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CN111777604B - A kind of synthetic method of 2-aminothiazole pyrimidine as CDK2 inhibitor - Google Patents

A kind of synthetic method of 2-aminothiazole pyrimidine as CDK2 inhibitor Download PDF

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CN111777604B
CN111777604B CN202010690254.6A CN202010690254A CN111777604B CN 111777604 B CN111777604 B CN 111777604B CN 202010690254 A CN202010690254 A CN 202010690254A CN 111777604 B CN111777604 B CN 111777604B
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李剑
温金侠
刘莉
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Changzhou University
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Abstract

本发明涉及有机合成及药物技术领域，具体公开了一种作为CDK/2抑制剂的2‑胺基噻唑嘧啶的合成方法。合成步骤为：氨基转化为异硫氰酸酯、与伯胺反应生成硫脲、Hantzsch噻唑合成反应，氟化反应以及烯胺酮与盐酸胍的缩合形成嘧啶环。该法经过5步反应，总收率达到35％‑48％。本发明的优点在于：在氟化部分，采用光催化来代替传统的氟化方法，整个工艺的产率大大增加，在氟化这步反应使得产率从35％提高至85％，而且相对于传统在低温冰盐浴中氟化方法，该法条件更温和，只需在室温下进行，是一条合成CDK/2抑制剂2‑胺基噻唑嘧啶的较佳的工艺。The invention relates to the technical field of organic synthesis and medicine, and specifically discloses a method for synthesizing 2-aminothiazopyrimidine as a CDK/2 inhibitor. The synthesis steps are as follows: amino group is converted into isothiocyanate, reacted with primary amine to generate thiourea, Hantzsch thiazole synthesis reaction, fluorination reaction and condensation of enaminone and guanidine hydrochloride to form pyrimidine ring. The method goes through 5 steps of reaction, and the total yield reaches 35%-48%. The advantages of the present invention are: in the fluorination part, photocatalysis is used to replace the traditional fluorination method, and the yield of the whole process is greatly increased. The traditional fluorination method in a low-temperature ice-salt bath has milder conditions and only needs to be carried out at room temperature. It is a better process for synthesizing CDK/2 inhibitor 2-aminothiazopyrimidine.

Description

Synthesis method of 2-aminothiazole pyrimidine serving as CDK2 inhibitor
Technical Field
The invention relates to the technical field of organic synthesis and medicines, and particularly discloses a method for synthesizing 2-aminothiazole pyrimidine serving as a CDK/2 inhibitor.
Background
Cancer cells have an unlimited proliferation, disrupting the circulatory regulation of the cell, leading to a disturbance in the orderly division of the cell. Inhibitors of cyclin-dependent kinases (CDKs) which allow the cell cycle to be continuously operated, play a crucial role in cell cycle control, and are also one of the most promising fields of cancer therapy. Researchers at home and abroad have reported various types of Adenosine Triphosphate (ATP) -competitive CDK inhibitors, and some have been used in clinical diagnostics (Fischer, p.m.; Gianella-Borradori, a.exp.opin.invest.drugs 2003,12, 955.).
2-aminothiazolopyrimidines have been shown to be moderately potent CDK inhibitors (Wang, S.; Meads, C.; Wood, G et. al, J med. chem.,2004,47, 1662; Tadesse, S.; Yu, M.; Mekonen, L.B. et. al, J Med. chem.2017,60,1892.). The introduction of halogen atoms into drugs can affect the charge distribution of drug molecules, thereby enhancing the electrical binding with receptors. Because the electron-withdrawing effect of fluorine atoms is stronger, fluorine-containing medicaments account for a certain proportion of clinical medicaments. However, the traditional fluorination reaction needs fluorine reagent at low temperature and is kept at-5 ℃ for 3 hours, and the yield is only about 35%. The post-treatment is also complicated and requires a column-passing method to obtain a pure compound. Therefore, it is of great significance to develop a simple and efficient fluorination reaction.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a simple photocatalytic preparation method of 2-aminothiazole pyrimidine serving as a CDK/2 inhibitor, and provide a synthetic method which is simple to operate and high in efficiency so as to meet the production requirement.
