CN103242297A - Preparation method of 5-difluoro methoxyl-2-[[(4-chlorine-3-methoxyl-2-pyridyl)-methyl]sulfo-1H-benzimidazole-hydrate - Google Patents

Abstract

The invention relates to a preparation method of 5-difluoro methoxyl-2-[[(4-chlorine-3-methoxyl-2-pyridyl)-methyl]sulfo-1H-benzimidazole-hydrate. The invention also provides a preparation method of another intermediate 5-difluoro methoxyl-2-[[(4-chlorine-3-methoxyl-2-pyridyl)-methyl]sulfo-1H-benzimidazole-hydrate.

Description

A kind of 5-difluoro-methoxy-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate

Technical field

The present invention relates to a kind of 5-difluoro-methoxy-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate.

Background technology

5-difluoro-methoxy-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-1H-benzoglyoxaline monohydrate is a kind of intermediate of synthetic pantoprazole.The at present synthetic employed intermediate of pantoprazole generally is 2-chloromethyl-3, the 4-dimethoxy pyridine hydrochloride the invention provides another intermediate 5-difluoro-methoxy-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate.

Preparation pantoprazole intermediate 2-chloromethyl-3, the patent that the 4-dimethoxy pyridine hydrochloride is relevant has: the patent No.: CN101875629A patent name: the industrial production process of pantoprazole intermediate pyridine hydrochloride; The patent No.: CN102304083A patent name: a kind of 2-chloromethyl-3, the preparation method of 4-dimethoxy pyridine hydrochloride and the application's method are inequality.

Summary of the invention

The purpose of this invention is to provide a kind of 5-difluoro-methoxy-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate.

A kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps: a, in reactor, add sodium hydroxide solution, after adding voitol and being stirred to dissolving, add methyl-sulfate again, temperature reaction, cooling adds methylene chloride and extracts, and methylene dichloride is reclaimed in the extracting solution distillation;

B, in reclaiming still behind the methylene dichloride, distillation adds water and ammoniacal liquor temperature reaction; Decompression is slowly dried feed liquid after removing the interior ammonia of still;

C, will dry material and put into reactor, in still, add methylene dichloride and phosphorus oxychloride, the intensification stirring and dissolving again; The reclaim under reduced pressure phosphorus oxychloride is put into the still that water is equipped with in lower floor with concentrated solution in the still, stirs hydrolysis; Cooling adds ammoniacal liquor in still; Standing separation is filtered;

D, filtrate is imported in the reactor, add phospho-wolframic acid again in still, heating up adds hydrogen peroxide, regulates PH=8; Add dichloromethane extraction, lower floor's extracting solution joins in the reactor;

Material all solidifies in e, the intensification distilled dichloromethane, still kettle; Add Glacial acetic acid and stir rising temperature for dissolving, add acetic anhydride, keep 85 ℃ of temperature in the kettle, 3.5 hours; Reclaim under reduced pressure Glacial acetic acid and acetic anhydride; Concentrated solution is cooled to 25 ℃, adds methyl alcohol and stir; Regulate PH=12,25 ℃ are incubated 4 hours down; Decompression is except the methyl alcohol in the feed liquid; Re-adjustment PH=7; Use dichloromethane extraction, it is standby to keep supernatant liquid;

F, reactor temperature are cooled to 10 ℃, add sulfur oxychloride in reactor; Reclaim under reduced pressure sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; Add dehydrated alcohol, add the ethyl acetate intensification again and stir, filter is got rid of in cooling, gets filter cake;

G, in reactor, add ethanol; Add 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline; Be warming up to 55 ℃, be incubated 30 minutes, drop into filter cake, be warming up to 60 ℃; Decompression recycling ethanol; Add water for cooling to 14 ℃, filter, dry, vacuum drying namely.

A kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps: a, in reactor, add water, add solid-state sodium hydroxide and be stirred to dissolving, after adding voitol again and being stirred to dissolving, add methyl-sulfate, be warming up to 58 ℃, be incubated 2.5 hours, be cooled to below 25 ℃, add methylene chloride and extract, methylene dichloride is reclaimed in 85 ℃ of distillations of extracting solution normal pressure;

B, in still behind the methylene dichloride is reclaimed in distillation, add water, add ammoniacal liquor, slowly be warming up to 85 ℃, be incubated 1.5 hours, be warming up to 88 ℃ again, be incubated 2 hours; Decompression slowly imports single-effect evaporator with feed liquid after removing the interior ammonia of still, and steaming water to moisture is 35% o'clock, feed liquid is led while hot entering the oven dry of bipyramid baker;

C, with in the bipyramid baker oven dry material put into reactor, in still, add methylene dichloride again, add phosphorus oxychloride, be warming up to 58 ℃ of stirring and dissolving, be warming up to 85 ℃ after, will expect that temperature remains on 85 ℃, be incubated 6 hours; Insulation finishes, and the reclaim under reduced pressure phosphorus oxychloride is cooled to 70 ℃; Concentrated solution in the still is put into the still that water is equipped with in lower floor, stir hydrolysis; Be cooled to below 25 ℃, in still, add ammoniacal liquor, regulate PH=8; Left standstill 2 hours, layer oily matter is isolated, and layer oily matter is put into strainer filter;

D, the strainer filtrate filtered is imported in the reactor, add phospho-wolframic acid again in still, be warming up to 82 ℃, be incubated after 30 minutes, add hydrogen peroxide, 85 ℃ are incubated 5.5 hours; Be cooled to below 25 ℃, regulate PH=8 with sodium hydroxide lye; Add dichloromethane extraction, lower floor's extracting solution joins in the reactor, stirs 30 minutes;

E, normal pressure are warming up to 85 ℃ of distilled dichloromethanes, 85 ℃ of following underpressure distillation methylene dichloride again, and material all solidifies in the still kettle; Add the Glacial acetic acid stirring and be warming up to 90 ℃, allow solid dissolve, add acetic anhydride, keep 85 ℃ of temperature in the kettle, 3.5 hours; Reclaim under reduced pressure Glacial acetic acid and acetic anhydride, to feed concentration greater than 80% o'clock; Concentrated solution is cooled to 25 ℃, adds methyl alcohol and stir; Regulate PH=12 with sodium hydroxide lye, 25 ℃ are incubated 4 hours down; Decompression kept 2 hours, utilized the methyl alcohol in the vacuum removal feed liquid; Regulate PH=7 with aqueous acetic acid again; Use dichloromethane extraction, it is standby to keep supernatant liquid, bleeds off lower floor's extracting solution;

F, reactor temperature are cooled to 10 ℃, add sulfur oxychloride in reactor; Be warming up to 23 ℃, be incubated 4 hours; Intensification degree to 50 ℃, reclaim under reduced pressure sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; Add dehydrated alcohol, add ethyl acetate again and be warming up to 55 ℃, stir maintenance down 1 hour, be cooled to 5 ℃, get rid of filter, get filter cake;

G, in reactor, add ethanol; Add 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline; Be warming up to 55 ℃, be incubated 30 minutes, disposable input filter cake is warming up to 60 ℃, treats stable back insulation 2 hours; Decompression recycling ethanol; Add water for cooling to 14 ℃, filter, dry, vacuum drying namely.

A kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps: a, in reactor, add water 1402kg, the solid-state sodium hydroxide 201kg that adds technical grade is stirred to dissolving, after the voitol 498kg of reprocessing industry level is stirred to dissolving, the methyl-sulfate 899kg that adds technical grade, dropwise, be warming up to 58 ℃, be incubated 2.5 hours, be cooled to below 25 ℃, the methylene dichloride 2002L of processing industry level extracts, and methylene dichloride is reclaimed in 85 ℃ of distillations of extracting solution normal pressure, does not stop distillation to there being the methylene dichloride overhead product;

B, in still behind the methylene dichloride is reclaimed in distillation, add water 397kg, add concentration and be 28% ammoniacal liquor 1304kg, slowly be warming up to 85 ℃, be incubated 1.5 hours, be warming up to 88 ℃ again, be incubated 2 hours; Be decompressed to vacuum tightness 0.09MPa, behind the ammonia in the removal still, feed liquid slowly imported single-effect evaporator, pressure in the vaporizer is reduced to vacuum tightness 0.09MPa, steaming water to moisture is 35% o'clock, feed liquid is led while hot entering the bipyramid baker, is decompressed to vacuum tightness 0.09MPa oven dry under 90 ℃;

