CN105461629B - A kind of preparation method of the formic acid esters of 3 fluoroalkyl 1H pyrazoles 4 - Google Patents

A kind of preparation method of the formic acid esters of 3 fluoroalkyl 1H pyrazoles 4 Download PDF

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CN105461629B
CN105461629B CN201510987841.0A CN201510987841A CN105461629B CN 105461629 B CN105461629 B CN 105461629B CN 201510987841 A CN201510987841 A CN 201510987841A CN 105461629 B CN105461629 B CN 105461629B
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preparation
pyrazoles
fluoroalkyl
silver
formic acid
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CN105461629A (en
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马军安
陈振
郑艳
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Tianjin University
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Tianjin University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Abstract

Compared with prior art, the invention provides a kind of preparation method of the formic acid esters of 3 fluoroalkyl 1H pyrazoles 4, including：By 3 nitro acrylate shown in formula (I), the fluoroalkyl diazonium compound shown in formula (II), catalyst, alkali compounds mix, react in organic solvent, obtain the formic acid esters of 3 fluoroalkyl 1H pyrazoles 4 shown in formula (III).Preparation method operating procedure provided by the invention is simple, and reaction condition is gentle, high income, and substrate universality is good, while product has higher purity.

Description

A kind of preparation method of 3- fluoroalkyls -1H- pyrazoles -4- formic acid esters
Technical field
The present invention relates to organic compound preparation technical field, more particularly to a kind of 3- fluoroalkyls -1H- pyrazoles -4- formic acid The preparation method of ester.
Background technology
3- fluoroalkyl -1H- pyrazoles -4- formic acid esters is a variety of core texture units with physiologically active molecule, for example, killing Microbial inoculum Penthiopyrad (A.K.Culbreath et al., Pest.Manag.Sci.2009,65-66.), Fluxapyroxad (S.Strathmann et al., Phytopathology 2011,101-172.), Isopyrazam (T.L.Harp et al., Asp.Appl.Biol.2011,106-113.) etc..Therefore it has important in medical pesticide field Application value.
The method for the synthesis 3- fluoroalkyl -1H- pyrazoles -4- formic acid esters reported, mainly utilizes α-fork alkene beta-ketoester With condensation reaction (M.J.Graneto, W.G.Phillips, the WO 9212970 (1992) of hydrazine；S.Pazenok, WO2009112157(2009)；S.Guillou et al.,Tetrahedron 2011,67,8451-8457；Santos Fustero,et al.,Chem.Rev.2011,111,6984-7034；F.Giornal et al.,J.Fluorine Chem.2013,152,2-11) it is made.It is not easy to obtain however, these synthetic methods have expensive starting materials, reactions steps multioperation is numerous Trivial, the problems such as regioselectivity and low yield, this undoubtedly limits its application.
The content of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of 3- fluoroalkyls -1H- pyrazoles -4- formic acid esters Preparation method, raw material is easy to get, and yield is higher.
The invention provides a kind of preparation method of 3- fluoroalkyls -1H- pyrazoles -4- formic acid esters, including：
By the 3- nitros acrylate shown in formula (I), the fluoroalkyl diazonium compound shown in formula (II), catalyst, alkalescence Compound is mixed, reacted in organic solvent, obtains the 3- fluoroalkyl -1H- pyrazoles -4- formic acid esters shown in formula (III)；
Wherein, RfFor difluoromethyl, trifluoromethyl or pentafluoroethyl group；R be methyl, ethyl, n-propyl, butyl, phenyl or Benzyl.
Preferably, the catalyst is any in silver oxide, silver carbonate, silver nitrate, silver acetate and silver trifluoromethanesulfonate It is one or more of.
Preferably, the alkali compounds is sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, phosphoric acid Any one or a few in potassium and triethylamine.
Preferably, the organic solvent be dichloromethane, chloroform, tetrahydrofuran, DMF, N, N- Any one or a few in dimethyl acetamide, benzene, toluene and acetonitrile.
Preferably, the temperature of the reaction is 0~50 DEG C.
Preferably, the time of the reaction is 3~24h.
Preferably, the 3- nitros acrylate, fluoroalkyl diazonium compound, catalyst, the mol ratio of alkali compounds For 1：(1~10)：(0.5~3)：(0~3).
Preferably, the reaction is carried out in inert gas.
Compared with prior art, the invention provides a kind of preparation method of 3- fluoroalkyls -1H- pyrazoles -4- formic acid esters, bag Include：By the 3- nitros acrylate shown in formula (I), the fluoroalkyl diazonium compound shown in formula (II), catalyst, alkali compounds Mix, react in organic solvent, obtain the 3- fluoroalkyl -1H- pyrazoles -4- formic acid esters shown in formula (III).It is provided by the invention Preparation method operating procedure is simple, and reaction condition is gentle, high income, and substrate universality is good, while product has higher purity.
Embodiment
The invention provides a kind of preparation method of 3- fluoroalkyls -1H- pyrazoles -4- formic acid esters, including：