A method for synthesizing 2-aminothiazole pyrimidine serving as CDK/2 inhibitor comprises the following process flow:
Figure BDA0002589099830000021
the method comprises the following specific steps:
(1) synthesis of isothiocyanate: adding an organic solvent, aniline or aminocyclopentane, carbon disulfide, 4-dimethylaminopyridine and an organic base into a flask, stirring for 30 minutes at room temperature, and cooling to-5 ℃. Di-tert-butyl dicarbonate (Boc) is added at this temperature2O). Stirring at-5 deg.C for 10 min, heating to room temperature, stirring for 30 min, detecting by TLC plate, drying the reaction solution by spin-drying, filtering off insoluble substance with diethyl ether, drying the filtrate by spin-drying, and recrystallizing with petroleum ether to obtain isothiocyanate.
Wherein, the organic solvent can be ethanol, tetrahydrofuran, acetone or dichloromethane, and the organic base is triethylamine; the molar ratio of aniline or aminocyclopentane, carbon disulfide and di-tert-butyl dicarbonate is 1:1: 0.9; the amount of triethylamine added was 10% mmol equivalent and the amount of 4-dimethylaminopyridine was 1% mmol equivalent.
(2) And (3) synthesizing thiourea: adding isothiocyanate and ammonia water into the reaction tube, stirring in an organic solvent at room temperature for 18-24 hours, and recrystallizing the precipitated solid with ethyl acetate to obtain the pure thiourea derivative.
Wherein the organic solvent is methanol or ethanol, and the ammonia water is excessive.
(3) Hantzsch thiazole synthesis: under the ice-water bath, a neutral anhydrous solvent, pyridine and thiourea derivatives are added into a flask, and 3-chloro-2, 4-pentanedione is slowly added dropwise. The temperature was then raised to room temperature, stirred for 4 hours and the reaction checked by TLC spot plate. The precipitated solid was recrystallized from ethyl acetate to obtain pure 2-aminothiazole.
Wherein the neutral anhydrous solvent can be acetonitrile or anhydrous methanol; the molar ratio of the thiourea derivative, the 3-chloro-2, 4-pentanedione and the pyridine is 1:1: 1.
(4) Synthesis of thiazole acrylamide: n, N-dimethylformamide-dimethylamine (DMF-DMA) and 2-aminothiazole were added to the flask. The reaction temperature was raised to 120 ℃ and the reaction was carried out for 6 hours. And detecting the reaction by TLC spot plates, concentrating the reaction solution after the reaction is finished, and recrystallizing ethyl acetate to obtain the thiazole acrylamide.
The molar ratio of the 2-aminothiazole to the N, N-dimethylformamide-dimethylamine is 1:2-1: 5.
(5) Fluorination reaction under the condition of illumination, thiazole acrylamide, a fluorine reagent, a photocatalyst and an organic solvent are added into a reaction tube, and the reaction is carried out for 1 hour at room temperature. And (3) detecting the reaction by TLC spot plates, concentrating the reaction solution after the reaction is finished, and recrystallizing petroleum ether to obtain the fluorinated thiazole acrylamide.
Wherein the fluorine reagent is [ 1-chloromethyl-4-fluorine-1, 4-diazotized bicyclo 2.2.2 octane bis (tetrafluoroborate) salt 3-methylamine-alizarin-diacetic acid, and the structural formula is shown in the specification
Figure BDA0002589099830000031
(CAS NO.140681-55-6)](ii) a The photocatalyst may be Ru (bpy)3(PF6)2Eosin Y or rhodamine B; the organic solvent may be acetonitrile, tetrahydrofuran, anhydrous ethanol or Dimethylacetamide (DMA).
The molar ratio of the thiazole acrylamide to the fluorine reagent is 1:1.2-1: 1.5.
The amount of photocatalyst added was 5% mmol equivalent.
