CN104478797A - Preparation method of nicotinamide fungicide namely boscalid - Google Patents
Preparation method of nicotinamide fungicide namely boscalid Download PDFInfo
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- CN104478797A CN104478797A CN201410740475.4A CN201410740475A CN104478797A CN 104478797 A CN104478797 A CN 104478797A CN 201410740475 A CN201410740475 A CN 201410740475A CN 104478797 A CN104478797 A CN 104478797A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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Abstract
The invention discloses a preparation method of a nicotinamide fungicide namely boscalid. The preparation method comprises the following steps: starting from a raw material namely para chlorobromobenzene, performing Grignard reaction, and synthesizing p-chlorobenzeneboronic acid; starting from ortho-nitroaniline, synthesizing o-nitro halogenated benzene, or directly synthesizing o-amino halogenated benzene; and under the action of specific catalysts, enabling p-chlorophenylboronic acid to perform a series of reactions such as coupling, reduction, amidation and the like with o-nitro halogenated benzene or o-amino halogenated benzene to prepare boscalid. The preparation method disclosed by the invention is simple to operate, high in yield, small in pollution, low in cost and high in purity, and is very suitable for industrial production.
Description
Technical field
The present invention relates to agricultural bactericide field, particularly relate to the preparation method of a kind of nicotinamide broad spectrum type sterilant boscalid amine and intermediate thereof.
Background technology
Boscalid amine is the Novel tobacco acid amide fungicides developed by BASF Aktiengesellschaft, is mainly used in preventing and treating gray mold, Powdery Mildew, various canker, brown heart and root rot etc., registers in 2004 in Britain, Germany and Switzerland.Boscalid amine belongs to succsinic acid ubiquinone reductase inhibitor in mitochondrial respiratory chain, has very strong rejection ability to the sprouting of spore, and with other sterilant without cross resistance.Boscalid amine is Novel tobacco acid amide fungicides, fungicidal spectrum is wider, almost there is activity to all types of fungal disease, to preventing and treating, Powdery Mildew, gray mold, sclerotium disease and various cankers etc. are very effective, and also effective to the resistance bacterium of other medicament, be mainly used in the control comprising the diseases such as rape, grape, fruit tree, vegetables and field crop.
Its mechanism of action is shifted in plant by blade face infiltration, suppresses mitochondrial succinate acid esters desaturase, hinder tricarboxylic acid cycle; make amino acid, sugar lacks, energy reduces; the division of interference cell and growth, have neural activity to disease, has protection and therapeutic action.Suppress spore germination, the extension of bacterium pipe, mycelial growth and sporocyte to form the main phase of fungal growth and breeding, germicidal action is directly caused by parent active agent, does not have corresponding metabolic activity.With derosal, Sukeling etc. without cross resistance.
The English name of boscalid amine is Boscalid, the chemistry chloro-N-of 2-(4 '-chlordiphenyl-2-base) niacinamide by name, molecular structural formula as shown in the formula:
The sales volume of boscalid amine in 2009 reaches 2.80 hundred million dollars, and it is not applied for a patent in China, and the administrative protection phase also expires on November 6th, 2012.Domestic except BASF AG at present, do not produce the producer of boscalid amine.Up to now, the route of synthesis boscalid amine, according to the patent literature mainly chloro-2 '-phenylaniline of first synthetic intermediate 4-, then reacts with 2-chloronicotinoyl chloride or reacts under the effect of condensing agent with 2-chlorine apellagrin, finally obtaining boscalid amine.
1) be raw material through the chloro-2 '-phenylaniline of p-diaminodiphenyl intermediate 4-with o-chloronitrobenzene, with Suziki linked reaction occurred under the catalysis of palladium (II) to chlorophenylboronic acid obtain the chloro-2 '-nitrobiphenyl of intermediate 4-: Adv. Syn. & Cat. 252,3089-3097,2010, report Pd (PPh
3)
4as catalyzer, propyl carbinol is as solvent, and 160 DEG C are reacted 15min, productive rate 91%, WO2006092429 report PdCl
2as catalyzer, triphenyl phosphorus is as cocatalyst, and THF is as solvent, and 66 DEG C of reaction 18h yields are 99%, and the consumption of catalyzer is all very many, makes its preparation cost very expensive, is not suitable for industrial production.Tetrahedron, 66,2301 ~ 2305,2010, report PdCl
2load is as catalyzer on 4A molecular sieve, and DMF is as solvent, and 120 DEG C of reaction 18h, yield is 90%, but our a large amount of experiment finds that it is difficult to realize catalyzer and applies mechanically, and is not suitable for amplification experiment a little.
The chloro-2 '-nitrobiphenyl of 4-is again through iron powder (Adv. Synth. Catal. 2009,351,649-655) or SnCl
2(Chem.Commun. 2007,2926-2928) reduction obtains the chloro-2 '-phenylaniline of intermediate 4-, and the productive rate reported in above-mentioned document is respectively 94% and 88%, and still some is on the low side for the reaction yield transformed relative to equivalent.
Finally, the chloro-2 '-phenylaniline of 4-and the condensation of 2-chloronicotinoyl chloride obtain target product boscalid amine.The method raw materials cost is relatively cheap to be easy to get, but adopt triethylamine as the acid binding agent of synthesis boscalid amine, under our great many of experiments finds its program, side reaction is more, yield is on the low side, and side reaction impurity (our a large amount of experiment finds that Main By product is dibasic tertiary amine product) is very difficult to process.
2) with adjacent Iodoaniline or o-bromoaniline for raw material, report adjacent Iodoaniline in EP0545099 and Suzuki is occurred to chlorophenylboronic acid react and prepare the chloro-2 '-phenylaniline of intermediate 4-, report o-bromoaniline in US20100184739 and Suzuki is occurred to chlorophenylboronic acid react and prepare the chloro-2 '-phenylaniline of intermediate 4-, but it adopts the Pd of extremely costliness
2(dba)
3make catalyzer, consumption is very large, adds P (t-Bu) simultaneously
3as cocatalyst.Expensive raw materials cost, makes reaction scheme lose actual using value.
3) Synlett, (14), 2064-2068,2011, in report selectivity Mg and insert and replace chlorinated aromatic hydrocarbons method: by cheap raw material 1,4-dichlorobenzene sets out, prepare Grignard reagent through LiCl catalysis, but we adopt the preparation of such scheme to find unsatisfactory, react not thorough, yield is on the low side, is not suitable for iodine.And linked reaction needs the part SPhos adding special expensive, raw materials cost is expensive, and reaction conditions is comparatively harsh, is also not suitable for large-scale production.
