WO2020181646A1 - 一种三唑类化合物的制备方法 - Google Patents
一种三唑类化合物的制备方法 Download PDFInfo
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- WO2020181646A1 WO2020181646A1 PCT/CN2019/086613 CN2019086613W WO2020181646A1 WO 2020181646 A1 WO2020181646 A1 WO 2020181646A1 CN 2019086613 W CN2019086613 W CN 2019086613W WO 2020181646 A1 WO2020181646 A1 WO 2020181646A1
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- 0 Cc1n[n]c(*)n1 Chemical compound Cc1n[n]c(*)n1 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Definitions
- the invention relates to a preparation method of triazole compounds.
- Triazole compounds have bactericidal biological activity. They are not only high in activity, unique in action mechanism, and environmentally friendly, but also have specific effects on difficult-to-control diseases such as rice blast, downy mildew, gray mold and wilt. It is mainly used for the prevention and control of sheath blight, rust, early blight, leaf spot, scab and powdery mildew on fruit trees, vegetables, wheat, potatoes, beans, melons and other crops. It has excellent control effects on vegetables and fruits. Many other fungal diseases have good protection and treatment effects, and have the characteristics of long lasting effect, and no cross-resistance with other fungicides. It also has the characteristics of not polluting the environment, agricultural products, and killing natural enemies. It is an ideal fungicide for preventing and controlling citrus scab, spotted leaf disease and other crop resistant diseases in various countries.
- Triazole compound is a systemic triazole fungicide with protective and therapeutic effects. It can be absorbed by roots, stems and leaves, and can be quickly transmitted upwards in the plant body to prevent ascomycetes and basidiomycetes. Diseases caused by deuteromycetes, especially wheat rot, powdery mildew, rust, root rot, rice chalcogenide, and banana leaf spot.
- the present invention provides an improved method for preparing triazole compounds.
- the method uses formula III as the main raw material and formula IV to carry out a substitution reaction under alkaline conditions to synthesize the triazole compound represented by formula V.
- the product has high yield, high purity, no pollution, green environmental protection and suitable for modern industrial production.
- R a , R b are each independently selected from -CH 3, -CF 3, -CF 2 H or phenyl;
- R a, R b may be the same or different;
- R c, R d, R e are each independently selected from hydrogen, C 1 -C 6 alkyl, acyl, ester, dialkyl or amide group, R f is selected from C 1 -C 6 alkyl;
- R 2 is selected from -OH, -OR g , -NR h R i , or -SR j ;
- R g is selected from C 1 -C 6 alkyl;
- R h and R i are each independently selected from hydrogen, C 1 -C 6 Alkyl, acyl, ester, dialkyl or amide group,
- R j is selected from hydrogen, alkyl, ester or phenyl;
- R 3 is selected from H, -COR k , -CN, -SO 2 R l , -SOR m , -POR n R o R p , -NO, or -NO 2 ;
- R k , R l , R m are each independently Selected from hydrogen, C 1 -C 6 alkyl, phenyl or hetero group;
- R n , Ro , R p are each independently selected from hydrogen, C 1 -C 6 alkyl, acyl, ester or dialkyl;
- R 4 and R 5 are each independently selected from H, -COOH, -COOR q , -CN, -OH, -SH, -SR s , -NH 2 , -N + ⁇ N, -SSR t , or -COR u ;
- R q , R s , R t are each independently selected from C 1 -C 6 alkyl;
- R 4 , R 5 are the same or different;
- R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from H, Cl, Br, F, I, -NO 2 , -OR v , -NH 2 , -N + ⁇ N, heterocyclic substitution Group or -NH-NH 2 ;
- R v is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or unsaturated monocyclic hydrocarbon group, aromatic hydrocarbon group or aromatic hydrocarbon substituent;
- X is selected from H, Cl, Br, I, F, -OR w , -NR x , -SR y , -OCOR z , imidazolyl, N-containing heterocycle, or sulfur-containing heterocycle.
- C 1 -C 6 alkyl group of the present invention can be linear alkyl, linear alkyl or cycloalkyl; specifically, it can be selected from methyl, ethyl, propyl, butyl, pentyl Or hexyl.
- R 1 and R 2 are each independently selected from H, F, Cl, Br, I, -CN, -OCH 3 or -OCH 2 CH 3 ;
- R 3 is selected from -OH, -OCH 3 or -OCH 2 CH 3 .