(6) Formation of pyrimidine ring fluoride, guanidine hydrochloride and inorganic base were added to the reaction tube and refluxed in diethylene glycol monomethyl ether for 6 hours. The inorganic base may be sodium hydroxide or potassium hydroxide.
The molar ratio of the fluorinated thiazole acrylamide to the guanidine hydrochloride to the inorganic base is 1:1: 2.
The structural formula of the 2-aminothiazole pyrimidine or the pharmaceutically acceptable salt thereof prepared by the method is shown as the formula (I):
Figure BDA0002589099830000041
the invention has the advantages that: 2-aminothiazole pyrimidine is an important CDK/2 inhibitor and has wide application in medicine and pharmacology. The method of the invention uses fluorine reagent to carry out fluorine addition under the photocatalysis condition, can carry out reaction at room temperature, and shortens the time to 1 hour. The yield reaches 83-85%, and the fluoride can be obtained by simple recrystallization in the post-treatment. The new method is more mild and convenient, the yield is improved from the traditional 35 percent to 85 percent, and the yield is greatly improved.
Detailed Description
The reaction process and the structural formula of the obtained product are shown in the specification
Figure BDA0002589099830000042
Example 12- (Cyclopentylamine) -4-methylthiazole-2-fluoro-propenone 6a
The flask was charged with anhydrous ethanol (3mL), aminocyclopentane (44mmol), carbon disulfide (44mmol) and triethylamine (4.4mmol), stirred at room temperature for 30 minutes and cooled to-5 ℃. At this temperature, di-tert-butyl dicarbonate (Boc) is added in solution2O) (4.36mmol) in absolute ethanol (2mL), 4-dimethylaminopyridine (4.5% mmol). Stirring at-5 deg.C for 10 min, heating to room temperature, stirring for 30 min, detecting by TLC spot plate, drying the reaction solution, filtering off insoluble substance with diethyl ether, drying the filtrate, and recrystallizing with petroleum ether to obtain isothiocyanate with yield of 88%.
Isothiocyanate (50mmol) and ammonia (30mL) were added to the reaction tube, and stirred in methanol at room temperature for 20 hours, and the precipitated solid was recrystallized from ethyl acetate to give pure thiourea in 85% yield.
In an ice-water bath, anhydrous methanol (15mL), pyridine (1.5mL) and thiourea (48mmol) were added to the flask, and 3-chloro-2, 4-pentanedione (48mmol) was slowly added dropwise. The temperature was then raised to room temperature, stirred for 4 hours and the reaction checked by TLC spot plate. The precipitated solid was recrystallized from ethyl acetate to obtain pure 2-aminothiazole in a yield of 90%.
Into the flask were added N, N-dimethylformamide-dimethylamine (DMF-DMA, 38mmol) and 2-aminothiazole (21 mmol). The reaction temperature was raised to 120 ℃ and the reaction was carried out for 6 hours. And detecting the reaction by a TLC spot plate, concentrating the reaction solution after the reaction is finished, and recrystallizing by ethyl acetate to obtain the thiazole acrylamide with the yield of 79%.
Under the condition of illumination, compound thiazole acrylamide 5a (2.0mmol), fluorinating agent (3.0mmol), tris (2,2' -bipyridine) ruthenium bis (hexafluorophosphate) salt Ru (bpy)3(PF6)2(5% mmol) and dry acetonitrile (15mL) were added to a 50mL flask and the reaction was stirred at room temperature for 1 hour. TLC spot plate detection reaction, after finishing the reaction, concentrating the reaction solution, recrystallizing with petroleum ether, and filtering to obtain pure compound 6a with the yield of 85%.1H NMR(500MHz,CDCl3)δ6.88(d,J＝24.8Hz,1H),3.78-3.74(m,1H),3.08(s,6H),2.54(s,3H),2.02-2.08(m,2H),1.55-1.74(m,6H).