4) Advanced Synthesis & Catalysis, 351,649-655,2009, take o-Nitraniline as starting raw material, through diazotization, linked reaction, reduction and with the condensation of 2-chloronicotinoyl chloride, obtain boscalid amine.When we adopt this experimental technique, find that its yield is on the low side, condition is comparatively just carved, and is not suitable for scale operation.
5) the chloro-2 '-phenylaniline of intermediate 4-and raw material 2-chlorine apellagrin obtain boscalid amine under the effect of condensing agent.Use condensing agent to there is cost higher, the shortcomings such as reaction is not thorough, aftertreatment difficulty, practical application in industry is worth little, and a large amount of by products produces.
6) report with p-Chlorobenzoic acid amide to be starting raw material in WO 2010000856, obtain boscalid amine through diazotization, coupling, Boc protection, condensation and deprotection.When we adopt the program, find that this route is longer, waste liquid is more, and former step reaction yield is on the low side, and side reaction is on the high side, and total recovery is lower, thus causes high expensive.
In view of boscalid amine has the advantages such as fungicidal activity excellence, fungicidal spectrum be wide, environmentally friendly and necessity of market heavy demand, find a kind of productive rate high, be easy to control, dangerous little, with low cost, and the synthetic method of applicable suitability for industrialized production needs and technique are comparatively urgent at present.
Summary of the invention
The technical problem that the present invention mainly solves is to provide that a kind of step is few, yield is high, controllability is strong, cost is lower and the synthetic method of the nicotinamide broad spectrum type sterilant boscalid amine of applicable suitability for industrialized production and intermediate thereof.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is: the preparation method providing a kind of nicotinamide sterilant boscalid amine, comprising step is: temperature is that at-40 ~ 50 DEG C, in alkali and solvent, the chloro-2 '-amido biphenyl of 4-and 2-chloronicotinoyl chloride react, then aftertreatment recrystallization obtains boscalid amine
;
The molar ratio preparing alkali, the chloro-2 '-amido biphenyl of 4-, 2-chloronicotinoyl chloride described in boscalid amine reaction is 1 ~ 5:0.8 ~ 2:1, and described alkali is triethylamine, DMA, N, N-Diethyl Aniline, DIPEA, M
2cO
3, MHCO
3, M
3pO
4, M
2hPO
4in any at least one, wherein M is any at least one in Li, Na, K, in described recrystallization with solvent be in methyl alcohol, ethanol, propyl alcohol, Virahol, methylene dichloride, chloroform, toluene at least any one;
Wherein said 4-chloro-2 '-amido biphenyl can with to chlorophenylboronic acid and adjacent nitro halogeno-benzene for raw material obtains the chloro-2 '-nitrobiphenyl of 4-through coupling, obtains through reduction reaction, or with to chlorophenylboronic acid and adjacent amido halogeno-benzene for raw material obtains;
The building-up process of the chloro-2 '-amido biphenyl of described 4-is: at 50-150 DEG C, will to chlorophenylboronic acid and adjacent nitro halogeno-benzene
in the first alkali, the first catalyzer, the second catalyzer and the first reaction solvent, there is linked reaction, adopt the first solvent recrystallization to obtain the chloro-2 '-nitrobiphenyl of 4-through aftertreatment
, then at 50-140 DEG C in reductive agent, the 3rd catalyzer, the second reaction solvent, 4-chloro-2 '-nitrobiphenyl generation reduction reaction, adopts the second solvent recrystallization to prepare the chloro-2 '-phenylaniline of 4-through aftertreatment
;
Described first alkali is M
2cO
3, MHCO
3, any one in MOH, wherein M is any at least one in Li, Na, K, Cs, described first catalyzer is nickelous chloride, nickelous acetate, acetylacetonate nickel, nickel powder/nano-nickel powder/reduced nickel powder, two (triphenylphosphine) nickelous chloride (II), dibromo two (triphenyl phosphorus) changes nickel, four (triphenylphosphine) nickel (0), magnetic Nano microsphere nickel-loaded class catalyzer, palladium carbon, Palladous chloride, palladium, tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II), two (acetonitrile) Palladous chloride (II), palladium trifluoroacetate (II), magnetic Nano microsphere supported palladium class catalyzer (I, II, III, IV model) in any one, described second catalyzer is R
4any at least one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any at least one, X is any at least one in Cl, Br, I, sulfate ion, nitrate ion, phosphate anion, described first reaction solvent is DMF, N, N-diethylformamide, N,N-dimethylacetamide, dioxane, methyl-sulphoxide, water, THF, ethanol, methyl alcohol, propyl alcohol, any at least one in Virahol, toluene, described adjacent nitro halogeno-benzene
in X be any at least one in Cl, Br, I, described first solvent adopted in described recrystallization is any at least one in methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, toluene, the described molar ratio to chlorophenylboronic acid, adjacent nitro halogeno-benzene, the first alkali, the first catalyzer, the second catalyzer is 0.8 ~ 2: 1: 0.5 ~ 3: 0.01% ~ 5%: 0.05 ~ 0.5,
Described reductive agent is SnCl
2, any at least one in iron powder; Described 3rd catalyzer is R
4any at least one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any at least one, X is any at least one in Cl, Br, I, acetate ion, sulfate ion; Described second reaction solvent is any at least one in methyl alcohol, ethanol, propyl alcohol, Virahol, water, DMF, THF, toluene; The molar ratio of the chloro-2 '-nitrobiphenyl of described 4-, reductive agent, the 3rd catalyzer is 1:2 ~ 5:0.1 ~ 1; Described second solvent adopted in described recrystallization is any at least one in water, methyl alcohol, ethanol, propyl alcohol, Virahol, acetone;
The building-up process of the chloro-2 '-amido biphenyl of described 4-is: at 50-150 DEG C, will to chlorophenylboronic acid and adjacent amido halogeno-benzene
in the second alkali, the 4th catalyzer, the 5th catalyzer and the 3rd reaction solvent, there is linked reaction, adopt the 3rd solvent recrystallization to prepare the chloro-2 '-amido biphenyl of 4-through aftertreatment
;
Described second alkali is M
2cO
3, MHCO
3, any one in MOH, wherein M is any at least one in Li, Na, K, Cs, described 4th catalyzer is nickelous chloride, nickelous acetate, acetylacetonate nickel, nickel powder/nano-nickel powder/reduced nickel powder, two (triphenylphosphine) nickelous chloride (II), dibromo two (triphenyl phosphorus) changes nickel, four (triphenylphosphine) nickel (0), magnetic Nano microsphere nickel-loaded class catalyzer, palladium carbon, Palladous chloride, palladium, tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II), two (acetonitrile) Palladous chloride (II), palladium trifluoroacetate (II), magnetic Nano microsphere supported palladium class catalyzer (I, II, III, IV model) in any one, described 5th catalyzer is R
4any at least one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any at least one, X is any at least one in Cl, Br, I, sulfate ion, nitrate ion, phosphate anion, described 3rd reaction solvent is DMF, N, N-diethylformamide, N,N-dimethylacetamide, dioxane, methyl-sulphoxide, water, THF, ethanol, methyl alcohol, propyl alcohol, any at least one in Virahol, toluene, described adjacent amido halogeno-benzene
in X be any at least one in Cl, Br, I, described 3rd solvent adopted in described recrystallization is any at least one in water, methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, toluene, the described molar ratio example to chlorophenylboronic acid, adjacent amido halogeno-benzene, the second alkali, the 4th catalyzer, the 5th catalyzer is 0.8 ~ 2: 1: 0.5 ~ 3: 0.01% ~ 5%: 0.05 ~ 0.5.