- the compound represented by Formula I is selected from methyl haloacetate, ethyl haloacetate, methyl 2-haloacetoacetate, ethyl 2-haloacetoacetate, and halomalonic acid Dimethyl, ethyl halogenated malonate, methyl cyanoacetate or ethyl cyanoacetate, methyl methoxyacetate, ethyl methoxyacetate, methyl ethoxyacetate, ethyl ethoxyacetate ester.
- R 4 and R 5 are each independently selected from H, -COOH, -CN, -OH, -SH, -NH 2 , or -N + ⁇ N.
- R 6 , R 7 , R 8 , R 9 , R 10 are each independently selected from H, Cl, Br, F, I, -NO 2 , -NH 2 , -N + ⁇ N , Or -NH-NH 2 ;
- X is selected from H, Cl, Br, I or F.
- R 1 , X, R 8 , and R 10 are each independently Cl or F;
- R 2 is -OR g , and R g is selected from C 1 -C 6 alkyl; preferably, R g Is methyl, ethyl, propyl, butyl, pentyl or hexyl;
- R 3 , R 4 , R 5 , R 6 , R 7 , and R 9 are each independently H.
- the triazole compound represented by formula V can be prepared.
- the base is preferably sodium hydrogen, triethylamine, N,N-dimethylaniline, DBU, diisopropylethylamine, sodium methoxide, sodium ethoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide Any one or a combination of several.
- the preparation method of the triazole compound represented by formula V includes the following steps:
- the compound represented by formula I is selected from methyl haloacetate, ethyl haloacetate, methyl 2-haloacetoacetate, ethyl 2-haloacetoacetate, dimethyl halomalonate Any of esters, ethyl halogenated malonate, methyl cyanoacetate, ethyl cyanoacetate, etc.
- the acid binding agent is potassium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate, DBU (1,8-diazabicycloundec-7-ene ), any one or a combination of several of triethylamine, N,N-dimethylaniline and diisopropylethylamine, preferably potassium carbonate. Studies have found that the use of the above acid binding agents can significantly increase the reaction rate.
- the solvent is methanol, acetonitrile, toluene or DMF (N,N-dimethylformamide), more preferably acetonitrile.
- the stirring and mixing temperature is 0-30°C;
- the temperature of the heat preservation reaction is 0-120°C, more preferably 0-30°C; research has found that at this preferred temperature, the production of by-products can be significantly reduced.
- the temperature retention reaction time is 6-12 hours, more preferably 8-10 hours.
- the molar ratio of the compound represented by formula II, the compound represented by formula I, and the acid binding agent is 1:(1.1-2):(1.1-2), more preferably 1:(1.1-1.5):(1.1 -1.5);
- the solvent is toluene, THF (tetrahydrofuran), methyltetrahydrofuran, benzene, DMF, DMAC, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, cyclohexane, xylene Any one or more of them. Studies have found that the selection of these solvents can significantly increase the reaction yield.
- the base is sodium hydrogen, triethylamine, N,N-dimethylaniline, DBU, diisopropylethylamine, sodium methoxide, sodium ethoxide, potassium methoxide, sodium tert-butoxide, tert-butanol Any one or a combination of several of potassium is more preferably sodium hydrogen or triethylamine.
- the stirring and mixing temperature and the holding reaction temperature are respectively -15 to 20°C, more preferably 5-10°C;
- the reaction time for the temperature preservation is 1-6 hours, more preferably 2-4 hours;
- the molar ratio of the compound represented by formula III, the compound represented by formula IV, and the base is 1:(1.0-1.5):(3-5), more preferably 1:(1.1-1.2):(2.5-3 ).
- Acid binding agent, alkali and solvent are easy to recycle and apply;
- Yield of compound represented by formula III (mass of compound represented by formula III ⁇ content of compound represented by formula III ⁇ 100%)/(molar weight of compound represented by formula II ⁇ molar mass of structural compound represented by formula III)
- the purity of the structure compound represented by formula III is determined by gas chromatography; the purity of the structure compound represented by formula V is determined by liquid chromatography.
- the reaction route is as follows:
- R 1 is Cl;
- R 2 is -OCH 3 ;
- R 3 , R 4 , and R 5 are each independently H.
