CN101139308B - Method for preparing bactericidal agent intermediate (E)-2-(2'-chloromethyl)phenyl-2-methoxy imino methyl acetate - Google Patents
Method for preparing bactericidal agent intermediate (E)-2-(2'-chloromethyl)phenyl-2-methoxy imino methyl acetate Download PDFInfo
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Abstract
The preparation method of the fungicide intermediate (E)-2-(2'-chloromethyl)-2-methicillin imino acetic methyl ester is: 1) the phenyl phthalate and the thionyl dihalide react with the influence of acatalyst; the catalyst is the Louis acid and phosphonic derivative; 2) the product of the first step and the alkali metal cyanide react with the influence of the organic solvent and phase transfer catalyst; the organic solvent is selected from the non-polar aromatic solvent or the halogen hydrocarbon; the phase transfer catalyst is selected from the halide of the four-level nitride or the ammoniumsalt; the alkali metal cyanide is selected from the sodium cyanide and potassium cyanide; 3) the products of the second step and the methanol react under the condition with the organic solvent and the chlorinated hydrogen; 4) the products of the third step and the methicillin amine hydrochloride under the condition with the organic solvent; thus, the target product can be got. The energy consumption and production risk of the present invention are obviously lowered; the relative collection rate is high; the safety in the production process is improved; and the present invention has no drawbacks such as the obstruction.
Description
Technical field
The present invention relates to a kind of formula (I) intermediates preparation, be specifically related to the preparation method of a kind of (E)-2-that in preparation agricultural fungicidal methoxy acrylic (as kresoxim-methyl), is used as the compound of intermediate (2 '-chloromethyl) phenyl-2-methoxy imino methyl acetate.
Background technology
The compound that the application relates to is intermediate (the E)-2-of mycocidal methoxy acrylic derivative in preparation process (2 '-chloromethyl) phenyl-2-methoxy imino methyl acetate, i.e. a compound shown in the formula (I).Relate to the preparation method of this compound in the prior art, following relevant programme arranged.
Patent DE 2835440 is disclosed to be the synthetic method of the product o-chloromethyl benzoic acid chlorides of step 1) of the present invention, be with corresponding methyl substituted Benzoyl chloride and chlorine halogenating reaction, obtain product through rectifying again, the shortcoming of this method is that reaction can only generate the product about 20%, the dihalo deposits yields is just arranged, and rectifying need consume lot of energy, and yield is lower relatively.
Patent WO9712854 discloses a kind of in the presence of triphenylphosphine oxide, and at 170 ℃, phthalide and phosgene reaction prepare the method for o-chloromethyl benzoic acid chlorides, and phosgene toxicity is big, and difficult treatment has increased the risk on the safety.
In patent US6222060, the reaction of phthalide and thionyl chloride, quaternary ammonium salt and lewis acidic in the presence of carry out.Quaternary ammonium salt has sublimation, can cause device to block, and quaternary ammonium salt can also disturb the distillation purifying of o-chloromethyl benzoic acid chlorides.
Patent CN1037175 report be step 2 of the present invention) the synthetic method of product o-chloromethyl formyl cyanogen, the shortcoming of this method is to need to add 1% hydrochloric acid reaction mixture pH value is transferred to 10.5, the prussic acid generation just can be arranged, prussic acid acute toxicity LC in the system
50: 357mg/m
3, suck high density prussic acid gas in people's short period of time, immediately breath stopped and death has increased the risk on the safety for production significantly.
Patent DE2708189 provides a kind of synthetic method of methyl benzoylformate, but not too suitable in this method step 3) of the present invention.
Summary of the invention
The objective of the invention is deficiency, provide a kind of and be suitable for sterilant intermediate (the E)-2-of large-scale commercial production (2 '-chloromethyl) phenyl-preparation method 2-methoxy imino methyl acetate, complete at various preparation methods in the above-mentioned prior art.The consumption of energy will obviously reduce during this method is produced; Yield is higher relatively, does not have disadvantages such as toxicant and device obstruction in the production process.
The scheme of finishing the foregoing invention task is:
The preparation method of sterilant intermediate (E)-2-(2 '-chloromethyl) phenyl-2-methoxy imino methyl acetate, described intermediate (E)-2-(2 '-chloromethyl) phenyl-2-methoxy imino methyl acetate is the compound shown in the formula (I):
Wherein X is a haloid element, and preferred X is bromine or chlorine (particularly chlorine), and this method may further comprise the steps:
1). in the presence of catalyzer, make the phthalanone (phthalide) and the reaction of thionyl dihalo-of formula (II), thionyl dihalo-consumption is based on the amount meter of phthalide, is 1.0～5.0mol, preferred 1.0～1.5mol; In the catalyzer, the Lewis acid consumption is based on the amount meter of phthalanone, is 0.001～0.2mol; Preferred 0.03～0.05mol; The phosphine-derivatives consumption is based on the amount meter of phthalanone, is 0.001～0.2mol;
Described catalyzer is the Lewis acid of boron-containing compound and the phosphine-derivatives shown in the formula (III), and wherein used Lewis acid is selected from boric acid or trimethyl borate; Phosphine-derivatives is selected from triphenylphosphine oxide or triphenylphosphine:
2). the product that makes step 1) reacts with alkali metal cyanide in the presence of suitable organic solvent and phase-transfer catalyst; The consumption of phase-transfer catalyst is based on the amount of the product of step 1) and calculates 0.005～0.1mol, particularly 0.01～0.05mol; The consumption of alkali metal cyanide is based on the amount of the product of step 1) and calculates 1.0～2.0mol, particularly 1.1～1.3mol;
Described organic solvent is selected from the aromatic hydrocarbons (as benzene, toluene, Mixed XYLENE) in the non-polar solvent; Halogenated hydrocarbon (as methylene dichloride, ethylene dichloride); Described phase-transfer catalyst is selected from the halogenide class (as tetraethylammonium chloride, tetraethyl-ammonium bromide, bromination tetrapropylammonium, TBAC tetrabutylammonium chloride or bromination tetrabutylammonium) of level Four nitride; Ammonium salt class (as: benzyl triethylammonium chloride, bromination benzyl three second ammoniums, zephiran chloride three fourth ammoniums or bromination benzyl three fourth ammoniums), preferred especially bromination tetrabutylammonium; The preferred sodium cyanide of described alkali metal cyanide, potassium cyanide, preferred especially sodium cyanide.