In a preferred embodiment of the present invention, described alkali is M
2cO
3, MHCO
3, M
3pO
4, M
2hPO
4in any at least one, wherein M is any at least one in Li, Na, K; The molar ratio of the chloro-2 '-amido biphenyl of described alkali, 4-, 2-chloronicotinoyl chloride is 1 ~ 2:0.8 ~ 1.5:1; Generating range of reaction temperature described in boscalid amine reaction is-20 ~ 10 DEG C; Be ethanol or Virahol with solvent in described recrystallization.
In a preferred embodiment of the present invention, with to chlorophenylboronic acid and adjacent nitro halogeno-benzene for raw material obtains in the reaction of the chloro-2 '-nitrobiphenyl of described 4-: described adjacent nitro halogeno-benzene be in o-nitrochlorobenzene, adjacent Nitrobromobenzene, adjacent nitro phenyl-iodide any one; The temperature obtaining adopting in the chloro-2 '-nitrobiphenyl of 4-is 70-150 DEG C; Described first alkali is M
2cO
3, wherein M is any at least one in Li, Na, K; Described first catalyzer is any one in palladium carbon, Palladous chloride, palladium, tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II), two (acetonitrile) Palladous chloride (II), palladium trifluoroacetate (II), magnetic Nano microsphere supported palladium class catalyzer (I, II, III, IV model); Described second catalyzer is R
4any one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any one, X is any one in Cl, Br, I; Described first reaction solvent is ethanol, water, DMF; The described molar ratio example to chlorophenylboronic acid, adjacent nitro halogeno-benzene, the first alkali, the first catalyzer, the second catalyzer is 1 ~ 2:1:0.8 ~ 2:0.01% ~ 1%:0.05 ~ 0.5; Described first solvent adopted in described recrystallization is ethanol, Virahol, propyl alcohol;
Described reductive agent is iron powder; Described 3rd catalyzer is R
4any one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any one, X is any one in Cl, Br, I; Described reductive agent, the 3rd catalyzer, the chloro-2 '-nitrobiphenyl molar ratio of 4-are 2 ~ 5:0.1 ~ 2:1; Obtaining temperature condition described in the chloro-2 '-phenylaniline of 4-is 60-120 DEG C; Described second reaction solvent is the mixed solvent of ethanol, methyl alcohol or isopropyl alcohol and water; Described second solvent is ethanol or Virahol.
In a preferred embodiment of the present invention, with to chlorophenylboronic acid and adjacent amido halogeno-benzene for raw material obtains in the reaction of described 4-chloro-2 '-amido biphenyl: described adjacent amido halogeno-benzene be in adjacent amido chlorinated benzene, adjacent amido bromobenzene, adjacent amido phenyl-iodide any one; Described temperature of reaction is 70-150 DEG C; Described second alkali is M
2cO
3, wherein M is any at least one in Li, Na, K, Cs; Described 4th catalyzer is any one in palladium carbon, Palladous chloride, palladium, tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II), two (acetonitrile) Palladous chloride (II), palladium trifluoroacetate (II), magnetic Nano microsphere supported palladium class catalyzer (I, II, III, IV model); Described 5th catalyzer is R
4any at least one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any at least one, X is any at least one in Cl, Br, I; Described 3rd reaction solvent is ethanol, water, DMF; The described molar ratio to chlorophenylboronic acid, adjacent amido halogeno-benzene, the second alkali, the 4th catalyzer, the 5th catalyzer is 1 ~ 2:1:0.8 ~ 2:0.01% ~ 1%:0.05 ~ 0.5; Described 3rd solvent is ethanol, Virahol, propyl alcohol.
In a preferred embodiment of the present invention, the described preparation method to chlorophenylboronic acid is: at 40 ~ 140 DEG C, will to halo chlorobenzene
react in the 6th catalyzer and the 4th reaction solvent with metal magnesium chips, be prepared into Grignard reagent
; The Grignard reagent will prepared at-40 ~ 0 DEG C again
with boric acid three alkane ester B (OR)
3reaction, and at 0 ~ 40% hydrolyzed under acidic conditions and aftertreatment obtains crude product, crude product obtains chlorophenylboronic acid through recrystallization
;
Described to halo chlorobenzene
middle X is Cl, Br, I; Described 6th catalyzer is iodine, glycol dibromide; Described 4th reaction solvent is any at least one in ether, tetrahydrofuran (THF) (THF), methyl ring amyl ether, 2-methyltetrahydrofuran (2-Me-THF), propyl ether, isopropyl ether, t-butyl methyl ether, n-butyl ether; Described boric acid three alkane ester B (OR)
3in R be C
1-C
4alkyl; Described hydrolysis acid is hydrochloric acid, Hydrogen bromide, phosphoric acid, any at least one in sulfuric acid; Described recrystallization is any at least one in water, methyl alcohol, ethanol, acetone, propyl alcohol, Virahol with the 4th solvent; Described to halogen chlorobenzene, MAGNESIUM METAL, B (OR)
3molar ratio be 1 ︰ 1 ~ 2 ︰ 1 ~ 3.
In a preferred embodiment of the present invention, described to halo chlorobenzene
for para chlorobromobenzene; Described B (OR)
3middle R is normal-butyl; Described 6th catalyzer is iodine; Described to halogen chlorobenzene, MAGNESIUM METAL, B (OR)
3molar ratio be 1 ︰ 1 ~ 1.2 ︰ 1 ~ 1.5; Described 4th reaction solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran; Described hydrolysis acid for massfraction be the sulfuric acid of 5 ~ 20%; Described 4th solvent is water.