Example 22- (Aniline) -4-methylthiazole-2-fluoro-propenone 6b
Anhydrous ethanol (3mL), aniline (44mmol), carbon disulfide (44mmol) and triethylamine (4.4mmol) were added to the flask, stirred at room temperature for 30 minutes and then cooled to-5 ℃. At this temperature, di-tert-butyl dicarbonate (Boc) is added in solution2O) (4.36mmol) in absolute ethanol (2mL), 4-dimethylaminopyridine (4.5% mmol). Stirring at-5 deg.C for 10 min, heating to room temperature, stirring for 30 min, detecting by TLC spot plate, drying the reaction solution, filtering off insoluble substance with diethyl ether, drying the filtrate, and recrystallizing with petroleum ether to obtain isothiocyanate with yield of 75%.
Isothiocyanate (50mmol) and ammonia (30mL) were added to the reaction tube, and stirred in methanol at room temperature for 24 hours, and the precipitated solid was recrystallized from ethyl acetate to give pure thiourea in a yield of 90%.
In an ice-water bath, anhydrous methanol (15mL), pyridine (1.5mL) and thiourea (48mmol) were added to the flask, and 3-chloro-2, 4-pentanedione (48mmol) was slowly added dropwise. The temperature was then raised to room temperature, stirred for 4 hours and the reaction checked by TLC spot plate. The precipitated solid was recrystallized from ethyl acetate to obtain pure 2-aminothiazole in a yield of 85%.
The flask was charged with 2-aminothiazole 4(21mmol) and N, N-dimethylformamide-dimethylamine (DMF-DMA, 42 mmol). The reaction temperature was raised to 120 ℃ and the reaction was carried out for 6 hours. Detecting the reaction by TLC point plate, concentrating the reaction solution after the reaction is finished, and recrystallizing ethyl acetate to obtain thiazole acrylamide with the yield of 79 percent
Under the condition of illumination, compound thiazole acrylamide 5b (2.0mmol), fluorinating agent (3.0mmol), tris (2,2' -bipyridine) ruthenium bis (hexafluorophosphate) salt Ru (bpy)3(PF6)2(5% mmol) and dry acetonitrile (15mL) were added to a 50mL flask and the reaction was stirred at room temperature for 1 hour. The reaction was checked by TLC plate chromatography, after completion the reaction was concentrated, recrystallized from petroleum ether and filtered to give pure compound 6b in 83% yield.1H NMR(500MHz,CDCl3)δ10.40(br,1H),7.23-7.18(m,2H),6.83-6.81(m,1H),6.45(d,J＝8.4Hz,2H),6.18-6.15(m,1H),3.78-3.74(m,1H),3.06(s,6H),2.22-2.18(m,1H),1.55-1.74(m,3H).
Example 3
Under the illumination condition, the compound thiazole acrylamide 5b (2.0mmol), a fluorine reagent (2.4mmol), tris (2,2' -bipyridine) ruthenium bis (hexafluorophosphate) salt Ru (bpy)3(PF6)2(5% mmol) and dry acetonitrile (15mL) were added to a 50mL flask and the reaction was stirred at room temperature for 1 hour. TLC spot plate detection reaction, after finishing reaction, concentrating the reaction solution, recrystallizing with petroleum ether, and filtering to obtain pure compound 6b with the yield reaching 70%.
Example 4
Thiazole acrylamide (2.0mmol), a fluorine reagent (3.0mmol), pyrrhone Y (5% mmol) and anhydrous acetonitrile (15mL) were added to a 50mL flask under light conditions, and the reaction was stirred at room temperature for 1 hour. The reaction was checked by TLC plate chromatography, after completion the reaction was concentrated, recrystallized from petroleum ether and filtered to give pure compound 6a in 52% yield.
Example 5
Under the illumination condition, compound 5a (2.0mmol), fluorine reagent (3.0mmol), tris (2,2' -bipyridine) ruthenium bis (hexafluorophosphate) salt Ru (bpy)3(PF6)2(5% mmol) and dry methanol (15mL) were added to a 50mL flask and the reaction was stirred at room temperature for 1 hour. TLC spot plate detection reactionAfter the reaction is finished, the reaction solution is concentrated, recrystallized by petroleum ether and filtered to obtain pure compound 6a, and the yield reaches 72%.