C, with in the bipyramid baker oven dry material put into reactor, the methylene dichloride 1802kg that adds technical grade again in the still, the phosphorus oxychloride 2097L of processing industry level, dropwise, with steam reactor slowly is warming up to 58 ℃, start stirring, treat the material dissolution in the still, after being warming up to 85 ℃, will expect that temperature remains on 85 ℃, be incubated 6 hours; Insulation finishes, and is decompressed to vacuum tightness 0.09MPa, reclaims phosphorus oxychloride, be decompressed to terminal point after, logical slightly water coolant will be expected temperature drop to 70 ℃, close vacuum and open emptying; Concentrated solution in the still is put into the still that 3000kg water is equipped with in lower floor while hot, stir hydrolysis, blowing finishes and continues to stir 2 hours, and is abundant to the whole hydrolysis of material; Continue logical water coolant and will expect below the temperature drop to 25 ℃, slowly drip concentration in the still and be 28% ammoniacal liquor, adjusting PH=8; Stop stirring and left standstill 2 hours, layer oily matter is isolated, and layer oily matter is put into strainer filter;

D, the strainer filtrate filtered is imported in the reactor, the phospho-wolframic acid 184L of processing industry level in the still is warming up to 82 ℃ again, be incubated after 30 minutes, begins to drip concentration and be 30% hydrogen peroxide 8499L, dropwises, and 85 ℃ are incubated 5.5 hours; Logical icy salt solution is cooled to below 25 ℃, is that 30% sodium hydroxide lye is regulated PH=8 with concentration; Add the dichloromethane extraction of technical grade, lower floor's extracting solution joins in the reactor, stirs 30 minutes;

E, in the reacting kettle jacketing logical 90 ℃ of hot water, be warming up to 85 ℃ of distilled dichloromethanes under the first normal pressure, be decompressed to vacuum tightness 0.09MPa distilled dichloromethane under 85 ℃ again, the distillation end point phenomenon is that material all solidifies in the still; Add the Glacial acetic acid 352kg of technical grade, return-flow system is opened, and starts to stir, and after stirring is normal, keeps stirring; Be warming up to 90 ℃, allow solid dissolve, slowly add the acetic anhydride 1500L of technical grade, after dropwising, keep 85 ℃ of temperature in the kettle, 3.5 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim Glacial acetic acid and acetic anhydride, to feed concentration greater than 80% o'clock; Concentrated solution is cooled to 25 ℃, adds the methyl alcohol 400kg of technical grade, stir 30 minutes to even; Be that 30% sodium hydroxide lye is regulated PH=12 with concentration, 25 ℃ of insulations 4 hours down; Be decompressed to vacuum tightness 0.09MPa, kept 2 hours, utilize the methyl alcohol in the vacuum removal feed liquid; Be that aqueous acetic acid more than 90% is regulated PH=7 with concentration again; With the dichloromethane extraction of technical grade, it is standby to keep supernatant liquid, bleeds off lower floor's extracting solution;

F, reacting kettle jacketing feed icy salt solution, and making reactor temperature is 10 ℃, add the sulfur oxychloride 1198kg of technical grade in the reactor; After dropwising, be warming up to 23 ℃, be incubated 4 hours; The logical hot water of reacting kettle jacketing makes the temperature of reactor the inside reach 50 ℃, is decompressed to vacuum tightness 0.09MPa and reclaims sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; After adding dehydrated alcohol 480kg, add the ethyl acetate 1000kg of technical grade again, be warming up to 55 ℃, stir down and kept 1 hour, logical cooling water temperature to 5 ℃ gets rid of filter, gets filter cake;

G, add 95% ethanol 1802kg in the reactor, stirred 20 minutes; 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline the 500kg that adds technical grade; Be warming up to 55 ℃, be incubated 30 minutes, disposable input filter cake 500kg is warming up to 60 ℃, treats stable back insulation 2 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim ethanol; Add water 2500kg, logical water of condensation is cooled to 14 ℃, filters, and dries, and vacuum tightness 0.05MPa, 105 ℃ of following oven dry are namely.

A kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, after it is characterized in that containing following steps: a, in reactor, adding water and dissolution of sodium hydroxide, add the voitol dissolving again, add methyl-sulfate, heat up, be incubated, lower the temperature, the extraction that adds methylene chloride, extracting solution are steamed to not going out to heat up in a steamer;

B, in still, add water and ammoniacal liquor, heat up, insulation, heat up again, insulation again; Remove ammonia, feed liquid is imported vaporizer, steam water, enter the bipyramid oven dry;

C, in still, add methylene chloride and phosphorus oxychloride, heat up, stir, heat up, will expect that temperature is incubated; Reclaim phosphorus oxychloride; Fall the material temperature, close vacuum and open emptying; Concentrated solution is put into still, and hydrolysis is stirred; Fall the material temperature, regulate pH value; Leave standstill, separate, filter;

