CN104016915A - Preparation method of boscalid - Google Patents
Preparation method of boscalid Download PDFInfo
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- CN104016915A CN104016915A CN201410298571.8A CN201410298571A CN104016915A CN 104016915 A CN104016915 A CN 104016915A CN 201410298571 A CN201410298571 A CN 201410298571A CN 104016915 A CN104016915 A CN 104016915A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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Abstract
The invention relates to the field of compound preparation, particularly a preparation method of a novel bactericide boscalid. The method comprises the following steps: in a polar aprotic solvent or high boiling solvent, carrying out Suzuki reaction on a palladium catalyst p-chlorophenylboric acid and o-acetaminobrombenzene in the presence of alkali and quaternary ammonium salt to obtain an intermediate product 4'-chloro-2-acetaminobiphenyl; and deprotecting the intermediate product in the presence of concentrated hydrochloric acid, and condensing with 2-chloronicotinoyl chloride. According to the method, the Pd(OH)2/C is used as the catalyst to perform the Suzuki coupling reaction, and is recovered and reutilized many times; and thus, compared with the prior art, the method provided by the invention greatly saves the catalyst cost, is convenient for recovering the catalyst, and avoids using the high-cost raw material o-iodoaniline.
Description
Technical field
The present invention relates to compound preparation field, particularly a kind of preparation method of new type bactericide boscalid amine.
Background technology
Boscalid amine (popular name: full name Boscalid) is N-(4 '-chloro-2-xenyl)-2-chloro-3-pyridyl methane amide, the Novel tobacco amides systemic fungicide of being developed by BASF Aktiengesellschaft at first, more than 50 countries such as Europe, the U.S. have been obtained for the registration of 80 kinds of diseases of 100 kinds of crop controls, be succsinic acid ubiquinone reductase inhibitor in mitochondrial respiratory chain, it mainly prevents and treats numerous diseases such as Powdery Mildew, gray mold, sclerotium disease, brown heart and root rot.Can be used for comprising the control of the relevant diseases of crop such as rape, grape, fruit tree, tomato, vegetables and field crop.Its mechanism of action agent is unique, without cross resistance, crop safety and favourable ecological effect and toxicity data is shown to boscalid amine is a kind of important new type bactericide with other medicines.
At present, boscalid amine mainly be take adjacent Iodoaniline and be starting raw material to chlorobenzene boric acid, four (triphenyl phosphorus) palladium (or, palladium charcoal) is catalyzer, mineral alkali and other auxiliary reagent solution back flow reaction, one step makes 2-(4-chloro-phenyl-) aniline, then be dissolved in methylene dichloride, at room temperature drip the stirring of 2-chloronicotinoyl chloride and obtain target product.Although reduced single step reaction, there are 2 problems, the first is used homogeneous palladium catalysts as tetrakis triphenylphosphine palladium, not only reclaims difficulty, but also can increase residual heavy metal palladium in product; Its two, even if use callable palladium carbon, but adjacent Iodoaniline price is high, also all can make the production cost of boscalid amine be unsuitable for industrialization higher than its market value.
Therefore, provide a kind of catalyzer can reuse, avoid using the preparation method of the boscalid amine of the adjacent Iodoaniline of expensive raw material, there is realistic meaning.
Summary of the invention
In view of this, the invention provides a kind of preparation method of new type bactericide boscalid amine.The method is used Pd (OH)
2/ C is catalyzer, carries out Suzuki linked reaction, and repeatedly reclaims and reuse, and the existing technology of comparing, has saved catalyzer cost greatly, facilitates catalyst recovery utilization, and has avoided using the adjacent Iodoaniline of expensive raw material.
In order to realize foregoing invention object, the invention provides following technical scheme:
The invention provides a kind of preparation method of boscalid amine, in polar aprotic solvent or high boiling solvent, under alkali and quaternary ammonium salt existence, palladium catalyst reacts with the Suzuki of adjacent kharophen bromobenzene chlorobenzene boric acid and obtains intermediate product 4 '-chloro-2-kharophen biphenyl; Described intermediate product under concentrated hydrochloric acid exists after deprotection with the condensation of 2-chloronicotinoyl chloride, obtain.