Example 6
Under the illumination condition, compound 5a (2.0mmol), fluorine reagent (3.0mmol), tris (2,2' -bipyridine) ruthenium bis (hexafluorophosphate) salt Ru (bpy)3(PF6)2(5% mmol) and tetrahydrofuran (15mL) were added to a 50mL flask and the reaction was stirred at room temperature for 1 hour. The reaction was checked by TLC plate chromatography, after completion the reaction was concentrated, recrystallized from petroleum ether and filtered to give pure compound 6a in 52% yield.
Example 7N-Cyclopentan-2-amino 5-Fluorothiazolopyrimidine 7a
Adding the compound 6a (2.0mmol), NaOH (4.0mmol), guanidine hydrochloride (4.0mmol) and diethylene glycol monomethyl ether (15mL) into a 50mL flask, raising the reaction temperature to 130 ℃ for reflux reaction for 6 hours, detecting the reaction by a TLC point plate, drying the filtrate by spinning, and further separating and purifying the crude product by silica gel column chromatography to obtain 7a.1H NMR(500MHz,CDCl3)δ8.07(d,J＝3.5Hz,1H,),5.75(d,J＝5.8Hz,1H,),5.06(s,2H),3.83-3.79(m,1H),2.52(d,J＝2.5Hz,3H),2.12-2.05(m,2H),1.76-1.58(m,6H).
Example 8N-phenyl-2-amino-5-fluorothiazolopyrimidine 7b
7b synthetic procedure reference is made to 7a.1H NMR(500MHz,CDCl3)δ10.36(br,1H),8.62(d,J＝7.8Hz,1H),7.25-7.21(m,2H),6.85-6.83(m,1H),6.54(s,1H),6.45(d,J＝8.2Hz,2H),3.82-3.76(m,1H),2.56-2.53(m,1H),1.09-1.06(m,3H).
Comparative example 1
Compound 5a (2.0mmol), fluoro reagent (3.0mmol), tris (2,2' -bipyridine) ruthenium bis (hexafluorophosphate) salt Ru (bpy) were placed in a tin foil-coated flask in the dark3(PF6)2(5% mmol) and dry acetonitrile (15mL) were added to a 50mL flask and the reaction was stirred at room temperature for 1 hour. The reaction was detected by TLC plate and found to be non-reactive.
The present invention is not limited to the above-described embodiments, and any obvious improvements, substitutions or modifications can be made by those skilled in the art without departing from the spirit of the present invention.

Claims (7)

1.一种2-胺基噻唑嘧啶的合成方法，其特征在于，所述合成方法步骤如下：1. a synthetic method of 2-aminothiazole pyrimidine, is characterized in that, described synthetic method steps are as follows: （1）氨基转化为异硫氰酸酯: 在烧瓶中加入有机溶剂，苯胺或氨基环戊烷、二硫化碳、4-二甲氨基吡啶和有机碱，在0-23℃下搅拌30分钟后冷却至-5℃，加入二碳酸二叔丁酯（Boc2O），继续在-5℃下搅拌10分钟后，将反应温度升高至室温，搅拌30分钟，TLC点板检测反应，结束后将反应液旋干，用乙醚过滤掉不溶物，旋干滤液，用石油醚重结晶得异硫氰酸酯；其结构式为R1NCS，R1=Ph或c-Pent；(1) Conversion of amino group to isothiocyanate: add organic solvent, aniline or aminocyclopentane, carbon disulfide, 4-dimethylaminopyridine and organic base to the flask, stir at 0-23 °C for 30 minutes and then cool to -5 °C, add di-tert-butyl dicarbonate (Boc 2 O), continue to stir at -5 °C for 10 minutes, raise the