Preparation and application of flonicamid intermediate

Abstract

The invention discloses preparation and application of a flonicamid intermediate, and particularly relates to preparation and application of compounds as shown in a formula III and a formula IV. The preparation method of the compound shown in the formula III comprises the following steps: taking a compound shown in the formula I as an initial raw material, carrying out condensation reaction on the compound shown in the formula I and a compound shown in the formula II to obtain the compound shown in the formula III, and the synthesis route is as follows: # imgabs0 #, and X, Y1 and R are defined in the description. According to the preparation method of the compound shown in the formula IV, the synthetic route is as follows: # imgabs1 #, and R is defined in the specification. Compared with the prior art, the method has the advantages of low cost, mild conditions, easiness in industrialization and the like.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis, and specifically relates to the preparation and application of a flonicamid intermediate

[0002] In particular, it relates to a method for preparing a flonicamid intermediate 4-(trifluoromethyl)nicotinic acid and its derivatives. Background Art

[0003] 4-Trifluoromethylnicotinic acid and its derivatives are trifluoromethyl-containing nitrogen heterocyclic compounds, which are key intermediates for the synthesis of pesticides and medicines. 4-Trifluoromethylnicotinic acid and its derivatives with pyridine heterocyclic structures have unique biological activities and mechanisms of action in organisms, especially flonicamid, which obtained the temporary registration certificate for pesticide products in my country in 2007. It can not only effectively control piercing-sucking mouthparts pests such as aphids by hindering the sucking of pests, but also is still effective against pests with drug resistance, which can solve the increasingly serious problem of pest resistance. Therefore, it is of great significance to develop a simple and efficient synthesis route and process for 4-trifluoromethylnicotinamide.

[0004] The synthesis methods of 4-trifluoromethylnicotinic acid and its derivatives in the prior art mainly include the following routes:

[0005] Route 1: European Patent EP0744400A2 and Japanese Patent JP2007210923A report a method of using trifluoroacetyl chloride or trifluoroacetic anhydride as the starting material, acylation, aminolysis, condensation under alkaline conditions, and then ring-closing hydrolysis to obtain 4-trifluoromethylnicotinic acid. The above route has the following major defects: 1) the raw materials methyl 3-methoxyacrylate and methyl 3,3-dimethoxypropionate have poor stability and are expensive; 2) the ring-closing yield is low, the main reason for which is the generation of isomerized impurities.

[0006]

[0007] Route 2: European Patent EP1460071 reports that the synthesis is carried out using 3-methoxyacrylonitrile and 3,3-dimethoxyacrylonitrile as raw materials. Although the defect of isomeric impurities in the ring-closing reaction is overcome, the defect of expensive raw materials exists.

[0008]

[0009] In view of the various defects in the synthesis process of the above-mentioned flonicamid intermediate 4-trifluoromethylnicotinic acid and its derivatives, there is an urgent need in the art to develop a route suitable for industrial production. Summary of the invention

[0010] In view of the problems existing in the current production technology of 4-trifluoromethylnicotinic acid and its derivatives, the present invention provides a new raw material. The technical solution provided can solve the problems of high raw material cost and large amount of three wastes, and achieve the goal of cyclization without impurities and high yield, thereby improving the market competitiveness of the product.

[0011] The present invention first provides a method for synthesizing an intermediate compound of formula III of 4-trifluoromethylnicotinic acid and its derivatives. The method overcomes the defect of expensive reaction raw materials in the prior art. The raw materials for preparing the compound of formula III are easy to obtain, low in cost and high in yield, which can reduce the synthesis cost of the compound of formula III and simultaneously reduce the synthesis cost of the subsequent intermediate compound 4-trifluoromethylnicotinic acid and its derivatives.

[0012] The present invention first provides a method for preparing a compound of formula III, which comprises the following steps: a compound of formula I and a compound of formula II undergo a condensation reaction to obtain a compound of formula III. The synthetic route is as follows:

[0013]

[0014] in,

[0015] X and Y are independently selected from halogen, -OR a , R b -SO2O- or -NR c R d ;

[0016] R is an alkoxy group;

[0017] R a , R b , R c , R d are independently selected from hydrogen, alkyl or aryl;

[0018] The condition is that one of X and Y must be selected from -NRcRd, and X and Y substituents cannot be the same substituent at the same time.