Described Suzuki reaction is with Pd (OH)
2/ C is catalyzer, under alkali and quaternary ammonium salt exist, in DMF, carrying out.Reaction formula is as follows:
Under concentrated hydrochloric acid exists, the ethanoyl removing in 4 '-chloro-2-kharophen biphenyl obtains 4 '-chloro-2-phenylaniline hydrochloride, and its reaction formula is as follows:
Under diisopropyl ethyl amine (DIEA) exists, in dry methylene dichloride, complete the condensation of 4 '-chloro-2-phenylaniline hydrochloride and 2-chloronicotinoyl chloride, its reaction formula is as follows:
In some embodiments of the invention, described palladium catalyst Pd (OH)
2/ C.
In some embodiments of the invention, described condensation is specially under diisopropyl ethyl amine (DIEA) exists, in dry methylene dichloride, and 4 '-chloro-2-phenylaniline hydrochloride and the condensation of 2-chloronicotinoyl chloride.
In some embodiments of the invention, the mol ratio of described palladium catalyst and adjacent kharophen bromobenzene is 0.5～1:100.
In some embodiments of the invention, described alkali is selected from salt of wormwood or seven water potassiumphosphates.
In some embodiments of the invention, described quaternary ammonium salt is selected from Tetrabutyl amonium bromide (TBAB) or cetyl trimethylammonium bromide (CTAB).
In some embodiments of the invention, described polar aprotic solvent is selected from DMF.
In some embodiments of the invention, described deprotection, for removing ethanoyl, is specially under 36% hydrochloric acid existence, removes ethanoyl in tetrahydrofuran solution.
The boscalid amine that the present invention also provides above-mentioned preparation method to make.
The invention provides a kind of preparation method of boscalid amine, in polar aprotic solvent or high boiling solvent, under alkali and quaternary ammonium salt existence, palladium catalyst reacts with the Suzuki of adjacent kharophen bromobenzene chlorobenzene boric acid and obtains intermediate product 4 '-chloro-2-kharophen biphenyl; Described intermediate product under concentrated hydrochloric acid exists after deprotection with the condensation of 2-chloronicotinoyl chloride, obtain.
In the method, with Pd (OH)
2/ C is catalyzer, and in DMF, under alkali and quaternary ammonium salt existence, catalysis is reacted with the Suzuki of adjacent kharophen bromobenzene chlorobenzene boric acid and obtained key intermediate species 4 '-chloro-2-kharophen biphenyl.Catalyst P d (OH)
2/ C reuses 6 times, still keeps catalytic activity.The yield that 4 '-chloro-2-kharophen biphenyl reacts with 88% with 2-chloronicotinoyl chloride take off ethanoyl under concentrated hydrochloric acid exists after obtains boscalid amine.The method, because noble metal catalyst is recycled, is not used containing iodine raw material again simultaneously, greatly reduces production cost, completely can industrialization.
The present invention uses Pd (OH)
2/ C is catalyzer, carries out Suzuki linked reaction, and repeatedly reclaims and reuse, and the existing technology of comparing, has saved catalyzer cost greatly, facilitates catalyst recovery utilization, and has avoided using the adjacent Iodoaniline of expensive raw material.
Accompanying drawing explanation
Fig. 1 shows the hydrogen spectrogram of 4 '-chloro-2-kharophen biphenyl in embodiment 1;
The hydrogen spectrum of the product 4 '-chloro-2-kharophen biphenyl hydrochloride salt of Fig. 2 embodiment 3 preparations;
Fig. 3 shows the hydrogen spectrum of the product boscalid amine of embodiment 4 preparations.
Embodiment
The invention discloses a kind of preparation method of new type bactericide boscalid amine, those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications as herein described or suitably change and combination within not departing from content of the present invention, spirit and scope, realizes and apply the technology of the present invention.