reaction temperature to room temperature, stir for 30 minutes, TLC spot plate to detect the reaction, after the completion of the reaction The liquid is spin-dried, the insolubles are filtered out with ether, the filtrate is spin-dried, and recrystallized with petroleum ether to obtain isothiocyanate; its structural formula is R 1 NCS, R 1 =Ph or c-Pent; （2）硫脲的生成：(2) The formation of thiourea: 向反应管中加入异硫氰酸酯和氨水，在有机溶剂中室温搅拌18-24小时，析出的固体用乙酸乙酯重结晶得到纯净的硫脲衍生物Add isothiocyanate and ammonia water to the reaction tube, stir in an organic solvent at room temperature for 18-24 hours, the precipitated solid is recrystallized with ethyl acetate to obtain pure thiourea derivatives
Figure DEST_PATH_IMAGE002
；
Figure DEST_PATH_IMAGE002
; （3）Hantzsch噻唑合成：冰水浴下，在烧瓶中加入无水溶剂，吡啶和硫脲衍生物，缓慢滴加3-氯-2,4-戊二酮，然后将温度升至室温，搅拌4小时，TLC点板检测反应，析出的固体用乙酸乙酯重结晶得到纯净的2-胺基噻唑；其结构式为：
Figure DEST_PATH_IMAGE004
；(3) Hantzsch thiazole synthesis: under ice-water bath, add anhydrous solvent, pyridine and thiourea derivatives to the flask, slowly add 3-chloro-2,4-pentanedione dropwise, then raise the temperature to room temperature, stir for 4 hours, TLC spot plate detection reaction, the separated solid is recrystallized with ethyl acetate to obtain pure 2-aminothiazole; Its structural formula is:
Figure DEST_PATH_IMAGE004
; （4）噻唑丙烯酰胺的合成：向反应管中加入N,N-二甲基甲酰胺-二甲胺（DMF-DMA）和2-胺基噻唑，将反应温度升至120℃反应6小时，TLC点板检测反应，反应后处理是将反应液浓缩，乙酸乙酯重结晶得到噻唑丙烯酰胺；其结构式为：
Figure DEST_PATH_IMAGE006
；(4) Synthesis of thiazole acrylamide: N,N -dimethylformamide-dimethylamine (DMF-DMA) and 2-aminothiazole were added to the reaction tube, and the reaction temperature was raised to 120°C for 6 hours. TLC spot plate detects the reaction, and the post-reaction treatment is to concentrate the reaction solution and recrystallize from ethyl acetate to obtain thiazole acrylamide; its structural formula is:
Figure DEST_PATH_IMAGE006
; （5）氟化反应：在光照条件下，向反应管中加入噻唑丙烯酰胺，氟试剂、光催化剂和有机溶剂，在室温下反应 1小时；反应后采用乙醚重结晶得到氟化物；其结构式为：
Figure DEST_PATH_IMAGE008
；(5) Fluorination reaction: under light conditions, add thiazole acrylamide, fluorine reagent, photocatalyst and organic solvent to the reaction tube, and react at room temperature for 1 hour; after the reaction, use diethyl ether to recrystallize to obtain fluoride; its structural formula is :
Figure DEST_PATH_IMAGE008
; 氟试剂为 [1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐3-甲基胺-茜素-二乙酸，其结构式为
Figure DEST_PATH_IMAGE010
；The fluorine reagent is [1-chloromethyl-4-fluoro-1,4-diazonium bicyclic 2.2.2 octane bis(tetrafluoroborate) salt 3-methylamine-alizarin-diacetic acid, and its structural formula is
Figure DEST_PATH_IMAGE010
