative Example 1

[0183] The reaction steps and operations were the same as in Example 1, except that the reaction was carried out without light. The reaction was stopped, and the target product 4 was not obtained after the same post-treatment as described above, indicating that the reaction cannot proceed without light.

[0184] Comparative Example 2

[0185] The reaction steps and operations were the same as in Example 1, except that the reaction time was 1 hour. The reaction was stopped, and after post-processing, the target product 4 (43.2 mg, yield 43%) was obtained, indicating that reducing the reaction time was detrimental to the reaction.

[0186] Comparative Example 3

[0187] The reaction steps and operations were the same as in Example 1, except that N,N-dimethylformamide was used as the solvent. The reaction was stopped, and after post-treatment, the target product 4 (44.5 mg, yield 44%) was obtained, indicating that using N,N-dimethylformamide as a solvent is not conducive to the reaction.

[0188] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A thiazopyrimidine compound, characterized in that, The structural formula of the thiazopyrimidine compound is as follows: Wherein, R1 is alkyl or alkenyl; R2 is alkyl, phenyl, or p-methoxy-substituted phenyl or p-fluorine-substituted phenyl; R3 is phenyl, naphthyl, or p-hydroxy-substituted phenyl or p-methoxy-substituted phenyl; and R4 is phenyl, or p-chloro-substituted phenyl or p-methoxy-substituted phenyl.

2. A method for preparing a thiazopyrimidine compound as described in claim 1, characterized in that, R1-R4 are as defined in claim 1.

3. The method for preparing thiazopyrimidine compounds according to claim 2, characterized in that, Using pyrimidinethione as a raw material, it reacts with α-bromocinnamaldehyde under visible light irradiation to generate thiazopyrimidine compounds.

4. The method for preparing thiazopyrimidine compounds according to claim 3, characterized in that, The molar ratio of pyrimidinethione to α-bromocinnamaldehyde is 1:1-5:

8.

5. The method for preparing thiazopyrimidine compounds according to claim 3, characterized in that, The visible light irradiation is selected from one or more light sources selected from 5000-5500K white light, 395-400nm violet light, and 460-465nm blue light, and the power of the irradiation light source is 6-10W.

6. The method for preparing thiazopyrimidine compounds according to claim 3, characterized in that, The reaction time is 1-24 hours, the reaction temperature is room temperature, and the reaction atmosphere is air.

7. The method for preparing thiazopyrimidine compounds according to claim 3, characterized in that, The reaction solvent is one or more of dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylacetamide.

8. The use of a thiazopyrimidine compound as described in claim 1 or a thiazopyrimidine compound prepared by the method described in claims 2 and 3 in a pharmaceutical formulation.

9. The application according to claim 8, characterized in that, The thiazopyrimidine compounds are used as pharmaceutical intermediates or pharmaceutical molecules.

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