- the reaction route is as follows:
- R 2 is -OCH 3 ;
- R 3 , R 4 , R 5 , R 6 , R 7 , and R 9 are each independently H;
- X, R 8 , and R 10 are each independently Cl.
- the compound represented by formula III can be prepared according to the method of embodiment 1.
- the reaction route is as follows:
- R 2 is -OCH 3 ;
- R 3 , R 4 , R 5 , R 6 , R 7 , and R 9 are each independently H;
- X is Cl;
- R 8 and R 10 are each independently F.
- the compound represented by formula III can be prepared according to the method of embodiment 1.
- Example 2 The only difference from Example 2 is that the sodium hydrogen is replaced with the same amount of DBU to obtain 180.4 g of the compound represented by formula V. After calculation, the yield was 57.4%; after testing, the purity of the pure product was 98.0%.
- Example 2 The only difference from Example 2 is that 3.0 mol of sodium hydrogen is slowly added dropwise at 30° C. to obtain 240.5 g of the compound represented by formula V. After calculation, the yield was 75.0%; after testing, the purity of the pure product was 98.0%.
- the invention provides a preparation method of triazole compounds.
- the synthetic route of the method is as follows: the compound represented by formula III is used as the main raw material to carry out substitution reaction with the compound represented by formula IV under basic conditions to synthesize the triazole compound represented by formula V.
- the method has the following advantages: simple operation, low cost, no pollution, high yield, green, safe and environmentally friendly, suitable for modern industrialized production, and has good economic value and application prospects.
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Abstract
本发明公开了一种三唑类化合物的制备方法，合成路线如下：采用式III所示化合物为主要原料与式IV所示化合物在碱性条件下进行取代反应，合成式V所示的三唑类化合物。本方法具有以下优点：操作简单，成本低，无污染，收率高，绿色安全环保，适合现代工业化生产。
Description
本发明涉及三唑类化合物的制备方法。