In a preferred embodiment of the present invention, the preparation method of described adjacent nitro halogeno-benzene is: under-40 ~ 10 DEG C of acidic conditionss, and o-Nitraniline and Sodium Nitrite react prepares diazonium salt solution; Described diazonium salt solution is at-40 ~ 80 DEG C and under the 7th catalyzer existence condition, react with haloid acid HX, and through wet distillation, the 5th solvent recrystallization, obtains adjacent nitro halogeno-benzene
;
Described reaction acid is any one in hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid; In described haloid acid HX, X is any at least one in Cl, Br, I; Described 7th catalyzer is MX, and M is wherein any at least one in Cu, Ni, and X is any at least one in Cl, Br, I, CN; The mol ratio of described o-Nitraniline and reaction acid, Sodium Nitrite, the 7th catalyzer MX is 1: 1 ~ 6: 1 ~ 1.5: 0.1 ~ 1; Described recrystallization is water, methyl alcohol, ethanol, propyl alcohol with the 5th solvent, Virahol, any at least one in acetone, benzene, toluene.
In a preferred embodiment of the present invention, described reaction acid is sulfuric acid; Described 7th catalyzer MX is CuX, and wherein X is Cl, Br, I; The mol ratio of described o-Nitraniline, reaction acid, Sodium Nitrite, the 7th catalyzer is 1:2 ~ 6:1 ~ 1.5:0.1 ~ 1; The described temperature preparing diazonium salt solution is-20 ~ 0 DEG C; Described diazonium salt and o-Nitraniline range of reaction temperature are-20 ~ 40 DEG C; The 5th solvent adopted in described recrystallization is ethanol, Virahol.
In a preferred embodiment of the present invention, the preparation method of described 2-chloronicotinoyl chloride is: at 20 ~ 100 DEG C, and 2-chlorine apellagrin and chlorination reagent react in the 5th reaction solvent, prepare 2-chloronicotinoyl chloride through underpressure distillation
; Described 5th reaction solvent is any at least one in methylene dichloride, trichloromethane, 1,2-ethylene dichloride, thionyl chloride, phosphorus oxychloride; Described chlorination reagent is any at least one in thionyl chloride, phosphorus oxychloride; The molar ratio example of 2-chlorine apellagrin and chlorination reagent is 1:1 ~ 20.
In a preferred embodiment of the present invention, described 5th reaction solvent is any at least one in methylene dichloride, trichloromethane, thionyl chloride; Described chlorination reagent is thionyl chloride; The molar ratio example of described chlorination reagent and 2-chlorine apellagrin is 2 ~ 6:1; The described range of reaction temperature obtaining 2-chloronicotinoyl chloride is 30 ~ 60 DEG C.
The invention has the beneficial effects as follows: the preparation method of nicotinamide sterilant boscalid amine of the present invention, from raw material para chlorobromobenzene, synthesis, to chlorophenylboronic acid, from the o-Nitraniline adjacent nitro halogeno-benzene of synthesis or from adjacent amino halogen benzene, prepares boscalid amine through reactions such as catalyzer coupling, reduction, amidations, this preparation method is simple to operate, with low cost, yield is high, and purity is high, pollute little, be very applicable to suitability for industrialized production.
Technical scheme of the present invention represents by following concrete synthetic route:
B (OR) in formula
3middle R is C
1~ C
4saturated hydrocarbyl or alkyl, R
4in NX, R is C
1~ C
18saturated hydrocarbyl or alkyl, X is any one in Cl, Br, I.
Embodiment
Be clearly and completely described to the technical scheme in the embodiment of the present invention below, obviously, described embodiment is only a part of embodiment of the present invention, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making other embodiments all obtained under creative work prerequisite, belong to the scope of protection of the invention.
Embodiment one:
There is provided a kind of preparation method of nicotinamide sterilant boscalid amine, comprising step is:
(1) to the preparation (Compound II per) of chlorophenylboronic acid
Under nitrogen protection, directly in 20 liters of reactors, add successively: magnesium chips 0.55Kg, 2-methyltetrahydrofuran 5.0Kg.Temperature rising reflux, drips the 2-methyl THF solution of the 1Kg of para chlorobromobenzene 3.80Kg.Dropwising rear back flow reaction keeps after 4-5h reacts completely, stopped reaction, cool to room temperature.By (i-PrO)
3the 4.0 Kg 2-methyltetrahydrofuran solution of B 5.20 Kg add in 50 liters of reactors, under not higher than 0 DEG C of condition, drip the above-mentioned Grignard reagent prepared; After dropwising, continue to maintain low temperature and stir 10h; Then add the HCl 16L of 20%, stir 1h, add 5L toluene, extraction, suction filtration; Solid continues to stir suction filtration with 5L toluene, and merge liquid, separate aqueous phase, aqueous phase uses 1L x 4 toluene wash again, merges organic phase; Organic phase Na
2sO
4after drying, suction filtration, obtains organic phase.Organic phase adopts rectification under vacuum, reclaims 2-methyltetrahydrofuran and Virahol and toluene thereof, acquisition white solid at the bottom of still.White solid is the crude product to chlorophenylboronic acid, and its product adopts water to carry out recrystallization, and directly obtain HPLC purity and be greater than the white crystalline of 99% to chlorophenylboronic acid 2.64Kg, yield 85%, HPLC purity is greater than 99%.
(2) preparation (compound IV) of the chloro-2 '-nitrobiphenyl of 4-
N
2under protection, will add in 20L reactor chlorophenylboronic acid 4.0Kg, o-chloronitrobenzene 3.15 Kg, triphenylphosphine 145g, Palladous chloride 25g, Anhydrous potassium carbonate 3.4 Kg, tetrabutylammonium chloride 65 g, DMF 5L.Be warming up to 130 DEG C, reaction 10h.After completion of the reaction, decompression steams DMF, adds the extraction of 20L toluene.Organic phase underpressure distillation, remaining solid ethyl alcohol recrystallization, obtain yellow macrocrystalline shape solid 4-chloro-2 '-nitrobiphenyl 4.44 Kg, yield 95%, HPLC purity is greater than 99%.