[0019] The present invention also discloses a method for preparing a compound of formula IV, which comprises the following steps: a compound of formula III is subjected to a cyclization reaction to obtain a compound of formula IV, and the synthetic route is as follows: Wherein, R is an alkoxy group, preferably a C1-C6 alkoxy group, and more preferably an isopropoxy group.

[0020] The present invention also discloses a one-pot method for preparing a compound of formula IV, which comprises the following steps:

[0021] Step 1) condensing the compound of formula I with the compound of formula II to obtain the compound of formula III;

[0022] Step 2) cyclizing the compound of formula III to obtain formula IV;

[0023] Its synthetic route is as follows:

[0024] Wherein, X and Y are independently selected from halogen, -OR a , R b -SO2O- or -NR c R d ;

[0025] R is an alkoxy group;

[0026] R a , R b , R c , R d are independently selected from hydrogen, alkyl or aryl;

[0027] The condition is that one of X and Y must be selected from -NR c R d , and the X and Y substituents cannot be the same group at the same time. Finally, the present invention also discloses compounds of formula II' and formula III',

[0028]

[0029] Wherein, Y is selected from chlorine, bromine or iodine; R' is a C1-C6 alkoxy group, preferably an isopropoxy group.

[0030] Beneficial effects of the present invention

[0031] 1. The compound of formula II used in the present invention replaces 3-methoxy methyl acrylate, 3,3-dimethoxy methyl propionate, 3-methoxy acrylonitrile and 3,3-dimethoxy acrylonitrile in the prior art to synthesize the compound of formula III, which can greatly reduce the cost, overcome the problem of expensive raw material cost, and the new process cost is lower.

[0032] 2. Overcome the problems of poor raw material stability, harsh reaction conditions and unsuitability for industrialization in the prior art.

[0033] 3. The preferred method of preparing the compound of formula IV from the compound of formula III can solve the problems of low cyclization yield and large impurities in the prior art. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "including" will be understood to include the stated components or steps, without excluding other material components or steps.

[0035] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0036] Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0037] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0038] The term "alkyl" as used herein (and in other groups containing alkyl, for example the alkyl moiety of alkoxy, the alkyl moiety of arylalkyl) denotes in each case a straight-chain or branched alkyl group having usually 1 to 20 carbon atoms, frequently 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in particular 1 to 3 carbon atoms. Examples of C1-C4-alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl). Examples of C1-C6-alkyl radicals are, in addition to the radicals mentioned for C1-C4-alkyl radicals, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl.

[0039] The term halogen according to the present invention means fluorine, chlorine, bromine or iodine.

[0040] In the present invention, "aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, such as phenyl or naphthyl, but is not limited thereto.

[0041] Specifically, the present invention provides a method for preparing a compound of formula III, which comprises the following steps: a compound of formula I and a compound of formula II undergo a condensation reaction to obtain a compound of formula III. The synthetic route is as follows:

[0042]

[0043] in,

[0044] X and Y are independently selected from halogen, -OR a , R b -SO2O- or -NR c R d ;

[0045] R is an alkoxy group;

[0046] R a , R b , R c , R d are independently selected from hydrogen, alkyl or aryl;

[0047] The condition is that one of X and Y must be selected from -NR c R d , and the X and Y substituents cannot be the same.

[0048] Preferably, in some embodiments, X and Y are independently selected from Cl, Br, iodine, -OC2H5, -NH2 or -OTs (p-toluenesulfonyl).

[0049] Preferably, R is a C1-C6 alkoxy group, and isopropoxy is particularly preferred.

[0050] In the above preparation method, the condensation reaction formula I compound is contacted with the formula II compound in an organic solvent with an acidifying agent to prepare the formula III compound. Preferably, the formula I compound is added dropwise to the formula II compound in an organic solvent with an acidifying agent under temperature control conditions, and the temperature is kept for reaction after the addition of the formula II compound; preferably, the temperature control refers to controlling the reaction temperature to -10-20°C, preferably -5-15°C; the temperature is kept for reaction for 1-10 hours, preferably 4-6 hours after the addition of the formula II compound.

[0051] In the above preparation method, the temperature control comprises dropwise adding the compound of formula II at the reaction temperature.