In the preparation method of new type bactericide boscalid amine provided by the invention, raw materials used and reagent all can be buied by market.
Reaction process is monitored by thin-layer chromatography, and spot is with ultraviolet lamp or contain Ce (NH
4)
2(NO
3)
6(0.5g) with (NH
4)
6mo
7o
244H
2o (24.0g) is at 6%H
2sO
4(500mL) yellow solution colour developing.The proton nmr spectra of reaction product is measured by Varian mercury plus400MHz nuclear magnetic resonance analyser (TMS is interior mark), ESI mass spectrum is by ESQUIRE Ion Trap LC/MS liquid chromatography/mass spectrometry combined instrument Analysis deterrmination, and the mixture that reaction finishes and the purity of target product are analyzed (Kromasil C with Agilent1260 type high performance liquid chromatograph
18stainless steel column, 250mm * 4.6mm, methanol-water mixture solvent, 65:35V/V is moving phase, flow velocity 1.0mL/min, photodiode array detector, wavelength 236nm, column temperature, 35 ℃).
Below in conjunction with embodiment, further set forth the present invention:
Embodiment 14 ' preparation of-chloro-2-kharophen biphenyl
2-kharophen bromobenzene (21.4g, 0.1mol), to chlorobenzene boric acid (18.7g, 0.12mol), 10% Pd (OH)
2/ C (0.14g, the Pd of 1mmol (OH)
2), Tetrabutyl amonium bromide (6g) (or quaternary ammonium salt of other identical equivalents), 7 water potassiumphosphates (64g) (or mineral alkali of other identical equivalents) (100mL) stir with DMF (or other solvents) at the temperature of setting, after TLC monitoring has been reacted, stopped reaction, filter, filtrate is diluted by ethyl acetate (500mL), NaOH solution (300mL) washing, saturated aqueous common salt (3 * 500mL) washing with 1M, with after anhydrous sodium sulfate drying, boil off solvent, obtain product 24.2g, yield 99%.
1H?NMR(400MHz,CDCl
3)δ8.20(d,J＝6.4Hz,1H),7.46(d,J＝6.4Hz,2H),7.41-7.36(m,1H),7.31(d,J＝6.4Hz,2H),7.24-7.16(m,2H),6.90(s,br,1H,NH),2.04(s,3H)。ESI-MS,m/z,[M+H]
+：246.2。Filter cake is used with recirculation after a small amount of water washing.
As stated above, take to chlorobenzene boric acid and adjacent kharophen bromobenzene is raw material, and the reaction result under different condition is listed in table 1, wherein adjacent kharophen bromobenzene and Pd (OH)
2mol ratio be 100:1.
The yield of 4 '-chloro-2-kharophen biphenyl under table 1 different condition
The analytical results of note: a:HPLC, TBAB-Tetrabutyl amonium bromide; TBAI-tetrabutylammonium iodide; CTAB-cetyl trimethylammonium bromide; DMB-dimethylbenzene.
The result of table 1 shows, when temperature of reaction is 80 ℃, while there is no quaternary ammonium salt, react 48 hours, trace all only detected and obtain product, be warming up to 120 ℃, react 48 hours, also 5% adjacent kharophen bromobenzene only detected and be converted into product, this explanation, quaternary ammonium salt also has considerable effect in reaction.When temperature of reaction is 80 ℃, use K
2cO
3for alkali, the speed of response that Tetrabutyl amonium bromide (TBAB) is auxiliary agent is slower, needs 48 hours, and reaction just completes substantially, but when temperature of reaction is brought up to 125 ℃, in the situation that other reaction conditionss are identical, within 13 hours, just reacts complete.We have also investigated other alkali and the impact of quaternary ammonium salt on reaction, find when other conditions are constant, with K
3pO
47H
2o is that the reaction of alkali is the fastest, within 11 hours, just can react complete, and with Na
2cO
3for the reaction of alkali the slowest.Need just can complete reaction in 21 hours.When other conditions are constant, the reaction that the tetrabutylammonium iodide of take is auxiliary agent is best, while making alkali with salt of wormwood, within 9 hours, completes reaction, uses K
3pO
47H
2when O makes alkali, within 8 hours, just can react completely, this may be because I-can with bromobenzene in bromine generating unit divide displacement, thereby the cause of accelerated reaction.Cetyl trimethylammonium bromide (CTAB) although better than Tetrabutyl amonium bromide (TBAB), there is no significant difference, but consider containing iodine reagent expensively, during industrialization, can increase cost, industrial generally as far as possible avoiding used.