3). make step 2) product under suitable organic solvent and hydrogenchloride condition, react with methyl alcohol; The consumption of hydrogenchloride is based on step 2) the amount of product calculate 5～50mol, particularly 10～15mol; The consumption of methyl alcohol is based on step 2) the amount of product calculate 2～30mol, particularly 5～10mol;
4). the product of step 3) is reacted with methoxamine hydrochloride in the presence of suitable organic solvent; The consumption of methoxamine hydrochloride is based on the amount of the product of step 3) and calculates 1～5mol, particularly 1.0～1.5mol; Promptly obtain the object product.
Described halogen is bromine or chlorine; Preferred chlorine;
The described thionyl dihalo-of step 1) is a thionyl chloride;
Described " based on the amount meter of phthalide " is meant: the amount of establishing phthalide is 1mol;
Step 2) described alkali metal cyanide is a sodium cyanide, is to participate in reaction with aqueous solution form, and concentration is 5%～50%, particularly preferred 15%～30%;
Described aromatic hydrocarbons organic solvent is a toluene, and the consumption of toluene is based on the amount of the product of step 1) and calculates 3.0～10 times of amounts, particularly 4～6 times of amounts;
The described organic solvent of step 3) is a methyl tertiary butyl ether, and the consumption of methyl tertiary butyl ether is based on step 2) the amount of product calculate 2～10 times of amounts, particularly 4～6 times of amounts;
The described solvent of step 4) is a methyl alcohol, and the consumption of methyl alcohol is 2～20 times of product of step 3); 2～5 times of amounts particularly;
More the scheme of You Huaing is, the concrete operations step is as follows:
1). the preparation of o-chloromethyl benzoic acid chlorides
The phthalanone of regulation ratio (phthalide), trimethyl borate, triphenylphosphine oxide are added in the reaction flask, are heated to 130 ℃ under stirring, with 3～5 hours, in reaction flask, drip thionyl chloride, after this, mixture reacted 5 hours at 130 ℃ again, the underpressure distillation of reaction ejecta;
2). the preparation of o-chloromethyl formyl cyanogen
The sodium cyanide of regulation ratio, water are added in the reaction flask, make sodium cyanide be dissolved into the aqueous solution under stirring, add Tetrabutylammonium bromide, toluene then, with about about 30 minutes time, the toluene solution of o-chloromethyl benzoic acid chlorides is added drop-wise in the reaction mixture, controlled temperature is below 35 ℃ during this time, reacted about 2 hours at 35～40 ℃ again after adding, phase-splitting, organic phase washes with water twice and with 1.0% following weight concentration salt acid elution once, use dried over mgso then, decompression steams solvent, and decompression steams product again;
3). the o-chloromethyl formyl cyanogen of regulation ratio, methyl tertiary butyl ether is added in the reaction flask, make the dissolving of o-chloromethyl formyl cyanogen under stirring, use the icy salt solution cooling then, temperature is reached about-8 ℃, import the hydrogen chloride gas of specified amount, during controlled temperature below 0 ℃, led in about 5 hours, stirred 16 hours at 20～25 ℃ then, add methyl alcohol again, back flow reaction 10 hours, cool to room temperature, add water, phase-splitting, water with the methyl tertiary butyl ether extraction once washes with water three times after the organic phase merging, uses dried over mgso then, normal pressure steams solvent, gets crude product.
Crude product is dropped in the reaction flask, add toluene, 38% hydrochloric acid is warming up to 20 ℃ of insulations 10 hours under stirring, move into the separating funnel layering, divide and abandon lower floor's sour water layer, organic layer is washed to neutrality, uses dried over mgso then, underpressure distillation piptonychia benzene, decompression steams product again, gets o-chloromethyl formyl methyl-formiate;
4). the product of the step 3) of regulation ratio, methoxamine hydrochloride and methyl alcohol are added in the reaction flask, are heated to backflow, about 10～12 hours under stirring, be cooled to then below 20 ℃, add toluene, make temperature below 20 ℃, import the hydrogen chloride gas of specified amount, stirred 24 hours at 20～25 ℃ then, add water, phase-splitting, water with the toluene extraction once, organic phase washes with water three times after merging, use dried over mgso then, decompression steams solvent, gets crude product; Add methyl alcohol, being warming up to refluxes makes its dissolving, is cooled to 10 ℃ of suction filtrations, the product that must wet, and 30～40 ℃ of oven dry, must (E)-2-(2 '-chloromethyl) phenyl-2-methoxy imino methyl acetate.
The risk of method energy expenditure provided by the invention and safety in production obviously reduces; Relatively yield is higher, the security of the production process disadvantages such as device obstruction that are improved not.
Description of drawings
Fig. 1 is the process flow sheet of the inventive method.