By the 3- nitros acrylate shown in formula (I), the fluoroalkyl diazonium compound shown in formula (II), catalyst, alkalescence Compound is mixed, reacted in organic solvent, obtains the 3- fluoroalkyl -1H- pyrazoles -4- formic acid esters shown in formula (III)；
Wherein, RfFor difluoromethyl, trifluoromethyl or pentafluoroethyl group；R be methyl, ethyl, n-propyl, butyl, phenyl or Benzyl.
Preparation method operating procedure provided by the invention is simple, and reaction condition is gentle, high income, and substrate universality is good, together When product there is higher purity.
Above-mentioned reaction equation is as follows：
Wherein, RfPreferably difluoromethyl, trifluoromethyl or pentafluoroethyl group.
R is preferably methyl, ethyl, n-propyl, butyl, phenyl or benzyl.
The catalyst is preferably any one in silver oxide, silver carbonate, silver nitrate, silver acetate and silver trifluoromethanesulfonate It is or several.
The alkali compounds is preferably sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate With any one or a few in triethylamine.
The organic solvent is preferably dichloromethane, chloroform, tetrahydrofuran, DMF, N, N- bis- Any one or a few in methylacetamide, benzene, toluene and acetonitrile.
The temperature of the reaction is preferably 0~50 DEG C；The time of the reaction is preferably 3~24h.
The 3- nitros acrylate, fluoroalkyl diazonium compound, catalyst, the mol ratio of alkali compounds are preferably 1： (1~10)：(0.5~3)：(0~3), more preferably 1：(4~10)：(1~3)：(1~3).
After above-mentioned reaction terminates, preferably also include：
The metal and inorganic salts being filtered to remove in system, organic solvent washing filter residue, filtrate and cleaning solution merge, decompression Solvent is distilled off, residue is dissolved in dichloromethane, is washed using saturated ammonium chloride solution, after drying, using column chromatography Method is purified.
The organic solvent of above-mentioned washing filter residue is preferably ethyl acetate；The leacheate of column chromatography is preferably petroleum ether and acetic acid The mixed solution of ethyl ester.
Currently preferred, above-mentioned reaction is carried out in the environment of inert gas.The inert gas can be this area Known inert gas, the present invention is to this and is not particularly limited.Preferably argon gas.
In order to further illustrate the present invention, with reference to embodiment to 3- fluoroalkyls -1H- pyrazoles -4- provided by the invention The preparation method of formic acid esters is described in detail.
The preparation of embodiment 13- Trifluoromethyl-1 H- pyrazoles -4- Ethyl formates
Ag is weighed into a drying 100mL Schlenk reaction bulbs2O (0.17g, 0.75mmol), Na3PO4(0.12g, 0.75mmol), 3- nitros ethyl acrylate (0.73g, 0.5mmol), displacement argon gas 3 times, CF is added into system3CHN2THF Solution (0.2M, 25mL), is stirred at room temperature 3h.TLC monitoring reactions are complete, the metal and inorganic salts being filtered to remove in system, acetic acid Ethyl ester washs filter residue, and organic phase merges, and removes solvent under reduced pressure, and residue is dissolved in dichloromethane, saturated ammonium chloride solution washing, nothing Aqueous sodium persulfate is dried, column chromatography (leacheate：Petrol ether/ethyl acetate=10/1~5/1) it can obtain target product 3- trifluoros Methyl isophthalic acid H- pyrazoles -4- Ethyl formate 0.65g, yield 72%, high performance liquid chromatography (HPLC) purity is up to 99%.
It is as a result as follows using magnetic resonance detection product structure：
1H NMR(400MHz,CDCl3) δ 13.41 (s, 1H), 8.24 (s, 1H), 4.36 (q, J=7.1Hz, 2H), 1.38 (t, J=7.1Hz, 3H).
19F NMR(376MHz,CDCl3)δ-61.85(s)。
13C NMR(100MHz,CDCl3) δ 161.0,142.1 (q, J=38.1Hz), 135.5,120.8 (q, J= 267.7Hz),113.5,61.4,14.2。
The preparation of embodiment 23- Trifluoromethyl-1 H- pyrazoles -4- methyl formates
Using the identical method of embodiment 1, using silver carbonate as catalyst, sodium carbonate is alkali, and dichloromethane is solvent, 3- nitre Base methyl acrylate, silver carbonate, sodium carbonate and 2,2,2- trifluoro aziethanes are using mol ratio as 1/3/3/8 mixing, at 40 DEG C 12h is reacted, 3- Trifluoromethyl-1 H- pyrazoles -4- methyl formates is synthesized, post-processes same embodiment 1, yield 70%, high-efficient liquid phase color (HPLC) purity is composed up to 99%.
It is as a result as follows using magnetic resonance detection product structure：
1H NMR(400MHz,CDCl3)δ13.32(s,1H),8.17(s,1H),4.18(s,3H)。
19F NMR(376MHz,CDCl3)δ-61.79(s)。
13C NMR(100MHz,CDCl3) δ 162.2,141.9 (q, J=37.9Hz), 138.7,122.1 (q, J= 268.0Hz),112.5,59.6。
The preparation of embodiment 33- Trifluoromethyl-1 H- pyrazoles -4- propyl formates
Using the identical method of embodiment 1, using silver nitrate as catalyst, sodium acetate is alkali, and toluene is solvent, 3- nitros third Olefin(e) acid propyl ester, silver nitrate, sodium acetate and 2,2,2- trifluoro aziethanes are using mol ratio as 1/2/2/4 mixing, in 50 DEG C of reactions 6h, 3- Trifluoromethyl-1 H- pyrazoles -4- propyl formates are synthesized, post-process same embodiment 1, yield 75%, high performance liquid chromatography (HPLC) purity is up to 99%.