Impact for solvent on reaction, except DMF, we have also investigated the Suzuki reaction in dimethylbenzene, toluene and ethylene glycol, and its effect is all not so good as the good of DMF.According to above experimental result, when selecting the reaction conditions of synthetic boscalid amine intermediate, we determine K
3pO
47H
2o is alkali, and Tetrabutyl amonium bromide (TBAB) is auxiliary agent, catalysis reacting chlorobenzene boric acid and adjacent kharophen bromobenzene in DMF.
Embodiment 2 Pd (OH)
2the recycle of/C
2-kharophen bromobenzene (21.4g, 0.1mol), containing Pd (OH) that chlorobenzene boric acid (21.4g, 0.1mol), embodiment 1 are filtered out
2/ C, Tetrabutyl amonium bromide (6g), K
3pO
47H
2o (64g) and DMF (100mL), the point that is reacted to TLC monitoring 2-kharophen bromobenzene at 125 ℃ disappears, and aftertreatment is the same, the results are shown in Table 2.
Table 2 Pd (OH)
2the result of the recycle of/C
The result of table 2 shows, in the circulation of first 2 times, the activity of catalyzer there is not change substantially, reacts 11 hours, just can make Suzuki reaction carry out completely, and since the 3rd time, activity decreases, and need to increase the reaction times just can complete reaction.While being recycled to the 6th time, need 14 hours ability substantially to complete reaction.But all things considered, Pd (OH)
2/ C, when synthetic 4 '-chloro-2-kharophen biphenyl, can be repeatedly used, and this will reduce the use cost of catalyzer greatly, is convenient to industrialization.
Embodiment 34 '-chloro-2-kharophen biphenyl deacetylation
The 4 '-chloro-2-kharophen biphenyl (9.2g that embodiment 1 makes, 3.7mmol), the mixture return stirring 24h that concentrated hydrochloric acid (20mL) and tetrahydrofuran (THF) (20mL) form, after TLC monitoring has been reacted, evaporates tetrahydrofuran (THF) and the water of half.After cooling, add isopropyl ether (10mL), after stirring evenly, 4-6 ℃ of placement, spend the night.Filter, filter cake with cold isopropyl ether washing once, the product 4 ' of vacuum drying-chloro-2-phenylaniline hydrochloride (6.4g, 72%), filtrate concentrates after half, then places and spend the night under 4-6 ℃ of condition, has again crystallization, filter to obtain product 1.5g (16.9%), adding up to yield is 88.9%.Nuclear-magnetism detected result:
1h NMR (400MHz, DMSO-d
6) δ 7.60-7.50 (dd, J=10.4Hz, J=12.4,8.8Hz), 7.51-7.42 (m, 2H), 7.39-7.31 (m, 2H).After testing, products obtained therefrom is 4 '-chloro-2-kharophen biphenyl hydrochloride salt.