[0052] In the above preparation method, the organic solvent is selected from any one or combination of methanol, ethanol, isopropanol, tetrahydrofuran, DMF, DMAC, DMSO, NMP, and toluene, preferably methanol and DMF. The acid-binding agent is an organic base or an inorganic base, preferably triethylamine, pyridine, potassium hydroxide, sodium hydroxide, potassium isopropoxide, sodium isopropoxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium amide, sodium ethoxide, sodium hydrogen, and sodium, preferably sodium methoxide; preferably, in the above preparation method, the molar ratio of the compound I, the compound of formula II, and the acid-binding agent is 1:1.0-1.5:1.0-1.75, more preferably 1:1.0-1.2:1.0-1.1.

[0053] The present invention also provides a method for preparing a compound of formula IV, which comprises the following steps: a compound of formula III is subjected to a cyclization reaction to obtain a compound of formula IV, and the synthetic route is as follows: Wherein, R is an alkoxy group, preferably a C1-C6 alkoxy group, and more preferably an isopropoxy group.

[0054] In the above method for preparing the compound of formula IV, the cyclization reaction temperature is 30-100°C, preferably 50-70°C. The cyclization reaction is carried out in an organic solvent, and the organic solvent is selected from any one or combination of methanol, ethanol, isopropanol, tetrahydrofuran, DMF, DMAC, DMSO, NMP, and toluene, preferably methanol and DMF. An acid binding agent needs to be added in the cyclization reaction, and the acid binding agent is an organic base or an inorganic base, preferably triethylamine, pyridine, potassium hydroxide, sodium hydroxide, potassium isopropoxide, sodium isopropoxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium amide, sodium ethoxide, sodium hydrogen, sodium, any one or combination, preferably sodium methoxide. The molar ratio of the compound of formula III to the acid binding agent is 1:1.0-1.75, more preferably 1:1.0-1.1.

[0055] The present invention also provides a method for preparing a one-pot meal of formula IV, comprising the following steps:

[0056] Step 1) condensing the compound of formula I with the compound of formula II to obtain the compound of formula III;

[0057] Step 2) cyclizing the compound of formula III to obtain formula IV;

[0058] Its synthetic route is as follows:

[0059]

[0060] Wherein, X and Y are independently selected from halogen, -OR a , R b -SO2O- or -NR c R d ;

[0061] R is an alkoxy group;

[0062] R a , R b , R c , R d are independently selected from hydrogen, alkyl or aryl;

[0063] The condition is that one of X and Y must be selected from -NR c R d , and the X and Y substituents cannot be the same substituent at the same time.

[0064] In the above one-pot preparation process, the compound of formula I in step 1) is contacted with the compound of formula II in an organic solvent with an acidifying agent to prepare a compound of formula III. The compound of formula I is added dropwise to the compound of formula II in an organic solvent with an acidifying agent under temperature control conditions, and the reaction is kept warm after the addition of the compound of formula II; preferably, the temperature control refers to controlling the reaction temperature to -10-20°C, preferably -5-15°C; the reaction time after the addition of the compound of formula II is 1-10 hours, preferably 4-6 hours. The organic solvent is selected from any one or combination of methanol, ethanol, isopropanol, tetrahydrofuran, DMF, DMAC, DMSO, NMP, and toluene, preferably methanol and DMF. The acid-binding agent is an organic base or an inorganic base, preferably any one or combination of triethylamine, pyridine, potassium hydroxide, sodium hydroxide, potassium isopropoxide, sodium isopropoxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium amide, sodium ethoxide, sodium hydrogen, and sodium, preferably sodium methoxide; preferably, the acid-binding agent required for the two-step reaction is added at one time in the one-pot method, and the molar ratio of the compound I, the compound of formula II and the acid-binding agent is 1:1.0-1.5:2.0-3.5, more preferably 1:1.0-1.2:2.0-2.2. The cyclization temperature in step 2) is 30-100°C, preferably 50-70°C. After the reaction in step 1) is completed, the temperature is directly raised to carry out the ring-closing reaction in step 2).

[0065] Preferably, the compound of formula II is selected from the compound of formula II', and the compound of formula III is selected from the compound of formula III'.

[0066]

[0067] Wherein, Y is selected from chlorine, bromine or iodine; R' is a C1-C6 alkoxy group, preferably an isopropoxy group.