D, add phospho-wolframic acid in still, heat up, insulation adds hydrogen peroxide, insulation; Cooling, alkali lye is regulated; Dichloromethane extraction, extracting solution are incorporated in the reactor, stir;

E, in the reacting kettle jacketing logical hot water, be distilled to material and all solidify; Add Glacial acetic acid, open return-flow system, stir; Heat up, add aceticanhydride, insulation; Reclaim Glacial acetic acid and aceticanhydride, with the concentrated solution cooling, add methyl alcohol, stir; Regulate PH, insulation; Methyl alcohol is drawn in decompression; Regulate PH; Use dichloromethane extraction;

F, to chuck cooling, add the chlorination sulfoxide; Heat up, be incubated; Logical hot water reclaims sulfur oxychloride and methylene dichloride; Add dehydrated alcohol and ethyl acetate, heat up, stir, filter is got rid of in cooling, gets filter cake;

G, in reactor, add ethanol, stir; Add 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline; Heat up, insulation drops into filter cake, heats up insulation; Reclaim ethanol; Add water, cooling is filtered, and dries oven dry.

A kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, after it is characterized in that containing following steps: a, in reactor, adding water and sodium hydroxide and be stirred to dissolving, add voitol again and be stirred to dissolving, add methyl-sulfate, be warming up to 55～65 ℃, be incubated 1.5～2.5 hours, be cooled to below 25 ℃, extraction adds methylene chloride, extracting solution distills down for 80～90 ℃ and reclaims methylene dichloride, heats up in a steamer to can not distilling.

B, reclaim suction water and ammoniacal liquor in the still behind the methylene dichloride to distillation, be warming up to 80～90 ℃, be incubated 0.5～1.5 hour, be warming up to 85～95 ℃ again, be incubated 1.5～2.5 hours.Ammonia is removed in decompression, and feed liquid is imported vaporizer, and water is steamed in decompression, and feed liquid is imported bipyramid while hot, the decompression oven dry.

C, with in the bipyramid baker oven dry material put into reactor, in still, add methylene chloride and phosphorus oxychloride again, dropwise, be warming up to 55～65 ℃, stirring and dissolving is warming up to 80～90 ℃, will expect that temperature remains on 80～90 ℃, is incubated 6.5～7.5 hours.Insulation finishes, and the reclaim under reduced pressure phosphorus oxychloride under the decompression state, will expect that temperature drop is low to moderate 65～75 ℃, closes vacuum and opens emptying.Concentrated solution in the still is put into the another one still, stir hydrolysis.Continue logical water coolant and fall the material temperature to below 25 ℃, dropping ammonia in the still is regulated pH value.Stop to stir and leave standstill, layer oily matter is separated, layer oily matter is filtered.

D, the strainer filtrate filtered is imported in the reactor, in still, adds phospho-wolframic acid again, be warming up to 75～85 ℃, be incubated 20～40 minutes, drip hydrogen peroxide after, 80～90 ℃ are incubated 5.5～6.5 hours.Logical ice sodium chloride brine is cooled to below 25 ℃, regulates PH with sodium hydroxide lye.Use dichloromethane extraction, lower floor's extracting solution is incorporated in the reactor, stirs.

E, in the reacting kettle jacketing logical hot water, first normal pressure is warming up to about 75～85 ℃, 75～85 ℃ of underpressure distillation methylene dichloride are distilled to material and all solidify again.Add Glacial acetic acid, open return-flow system, start and stir, after stirring is normal.Heat up, allow solid dissolve, drip aceticanhydride, 80～90 ℃ are incubated 3.5～4.5 hours.Reclaim under reduced pressure Glacial acetic acid+aceticanhydride.With the concentrated solution cooling, add methyl alcohol, be stirred to evenly.Transfer to PH with sodium hydroxide lye, 20～30 ℃ are incubated 3.5～4.5 hours.Reduced pressure 1.5～2.5 hours, and utilized the methyl alcohol in the vacuum removal feed liquid.Regulate PH with aqueous acetic acid again.Use dichloromethane extraction, keep the standby lower floor's extracting solution that bleeds off of supernatant liquid.