The preparation of embodiment 4 boscalid amines
The 4 '-chloro-2-phenylaniline hydrochloride (24g that embodiment 3 makes, the mixture that 0.1mol), dry methylene dichloride (200mL) and diisopropyl ethyl amine (30mL) form is under 0-5 ℃ of stirring, drip the solution that step 2-chloronicotinoyl chloride (18.5g, 0.105mol) and methylene dichloride (50mL) form.After being raised to room temperature, stir again 3h.When TLC monitors after the some disappearance of all 2-(4-chloro-phenyl-) anilinechloride, stopped reaction.In reaction system, add again methylene dichloride (200mL), with saturated sodium bicarbonate solution washing 2 times, then wash with water 1 time.Organic phase, with after anhydrous sodium sulfate drying, evaporates methylene dichloride and obtains thick product (yield 100%).Head product obtains product 25g by recrystallizing methanol, yield 72.9%.Filtrate is reclaimed after evaporate to dryness, then recrystallization obtains product 6g (17.5%), total yield 90.4%.Fusing point 141-143 ℃.Purity (HPLC) 99%, nuclear-magnetism detected result:
1h NMR (400MHz, CDCl3), δ: 8.45 (dd, J=4.8,2.0Hz, 1H), 8.41 (d, J=8.4Hz), 8.20-8.10 (m, 2H, containing 1 NH), 7.50-7.42 (m, 3H), 7.36-7.31 (m, 3H), (7.28-7.26 m, 2H).ESI-MS,m/z,[M+H]
+:343.1。After testing, products obtained therefrom is boscalid amine.
The preparation of embodiment 5 boscalid amines
Adjacent kharophen bromobenzene (21.4g, 0.1mol), to chlorobenzene boric acid (18.7g, 0.12mol), 10% Pd (OH)
2/ C (0.14g, the Pd of 0.5mmol (OH)
2), Tetrabutyl amonium bromide (6g) (or quaternary ammonium salt of other identical equivalents), 7 water potassiumphosphates (64g) (or mineral alkali of other identical equivalents) (100mL) stir with DMF (or other solvents) at the temperature of setting, after TLC monitoring has been reacted, stopped reaction, filter, filtrate is diluted by ethyl acetate (500mL), NaOH solution (300mL) washing, saturated aqueous common salt (3 * 500mL) washing with 1M, with after anhydrous sodium sulfate drying, boil off solvent, obtain product 24.5g, yield～100%.
1H?NMR(400MHz,CDCl
3)δ8.20(d,J＝6.4Hz,1H),7.46(d,J＝6.4Hz,2H),7.41-7.36(m,1H),7.31(d,J＝6.4Hz,2H),7.24-7.16(m,2H),6.90(s,br,1H,NH),2.04(s,3H)。ESI-MS,m/z,[M+H]
+：246.2。Filter cake is used with recirculation after a small amount of water washing.
4 '-chloro-2-kharophen biphenyl (9.2g, 3.7mmol), the mixture return stirring 24h that concentrated hydrochloric acid (20mL) and tetrahydrofuran (THF) (20mL) form, after TLC monitoring has been reacted, evaporates tetrahydrofuran (THF) and the water of half.After cooling, add isopropyl ether (10mL), after stirring evenly, 4-6 ℃ of placement, spend the night.Filter, filter cake with cold isopropyl ether washing once, the product 4 ' of vacuum drying-chloro-2-phenylaniline hydrochloride (6.5g, 73.2%), filtrate concentrates after half, then places and spend the night under 4-6 ℃ of condition, has again crystallization, filter to obtain product 1.45g (16.3%), adding up to yield is 89.5%.Nuclear-magnetism detected result:
1h NMR (400MHz, DMSO-d
6) δ 7.60-7.50 (dd, J=10.4Hz, J=12.4,8.8Hz), 7.51-7.42 (m, 2H), 7.39-7.31 (m, 2H).After testing, products obtained therefrom is 4 '-chloro-2-kharophen biphenyl hydrochloride salt.