三唑类化合物具有杀菌生物活性，不仅活性高、作用机理独特、对环境友好，而且对难防治的病害如稻瘟病、霜霉病、灰霉病和立枯病等都有特效。主要用于果树、蔬菜、小麦、马铃薯、豆类、瓜类等作物上防除纹枯病、锈病、早疫病、叶斑病、黑星病、白粉病有优良的防治效果，对蔬菜和瓜果等多种真菌性病害具有很好的保护和治疗作用，并具有持效期长的特点，与其他杀菌剂无交互抗性。且具有不污染环境、不污染农产品、不杀伤天敌的特点，是目前各国防治柑橘疮痂病、斑点落叶病等作物抗性病害的理想杀菌剂。
三唑类化合物是一种具有保护和治疗作用的内吸性三唑类杀菌剂，可被根、茎、叶部吸收，并能很快地在植物株体内向上传导，防治子囊菌，担子菌和半知菌引起的病害，特别是对小麦全蚀病、白粉病、锈病、根腐病，水稻恶菌病，香蕉叶斑病具有较好的防治效果。
发明内容
本发明提供一种改进的三唑类化合物的制备方法，该方法采用式III为主要原料与式IV在碱性条件下进行取代反应合成式V所示的三唑类化合物。产品收率高、纯度高，无污染，绿色环保适宜于现代化工业生产。
本发明采取如下的技术方案：
一种下式V所示三唑类化合物的制备方法，其反应路线如下：
其中：
R
1选自F、Cl、Br、I、R
a-S(＝O)-O-、R
bSO
3-、-N
+≡N、-NR
cR
dR
e或-OR
f；R
a、R
b各自独立地选自-CH
3、-CF
3、-CF
2H或苯基；R
a、R
b可以相同也可以不同；R
c、R
d、R
e各自独立地选自氢、C
1-C
6烷基、酰基、酯基、二烷基或酰胺基，R
f选自C
1-C
6烷基；
R
2选自-OH、-OR
g、-NR
hR
i、或-SR
j；R
g选自C
1-C
6烷基；R
h、R
i各自独立地选自氢、C
1-C
6烷基、酰基、酯基、二烷基或酰胺基，R
j选自氢、烷基、酯基或苯基；
R
3选自H、-COR
k、-CN、-SO
2R
l、-SOR
m、-POR
nR
oR
p、-NO、或-NO
2；R
k、R
l、R
m各自独立地选自氢、C
1-C
6烷基、苯基或杂基；R
n、R
o、R
p各自独立地选自氢、C
1-C
6烷基、酰基、酯基或二烷基；
R
4、R
5各自独立地选自H、-COOH、-COOR
q、-CN、-OH、-SH、-SR
s、-NH
2、-N
+≡N、-S-S-R
t、或-COR
u；R
q、R
s、R
t各自独立地选自C
1-C
6烷基；R
4、R
5相同或不同；
R
6、R
7、R
8、R
9、R
10各自独立地选自H、Cl、Br、F、I、-NO
2、-OR
v、-NH
2、-N
+≡N、杂环取代基或-NH-NH
2；R
v选自C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基或不饱和单环烃基、芳香烃基或者芳香烃取代基；
X选自H、Cl、Br、I、F、-OR
w、-NR
x、-SR
y、-OCOR
z、咪唑基、含N杂环、或含硫杂环。
进一步地，本发明所述C
1-C
6烷基可为直链烷基、直链烷基或环烷基；具体地，可选自甲基、乙基、丙基、丁基、戊基或己基。
在本发明一些实施方式中，R
1、R
2各自独立地选自H、F、Cl、Br、I、-CN、-OCH
3或-OCH
2CH
3；R
3选自-OH、-OCH
3或-OCH
2CH
3。
在本发明一些实施方式中，式I所示化合物选自卤代乙酸甲酯、卤代乙酸乙酯、2-卤代乙酰乙酸甲酯、2-卤代乙酰乙酸乙酯、卤代丙二酸二甲酯、卤代丙二酸乙酯、氰基乙酸甲酯或氰基乙酸乙酯、甲氧基乙酸甲酯、甲氧基乙酸乙酯、乙氧基乙酸甲酯、乙氧基乙酸乙酯。
在本发明一些实施方式中，R
4、R
5各自独立地选自H、-COOH、-CN、 -OH、-SH、-NH
2、或-N
+≡N。
在本发明一些实施方式中，R
6、R
7、R
8、R
9、R
10各自独立地选自H、Cl、Br、F、I、-NO
2、-NH
2、-N
+≡N、或-NH-NH
2；X选自H、Cl，Br，I或F。
在本发明一些实施例中，R
1、X、R
8、R
10各自独立地为Cl或F；R
2为-OR
g，R
g选自C
1-C
6烷基；优选地，R
g为甲基、乙基、丙基、丁基、戊基或己基；R
3、R
4、R
5、R
6、R
7、R
9各自独立地为H。
进一步地，以式III所示化合物为主要原料与式IV所示化合物在碱性条件下进行取代反应，可以制得式V所示的三唑类化合物。所述碱优选为钠氢、三乙胺、N,N-二甲基苯胺、DBU、二异丙基乙胺、甲醇钠、乙醇钠、甲醇钾、叔丁醇钠、叔丁醇钾中的任何一种或几种的组合。
具体地，上述式V所示三唑类化合物的制备方法包括如下步骤：
1)式III所示化合物的制备：
将式II所示化合物、缚酸剂、溶剂在一定温度下搅拌混合，缓慢滴加式I所示化合物，保温反应，回收溶剂，即可。