F, reacting kettle jacketing feed the ice sodium chloride brine, make reactor temperature be down to about 5～15 ℃ dripping thionyl chloride.After dropwise reaction is complete, be warming up to about 20～30 ℃, be incubated 3.5～4.5 hours.Logical hot water makes reactor temperature reach 45～55 ℃ in the reacting kettle jacketing, reclaim under reduced pressure sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still.After adding dehydrated alcohol, add ethyl acetate again, be warming up to 50～60 ℃, be incubated 0.5～1.5 hour and constantly stirring, logical cooling water temperature to 0～10 ℃ gets rid of filter, gets filter cake.

G, in reactor, add ethanol, be stirred to evenly.Add 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline.Be warming up to 50～60 ℃, be incubated 20～40 minutes, drop into filter cake, be warming up to 55～65 ℃, be incubated 1.5～2.5 hours.Decompression recycling ethanol.Add water, logical water of condensation is cooled to about 10～20 ℃, filters, and dries, and oven dry namely.

A kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps:

A, in reactor, add water 1400 ± 5kg, the solid-state sodium hydroxide 200 ± 5kg that adds technical grade is stirred to dissolving, after the voitol 500 ± 5kg that adds technical grade again is stirred to dissolving, add the methyl-sulfate 900 ± 5kg of technical grade, dropwise, be warming up to 55～65 ℃, be incubated 1.5～2.5 hours, be cooled to below 25 ℃, the methylene dichloride 2000 ± 5L that adds technical grade extracts, methylene dichloride is reclaimed in 80～90 ℃ of distillations of extracting solution normal pressure, does not stop distillation to there being the methylene dichloride overhead product.

B, in still behind the methylene dichloride is reclaimed in distillation, add water 400 ± 5kg, add concentration and be ammoniacal liquor 1300 ± 5kg of about 28%, slowly be warming up to 80～90 ℃, be incubated 0.5～1.5 hour, be warming up to 85～95 ℃ again, be incubated 1.5～2.5 hours; Be decompressed to vacuum tightness 0.08～0.09MPa, behind the removal ammonia, feed liquid slowly imported single-effect evaporator, pressure in the vaporizer is reduced to vacuum tightness 0.08～0.09MPa, steam water to moisture and be about at 35% o'clock, feed liquid is imported bipyramid while hot, be decompressed to vacuum tightness 0.08～0.09MPa oven dry under 90 ℃.

C, with in the bipyramid baker oven dry material put into reactor, methylene dichloride 1800 ± the 5kg that adds technical grade again in the still, phosphorus oxychloride 2100 ± the 5L that adds technical grade, dropwise, with steam reactor slowly is warming up to 55～65 ℃, start stirring, treat the material dissolution in the still, after being warming up to 80～90 ℃, will expect that temperature remains on 80～90 ℃, be incubated 6.5～7.5 hours; Insulation finishes, and is decompressed to vacuum tightness 0.08～0.09MPa, reclaims phosphorus oxychloride, be decompressed to terminal point after, logical slightly water coolant will expect to close vacuum and open emptying about temperature drop to 65～75 ℃; Concentrated solution in the still is put into lower floor while hot 3000 ± 5kg water still is housed, stir hydrolysis, blowing finishes and continues to be stirred to 1.5～2.5 hours, and is abundant to the whole hydrolysis of material; Continue logical water coolant and will expect below the temperature drop to 25 ℃, slowly drip concentration in the still and be about 28% ammoniacal liquor, the scope of adjusting PH is 7～9; Stop stirring and left standstill 1.5～2.5 hours, layer oily matter is separated, and layer oily matter is put into strainer filter.

D, the strainer filtrate filtered is imported in the reactor, add the phospho-wolframic acid 180 ± 5L of technical grade again in the still, be warming up to 75～85 ℃, be incubated after 20～40 minutes, begin to drip concentration and be hydrogen peroxide 850 ± 5L of about 30%, dropwise, 80～90 ℃ of insulations 5.5～6.5 hours; Logical icy salt solution is cooled to below 25 ℃, is that the scope that 30% sodium hydroxide lye is regulated PH is 7～9 with concentration; Add the dichloromethane extraction of technical grade, lower floor's extracting solution is incorporated in the reactor, stirs 10～30 minutes.