[0068] The study found that when R' is isopropoxy, Formula II' is used as an excellent intermediate to synthesize Formula III'. Formula III' can effectively prevent the generation of isomeric impurities during the cyclization process when synthesizing Formula IV compounds, thereby improving the reaction yield and achieving unexpected technical effects.

[0069] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0070] The present invention will be described in detail below by way of examples. In the following examples:

[0071] The amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260).

[0072] The conversion and selectivity of the reaction were calculated by the following formula:

[0073] Yield = actual mass of target product / theoretical mass of target product × 100%

[0074] Unless otherwise specified, all raw materials used were commercially available or homemade.

[0075] Example 1

[0076] In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 13.9 g (0.1 mol) of 4-amino-1,1,1-trifluoro-3-butene-2-one, 50 ml of methanol and 10 ml of DMF were added, and the temperature was kept at 5°C. 10.8 g of sodium methoxide was added, and then 14.5 g of methyl 3-chloroacrylate (homemade) was added dropwise. The reaction was stirred for 5 hours. HPLC detected that the raw materials were complete, and then the temperature was raised to 60°C and the reaction was carried out for 3 hours. After the raw materials reacted completely, the solvent was removed, water was added and the mixture was extracted with ethyl acetate (EA). After the solvent was removed, 16.4 g of methyl 4-trifluoromethylnicotinate was obtained with a yield of 80%, and isomeric compounds accounted for 15%.

[0077] Example 2

[0078] The difference from Example 1 is that 3-methoxyacrylate isopropyl is used instead of 3-chloroacrylate methyl, and other molar ratios remain unchanged, to obtain 20.7 g of 4-trifluoromethylnicotinate isopropyl, with a yield of 89%, and isomeric compounds accounting for 0.2%.

[0079] Example 3

[0080] The difference from Example 1 is that 3-chloroacrylate ethyl is used instead of 3-chloroacrylate methyl, and other molar ratios remain unchanged, to obtain 17.3 g of 4-trifluoromethylnicotinate ethyl ester with a yield of 79%, of which isomeric compounds account for 6%.

[0081] Example 4

[0082] The difference from Example 1 is that 3-methyl chloroacrylate is replaced by 3-isopropyl p-toluenesulfonate, and other molar ratios remain unchanged, to obtain 21.4 g of 4-trifluoromethylnicotinate isopropyl, with a yield of 92%, and isomeric compounds accounting for 0.2%.

[0083] Example 5

[0084] The difference from Example 1 is that 3-chloroacrylate isopropyl is used instead of 3-chloroacrylate methyl, and other molar ratios remain unchanged, to obtain 21.0 g of 4-trifluoromethylnicotinate isopropyl, with a yield of 90%, and isomeric compounds accounting for 0.3%.

[0085] Compound 3-(-4,4,4-trifluoro-3-oxybutyl-1-en-1-yl)amino)acrylate isopropyl ester, NMR data are as follows:

[0086] 1 H NMR (500MHz, CDCl3) δ8.91 (1H, d, J = 15.0Hz, C H ),8.86(1H,d,J=15.2Hz,C H ),5.64(1H,d,J=15.1Hz,C H ),5.13(1H,d,J=14.8Hz,C H ),4.95(1H,m,J=6.8Hz,C H (CH3)2),1.58(1H,s,N H ),1.26(6H,d,J=6.8Hz,2C H 3).

[0087] The NMR data of 4-trifluoromethylnicotinate isopropyl ester are as follows:

[0088] 1 H NMR(500MHz,CDCl3)δ9.09(1H,s,N H ),8.97(1H,d,J=5.1Hz,Ar H ),7.62(1H,d,J=4.9Hz,Ar H ),5.29(1H,m,J=6.8Hz,C H (CH3)2),6H,d,J=6.8Hz,2C H 3).

[0089] Example 6

[0090] The difference from Example 1 is that sodium methoxide is replaced by potassium methoxide, and other molar ratios remain unchanged, to obtain 14.0 g of methyl 4-trifluoromethylnicotinate with a yield of 68%, and the isomeric compounds account for 16%.

[0091] Example 7

[0092] The difference from Example 2 is that triethylamine replaces sodium methoxide, and other molar ratios remain unchanged, to obtain 14.2 g of methyl 4-trifluoromethylnicotinate with a yield of 65%, and the isomeric compounds account for 15%.