作为优选方案，所述式I所示化合物选自卤代乙酸甲酯、卤代乙酸乙酯、2-卤代乙酰乙酸甲酯、2-卤代乙酰乙酸乙酯、卤代丙二酸二甲酯、卤代丙二酸乙酯、氰基乙酸甲酯、氰基乙酸乙酯等中任一种。
作为优选方案，所述缚酸剂为碳酸钾、氢氧化钾、氢氧化钠、碳酸钠、碳酸氢钾、碳酸氢钠、DBU(1,8-二氮杂二环十一碳-7-烯)、三乙胺、N,N-二甲基苯胺、二异丙基乙胺中的任何一种或几种的组合，优选为碳酸钾。研究发现，使用以上缚酸剂可以显著提高反应速率。
作为优选方案，所述溶剂为甲醇、乙腈、甲苯或DMF(N,N-二甲基甲酰胺)，更优选为乙腈。研究发现使用以上溶剂可以显著提高反应选择性。
作为优选方案，所述搅拌混合温度为0-30℃；
作为优选方案，所述保温反应温度为0-120℃，更优选为0-30℃；研 究发现在该优选温度下，可以明显降低副产物产生。
作为优选方案，所述保温反应时间为6-12小时，更优选为8-10小时。
作为优选方案，式II所示化合物、式I所示化合物、缚酸剂的摩尔比例为1:(1.1-2)：(1.1-2)，更优选为1:(1.1-1.5):(1.1-1.5)；
2)式V所示化合物的制备：
将式III所示化合物、碱和溶剂在一定温度下搅拌混合，氮气保护下，缓慢滴加溶于溶剂的式IV所示化合物，保温反应，加水静止分层，回收有机相，脱溶剂，即可；
作为优选方案，所述溶剂为甲苯、THF(四氢呋喃)、甲基四氢呋喃、苯、DMF、DMAC、二氧六环、乙二醇二甲醚、乙二醇二乙醚、、环己烷、二甲苯中任一种或几种。研究发现，选用这些溶剂可以明显提高反应收率。
作为优选方案，所述碱为钠氢、三乙胺、N,N-二甲基苯胺、DBU、二异丙基乙胺、甲醇钠、乙醇钠、甲醇钾、叔丁醇钠、叔丁醇钾中的任何一种或几种的组合，更优选为钠氢或三乙胺。
作为优选方案，所述搅拌混合温度及保温反应温度分别为-15至20℃，更优选为5-10℃；
作为优选方案，所述保温反应时间为1-6h，更优选为2-4小时；
作为优选方案，式III所示化合物、式IV所示化合物、碱的摩尔比例为1:(1.0-1.5):(3-5)，更优选为1:(1.1-1.2):(2.5-3)。
本发明具有以下优点：
1)缚酸剂、碱及溶剂容易回收套用；
2)操作简单，成本低，收率高，对设备要求低；
3)无污染，绿色安全环保，适宜现代化工业生产。
下面结合实施例对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。
以下部分试剂购自百灵威科技有限公司。
以下实施例中总收率按照以下公式得到：
式III所示化合物收率＝(式III所示化合物的质量×式III所示化合物的含量×100％)/(式II所示结构化合物的摩尔量×式III所示结构化合物的摩尔质量)
式Ⅴ所示化合物收率＝(式Ⅴ所示化合物的质量×式Ⅴ所示化合物的含量×100％)/(式Ⅲ所示结构化合物的摩尔量×式Ⅴ所示结构化合物的摩尔质量)
以下实施例中式III所示结构化合物的纯度采用气相色谱法测定；式Ⅴ所示结构化合物的纯度采用液相色谱法测定。
实施例1
将1.0mol下式II所示化合物加入500ml四口瓶中，加入240ml甲苯，加入1.1mol缚酸剂碳酸钠，在90℃温度下搅拌，缓慢滴加1.1mol下式I所示化合物(西亚试剂，98％)，保温反应6小时，使用气相色谱分析仪检测化合物含量<1％，视为反应完毕，过滤固体，回收甲苯溶剂得下式III所示化合物119.5。经计算，收率为80.4％；经检测，纯品的纯度为95.0％。
反应路线如下：
其中，R
1为Cl；R
2为-OCH
3；R
3、R
4、R
5各自独立地为H。
实施例2
将1.0mol(141.1g)下式III所示的化合物加入1000ml四口瓶中，加入400gTHF溶剂(98％)，在5℃下缓慢加3.0mol钠氢，反应2h，再加入1.1mol下式IV所示化合物，继续反应2h，使用气相色谱分析仪测化合物含量<1％，视为反应完毕，加入200g水，搅拌30min，静止分层，将有机相在常压下进行脱溶剂，回收THF；得到下式V所示的化合物299.8g。经计算，收率为94％；经检测，纯品的纯度为98.5％。
反应路线如下：
其中，R
2为-OCH
3；R
3、R
4、R
5、R
6、R
7、R
9各自独立地为H；X、R
8、R
10各自独立地为Cl。
本实施例中，式III所示的化合物可按实施例1方法制备。
实施例3