E, in the reacting kettle jacketing logical 90 ℃ of hot water, be warming up to 75～85 ℃ of left and right sides distilled dichloromethanes under the first normal pressure, 75～85 ℃ are decompressed to vacuum tightness 0.08～0.09MPa distilled dichloromethane again, the distillation end point phenomenon is that material all solidifies in the still; Add the Glacial acetic acid 350 ± 5kg of technical grade, return-flow system is opened, and starts to stir, and after stirring is normal, keeps stirring; Be warming up to 85～95 ℃, allow solid dissolving, slowly add the acetic anhydride 1500 ± 5L of technical grade, after dropwising, kept 80～90 ℃ of temperature in the kettle 3.5～4.5 hours; Be decompressed to vacuum tightness 0.08～0.09MPa and reclaim Glacial acetic acid and acetic anhydride, to feed concentration greater than 80% o'clock; Concentrated solution is cooled to about 20～30 ℃, adds the methyl alcohol 400 ± 5kg of technical grade, stir about 10～30 minutes is to evenly; Be that the scope that 30% sodium hydroxide lye is regulated PH is 11～13,20～30 ℃ of insulations 3.5～4.5 hours with concentration; Be decompressed to vacuum tightness 0.08～0.09MPa, kept 1.5～2.5 hours, utilize the methyl alcohol in the vacuum removal feed liquid; Be that the scope that aqueous acetic acid more than 90% is regulated PH is 6～8 with concentration again; With the dichloromethane extraction of technical grade, it is standby to keep supernatant liquid, bleeds off lower floor's extracting solution.

F, reacting kettle jacketing feed icy salt solution, and making reactor temperature is about 5～15 ℃, add the sulfur oxychloride 1200 ± 5kg of technical grade in the reactor, after dropwising, are warming up to about 20～30 ℃, are incubated 3.5～4.5 hours; The logical hot water of reacting kettle jacketing makes the temperature in the reactor arrive 45～55 ℃, is decompressed to vacuum tightness 0.08～0.09MPa and reclaims sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; After adding dehydrated alcohol 480 ± 5kg, add the ethyl acetate 1000 ± 5kg of technical grade again, be warming up to about 50～60 ℃, stir maintenance down 0.5～1.5 hour, logical cooling water temperature to 0～about 10 ℃ gets rid of filter, gets filter cake.

G, add 95% ethanol, 1800 ± 5kg in the reactor, stirs 10～30 minutes to even; 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline 500 ± the 5kg that adds technical grade; Be warming up to 50～60 ℃, be incubated 20～40 minutes, disposable input filter cake 500 ± 5kg is warming up to 55～65 ℃, treats stable back insulation 1.5～2.5 hours; Be decompressed to vacuum tightness 0.08～0.09MPa and reclaim ethanol; Add about water 2500 ± 5kg, logical water of condensation is cooled to about 10～20 ℃, filters, and dries, and vacuum tightness 0.04～0.05MPa, 102～107 ℃ of oven dry are namely.

Embodiment

The present invention is described in further detail below in conjunction with embodiment, but the working of an invention mode is not limited thereto.

Embodiment 1: methyl a kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl)] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps: a, in reactor, add water 1400 ± 5kg, the solid-state sodium hydroxide 200 ± 5kg that adds technical grade is stirred to dissolving, after the voitol 500 ± 5kg that adds technical grade again is stirred to dissolving, methyl-sulfate 900 ± the 5kg that adds technical grade, dropwise, be warming up to 55～65 ℃, be incubated 1.5～2.5 hours, be cooled to below 25 ℃, methylene dichloride 2000 ± the 5L that adds technical grade extracts, methylene dichloride is reclaimed in 80～90 ℃ of distillations of extracting solution normal pressure, does not stop distillation to there being the methylene dichloride overhead product;

B, in still behind the methylene dichloride is reclaimed in distillation, add water 400 ± 5kg, add concentration and be ammoniacal liquor 1300 ± 5kg of about 28%, slowly be warming up to 80～90 ℃, be incubated 0.5～1.5 hour, be warming up to 85～95 ℃ again, be incubated 1.5～2.5 hours; Be decompressed to vacuum tightness 0.08～0.09MPa, behind the removal ammonia, feed liquid slowly imported single-effect evaporator, pressure in the vaporizer is reduced to vacuum tightness 0.08～0.09MPa, steam water to moisture and be about at 35% o'clock, feed liquid is imported bipyramid while hot, be decompressed to vacuum tightness 0.08～0.09MPa oven dry under 90 ℃;