It is as a result as follows using magnetic resonance detection product structure：
1H NMR(400MHz,CDCl3) δ 13.28 (s, 1H), 8.19 (s, 1H), 4.30 (t, J=6.9Hz, 2H), 1.94- 1.87 (m, 2H), 0.90 (t, J=7.0Hz, 3H).
19F NMR(376MHz,CDCl3)δ-61.84(s)。
13C NMR(100MHz,CDCl3) δ 161.8,142.1 (q, J=37.8Hz), 139.2,121.9 (q, J= 267.6Hz),112.3,63.8,21.9,10.3。
The preparation of embodiment 43- Trifluoromethyl-1 H- pyrazoles -4- phenyl formates
Using the identical method of embodiment 1, using silver acetate as catalyst, cesium carbonate is alkali, and tetrahydrofuran is solvent, 3- nitre Base phenyl acrylate, silver acetate, cesium carbonate and 2,2,2- trifluoro aziethanes are using mol ratio as 1/3/3/8 mixing, in room temperature Under the conditions of react 18h, synthesize 3- Trifluoromethyl-1 H- pyrazoles -4- phenyl formates, post-process same embodiment 1, yield 73%, efficiently Liquid chromatogram (HPLC) purity is up to 99%.
It is as a result as follows using magnetic resonance detection product structure：
1H NMR(400MHz,CDCl3)δ13.19(s,1H),8.17(s,1H),7.44-7.40(m,2H),7.31-7.21 (m,3H)。
19F NMR(376MHz,CDCl3)δ-61.94(s)。
13C NMR(100MHz,CDCl3) δ 165.2,149.4,141.8 (q, J=38.0Hz), 141.4,129.1, (125.5,122.1 q, J=267.6Hz), 121.6,111.1.
The preparation of embodiment 53- Trifluoromethyl-1 H- pyrazoles -4- benzyl formates
Using the identical method of embodiment 1, using silver trifluoromethanesulfonate as catalyst, potassium acetate is alkali, N, N- dimethyl methyls Acid amides (DMF) is solvent, 3- nitros benzyl acrylate, silver trifluoromethanesulfonate, potassium acetate and 2, and 2,2- trifluoro aziethanes are to rub Your proportioning is 1/2/2/5 mixing, and 24h is reacted under the conditions of 0 DEG C, synthesizes 3- Trifluoromethyl-1 H- pyrazoles -4- benzyl formates, rear place Reason is with embodiment 1, yield 80%, and high performance liquid chromatography (HPLC) purity is up to 99%.
It is as a result as follows using magnetic resonance detection product structure：
1H NMR(400MHz,CDCl3)δ13.16(s,1H),8.17(s,1H),7.49-7.45(m,2H),7.40-7.36 (m,3H),5.26(s,2H)。
19F NMR(376MHz,CDCl3)δ-61.82(s)。
13C NMR(100MHz,CDCl3) δ 165.9,141.8 (q, J=38.0Hz), 141.4,136.1,128.9, (127.6,127.1,122.1 q, J=267.6Hz), 111.1,65.7.
The preparation of embodiment 63- difluoromethyl -1H- pyrazoles -4- Ethyl formates
Using the identical method of embodiment 1, using silver oxide as catalyst, sodium phosphate is alkali, and tetrahydrofuran is solvent, 3- nitre Base ethyl acrylate, silver oxide, sodium phosphate and 2,2- difluoro aziethane are using mol ratio as 1/2/2/6 mixing, in room temperature bar 12h is reacted under part, 3- difluoromethyl -1H- pyrazoles -4- Ethyl formates is synthesized, post-processes same embodiment 1, yield 75%, efficient liquid Phase chromatogram (HPLC) purity is up to 99%.
It is as a result as follows using magnetic resonance detection product structure：
1H NMR(400MHz,CDCl3) δ 13.14 (s, 1H), 8.12 (s, 1H), 7.06 (d, J=58.4Hz, 1H), 4.43 (q, J=7.0Hz, 2H), 1.40 (t, J=7.0Hz, 3H).
19F NMR(376MHz,CDCl3) δ -112.0 (d, J=58.4Hz).
13C NMR(100MHz,CDCl3) δ 162.4,143.7 (t, J=29.2Hz), 135.3,110.2 (t, J= 234.6Hz),107.5,61.4,13.8。
The preparation of embodiment 73- pentafluoroethyl group -1H- pyrazoles -4- Ethyl formates
Using the identical method of embodiment 1, using silver acetate as catalyst, triethylamine is alkali, and dichloromethane is solvent, 3- nitre Base ethyl acrylate, silver acetate, triethylamine and 2,2,3,3,3- five fluorine diazonium propane are using mol ratio as 1/2/2/6 mixing, 0 6h is reacted under the conditions of DEG C, synthesizes 3- pentafluoroethyl group -1H- pyrazoles -4- Ethyl formates, post-processes same embodiment 1, yield 76% is high Effect liquid phase chromatogram (HPLC) purity is up to 99%.
It is as a result as follows using magnetic resonance detection product structure：
1H NMR(400MHz,CDCl3) δ 13.17 (s, 1H), 8.21 (s, 1H), 4.30 (q, J=7.1Hz, 2H), 1.29 (t, J=7.1Hz, 3H).
19F NMR(376MHz,CDCl3) δ -83.07 (t, J=3.8Hz, 3F), -111.41 (d, J=293.3Hz, 1F), - 112.83 (d, J=293.3Hz, 1F).
13C NMR(100MHz,CDCl3) δ 163.5,142.3 (t, J=32.6Hz), 141.4,127.9 (tq,1JC-F= 250.0Hz,2JC-F=40.0Hz), 126.2 (qt,1JC-F=284.0Hz,2), JC-F=35.0Hz 112.4,60.9,14.1.
From above-described embodiment, the present invention uses raw material simple and easy to get, 3- fluoroalkyl -1H- pyrazoles -4- is prepared Formic acid ester compound, there is higher yield and purity.
The explanation of above example is only intended to help the method and its core concept for understanding the present invention.It should be pointed out that pair For those skilled in the art, under the premise without departing from the principles of the invention, the present invention can also be carried out Some improvement and modification, these are improved and modification is also fallen into the protection domain of the claims in the present invention.