将1.0mol(141.1g)下式III所示的化合物加入1000ml四口瓶中，加入400g甲基四氢呋喃溶剂(98％)，，在5℃下缓慢滴加3.0mol钠氢，反应2h，再加入1.1mol下式IV所示化合物，继续反应2h，使用气相色谱分析仪测化合物含量<1％，视为反应完毕，加入200g水，搅拌30min，静止分层，将有机相在常压下进行脱溶剂，回收甲基四氢呋喃；得到下式V所示的化合物254.8g。经计算，收率为88.8％；经检测，纯品的纯度为98.0％。
反应路线如下：
其中，R
2为-OCH
3；R
3、R
4、R
5、R
6、R
7、R
9各自独立地为H；X为Cl；
R
8、R
10各自独立地为F。
本实施例中，式III所示的化合物可按实施例1方法制备。
实施例4
与实施例2的区别仅在于将钠氢替换为等量的DBU，得到式V所示的化合物180.4g。经计算，收率为57.4％；经检测，纯品的纯度为98.0％。
实施例5
与实施例2的区别仅在于在30℃下缓慢滴加3.0mol钠氢，得到式V所示的化合物240.5g。经计算，收率为75.0％；经检测，纯品的纯度为98.0％。
实施例6
基本上参照实施例1、2方法，将式I所示化合物中R
2替换为-OR
g，其中R
g分别为乙基、丙基、丁基、戊基或己基，制备式V所示的化合物。
实施例7
基本上参照实施例1、3方法，将式I所示化合物中R
2替换为-OR
g，其中R
g分别为乙基、丙基、丁基、戊基或己基，制备式V所示的化合物。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于此。在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，包括各个技术特征以任何其它的合适方式进行组合以及包括组合先后顺序，这些简单变型和组合同样应当视为本发明所公开的内容，均属于本发明的保护范围。
本发明提供一种三唑类化合物的制备方法。所述方法的合成路线如下：采用式III所示化合物为主要原料与式IV所示化合物在碱性条件下进行取代反应，合成式V所示的三唑类化合物。本方法具有以下优点：操作简单，成本低，无污染，收率高，绿色安全环保，适合现代工业化生产，具有较好的经济价值和应用前景。
Claims (10)
- 下式V所示三唑类化合物的制备方法，其特征在于，反应路线如下：
其中：R 1选自F、Cl、Br、I、R a-S(＝O)-O-、R bSO 3-、-N +≡N、-NR cR dR e或-OR f；R a、R b各自独立地选自-CH 3、-CF 3、-CF 2H或苯基；R a、R b相同或不同；R c、R d、R e各自独立地选自氢、C 1-C 6烷基、酰基、酯基、二烷基或酰胺基，R f选自C 1-C 6烷基；R 2选自-OH、-OR g、-NR hR i、或-SR j；R g选自C 1-C 6烷基；R h、R i各自独立地选自氢、C 1-C 6烷基、酰基、酯基、二烷基或酰胺基，R j选自氢、烷基、酯基或苯基；R 3选自H、-COR k、-CN、-SO 2R l、-SOR m、-POR nR oR p、-NO、或-NO 2；R k、R l、R m各自独立地选自氢、C 1-C 6烷基、苯基或杂基；R n、R o、R p各自独立地选自氢、C 1-C 6烷基、酰基、酯基或二烷基；R 4、R 5各自独立地选自H、-COOH、-COOR q、-CN、-OH、-SH、-SR s、-NH 2、-N +≡N、-S-S-R t、或-COR u；R q、R s、R t各自独立地选自C 1-C 6烷基；R 4、R 5相同或不同；R 6、R 7、R 8、R 9、R 10各自独立地选自H、Cl、Br、F、I、-NO 2、-OR v、-NH 2、-N +≡N、杂环取代基或-NH-NH 2；R v选自C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基或不饱和单环烃基、芳香烃基或者芳香烃取代基；X选自H、Cl、Br、I、F、-OR w、-NR x、-SR y、-OCOR z、咪唑基、含N杂环、或含硫杂环。 - 根据权利要求1所述的制备方法，其特征在于，所述C 1-C 6烷基 为直链烷基、直链烷基或环烷基；优选地，所述C 1-C 6烷基选自甲基、乙基、丙基、丁基、戊基或己基。
- 根据权利要求1所述的制备方法，其特征在于，R 1、R 2各自独立地选自H、F、Cl、Br、I、-CN、-OCH 3或-OCH 2CH 3；R 3选自-OH、-OCH 3或-OCH 2CH 3；或者，式I所示化合物选自卤代乙酸甲酯、卤代乙酸乙酯、2-卤代乙酰乙酸甲酯、2-卤代乙酰乙酸乙酯、卤代丙二酸二甲酯、卤代丙二酸乙酯、氰基乙酸甲酯或氰基乙酸乙酯、甲氧基乙酸甲酯、甲氧基乙酸乙酯、乙氧基乙酸甲酯、乙氧基乙酸乙酯。