C, with in the bipyramid baker oven dry material put into reactor, methylene dichloride 1800 ± the 5kg that adds technical grade again in the still, phosphorus oxychloride 2100 ± the 5L that adds technical grade, dropwise, with steam reactor slowly is warming up to 55～65 ℃, start stirring, treat the material dissolution in the still, after being warming up to 80～90 ℃, will expect that temperature remains on 80～90 ℃, be incubated 6.5～7.5 hours; Insulation finishes, and is decompressed to vacuum tightness 0.08～0.09MPa, reclaims phosphorus oxychloride, be decompressed to terminal point after, logical slightly water coolant will expect to close vacuum and open emptying about temperature drop to 65～75 ℃; Concentrated solution in the still is put into lower floor while hot 3000 ± 5kg water still is housed, stir hydrolysis, blowing finishes and continues to be stirred to 1.5～2.5 hours, and is abundant to the whole hydrolysis of material; Continue logical water coolant and will expect below the temperature drop to 25 ℃, slowly drip concentration in the still and be about 28% ammoniacal liquor, the scope of adjusting PH is 7～9; Stop stirring and left standstill 1.5～2.5 hours, layer oily matter is separated, and layer oily matter is put into strainer filter;

D, the strainer filtrate filtered is imported in the reactor, add the phospho-wolframic acid 180 ± 5L of technical grade again in the still, be warming up to 75～85 ℃, be incubated after 20～40 minutes, begin to drip concentration and be hydrogen peroxide 850 ± 5L of about 30%, dropwise, 80～90 ℃ of insulations 5.5～6.5 hours; Logical icy salt solution is cooled to below 25 ℃, is that the scope that 30% sodium hydroxide lye is regulated PH is 7～9 with concentration; Add the dichloromethane extraction of technical grade, lower floor's extracting solution stirred 10～30 minutes in reactor;

E, in the reacting kettle jacketing logical 90 ℃ of hot water, be warming up to 75～85 ℃ of left and right sides distilled dichloromethanes under the first normal pressure, 75～85 ℃ are decompressed to vacuum tightness 0.08～0.09MPa distilled dichloromethane again, the distillation end point phenomenon is that material all solidifies in the still; Add the Glacial acetic acid 350 ± 5kg of technical grade, return-flow system is opened, and starts to stir, and after stirring is normal, keeps stirring; Be warming up to 85～95 ℃, allow solid dissolving, slowly add the acetic anhydride 1500 ± 5L of technical grade, after dropwising, kept 80～90 ℃ of temperature in the kettle 3.5～4.5 hours; Be decompressed to vacuum tightness 0.08～0.09MPa and reclaim Glacial acetic acid and acetic anhydride, to feed concentration greater than 80% o'clock; Concentrated solution is cooled to about 20～30 ℃, adds the methyl alcohol 400 ± 5kg of technical grade, stir about 10～30 minutes is to evenly; Be that the scope that 30% sodium hydroxide lye is regulated PH is 11～13,20～30 ℃ of insulations 3.5～4.5 hours with concentration; Be decompressed to vacuum tightness 0.08～0.09MPa, kept 1.5～2.5 hours, utilize the methyl alcohol in the vacuum removal feed liquid; Be that the scope that aqueous acetic acid more than 90% is regulated PH is 6～8 with concentration again; With the dichloromethane extraction of technical grade, it is standby to keep supernatant liquid, bleeds off lower floor's extracting solution;

F, reacting kettle jacketing feed icy salt solution, and making reactor temperature is about 5～15 ℃, add the sulfur oxychloride 1200 ± 5kg of technical grade in the reactor, after dropwising, are warming up to about 20～30 ℃, are incubated 3.5～4.5 hours; The logical hot water of reacting kettle jacketing makes the temperature in the reactor arrive 45～55 ℃, is decompressed to vacuum tightness 0.08～0.09MPa and reclaims sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; After adding dehydrated alcohol 480 ± 5kg, add the ethyl acetate 1000 ± 5kg of technical grade again, be warming up to about 50～60 ℃, stir maintenance down 0.5～1.5 hour, logical cooling water temperature to 0～about 10 ℃ gets rid of filter, gets filter cake;

G, add 95% ethanol, 1800 ± 5kg in the reactor, stirs 10～30 minutes to even; 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline 500 ± the 5kg that adds technical grade; Be warming up to 50～60 ℃, be incubated 20～40 minutes, disposable input filter cake 500 ± 5kg is warming up to 55～65 ℃, treats stable back insulation 1.5～2.5 hours; Be decompressed to vacuum tightness 0.08～0.09MPa and reclaim ethanol; Add about water 2500 ± 5kg, logical water of condensation is cooled to about 10～20 ℃, filters, and dries, and vacuum tightness 0.04～0.05MPa, 102～107 ℃ of oven dry are namely;