4 '-chloro-2-phenylaniline hydrochloride (24g, the mixture that 0.1mol), dry methylene dichloride (200mL) and diisopropyl ethyl amine (30mL) form is under 0-5 ℃ of stirring, drip the solution that step 2-chloronicotinoyl chloride (18.5g, 0.105mol) and methylene dichloride (50mL) form.After being raised to room temperature, stir again 3h.When TLC monitors after the some disappearance of all 2-(4-chloro-phenyl-) anilinechloride, stopped reaction.In reaction system, add again methylene dichloride (200mL), with saturated sodium bicarbonate solution washing 2 times, then wash with water 1 time.Organic phase, with after anhydrous sodium sulfate drying, evaporates methylene dichloride and obtains thick product (yield 100%).Head product obtains product 25.8g by recrystallizing methanol, yield 75.2%.Filtrate is reclaimed after evaporate to dryness, then recrystallization obtains product 5.8g (16.9%), total yield 92.1%.Fusing point 141-143 ℃.Purity (HPLC) 98.4%, nuclear-magnetism detected result:
1h NMR (400MHz, CDCl3), δ: 8.45 (dd, J=4.8,2.0Hz, 1H), 8.41 (d, J=8.4Hz), 8.20-8.10 (m, 2H, containing 1 NH), 7.50-7.42 (m, 3H), 7.36-7.31 (m, 3H), 7.28-7.26 (m, 2H).ESI-MS,m/z,[M+H]
+:343.1。After testing, products obtained therefrom is boscalid amine.
The preparation of embodiment 6 boscalid amines
Adjacent kharophen bromobenzene (21.4g, 0.1mol), to chlorobenzene boric acid (18.7g, 0.12mol), 10% Pd (OH)
2/ C (0.14g, the Pd of 0.8mmol (OH)
2), Tetrabutyl amonium bromide (6g) (or quaternary ammonium salt of other identical equivalents), 7 water potassiumphosphates (64g) (or mineral alkali of other identical equivalents) (100mL) stir with DMF (or other solvents) at the temperature of setting, after TLC monitoring has been reacted, stopped reaction, filter, filtrate is diluted by ethyl acetate (500mL), NaOH solution (300mL) washing, saturated aqueous common salt (3 * 500mL) washing with 1M, with after anhydrous sodium sulfate drying, boil off solvent, obtain product 24.4g, yield 99.4%.
1H?NMR(400MHz,CDCl
3)δ8.20(d,J＝6.4Hz,1H),7.46(d,J＝6.4Hz,2H),7.41-7.36(m,1H),7.31(d,J＝6.4Hz,2H),7.24-7.16(m,2H),6.90(s,br,1H,NH),2.04(s,3H)。ESI-MS,m/z,[M+H]
+：246.2。Filter cake is used with recirculation after a small amount of water washing.
4 '-chloro-2-kharophen biphenyl (9.2g, 3.7mmol), the mixture return stirring 24h that concentrated hydrochloric acid (20mL) and tetrahydrofuran (THF) (20mL) form, after TLC monitoring has been reacted, evaporates tetrahydrofuran (THF) and the water of half.After cooling, add isopropyl ether (10mL), after stirring evenly, 4-6 ℃ of placement, spend the night.Filter, filter cake with cold isopropyl ether washing once, the product 4 ' of vacuum drying-chloro-2-phenylaniline hydrochloride (6.42g, 72.3%), filtrate concentrates after half, then places and spend the night under 4-6 ℃ of condition, has again crystallization, filter to obtain product 1.5g (16.9%), adding up to yield is 89.2%.Nuclear-magnetism detected result:
1h NMR (400MHz, DMSO-d
6) δ 7.60-7.50 (dd, J=10.4Hz, J=12.4,8.8Hz), 7.51-7.42 (m, 2H), 7.39-7.31 (m, 2H).After testing, products obtained therefrom is 4 '-chloro-2-kharophen biphenyl hydrochloride salt.