Embodiment
The following examples have illustrated the present invention.
271g (99%, 2.0mol) phthalanone (phthalide), (99%, 0.1mol) (99%, 0.1mol) triphenylphosphine oxide is added in the 500ml reaction flask 10.5g for trimethyl borate, 28.5g, be heated to 130 ℃ under stirring, with 3～5 hours, in reaction flask, drip 324.5g (99%, 2.7mol) thionyl chloride, dropwise, mixture reacted 5 hours at 130 ℃ again, and the underpressure distillation of reaction ejecta obtains product 366.4g; Purity 98% (GC), yield 95%.
120g (98%, 2.4mol) sodium cyanide, 470ml water is added in the 3000ml reaction flask, make sodium cyanide be dissolved into the aqueous solution under stirring, add 1544g toluene then, 16.2g (99%, 0.05mol) the bromination tetrabutylammonium, with about about 30 minutes time, with 386g (98%, 2.0mol) o-chloromethyl benzoic acid chlorides and 386g toluene mixing solutions be added drop-wise in the reaction mixture, controlled temperature reacted phase-splitting about 1 hour at 35～40 ℃ below 35 ℃ after adding again during this time, organic phase washes with water twice and with 1.0% following weight concentration salt acid elution once, use dried over mgso then, decompression steams solvent, and vacuum fractionation steams product 310g again, purity 96.3% (GC), yield 83.2%.
186.5g (96.3%, 1.0mol) o-chloromethyl formyl cyanogen, the 950g methyl tertiary butyl ether is added in the 2000ml reaction flask, make the dissolving of o-chloromethyl formyl cyanogen under stirring, use the icy salt solution cooling then, temperature is reached about-8 ℃, import the exsiccant hydrogen chloride gas (about 474.5g, 13mol), during controlled temperature below 0 ℃, led in about 5 hours, stirred 16 hours at 20～25 ℃ then, add again 194g (99%, 6.0mol) methyl alcohol, back flow reaction 10 hours, cool to room temperature adds water, move into the separating funnel phase-splitting, water with the methyl tertiary butyl ether extraction once, organic phase washes with water three times after merging, use dried over mgso then, normal pressure steams solvent, gets crude product 210g.
Crude product is dropped in the 1000ml reaction flask, add 400g toluene, 38% hydrochloric acid 300g, be warming up to 20 ℃ of insulations 10 hours under stirring, move into the separating funnel layering, divide and abandon lower floor's sour water layer, organic layer is washed to neutrality, use dried over mgso then, underpressure distillation piptonychia benzene, decompression steams product again, gets o-chloromethyl formyl methyl-formiate 160.5g, purity 95.4% (GC), yield 72%.
160.5g (95.4%, 0.72mol) o-chloromethyl formyl methyl-formiate, 70g (98%, 0.82mol) methoxamine hydrochloride and 321g methyl alcohol drops in the 1000ml reaction flask, be warming up to backflow under stirring, be incubated 10 hours, be cooled to below 20 ℃, add 480g toluene, import the exsiccant hydrogen chloride gas (about 286.5g, 7.85mol), during controlled temperature below 20 ℃, led in about 4 hours, stirred 6 hours at 20～25 ℃ then, add 300ml water and move into the separating funnel layering, lower aqueous layer extracts with 150ml toluene, merge organic layer and be washed to neutrality, use dried over mgso then, toluene is deviate from underpressure distillation, gets crude product 172g.
Crude product is dropped in the 500ml reaction flask, add 200ml methyl alcohol, it is molten entirely that stirring is warming up to backflow, crystallisation by cooling, 10 ℃ of suction filtrations, the product 156g that must wet, 30～40 ℃ of oven dry, (E)-2-(2 '-chloromethyl) phenyl-2-methoxy imino methyl acetate 142.5g, purity 98% (GC), yield 80.2%.
271g (99%, 2.0mol) phthalanone (phthalide), (99%, 0.06mol) (99%, 0.06mol) triphenylphosphine oxide is added in the 500ml reaction flask 3.8g for boric acid, 17g, be heated to 130 ℃ under stirring, with 3～5 hours, in reaction flask, drip 324.5g (99%, 2.7mol) thionyl chloride, dropwise, mixture reacted 5 hours at 130 ℃ again, and the underpressure distillation of reaction ejecta obtains product 366g; Purity 97% (GC), yield 94%.
162.5g (96%, 2.4mol) potassium cyanide, 460ml water is added in the 3000ml reaction flask, make potassium cyanide be dissolved into the aqueous solution under stirring, add 1544g toluene then, 23g (99%, 0.1mol) benzyl triethylammonium chloride, with about about 30 minutes time, with 386g (98%, 2.0mol) o-chloromethyl benzoic acid chlorides and 386g toluene mixing solutions be added drop-wise in the reaction mixture, controlled temperature reacted phase-splitting about 1 hour at 35～40 ℃ below 35 ℃ after adding again during this time, organic phase washes with water twice and with 1.0% following weight concentration salt acid elution once, use dried over mgso then, decompression steams solvent, and vacuum fractionation steams product 306g again, purity 95.5% (GC), yield 81.4%.
271g (99%, 2.0mol) phthalanone (phthalide), (99%, 0.1mol) (99%, 0.1mol) triphenylphosphine is added in the 500ml reaction flask 10.5g for trimethyl borate, 26.5g, be heated to 130 ℃ under stirring, with 3～5 hours, in reaction flask, drip 324.5g (99%, 2.7mol) thionyl chloride, dropwise, mixture reacted 5 hours at 130 ℃ again, and the underpressure distillation of reaction ejecta obtains product 370.5g; Purity 97% (GC), yield 95%.