(3) preparation (compound V) of the chloro-2 '-amido biphenyl of 4-
N
2under protection, chloro-for 4-2 '-nitrobiphenyl 1.69 Kg, iron powder 1.5Kg, ammonium chloride 3.0 Kg, ethanol 3.0 liters are joined in reactor.Under stirring, back flow reaction 2h.Filter, filtrate is distilled.Residuum adds water and ethyl acetate, stirs separatory.Organic phase evaporate to dryness obtains solid.Solid recrystallisation from isopropanol, obtain white solid 4-chloro-2 '-amido biphenyl 1.44 Kg, yield 97%, HPLC content is greater than 99%.
(4) preparation (compound VI) of 2-chloronicotinoyl chloride
N
2under protection, under room temperature, add in 10L reactor by 1 Kg 2-chlorine apellagrin and 3.5 Kg thionyl chlorides, tail gas adds Alkali absorption device.Back flow reaction 16 hours.Air distillation goes out unreacted thionyl chloride, and rectification under vacuum goes out product, and obtain White crystalline solid, obtain product 1.06 Kg, yield 94.6%, GC content is greater than 99%.
(5) preparation (compound VI I) of boscalid amine
N
2under protection, under room temperature, by the chloro-2 '-nitrobiphenyl of 2.0 Kg 4-and 15 liters of methylene dichloride, and salt of wormwood 1.7Kg adds in reactor.Not higher than under the condition of 0 DEG C, 5 L methylene dichloride of 2.0 Kg 2-chloronicotinoyl chlorides are slowly added in above-mentioned reaction solution.After being added dropwise to complete, then maintain reaction 5h.Add 5L water to stir, separatory also collects organic phase.Decompression evaporates organic phase, thick product ethyl alcohol recrystallization, obtains white solid boscalid amine 3.1 Kg, yield 93.1%, HPLC content 99%.
Embodiment two:
There is provided a kind of preparation method of nicotinamide sterilant boscalid amine, comprising step is:
(1) to the preparation (Compound II per) of chlorophenylboronic acid
Under nitrogen protection, directly in 20 liters of reactors, add successively: magnesium chips 0.55Kg, 2-methyltetrahydrofuran 5.0Kg.Temperature rising reflux, drips the 2-methyl THF solution of the 1Kg of para chlorobromobenzene 3.80Kg.Dropwise rear back flow reaction and keep 4-5h, stopped reaction, cool to room temperature.By (n-BuO)
3the 4.0 Kg 2-methyltetrahydrofuran solution of B 6.00 Kg add in 50 liters of reactors, under not higher than 0 DEG C of condition, drip the above-mentioned Grignard reagent prepared; After dropwising, stir 10h; Then the H of 10% is added
2sO
416L, stirs 1h, adds 5L toluene, extraction, suction filtration; Solid continues to stir suction filtration with 5L toluene, and merge liquid, separate aqueous phase, aqueous phase uses 1L x 4 toluene wash again, merges organic phase; Organic phase Na
2sO
4after drying, suction filtration, obtains organic phase.Organic phase rectification under vacuum, obtains white solid.White solid is the crude product to chlorophenylboronic acid, and its product can adopt water to carry out recrystallization, directly obtains HPLC purity and is greater than the white crystalline of 99% to chlorophenylboronic acid 2.58Kg, yield 83%.
(2) preparation (compound III) of o-bromonitrobenzene
N
2under protection, under room temperature, 1 Kg o-Nitraniline and 10 L concentrated hydrochloric acids are joined in aforesaid reaction vessel.Temperature in above-mentioned solution stirring borehole cooling to bottle is reached less than 0 DEG C.The water that 0.53 Kg Sodium Nitrite is dissolved in 1.2 L is configured to solution, slowly adds in aforesaid reaction vessel, stir 1 h.Not higher than under the condition of 0 DEG C, the HBr of 0.6 Kg CuBr and 2.0 L 40% is added in a new reactor, stir.The diazo liquid prepared is added drop-wise in above-mentioned reaction solution, after dropwising, continues reaction 1h.After reaction terminates, filter, dry, with recrystallisation from isopropanol, cooling is separated out, and filter, obtain yellow crystalline solid o-bromonitrobenzene 1.32 Kg, yield 90%, HPLC content is greater than 99%.
(3) preparation (compound IV) of the chloro-2 '-nitrobiphenyl of 4-
N
2under protection, will add in 20L reactor chlorophenylboronic acid 4.0Kg, o-bromonitrobenzene 4.04 Kg, 10% palladium carbon 100g, Anhydrous potassium carbonate 3.4 Kg, tetrabutylammonium iodide 100 g, DMF 5L.Be warming up to 130 DEG C, reaction 10h.React complete, decompression steams DMF, adds the extraction of 20L toluene.Organic phase underpressure distillation, remaining solid ethyl alcohol recrystallization, obtain yellow crystalline solid 4-chloro-2 '-nitrobiphenyl 4.39 Kg, yield 94%, HPLC purity is greater than 99%.
All the other steps are identical with embodiment one, obtain boscalid amine.
Embodiment three:
There is provided a kind of preparation method of nicotinamide sterilant boscalid amine, comprising step is:
(1) preparation (compound III) of o-iodonitrobenzene
N
2under protection, under room temperature, 1 Kg o-Nitraniline and 10 L concentrated hydrochloric acids are joined in aforesaid reaction vessel.Temperature in above-mentioned solution stirring borehole cooling to bottle is reached less than 0 DEG C.The water that 0.53 Kg Sodium Nitrite is dissolved in 1.2 L is configured to solution, slowly adds in aforesaid reaction vessel, stir 1 h.Not higher than under the condition of 0 DEG C, 1.5 Kg NaI are dissolved in the water of 1L and add in a new reactor, stir.The diazo liquid prepared is added drop-wise in above-mentioned reaction solution, after dropwising, continues reaction 1h.After reaction terminates, filter, dry, with ethyl alcohol recrystallization, cooling is separated out, and filter, obtain yellow solid o-iodonitrobenzene 1.35 Kg, yield 92%, HPLC content is greater than 99%.
(2) preparation (compound IV) of the chloro-2 '-nitrobiphenyl of 4-
N
2under protection, will to chlorophenylboronic acid 39 g, o-iodonitrobenzene 50 g, Ni nanoparticle Cl
210 g, Anhydrous potassium carbonate 35 g, tetrabutylammonium iodide 10 g, DMF 200mL add in four mouthfuls of reaction flasks.Be warming up to 140 DEG C, reaction 20h.React complete, decompression steams DMF, adds 20L toluene and the 10%NaOH aqueous solution, and washing is separated.Organic phase merges dry, underpressure distillation.Remaining solid dehydrated alcohol recrystallization, obtain the chloro-2 '-nitrobiphenyl 39.7g of 4-, yield 85%, HPLC content is greater than 99%.