; 光催化剂为Ru(bpy)3(PF6)2、曙红Y或罗丹明B；The photocatalyst is Ru(bpy) 3 (PF 6 ) 2 , eosin Y or rhodamine B; 噻唑丙烯酰胺和氟试剂的摩尔比为1:1.2-1:1.5；The molar ratio of thiazole acrylamide and fluorine reagent is 1:1.2-1:1.5; 光催化剂的加入量为5% mmol当量；The addition of photocatalyst is 5% mmol equivalent; （6）嘧啶环的形成：向反应管中加入氟化物，盐酸胍和无机碱，在二氧基乙醇中回流6小时；(6) Formation of pyrimidine ring: add fluoride, guanidine hydrochloride and inorganic base to the reaction tube, and reflux in dioxyethanol for 6 hours; 2-胺基噻唑嘧啶的结构式如式(I)所示The structural formula of 2-aminothiazopyrimidine is shown in formula (I)
Figure DEST_PATH_IMAGE012
Figure DEST_PATH_IMAGE012
 式(I)。Formula (I). 2.根据权利要求1所述的2-胺基噻唑嘧啶的合成方法，其特征在于，步骤（1）所述有机溶剂为：乙醇，四氢呋喃、丙酮或二氯甲烷；有机碱为三乙胺；苯胺或氨基环戊烷、二硫化碳和二碳酸二叔丁酯的摩尔比为1：1：0.9；三乙胺的加入量为苯胺或氨基环戊烷的10% mmol，4-二甲氨基吡啶用量为1% mmol 当量。2. The method for synthesizing 2-aminothiazopyrimidine according to claim 1, wherein the organic solvent in step (1) is: ethanol, tetrahydrofuran, acetone or dichloromethane; the organic base is triethylamine; The molar ratio of aniline or aminocyclopentane, carbon disulfide and di-tert-butyl dicarbonate is 1:1:0.9; the amount of triethylamine added is 10% mmol of aniline or aminocyclopentane, and the amount of 4-dimethylaminopyridine is 1% mmol equivalent. 3.根据权利要求1所述的2-胺基噻唑嘧啶的合成方法，其特征在于，步骤（2）所述有机溶剂为甲醇或乙醇，氨水过量。3 . The method for synthesizing 2-aminothiazopyrimidine according to claim 1 , wherein the organic solvent in step (2) is methanol or ethanol, and the ammonia water is excessive. 4 . 4.根据权利要求1所述的2-胺基噻唑嘧啶的合成方法，其特征在于，步骤（3）所述硫脲衍生物、3-氯-2,4-戊二酮和吡啶的摩尔比为1:1:1，无水溶剂为乙腈或无水甲醇。4. The method for synthesizing 2-aminothiazolepyrimidine according to claim 1, wherein the molar ratio of the thiourea derivative, 3-chloro-2,4-pentanedione and pyridine in step (3) The ratio is 1:1:1, and the anhydrous solvent is acetonitrile or anhydrous methanol. 5.根据权利要求1所述的2-胺基噻唑嘧啶的合成方法，其特征在于，步骤（4）所述2-胺基噻唑与N,N-二甲基甲酰胺-二甲胺的摩尔比为1:2-1:5。5. The method for synthesizing 2-aminothiazolepyrimidine according to claim 1, wherein the moles of the 2-aminothiazole and N,N -dimethylformamide-dimethylamine in step (4) are The ratio is 1:2-1:5. 6.根据权利要求1所述的2-胺基噻唑嘧啶的合成方法，其特征在于，步骤（5）所述有机溶剂为无水乙腈、四氢呋喃、无水甲醇或二甲基乙酰胺 (DMA)。6. The synthetic method of 2-aminothiazolepyrimidine according to claim 1, wherein the organic solvent in step (5) is anhydrous acetonitrile, tetrahydrofuran, anhydrous methanol or dimethylacetamide (DMA) . 7.根据权利要求1所述的2-胺基噻唑嘧啶的合成方法，其特征在于，步骤（6）所述无机碱为氢氧化钠或氢氧化钾；氟化噻唑丙烯酰胺、盐酸胍和无机碱的摩尔比为1:1:2。The method for synthesizing 2-aminothiazopyrimidine according to claim 1, wherein the inorganic base in step (6) is sodium hydroxide or potassium hydroxide; fluorinated thiazole acrylamide, guanidine hydrochloride and inorganic bases The molar ratio of base is 1:1:2.
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