Halogen in the described formula (I) is a bromine;
271g (99%, 2.0mol) phthalanone (phthalide), (98%, 0.06mol) (99%, 0.06mol) triphenylphosphine oxide is added in the 500ml reaction flask 3.8g for boric acid, 17g, be heated to 130 ℃ under stirring, with 3～5 hours, and Dropwise 5 52g in reaction flask (98%, 2.6mol) thionyl bromide, dropwise, mixture reacted 5 hours at 130 ℃ again, and the underpressure distillation of reaction ejecta obtains product 535g; Purity 95.6% (GC), yield 92%.
149g (96%, 2.2mol) potassium cyanide, 423ml water is added in the 3000ml reaction flask, make potassium cyanide be dissolved into the aqueous solution under stirring, add 1163g benzene then, 4.3g (99%, 0.02mol) tetraethyl-ammonium bromide, with about about 30 minutes time, with 581.5g (95.6%, 2.0mol) O-bromo methyl benzoyl bromide and 581.5g benzene mixing solutions be added drop-wise in the reaction mixture, controlled temperature reacted phase-splitting about 1 hour at 35～40 ℃ below 35 ℃ after adding again during this time, organic phase washes with water twice and with 1.0% following weight concentration salt acid elution once, use dried over mgso then, decompression steams solvent, gets product 453.2g, purity 92.5% (GC), yield 93.6%.
242g (92.5%, 1.0mol) the O-bromo methyl benzoyl cyanide, the 1450g methyl tertiary butyl ether is added in the 3000ml reaction flask, make the dissolving of O-bromo methyl benzoyl cyanide under stirring, use the icy salt solution cooling then, temperature is reached about-8 ℃, import the exsiccant hydrogen chloride gas (about 547.5g, 15mol), during controlled temperature below 0 ℃, led in about 6 hours, stirred 16 hours at 20～25 ℃ then, add again 161.5g (99%, 5.0mol) methyl alcohol, back flow reaction 10 hours, cool to room temperature adds water, move into the separating funnel phase-splitting, water with the methyl tertiary butyl ether extraction once, organic phase washes with water three times after merging, use dried over mgso then, normal pressure steams solvent, gets crude product 269g.
Crude product is dropped in the 1000ml reaction flask, add 500g toluene, 38% hydrochloric acid 300g, be warming up to 20 ℃ of insulations 10 hours under stirring, move into the separating funnel layering, divide and abandon lower floor's sour water layer, organic layer is washed to neutrality, use dried over mgso then, underpressure distillation piptonychia benzene, decompression steams product again, gets O-bromo methyl methyl benzoylformate 256g, purity 79.8% (GC), yield 79.5%.
256g (79.8%, 0.795mol) the O-bromo methyl methyl benzoylformate, 100g (98%, 0.82mol) methoxamine hydrochloride and 520g methyl alcohol drops in the 2000ml reaction flask, be warming up to backflow under stirring, be incubated 10 hours, be cooled to below 20 ℃, add 480g toluene, import the exsiccant hydrogen chloride gas (about 286.5g, 7.85mol), during controlled temperature below 20 ℃, led in about 4 hours, stirred 6 hours at 20～25 ℃ then, add 300ml water and move into the separating funnel layering, lower aqueous layer extracts with 150g toluene, merge organic layer and be washed to neutrality, use dried over mgso then, toluene is deviate from underpressure distillation, gets crude product 291g.
Crude product is dropped in the 500ml reaction flask, add 250ml methyl alcohol, it is molten entirely that stirring is warming up to backflow, crystallisation by cooling, 10 ℃ of suction filtrations, product 217.8g must wet, 40～50 ℃ of oven dry, (E)-2-(2 '-brooethyl) phenyl-2-methoxy imino methyl acetate 204.6g, purity 98% (GC), yield 88.1%.
271g (99%, 2.0mol) phthalanone (phthalide), 10.5g (99%, 0.1mol) trimethyl borate, 28.5g (99%, 0.1mol) triphenylphosphine oxide is added in the 1000ml reaction flask, be heated to 130 ℃ under stirring,, in reaction flask, drip 360.6g (99% with 3～5 hours, 3.0mol) thionyl chloride, dropwise, mixture reacted 5 hours at 126 ℃ again, the excessive thionyl chloride of reaction ejecta elder generation's normal pressure, underpressure distillation again obtains product 375.3g; Purity 98.2% (GC), yield 97.5%.
176g (96%, 2.6mol) potassium cyanide, 500ml water is added in the 5000ml reaction flask, make potassium cyanide be dissolved into the aqueous solution under stirring, add 1930g dimethylbenzene then, 21.2g (99%, 0.1mol) tetraethyl-ammonium bromide, with about about 30 minutes time, with 386g (98%, 2.0mol) o-chloromethyl benzoic acid chlorides and 386g dimethylbenzene mixing solutions be added drop-wise in the reaction mixture, controlled temperature reacted phase-splitting about 1 hour at 35～40 ℃ below 35 ℃ after adding again during this time, organic phase washes with water twice and with 1.0% following weight concentration salt acid elution once, use dried over mgso then, decompression steams solvent, and vacuum fractionation steams product 313.2g again, purity 96.8% (GC), yield 84.4%.