All the other steps are identical with embodiment one, obtain boscalid amine.
Embodiment four:
There is provided a kind of preparation method of nicotinamide sterilant boscalid amine, comprising step is:
(1) preparation (compound V) of the chloro-2 '-amido biphenyl of 4-
N
2under protection, will to chlorophenylboronic acid 40 g, adjacent chloramines base benzene 25.5 g, magnetic Nano microsphere load P dCl
2catalyzer (Pd content 1%) 20 g, Anhydrous potassium carbonate 35 g, tetrabutylammonium iodide 10 g, DMF 400mL add in four mouthfuls of reaction flasks.Be warming up to 130 DEG C, reaction 20h.React complete, filter, filtrate decompression steams DMF, adds 400 mL toluene and the 10% KOH aqueous solution, and washing is separated.Organic phase merges dry, underpressure distillation.Remaining solid dehydrated alcohol recrystallization, obtain 4-chloro-2 '-amido biphenyl 34.2g, yield 84%, HPLC content is greater than 99%.
All the other steps are identical with embodiment one, obtain boscalid amine.
Embodiment five:
There is provided a kind of preparation method of nicotinamide sterilant boscalid amine, comprising step is:
(1) preparation (compound V) of the chloro-2 '-amido biphenyl of 4-
N
2under protection, will to chlorophenylboronic acid 40 g, adjacent bromo-amine base benzene 34.4 g, magnetic Nano microsphere load P dCl
2catalyzer (Pd content 1%) 20 g, Anhydrous potassium carbonate 35 g, Tetrabutyl amonium bromide 10 g, DMF 400mL add in four mouthfuls of reaction flasks.Be warming up to 100 DEG C, reaction 20h.React complete, filter, filtrate decompression steams DMF, adds 400 mL toluene and the 10% KOH aqueous solution, and washing is separated.Organic phase merges dry, underpressure distillation.Remaining solid dehydrated alcohol recrystallization, obtain 4-chloro-2 '-amido biphenyl 45.2g, yield 90%, HPLC content is greater than 99%.
All the other steps are identical with embodiment one, obtain boscalid amine.
Embodiment six:
There is provided a kind of preparation method of nicotinamide sterilant boscalid amine, comprising step is:
(1) preparation (compound V) of the chloro-2 '-amido biphenyl of 4-
N
2under protection, will add in four mouthfuls of reaction flasks chlorophenylboronic acid 40 g, adjacent iodine amido benzene 43.8 g, 10% palladium carbon 2.5 g, Anhydrous potassium carbonate 35 g, Tetrabutyl amonium bromide 10 g, DMF 400mL.Be warming up to 100 DEG C, reaction 20h.React complete, filter, filtrate decompression steams DMF, adds 400 mL toluene and the 10% KOH aqueous solution, and washing is separated.Organic phase merges dry, underpressure distillation.Remaining solid dehydrated alcohol recrystallization, obtain 4-chloro-2 '-amido biphenyl 45.7g, yield 91%, HPLC content is greater than 99%.
All the other steps are identical with embodiment one, obtain boscalid amine.
The invention has the beneficial effects as follows:
One, the present invention is when preparing boscalid amine intermediate, adopts mixing first catalyzer and the second catalyzer conbined usage, with to chlorophenylboronic acid and nitro halogeno-benzene
(X can be Cl, Br, I at least any one) be raw material, and is single-minded linked reaction substantially, transformation efficiency transforms close to equivalent, and reaction preference is very high, decrease by product, simplify aftertreatment purification step, reduce the discharge of solid waste, technics comparing clean environment firendly;
Two, the present invention is when preparing boscalid amine intermediate, and adopt mixed catalyst, palladium and nickel metal-based catalysts, the consumption of relative conventional precious metal catalyzer greatly reduces, and yield increases substantially, and cost is reduced greatly;
Three, the present invention when preparing boscalid amine with M
2cO
3, MHCO
3, M
3pO
4, M
2hPO
4in any at least one be alkali (wherein M is any at least one in Li, Na, K), instead of triethylamine in the past, diisopropylethylamine, oxyhydroxide etc., greatly reduce side reaction, good reaction selectivity, thus productive rate is improved greatly.Reaction can be carried out under safe mild conditions, is more suitable for industrial production;
Four, the present invention is when preparing boscalid amine and intermediate thereof, and each step has all searched out suitable recrystallization solvent, and column chromatography separating purification step than before has more actual industrial production meaning.
In sum, the present invention, from raw material para chlorobromobenzene, synthesizes chlorophenylboronic acid, from the o-Nitraniline adjacent nitro halogeno-benzene of synthesis or from adjacent amino halogen benzene, through catalyzer coupling, reduction, or from adjacent amino halogen benzene, directly through catalyzer coupling, boscalid amine is prepared in the reaction such as amidation, this synthesis technique is simple to operate, with low cost, yield is high, and purity is high, pollute little, be very applicable to suitability for industrialized production.
The foregoing is only embodiments of the invention; not thereby the scope of the claims of the present invention is limited; every utilize description of the present invention to do equivalent structure or equivalent flow process conversion; or be directly or indirectly used in other relevant technical field, be all in like manner included in scope of patent protection of the present invention.