Claims (7)

1. a kind of preparation method of 3- fluoroalkyls -1H- pyrazoles -4- formic acid esters, including：
By the 3- nitros acrylate shown in formula (I), the fluoroalkyl diazonium compound shown in formula (II), catalyst, alkaline chemical combination Thing is mixed, reacted in organic solvent, obtains the 3- fluoroalkyl -1H- pyrazoles -4- formic acid esters shown in formula (III)；
Wherein, RfFor difluoromethyl, trifluoromethyl or pentafluoroethyl group；R is methyl, ethyl, n-propyl, butyl, phenyl or benzyl；
The catalyst is any one or a few in silver oxide, silver carbonate, silver nitrate, silver acetate and silver trifluoromethanesulfonate.
2. preparation method according to claim 1, it is characterised in that the alkali compounds is sodium carbonate, potassium carbonate, carbon Any one or a few in sour caesium, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate and triethylamine.
3. preparation method according to claim 1, it is characterised in that the organic solvent be dichloromethane, chloroform, Tetrahydrofuran, DMF, any one or a few in DMA, benzene, toluene and acetonitrile.
4. preparation method according to claim 1, it is characterised in that the temperature of the reaction is 0~50 DEG C.
5. preparation method according to claim 1, it is characterised in that the time of the reaction is 3~24h.
6. preparation method according to claim 1, it is characterised in that the 3- nitros acrylate, fluoroalkyl diazotising Compound, catalyst, the mol ratio of alkali compounds are 1：(1~10)：(0.5~3)：(0~3).
7. preparation method according to claim 1, it is characterised in that the reaction is carried out in inert gas.
CN201510987841.0A 2015-12-24 2015-12-24 A kind of preparation method of the formic acid esters of 3 fluoroalkyl 1H pyrazoles 4 Expired - Fee Related CN105461629B (en)

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