186.5g (96.3%, 1.0mol) o-chloromethyl formyl cyanogen, the 950g methyl tertiary butyl ether is added in the 2000ml reaction flask, make the dissolving of o-chloromethyl formyl cyanogen under stirring, use the icy salt solution cooling then, temperature is reached about-8 ℃, import the exsiccant hydrogen chloride gas (about 547.5g, 15mol), during controlled temperature below 0 ℃, led in about 6 hours, stirred 16 hours at 20～25 ℃ then, add again 323g (99%, 10.0mol) methyl alcohol, back flow reaction 10 hours, cool to room temperature adds water, move into the separating funnel phase-splitting, water with the methyl tertiary butyl ether extraction once, organic phase washes with water three times after merging, use dried over mgso then, normal pressure steams solvent, gets crude product 215g.
Crude product is dropped in the 1000ml reaction flask, add 400g dimethylbenzene, 38% hydrochloric acid 300g, be warming up to 20 ℃ of insulations 10 hours under stirring, move into the separating funnel layering, divide and abandon lower floor's sour water layer, organic layer is washed to neutrality, use dried over mgso then, underpressure distillation piptonychia benzene, decompression steams product again, gets o-chloromethyl formyl methyl-formiate 167.1g, purity 95.8% (GC), yield 75.2%.
167.1g (95.8%, 0.752mol) o-chloromethyl formyl methyl-formiate, 95.5g (98%, 1.13mol) methoxamine hydrochloride and 325g methyl alcohol drops in the 1000ml reaction flask, be warming up to backflow under stirring, be incubated 10 hours, be cooled to below 20 ℃, add 480g toluene, import the exsiccant hydrogen chloride gas (about 292g, 8.0mol), during controlled temperature below 20 ℃, led in about 4 hours, stirred 6 hours at 20～25 ℃ then, add 300ml water and move into the separating funnel layering, lower aqueous layer extracts with 150ml toluene, merge organic layer and be washed to neutrality, use dried over mgso then, toluene is deviate from underpressure distillation, gets crude product 181g.
Crude product is dropped in the 500ml reaction flask, add 200ml methyl alcohol, it is molten entirely that stirring is warming up to backflow, crystallisation by cooling, 10 ℃ of suction filtrations, product 165g must wet, 30～40 ℃ of oven dry, (E)-2-(2 '-chloromethyl) phenyl-2-methoxy imino methyl acetate 151.5g, purity 97.8% (GC), yield 81.5%.
Embodiment 6, and is substantially the same manner as Example 1, but following change is arranged:
135.5g (96%, 2.0mol) potassium cyanide, sodium bicarbonate 17g (0.2mol, 99.5%), 450ml water is added in the 5000ml reaction flask, make potassium cyanide be dissolved into the aqueous solution under stirring, add 4000ml dimethylbenzene then, 5.2g (99%, 0.02mol) the bromination tetrapropylammonium, with about about 30 minutes time, with 386g (98%, 2.0mol) o-chloromethyl benzoic acid chlorides and 400ml dimethylbenzene mixing solutions are added drop-wise in the reaction mixture, during controlled temperature below 35 ℃, reacted about 1 hour at 35～40 ℃ again after adding, phase-splitting, organic phase wash with water twice and with 1.0% following weight concentration salt acid elution once, use dried over mgso then, decompression steams solvent, vacuum fractionation steams product 297.4g again, purity 98% (GC), yield 81.1%.
183.3g (98%, 1.0mol) o-chloromethyl formyl cyanogen, the 950g methyl tertiary butyl ether is added in the 2000ml reaction flask, make the dissolving of o-chloromethyl formyl cyanogen under stirring, use the icy salt solution cooling then, temperature is reached about-8 ℃, import the exsiccant hydrogen chloride gas (about 365g, 10mol), during controlled temperature below 0 ℃, led in about 4 hours, stirred 16 hours at 20～25 ℃ then, add again 162g (99%, 5.0mol) methyl alcohol, back flow reaction 10 hours, cool to room temperature adds water, move into the separating funnel phase-splitting, water with the methyl tertiary butyl ether extraction once, organic phase washes with water three times after merging, use dried over mgso then, normal pressure steams solvent, gets crude product 201.6g.
Crude product is dropped in the 1000ml reaction flask, add 400g toluene, 38% hydrochloric acid 300g, be warming up to 20 ℃ of insulations 10 hours under stirring, move into the separating funnel layering, divide and abandon lower floor's sour water layer, organic layer is washed to neutrality, use dried over mgso then, underpressure distillation piptonychia benzene, decompression steams product again, gets o-chloromethyl formyl methyl-formiate 143.6g, purity 96.8% (GC), yield 65.3%.
143.6g (96.8%, 0.65mol) o-chloromethyl formyl methyl-formiate, 56g (98%, 0.66mol) methoxamine hydrochloride and 300g methyl alcohol drops in the 1000ml reaction flask, be warming up to backflow under stirring, be incubated 10 hours, be cooled to below 20 ℃, add 480g toluene, import the exsiccant hydrogen chloride gas (about 215g, 5.9mol), during controlled temperature below 20 ℃, led in about 4 hours, stirred 6 hours at 20～25 ℃ then, add 300ml water and move into the separating funnel layering, lower aqueous layer extracts with 150ml toluene, merge organic layer and be washed to neutrality, use dried over mgso then, toluene is deviate from underpressure distillation, gets crude product 152g.
Crude product is dropped in the 500ml reaction flask, add 150ml methyl alcohol, it is molten entirely that stirring is warming up to backflow, crystallisation by cooling, 10 ℃ of suction filtrations, the product 127g that must wet, 30～40 ℃ of oven dry, (E)-2-(2 '-chloromethyl) phenyl-2-methoxy imino methyl acetate 109.6g, purity 98% (GC), yield 68.4%.