Claims (10)
1. a preparation method for nicotinamide sterilant boscalid amine, is characterized in that, comprises step to be: temperature is that at-40 ~ 50 DEG C, in alkali and solvent, the chloro-2 '-amido biphenyl of 4-and 2-chloronicotinoyl chloride react, then aftertreatment recrystallization obtains boscalid amine
;
The molar ratio preparing alkali, the chloro-2 '-amido biphenyl of 4-, 2-chloronicotinoyl chloride described in boscalid amine reaction is 1 ~ 5:0.8 ~ 2:1, and described alkali is triethylamine, DMA, N, N-Diethyl Aniline, DIPEA, M
2cO
3, MHCO
3, M
3pO
4, M
2hPO
4in any at least one, wherein M is any at least one in Li, Na, K, in described recrystallization with solvent be in methyl alcohol, ethanol, propyl alcohol, Virahol, methylene dichloride, chloroform, toluene at least any one;
Wherein said 4-chloro-2 '-amido biphenyl can with to chlorophenylboronic acid and adjacent nitro halogeno-benzene for raw material obtains the chloro-2 '-nitrobiphenyl of 4-through coupling, obtains through reduction reaction, or with to chlorophenylboronic acid and adjacent amido halogeno-benzene for raw material obtains;
The building-up process of the chloro-2 '-amido biphenyl of described 4-is: at 50-150 DEG C, will to chlorophenylboronic acid and adjacent nitro halogeno-benzene
in the first alkali, the first catalyzer, the second catalyzer and the first reaction solvent, there is linked reaction, adopt the first solvent recrystallization to obtain the chloro-2 '-nitrobiphenyl of 4-through aftertreatment
, then at 50-140 DEG C in reductive agent, the 3rd catalyzer, the second reaction solvent, 4-chloro-2 '-nitrobiphenyl generation reduction reaction, adopts the second solvent recrystallization to prepare the chloro-2 '-phenylaniline of 4-through aftertreatment
;
Described first alkali is M
2cO
3, MHCO
3, any one in MOH, wherein M is any at least one in Li, Na, K, Cs, described first catalyzer is nickelous chloride, nickelous acetate, acetylacetonate nickel, nickel powder/nano-nickel powder/reduced nickel powder, two (triphenylphosphine) nickelous chloride (II), dibromo two (triphenyl phosphorus) changes nickel, four (triphenylphosphine) nickel (0), magnetic Nano microsphere nickel-loaded class catalyzer, palladium carbon, Palladous chloride, palladium, tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II), two (acetonitrile) Palladous chloride (II), palladium trifluoroacetate (II), magnetic Nano microsphere supported palladium class catalyzer (I, II, III, IV model) in any one, described second catalyzer is R
4any at least one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any at least one, X is any at least one in Cl, Br, I, sulfate ion, nitrate ion, phosphate anion, described first reaction solvent is DMF, N, N-diethylformamide, N,N-dimethylacetamide, dioxane, methyl-sulphoxide, water, THF, ethanol, methyl alcohol, propyl alcohol, any at least one in Virahol, toluene, described adjacent nitro halogeno-benzene
in X be any at least one in Cl, Br, I, described first solvent adopted in described recrystallization is any at least one in methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, toluene, the described molar ratio to chlorophenylboronic acid, adjacent nitro halogeno-benzene, the first alkali, the first catalyzer, the second catalyzer is 0.8 ~ 2: 1: 0.5 ~ 3: 0.01% ~ 5%: 0.05 ~ 0.5,
Described reductive agent is SnCl
2, any at least one in iron powder; Described 3rd catalyzer is R
4any at least one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any at least one, X is any at least one in Cl, Br, I, acetate ion, sulfate ion; Described second reaction solvent is any at least one in methyl alcohol, ethanol, propyl alcohol, Virahol, water, DMF, THF, toluene; The molar ratio of the chloro-2 '-nitrobiphenyl of described 4-, reductive agent, the 3rd catalyzer is 1:2 ~ 5:0.1 ~ 1; Described second solvent adopted in described recrystallization is any at least one in water, methyl alcohol, ethanol, propyl alcohol, Virahol, acetone;
The building-up process of the chloro-2 '-amido biphenyl of described 4-is: at 50-150 DEG C, will to chlorophenylboronic acid and adjacent amido halogeno-benzene
in the second alkali, the 4th catalyzer, the 5th catalyzer and the 3rd reaction solvent, there is linked reaction, adopt the 3rd solvent recrystallization to prepare the chloro-2 '-amido biphenyl of 4-through aftertreatment
;
Described second alkali is M
2cO
3, MHCO
3, any one in MOH, wherein M is any at least one in Li, Na, K, Cs, described 4th catalyzer is nickelous chloride, nickelous acetate, acetylacetonate nickel, nickel powder/nano-nickel powder/reduced nickel powder, two (triphenylphosphine) nickelous chloride (II), dibromo two (triphenyl phosphorus) changes nickel, four (triphenylphosphine) nickel (0), magnetic Nano microsphere nickel-loaded class catalyzer, palladium carbon, Palladous chloride, palladium, tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II), two (acetonitrile) Palladous chloride (II), palladium trifluoroacetate (II), magnetic Nano microsphere supported palladium class catalyzer (I, II, III, IV model) in any one, described 5th catalyzer is R
4any at least one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any at least one, X is any at least one in Cl, Br, I, sulfate ion, nitrate ion, phosphate anion, described 3rd reaction solvent is DMF, N, N-diethylformamide, N,N-dimethylacetamide, dioxane, methyl-sulphoxide, water, THF, ethanol, methyl alcohol, propyl alcohol, any at least one in Virahol, toluene, described adjacent amido halogeno-benzene
in X be any at least one in Cl, Br, I, described 3rd solvent adopted in described recrystallization is any at least one in water, methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, toluene, the described molar ratio example to chlorophenylboronic acid, adjacent amido halogeno-benzene, the second alkali, the 4th catalyzer, the 5th catalyzer is 0.8 ~ 2: 1: 0.5 ~ 3: 0.01% ~ 5%: 0.05 ~ 0.5.
2. preparation method according to claim 1, is characterized in that, described alkali is M
2cO
3, MHCO
3, M
3pO
4, M
2hPO
4in any at least one, wherein M is any at least one in Li, Na, K; The molar ratio of the chloro-2 '-amido biphenyl of described alkali, 4-, 2-chloronicotinoyl chloride is 1 ~ 2:0.8 ~ 1.5:1; Generating range of reaction temperature described in boscalid amine reaction is-20 ~ 10 DEG C; Be ethanol or Virahol with solvent in described recrystallization.
3. preparation method according to claim 1, it is characterized in that, with to chlorophenylboronic acid and adjacent nitro halogeno-benzene for raw material obtains in the reaction of the chloro-2 '-nitrobiphenyl of described 4-: described adjacent nitro halogeno-benzene be in o-nitrochlorobenzene, adjacent Nitrobromobenzene, adjacent nitro phenyl-iodide any one; The temperature obtaining adopting in the chloro-2 '-nitrobiphenyl of 4-is 70-150 DEG C; Described first alkali is M
2cO
3, wherein M is any at least one in Li, Na, K; Described first catalyzer is any one in palladium carbon, Palladous chloride, palladium, tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II), two (acetonitrile) Palladous chloride (II), palladium trifluoroacetate (II), magnetic Nano microsphere supported palladium class catalyzer (I, II, III, IV model); Described second catalyzer is R
4any one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any one, X is any one in Cl, Br, I; Described first reaction solvent is ethanol, water, DMF; The described molar ratio example to chlorophenylboronic acid, adjacent nitro halogeno-benzene, the first alkali, the first catalyzer, the second catalyzer is 1 ~ 2:1:0.8 ~ 2:0.01% ~ 1%:0.05 ~ 0.5; Described first solvent adopted in described recrystallization is ethanol, Virahol, propyl alcohol;
Described reductive agent is iron powder; Described 3rd catalyzer is R
4any one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any one, X is any one in Cl, Br, I; Described reductive agent, the 3rd catalyzer, the chloro-2 '-nitrobiphenyl molar ratio of 4-are 2 ~ 5:0.1 ~ 2:1; Obtaining temperature condition described in the chloro-2 '-phenylaniline of 4-is 60-120 DEG C; Described second reaction solvent is the mixed solvent of ethanol, methyl alcohol or isopropyl alcohol and water; Described second solvent is ethanol or Virahol.