[0093] Example 8

[0094] In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 16.8 g (0.1 mol) of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one, 50 ml of methanol and 10 ml of DMF were added, and the temperature was kept at 5°C. 10.8 g of sodium methoxide was added, and then 12.1 g of methyl 3-aminoacrylate was added dropwise. The reaction was stirred for 5 hours. HPLC detected that the raw materials were complete, and then the temperature was raised to 60°C and the reaction was carried out for 3 hours. After the raw materials reacted completely, the solvent was removed, water was added and the mixture was extracted with ethyl acetate. After the solvent was removed, 16.2 g of methyl 4-trifluoromethylnicotinate was obtained with a yield of 79%. The isomeric compounds accounted for 15%.

[0095] Example 9

[0096] The difference from Example 8 is that 3-aminoacrylate isopropyl ester replaces 3-chloroacrylate methyl ester, and other molar ratios remain unchanged, to obtain 20.8 g of 4-trifluoromethylnicotinate isopropyl ester of formula IV with a yield of 89%, and isomeric compounds account for 0.1%.

[0097] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing a compound of formula III, characterized in that: The method comprises the following steps: a compound of formula I and a compound of formula II undergo a condensation reaction to obtain a compound of formula III. The synthetic route is as follows: in, X and Y are independently selected from halogen, -OR a , R b -SO2O- or -NR c R d ; R is an alkoxy group; R a , R b , R c , R d are independently selected from hydrogen, alkyl or aryl; The condition is that one of X and Y must be selected from -NR c R d , and the X and Y substituents cannot be the same substituent at the same time.

2. The preparation method according to claim 1, characterized in that: X and Y are independently selected from Cl, Br, iodine, -OC2H5, -NH2 or -OTs (p-toluenesulfonyl).

3. The preparation method according to claim 1 or 2, characterized in that: R is a C1-C6 alkoxy group.

4. The preparation method according to claim 3, characterized in that: The condensation reaction comprises the step of contacting a compound of formula I with a compound of formula II in an organic solvent containing an acidifying agent to prepare a compound of formula III.

5. The preparation method according to claim 4, characterized in that: The condensation reaction process also includes adding the compound of formula I to the compound of formula II under temperature controlled conditions in an organic solvent with an acidifying agent, and keeping the temperature for reaction after the addition of the compound of formula II is complete; preferably, the temperature control refers to controlling the reaction temperature to -10-20°C, preferably -5-15°C; the insulation reaction time after the addition of the compound of formula II is 1-10 hours, preferably 4-6 hours.

6. The preparation method according to claim 5, characterized in that: The temperature control comprises dripping the compound of formula II at the reaction temperature and maintaining the reaction time for 4-6 hours.

7. The preparation method according to claim 6, characterized in that: The organic solvent is selected from any one or a combination of methanol, ethanol, isopropanol, tetrahydrofuran, DMF, DMAC, DMSO, NMP, and toluene, preferably methanol and DMF.

8. The preparation method according to claim 7, characterized in that: The acid-binding agent is an organic base or an inorganic base, preferably any one or a combination of triethylamine, pyridine, potassium hydroxide, sodium hydroxide, potassium isopropoxide, sodium isopropoxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium amide, sodium ethoxide, sodium hydrogen, and sodium, preferably sodium methoxide; preferably, the molar ratio of the compound I, the compound of formula II and the acid-binding agent is 1:1.0-1.5:1.0-1.75, more preferably 1:1.0-1.2:1.0-1.

1.

9. A method for preparing a compound of formula IV, characterized in that: The method comprises the following steps: a compound of formula III is cyclized to obtain a compound of formula IV, and the synthesis route is as follows: Wherein, R is an alkoxy group, preferably a C1-C6 alkoxy group, and more preferably an isopropoxy group.

10. The preparation method according to claim 9, characterized in that: The reaction temperature of the cyclization reaction is 0-100°C, preferably 50-80°C; the reaction time of the cyclization reaction is 1-10 hours, preferably 2-6 hours.

11. A compound characterized in that: Selected from compounds of formula II' and formula III', Wherein, Y is selected from chlorine, bromine or iodine; R' is a C1-C6 alkoxy group, preferably an isopropoxy group.

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