Embodiment 7, and is substantially the same manner as Example 1, but following change is arranged:
120g (98%, 2.4mol) sodium cyanide, 470ml water is added in the 3000ml reaction flask, make sodium cyanide be dissolved into the aqueous solution under stirring, add 1544g toluene then, 14.2g (98%, 0.05mol) TBAC tetrabutylammonium chloride, with about about 30 minutes time, with 386g (98%, 2.0mol) o-chloromethyl benzoic acid chlorides and 386g toluene mixing solutions be added drop-wise in the reaction mixture, controlled temperature reacted phase-splitting about 1 hour at 35～40 ℃ below 35 ℃ after adding again during this time, organic phase washes with water twice and with 1.0% following weight concentration salt acid elution once, use dried over mgso then, decompression steams solvent, and vacuum fractionation steams product 311g again, purity 96.2% (GC), yield 83.2%.
Embodiment 8, and is substantially the same manner as Example 1, but following change is arranged:
120g (98%, 2.4mol) sodium cyanide, 470ml water is added in the 3000ml reaction flask, make sodium cyanide be dissolved into the aqueous solution under stirring, add the 1544g methylene dichloride then, 13.9g (98%, 0.05mol) bromination benzyl three second ammoniums, with about about 30 minutes time, with 386g (98%, 2.0mol) o-chloromethyl benzoic acid chlorides and 386g methylene dichloride mixing solutions be added drop-wise in the reaction mixture, controlled temperature is below 35 ℃ during this time, after adding again about 1 hour of 40 ℃ of back flow reaction, phase-splitting, organic phase washes with water twice and with 1.0% following weight concentration salt acid elution once, use dried over mgso then, normal pressure steams solvent, and vacuum fractionation steams product 315g again, purity 95.5% (GC), yield 83.7%.
Embodiment 9, and is substantially the same manner as Example 1, but following change is arranged:
120g (98%, 2.4mol) sodium cyanide, 470ml water is added in the 3000ml reaction flask, make sodium cyanide be dissolved into the aqueous solution under stirring, add the 1544g ethylene dichloride then, 21g (98%, 0.05mol) bromination benzyl three fourth ammoniums, with about about 30 minutes time, with 386g (98%, 2.0mol) o-chloromethyl benzoic acid chlorides and 386g ethylene dichloride mixing solutions be added drop-wise in the reaction mixture, controlled temperature reacted phase-splitting about 1 hour at 35～40 ℃ below 35 ℃ after adding again during this time, organic phase washes with water twice and with 1.0% following weight concentration salt acid elution once, use dried over mgso then, normal pressure steams solvent, and vacuum fractionation steams product 322g again, purity 96.5% (GC), yield 86.5%.
Embodiment 10, and is substantially the same manner as Example 1, but following change is arranged:
120g (98%, 2.4mol) sodium cyanide, 470ml water is added in the 3000ml reaction flask, make sodium cyanide be dissolved into the aqueous solution under stirring, add 1544g toluene then, 18.8g (98%, 0.05mol) zephiran chloride three fourth ammoniums, with about about 30 minutes time, with 386g (98%, 2.0mol) o-chloromethyl benzoic acid chlorides and 386g toluene mixing solutions be added drop-wise in the reaction mixture, controlled temperature reacted phase-splitting about 1 hour at 35～40 ℃ below 35 ℃ after adding again during this time, organic phase washes with water twice and with 1.0% following weight concentration salt acid elution once, use dried over mgso then, decompression steams solvent, and vacuum fractionation steams product 313g again, purity 96.6% (GC), yield 84.1%.
Embodiment 11, and is substantially the same manner as Example 1, but following change is arranged:
The thionyl chloride consumption is 1.0mol based on the amount meter of phthalide;
Catalyzer is boric acid and triphenylphosphine oxide, and consumption is 0.03mol based on the amount meter of phthalide;
The consumption of the phase-transfer catalyst step 2) is calculated as 0.01 times of amount based on the amount of the product of step 1);
Described alkali metal cyanide is a potassium cyanide; Its consumption is calculated as 1.1 times of amounts based on the amount of the product of step 1);
Described organic solvent is a benzene;
The consumption of described organic solvent is based on the amount of the product of step 1) and calculates 3.0 times of amounts;
Described phase-transfer catalyst is a tetraethylammonium chloride;
The consumption of the hydrogenchloride described in the step 3) is based on step 2) the amount of product be calculated as 10 times of amounts; The consumption of methyl alcohol is based on step 2) the amount of product be calculated as 5 times of amounts;
The consumption of the methoxamine hydrochloride described in the step 4) is calculated as 1.0 times of amounts based on the amount of the product of step 3).
Embodiment 12, and is substantially the same manner as Example 1, but following change is arranged:
The thionyl chloride consumption is 50mol based on the amount meter of phthalide;
Catalyst levels is 0.05mol based on the amount meter of phthalide;
The consumption of the phase-transfer catalyst step 2) is calculated as 0.1 times of amount based on the amount of the product of step 1);
Described alkali metal cyanide is a potassium cyanide; Its consumption is calculated as 1.3 times of amounts based on the amount of the product of step 1);
Described organic solvent is an o-Xylol;
The consumption of described organic solvent is based on the amount of the product of step 1) and calculates 20 times of amounts;
Described phase-transfer catalyst is a tetraethyl-ammonium bromide;
The consumption of the hydrogenchloride described in the step 3) is based on step 2) the amount of product be calculated as 15 times of amounts; The consumption of methyl alcohol is based on step 2) the amount of product be calculated as 10 times of amounts;
The consumption of the methoxamine hydrochloride described in the step 4) is calculated as 1.5 times of amounts based on the amount of the product of step 3).