- 根据权利要求1或3所述的制备方法，其特征在于，R 4、R 5各自独立地选自H、-COOH、-CN、-OH、-SH、-NH 2、或-N +≡N。
- 根据权利要求1或3所述的制备方法，其特征在于，R 6、R 7、R 8、R 9、R 10各自独立地选自H、Cl、Br、F、I、-NO 2、-NH 2、-N +≡N、或-NH-NH 2；X选自H、Cl、Br、I或F。
- 根据权利要求1所述的制备方法，其特征在于，R 1、X、R 8、R 10各自独立地为Cl或F；R 2为-OR g，R g选自C 1-C 6烷基；R 3、R 4、R 5、R 6、R 7、R 9各自独立地为H；优选地，R g为甲基、乙基、丙基、丁基、戊基或己基。
- 根据权利要求1-6任一项所述的制备方法，其特征在于，式III所示化合物与式IV所示化合物在碱性条件下进行取代反应，制得式V所示的三唑类化合物；所述碱优选为钠氢、三乙胺、N,N-二甲基苯胺、DBU、二异丙基乙胺、甲醇钠、乙醇钠、甲醇钾、叔丁醇钠、叔丁醇钾中的任何一种或几种的组合。
- 根据权利要求1-7任一项所述的制备方法，其特征在于，包括如下步骤：1)将式II所示化合物、缚酸剂、溶剂在一定温度下搅拌混合，缓慢滴加式I所示化合物，保温反应，回收溶剂，制得式III所示化合物；所述缚酸剂优选为碳酸钾、氢氧化钾、氢氧化钠、碳酸钠、碳酸氢钾、碳酸氢钠、DBU、三乙胺、N,N-二甲基苯胺、二异丙基乙胺中的任何一种或几种的组合；和/或，所述溶剂为甲醇、乙腈、甲苯或DMF；2)将式III所示化合物、碱和溶剂在一定温度下搅拌混合，氮气保护下，缓慢滴加溶于溶剂的式IV所示化合物，保温反应，加水静止分层，回收有机相，脱溶剂，制得式V所示化合物；所述碱优选为钠氢、三乙胺、N,N-二甲基苯胺、DBU、二异丙基乙胺、甲醇钠、乙醇钠、甲醇钾、叔丁醇钠、叔丁醇钾中的任何一种或几种的组合；和/或，所述溶剂为甲苯、THF、甲基四氢呋喃、苯、DMF、DMAC、二氧六环、乙二醇二甲醚、乙二醇二乙醚、环己烷、二甲苯中任一种或几种。
- 根据权利要求8所述的制备方法，其特征在于，步骤1)中式II所示化合物、式I所示化合物、缚酸剂的摩尔比例为1:(1.1-2)：(1.1-2)，优选为1:(1.1-1.5):(1.1-1.5)；和/或，步骤2)中式III所示化合物、式IV所示化合物、碱的摩尔比例为1:(1.0-1.5):(3-5)，优选为1:(1.1-1.2):(2.5-3)。
- 根据权利要求8或9所述的制备方法，其特征在于，步骤1)中所述保温反应温度为0-120℃，优选为0-30℃；和/或，步骤2)中所述保温反应温度为-15至20℃，优选为5-10℃。
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| AU5929586A (en) * | 1985-07-15 | 1987-01-22 | Chemie Linz Aktiengesellschaft | Benzoyltriazolylacetic or benzoyl=riazolylthioacetic acid derivatives |
| WO1997047608A1 (fr) * | 1996-06-14 | 1997-12-18 | Toyama Chemical Co., Ltd. | Procede pour produire des 2-(1h-1,2,4-triazol-1-yl)acetophenones |
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| GREGORY M ANSTEAD, ENSIGN JEAN L, PETERSON CHAD S, KATZENELLENBOGEN JOHN A: "2-Arylindenes and 2-Arylindenones: Synthesis of Probes to Study the Binding Orientation of Unsymmetrical Nonsteroidal Ligands to the Estrogen Receptor", JOURNAL OF ORGANIC CHEMISTRY, vol. 54, no. 7, 31 December 1989 (1989-12-31), pages 1485 - 1491, XP055732500, ISSN: 0022-3263 * |
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