4. preparation method according to claim 1, it is characterized in that, with to chlorophenylboronic acid and adjacent amido halogeno-benzene for raw material obtains in the reaction of described 4-chloro-2 '-amido biphenyl: described adjacent amido halogeno-benzene be in adjacent amido chlorinated benzene, adjacent amido bromobenzene, adjacent amido phenyl-iodide any one; Described temperature of reaction is 70-150 DEG C; Described second alkali is M
2cO
3, wherein M is any at least one in Li, Na, K, Cs; Described 4th catalyzer is any one in palladium carbon, Palladous chloride, palladium, tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II), two (acetonitrile) Palladous chloride (II), palladium trifluoroacetate (II), magnetic Nano microsphere supported palladium class catalyzer (I, II, III, IV model); Described 5th catalyzer is R
4any at least one in NX quaternary ammonium salt, wherein R is H, C
1-C
18alkane in any at least one, X is any at least one in Cl, Br, I; Described 3rd reaction solvent is ethanol, water, DMF; The described molar ratio to chlorophenylboronic acid, adjacent amido halogeno-benzene, the second alkali, the 4th catalyzer, the 5th catalyzer is 1 ~ 2:1:0.8 ~ 2:0.01% ~ 1%:0.05 ~ 0.5; Described 3rd solvent is ethanol, Virahol, propyl alcohol.
5. preparation method according to claim 1, is characterized in that, the described preparation method to chlorophenylboronic acid is: at 40 ~ 140 DEG C, will to halo chlorobenzene
react in the 6th catalyzer and the 4th reaction solvent with metal magnesium chips, be prepared into Grignard reagent
; The Grignard reagent will prepared at-40 ~ 0 DEG C again
with boric acid three alkane ester B (OR)
3reaction, and at 0 ~ 40% hydrolyzed under acidic conditions and aftertreatment obtains crude product, crude product obtains chlorophenylboronic acid through recrystallization
;
Described to halo chlorobenzene
middle X is Cl, Br, I; Described 6th catalyzer is iodine, glycol dibromide; Described 4th reaction solvent is any at least one in ether, tetrahydrofuran (THF) (THF), methyl ring amyl ether, 2-methyltetrahydrofuran (2-Me-THF), propyl ether, isopropyl ether, t-butyl methyl ether, n-butyl ether; Described boric acid three alkane ester B (OR)
3in R be C
1-C
4alkyl; Described hydrolysis acid is hydrochloric acid, Hydrogen bromide, phosphoric acid, any at least one in sulfuric acid; Described recrystallization is any at least one in water, methyl alcohol, ethanol, acetone, propyl alcohol, Virahol with the 4th solvent; Described to halogen chlorobenzene, MAGNESIUM METAL, B (OR)
3molar ratio be 1 ︰ 1 ~ 2 ︰ 1 ~ 3.
6. preparation method according to claim 5, is characterized in that, described to halo chlorobenzene
for para chlorobromobenzene; Described B (OR)
3middle R is normal-butyl; Described 6th catalyzer is iodine; Described to halogen chlorobenzene, MAGNESIUM METAL, B (OR)
3molar ratio be 1 ︰ 1 ~ 1.2 ︰ 1 ~ 1.5; Described 4th reaction solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran; Described hydrolysis acid for massfraction be the sulfuric acid of 5 ~ 20%; Described 4th solvent is water.
7. preparation method according to claim 1, is characterized in that, the preparation method of described adjacent nitro halogeno-benzene is: under-40 ~ 10 DEG C of acidic conditionss, and o-Nitraniline and Sodium Nitrite react prepares diazonium salt solution; Described diazonium salt solution is at-40 ~ 80 DEG C and under the 7th catalyzer existence condition, react with haloid acid HX, and through wet distillation, the 5th solvent recrystallization, obtains adjacent nitro halogeno-benzene
;
Described reaction acid is any one in hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid; In described haloid acid HX, X is any at least one in Cl, Br, I; Described 7th catalyzer is MX, and M is wherein any at least one in Cu, Ni, and X is any at least one in Cl, Br, I, CN; The mol ratio of described o-Nitraniline and reaction acid, Sodium Nitrite, the 7th catalyzer MX is 1: 1 ~ 6: 1 ~ 1.5: 0.1 ~ 1; Described recrystallization is water, methyl alcohol, ethanol, propyl alcohol with the 5th solvent, Virahol, any at least one in acetone, benzene, toluene.
8. preparation method according to claim 7, is characterized in that, described reaction acid is sulfuric acid; Described 7th catalyzer MX is CuX, and wherein X is Cl, Br, I; The mol ratio of described o-Nitraniline, reaction acid, Sodium Nitrite, the 7th catalyzer is 1:2 ~ 6:1 ~ 1.5:0.1 ~ 1; The described temperature preparing diazonium salt solution is-20 ~ 0 DEG C; Described diazonium salt and o-Nitraniline range of reaction temperature are-20 ~ 40 DEG C; The 5th solvent adopted in described recrystallization is ethanol, Virahol.
9. preparation method according to claim 1, is characterized in that, the preparation method of described 2-chloronicotinoyl chloride is: at 20 ~ 100 DEG C, and 2-chlorine apellagrin and chlorination reagent react in the 5th reaction solvent, prepare 2-chloronicotinoyl chloride through underpressure distillation
; Described 5th reaction solvent is any at least one in methylene dichloride, trichloromethane, 1,2-ethylene dichloride, thionyl chloride, phosphorus oxychloride; Described chlorination reagent is any at least one in thionyl chloride, phosphorus oxychloride; The molar ratio example of 2-chlorine apellagrin and chlorination reagent is 1:1 ~ 20.
10. preparation method according to claim 9, is characterized in that, described 5th reaction solvent is any at least one in methylene dichloride, trichloromethane, thionyl chloride; Described chlorination reagent is thionyl chloride; The molar ratio example of described chlorination reagent and 2-chlorine apellagrin is 2 ~ 6:1; The described range of reaction temperature obtaining 2-chloronicotinoyl chloride is 30 ~ 60 DEG C.
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