Embodiment 13, and is substantially the same manner as Example 1, but following change is arranged:
The thionyl chloride consumption is 1.25mol based on the amount meter of phthalide;
Catalyst levels is 0.001mol based on the amount meter of phthalide;
The consumption of the phase-transfer catalyst step 2) is calculated as 0.005 times of amount based on the amount of the product of step 1);
Described alkali metal cyanide is a potassium cyanide; Its consumption is calculated as 1.0 times of amounts based on the amount of the product of step 1);
Described organic solvent is a p-Xylol;
The consumption of described organic solvent is based on the amount of the product of step 1) and calculates 20 times of amounts;
Described phase-transfer catalyst is the bromination tetrapropylammonium;
The consumption of the hydrogenchloride described in the step 3) is based on step 2) the amount of product be calculated as 5 times of amounts; The consumption of methyl alcohol is based on step 2) the amount of product be calculated as 2 times of amounts;
The consumption of the methoxamine hydrochloride described in the step 4) is calculated as 1 times of amount based on the amount of the product of step 3).
Embodiment 14, and is substantially the same manner as Example 1, but following change is arranged:
The thionyl chloride consumption is 1.25mol based on the amount meter of phthalide;
Catalyst levels is 0.2mol based on the amount meter of phthalide;
The consumption of the phase-transfer catalyst step 2) is calculated as 1.0 times of amounts based on the amount of the product of step 1);
Described alkali metal cyanide is a potassium cyanide; Its consumption is calculated as 2.0 times of amounts based on the amount of the product of step 1);
Described organic solvent is a m-xylene;
The consumption of described organic solvent is based on the amount of the product of step 1) and calculates 20 times of amounts;
Described phase-transfer catalyst is a TBAC tetrabutylammonium chloride;
The consumption of the hydrogenchloride described in the step 3) is based on step 2) the amount of product be calculated as 50 times of amounts; The consumption of methyl alcohol is based on step 2) the amount of product be calculated as 30 times of amounts;
The consumption of the methoxamine hydrochloride described in the step 4) is calculated as 5 times of amounts based on the amount of the product of step 3).
Embodiment 15, and is substantially the same manner as Example 1, but following change is arranged:
Step 1), in the preparation of o-chloromethyl benzoic acid chlorides, trimethyl borate is 0.04mol; Triphenylphosphine oxide is 0.03mol;
Step 2) organic solvent described in is a methylene dichloride;
Described phase-transfer catalyst is bromination benzyl three second ammoniums.
Embodiment 16, and is substantially the same manner as Example 1, but described organic solvent is a trichloromethane; Described phase-transfer catalyst is zephiran chloride three fourth ammoniums.
Embodiment 17, and is substantially the same manner as Example 1, but described organic solvent is a methyl alcohol; Described phase-transfer catalyst is bromination benzyl three fourth ammoniums.
Embodiment 18, and is substantially the same manner as Example 1, but described organic solvent is an ethanol; Described phase-transfer catalyst is the bromination tetrabutylammonium.
Claims (5)
1. sterilant intermediates preparation, described intermediate is the compound shown in the formula (I):
Wherein X is a haloid element, and this method may further comprise the steps:
1). in the presence of catalyzer, make the phthalanone (phthalide) and the reaction of thionyl dihalo-of formula (II), thionyl dihalo-consumption is based on the amount meter of phthalanone, is 1.0～5.0mol;
Described catalyzer is Lewis acid in the boron-containing compound and the phosphine-derivatives shown in the formula (III); Wherein, the Lewis acid consumption is based on the amount meter of phthalanone, is 0.001～0.2mol; The phosphine-derivatives consumption is based on the amount meter of phthalanone, is 0.001～0.2mol;
Should " phosphine-derivatives shown in the formula (III) " be triphenylphosphine oxide or triphenylphosphine;
2). the product that makes step 1) reacts with alkali metal cyanide in the presence of suitable organic solvent and phase-transfer catalyst; The consumption of phase-transfer catalyst is based on the amount of the product of step 1) and calculates 0.005～0.1mol; The consumption of alkali metal cyanide is based on the amount of the product of step 1) and calculates 1.0～2.0mol;
Described organic solvent is selected from aromatic hydrocarbons or the halogenated hydrocarbon in the non-polar solvent;
Described phase-transfer catalyst is selected from: tetraethylammonium chloride, tetraethyl-ammonium bromide, bromination tetrapropylammonium, TBAC tetrabutylammonium chloride, bromination tetrabutylammonium, benzyl triethylammonium chloride, bromination benzyl three second ammoniums, zephiran chloride three fourth ammoniums, or bromination benzyl three fourth ammoniums;
Described alkali metal cyanide is selected from sodium cyanide, potassium cyanide;
3). make step 2) product under suitable organic solvent and hydrogenchloride condition, react with methyl alcohol; The consumption of hydrogenchloride is based on step 2) the amount of product calculate 5～50mol; The consumption of methyl alcohol is based on step 2) the amount of product calculate 2～30mol;
4). the product of step 3) is reacted with methoxamine hydrochloride in the presence of suitable organic solvent; The consumption of methoxamine hydrochloride is based on the amount of the product of step 3) and calculates 1～5mol; Promptly obtain the object product.