4 '-chloro-2-phenylaniline hydrochloride (24g, the mixture that 0.1mol), dry methylene dichloride (200mL) and diisopropyl ethyl amine (30mL) form is under 0-5 ℃ of stirring, drip the solution that step 2-chloronicotinoyl chloride (18.5g, 0.105mol) and methylene dichloride (50mL) form.After being raised to room temperature, stir again 3h.When TLC monitors after the some disappearance of all 2-(4-chloro-phenyl-) anilinechloride, stopped reaction.In reaction system, add again methylene dichloride (200mL), with saturated sodium bicarbonate solution washing 2 times, then wash with water 1 time.Organic phase, with after anhydrous sodium sulfate drying, evaporates methylene dichloride and obtains thick product (yield 100%).Head product obtains product 25.3g by recrystallizing methanol, yield 73.8%.Filtrate is reclaimed after evaporate to dryness, then recrystallization obtains product 6.1g (17.7%), total yield 91.5%.Fusing point 141-143 ℃.Purity (HPLC) 98.7%, nuclear-magnetism detected result:
1h NMR (400MHz, CDCl3), δ: δ: δ: 8.45 (dd, J=4.8,2.0Hz, 1H), 8.41 (d, J=8.4Hz), 8.20-8.10 (m, 2H, containing 1 NH), 7.50-7.42 (m, 3H), 7.36-7.31 (m, 3H), 7.28-7.26 (m, 2H).ESI-MS,m/z,[M+H]
+:343.1。After testing, products obtained therefrom is boscalid amine.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (9)
1. the preparation method of a boscalid amine, it is characterized in that, in polar aprotic solvent or high boiling solvent, under alkali and quaternary ammonium salt existence, palladium catalyst reacts with the Suzuki of adjacent kharophen bromobenzene chlorobenzene boric acid and obtains intermediate product 4 '-chloro-2-kharophen biphenyl; Described intermediate product under concentrated hydrochloric acid exists after deprotection with the condensation of 2-chloronicotinoyl chloride, obtain.
2. preparation method according to claim 1, is characterized in that, described palladium catalyst Pd (OH)
2/ C.
3. preparation method according to claim 1, is characterized in that, described condensation is specially under diisopropyl ethyl amine (DIEA) exists, in dry methylene dichloride, and 4 '-chloro-2-phenylaniline hydrochloride and the condensation of 2-chloronicotinoyl chloride.
4. preparation method according to claim 1, is characterized in that, the mol ratio of described palladium catalyst and adjacent kharophen bromobenzene is 0.5 ~ 1:100.
5. preparation method according to claim 1, is characterized in that, described alkali is selected from salt of wormwood or seven water potassiumphosphates.
6. preparation method according to claim 1, is characterized in that, described quaternary ammonium salt is selected from Tetrabutyl amonium bromide or cetyl trimethylammonium bromide.
7. preparation method according to claim 1, is characterized in that, described polar aprotic solvent is selected from DMF.
8. preparation method according to claim 1, is characterized in that, described deprotection, for removing ethanoyl, is specially under 36% hydrochloric acid existence, removes ethanoyl in tetrahydrofuran solution.
9. the boscalid amine making according to the preparation method described in claim 1 to 8 any one.
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Cited By (3)
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| CN104478797A (en) * | 2014-12-09 | 2015-04-01 | 苏州至善化学有限公司 | Preparation method of nicotinamide fungicide namely boscalid |
| CN108997309A (en) * | 2018-07-17 | 2018-12-14 | 中国科学技术大学苏州研究院 | A kind of preparation method of pyrazoles -4- aryl derivatives |
| CN114292681A (en) * | 2021-12-28 | 2022-04-08 | 安阳市锐普农化有限责任公司 | Novel smoke agent ignition method |
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| US20110054183A1 (en) * | 2008-05-08 | 2011-03-03 | Basf Se | Method For Manufacturing Aryl Carboxamides |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104478797A (en) * | 2014-12-09 | 2015-04-01 | 苏州至善化学有限公司 | Preparation method of nicotinamide fungicide namely boscalid |
| CN108997309A (en) * | 2018-07-17 | 2018-12-14 | 中国科学技术大学苏州研究院 | A kind of preparation method of pyrazoles -4- aryl derivatives |
| CN114292681A (en) * | 2021-12-28 | 2022-04-08 | 安阳市锐普农化有限责任公司 | Novel smoke agent ignition method |
| CN114292681B (en) * | 2021-12-28 | 2024-03-19 | 安阳市锐普农化有限责任公司 | Novel smoke ignition method |
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| CN104016915B (en) | 2016-03-30 |
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