2. according to the described sterilant intermediates preparation of claim 1, it is characterized in that,
Halogen in the described formula (I) is bromine or chlorine;
Thionyl dihalo-consumption is 1.0～1.5mol based on the amount meter of phthalanone;
Lewis acid in the described catalyzer is selected from boric acid or trimethyl borate, and consumption is 0.03～0.05mol based on the amount meter of phthalanone; Described triphenylphosphine oxide or triphenylphosphine, consumption are 0.03～0.05mol based on the amount meter of phthalanone;
The consumption of the phase-transfer catalyst step 2) is calculated as 0.01～0.05mol based on the amount of the product of step 1);
The consumption of described alkali metal cyanide is calculated as 1.1～1.3mol based on the amount of the product of step 1);
Described aromatic hydrocarbons is selected from: benzene, toluene, Mixed XYLENE;
Described halogenated hydrocarbon methylene dichloride, ethylene dichloride;
The consumption of described organic solvent is based on the amount of the product of step 1) and calculates 3.0～20 times of amounts;
Described alkali metal cyanide is a sodium cyanide;
The consumption of the hydrogenchloride described in the step 3) is based on step 2) the amount of product be calculated as 10～15mol; The consumption of methyl alcohol is based on step 2) the amount of product be calculated as 5～10mol;
The consumption of the methoxamine hydrochloride described in the step 4) is calculated as 1.0～1.5mol based on the amount of the product of step 3).
3. according to the described sterilant intermediates preparation of claim 2, it is characterized in that,
Halogen in the described formula (I) is a chlorine;
The described thionyl dihalo-of step 1) is a thionyl chloride;
Step 2) described alkali metal cyanide is a sodium cyanide, is to participate in reaction with aqueous solution form, and concentration is 5%～50%;
Described aromatic hydrocarbons organic solvent is a toluene, and the consumption of toluene is based on the amount of the product of step 1) and calculates 3.0～10 times of amounts;
Described phase-transfer catalyst is the bromination tetrabutylammonium;
The described organic solvent of step 3) is a methyl tertiary butyl ether; The consumption of methyl tertiary butyl ether is based on step 2) the amount of product calculate 2～10 times of amounts;
The described solvent of step 4) is a methyl alcohol, and the consumption of methyl alcohol is 2～20 times of amounts of the product of step 3);
It is 1.0～1.5mol that the consumption of methoxamine hydrochloride calculates based on the amount of the product of step 3).
4. according to the described sterilant intermediates preparation of claim 3, it is characterized in that,
Step 2) concentration of described sodium cyanide solution is 15%～30%;
The consumption of described toluene is calculated as 4～6 times of amounts based on the amount of the product of step 1);
The consumption of the described methyl tertiary butyl ether of step 3) is based on step 2) the amount of product be calculated as 4～6 times of amounts;
The consumption of the described methyl alcohol of step 4) is 2～5 times of amounts of the product of step 3).
5. according to claim 1 or 2 or 3 or 4 described sterilant intermediates preparation, it is characterized in that the concrete operations step is:
1). the preparation of o-chloromethyl benzoic acid chlorides
The phthalanone of regulation ratio, trimethyl borate, triphenylphosphine oxide are added in the reaction flask, be heated to 130 ℃ under stirring, with 3～5 hours, in reaction flask, drip thionyl chloride, after this, mixture reacted 5 hours at 130 ℃ again, and the underpressure distillation of reaction ejecta obtains product;
2). the preparation of o-chloromethyl formyl cyanogen
The sodium cyanide of regulation ratio, water are added in the reaction flask, make sodium cyanide be dissolved into the aqueous solution under stirring, add bromination tetrabutylammonium, toluene then, with about about 30 minutes time, the toluene solution of o-chloromethyl benzoic acid chlorides is added drop-wise in the reaction mixture, controlled temperature is below 35 ℃ during this time, reacted about 2 hours at 35～40 ℃ again after adding, phase-splitting, organic phase washes with water twice and with 1.0% following weight concentration salt acid elution once, use dried over mgso then, decompression steams solvent, and decompression steams product again;
3). the o-chloromethyl formyl cyanogen of regulation ratio, methyl tertiary butyl ether is added in the reaction flask, being heated under stirring refluxes makes the dissolving of o-chloromethyl formyl cyanogen, use the icy salt solution cooling then, temperature is reached about-8 ℃, import the hydrogen chloride gas of specified amount, during controlled temperature below 0 ℃, led in about 5 hours, stirred 16 hours at 20～25 ℃ then, add methyl alcohol again, back flow reaction 10 hours, cool to room temperature, add water, phase-splitting, water with the methyl tertiary butyl ether extraction once washes with water three times after the organic phase merging, uses dried over mgso then, normal pressure steams solvent, gets crude product.
Crude product is dropped in the reaction flask, add toluene, 38% hydrochloric acid is warming up to 20 ℃ of insulations 10 hours under stirring, move into the separating funnel layering, divide and abandon lower floor's sour water layer, organic layer is washed to neutrality, uses dried over mgso then, underpressure distillation piptonychia benzene, decompression steams product again, gets o-chloromethyl formyl methyl-formiate;
4). the product of the step 3) of regulation ratio, methoxamine hydrochloride and methyl alcohol are added in the reaction flask, are heated to backflow, about 10～12 hours under stirring, be cooled to then below 20 ℃, add toluene, make temperature below 20 ℃, import the hydrogen chloride gas of specified amount, stirred 24 hours at 20～25 ℃ then, add water, phase-splitting, water with the toluene extraction once, organic phase washes with water three times after merging, use dried over mgso then, normal pressure steams solvent, gets crude product; Add methyl alcohol, being warming up to refluxes makes its dissolving, is cooled to 10 ℃ of suction filtrations, the product that must wet, and 30～40 ℃ of oven dry, must (E)-2-(2 '-chloromethyl) phenyl-2-methoxy imino methyl acetate.
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