Embodiment 2: methyl a kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl)] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps:

A, in reactor, add water 1395kg, the solid-state sodium hydroxide 195kg that adds technical grade is stirred to dissolving, after the voitol 495kg that adds technical grade again is stirred to dissolving, add the methyl-sulfate 895kg of technical grade, dropwise, be warming up to 55 ℃, be incubated 1.5 hours, be cooled to below 25 ℃, the methylene dichloride 1995L that adds technical grade extracts, methylene dichloride is reclaimed in 80 ℃ of distillations of extracting solution normal pressure, does not stop distillation to there being the methylene dichloride overhead product;

B, in still behind the methylene dichloride is reclaimed in distillation, add water 395kg, add concentration and be about 28% ammoniacal liquor 1295kg, slowly be warming up to 80 ℃, be incubated 0.5 hour, be warming up to 85 ℃ again, be incubated 1.5 hours; Be decompressed to vacuum tightness 0.08MPa, behind the ammonia in the removal still, feed liquid slowly imported single-effect evaporator, pressure in the vaporizer is reduced to vacuum tightness 0.08MPa, steam water to moisture and be about at 35% o'clock, feed liquid is imported bipyramid while hot, be decompressed to vacuum tightness 0.08MPa oven dry under 90 ℃;

C, with in the bipyramid baker oven dry material put into reactor, the methylene dichloride 1795kg that adds technical grade again in the still, the phosphorus oxychloride 2095L that adds technical grade, dropwise, with steam reactor slowly is warming up to 55 ℃, start stirring, treat the material dissolution in the still, after being warming up to 80 ℃, will expect that temperature remains on 80 ℃, be incubated 6.5 hours; Insulation finishes, and is decompressed to vacuum tightness 0.08MPa, reclaims phosphorus oxychloride, be decompressed to terminal point after, logical slightly water coolant will expect to close vacuum and open emptying about temperature drop to 65 ℃; Concentrated solution in the still is put into lower floor while hot 2995kg water still is housed, stir hydrolysis, blowing finishes and continues to be stirred to 1.5 hours, and is abundant to the whole hydrolysis of material; Continue logical water coolant and will expect below the temperature drop to 25 ℃, slowly drip concentration in the still and be about 28% ammoniacal liquor, adjusting PH=7; Stop stirring and left standstill 1.5 hours, layer oily matter is separated, and layer oily matter is put into strainer filter;

D, the strainer filtrate filtered is imported in the reactor, add the phospho-wolframic acid 175L of technical grade again in the still, be warming up to 75 ℃, be incubated after 20 minutes, begin to drip concentration and be about 30% hydrogen peroxide 845L, dropwise, 80 ℃ are incubated 5.5 hours; Logical icy salt solution is cooled to below 25 ℃, is 30% sodium hydroxide lye adjusting PH=7 with concentration; Add the dichloromethane extraction of technical grade, lower floor's extracting solution stirred 10 minutes in reactor;

E, in the reacting kettle jacketing logical 90 ℃ of hot water, be warming up to 75 ℃ of left and right sides distilled dichloromethanes under the first normal pressure, 75 ℃ are decompressed to vacuum tightness 0.08MPa distilled dichloromethane again, the distillation end point phenomenon is that material all solidifies in the still; Add the Glacial acetic acid 345kg of technical grade, return-flow system is opened, and starts to stir, and after stirring is normal, keeps stirring; Be warming up to 85 ℃, allow solid dissolving, slowly add the acetic anhydride 1495L of technical grade, after dropwising, kept 80 ℃ of temperature in the kettle 3.5 hours; Be decompressed to vacuum tightness 0.08MPa and reclaim Glacial acetic acid and acetic anhydride, to feed concentration greater than 80% o'clock; Concentrated solution is cooled to about 20 ℃, adds the methyl alcohol 395kg of technical grade, stir about 10 minutes is to evenly; Be that 30% sodium hydroxide lye is regulated PH=11 with concentration, 20 ℃ of insulations 3.5 hours; Be decompressed to vacuum tightness 0.08MPa, kept 1.5 hours, utilize the methyl alcohol in the vacuum removal feed liquid; Be that aqueous acetic acid more than 90% is regulated PH=6 with concentration again; With the dichloromethane extraction of technical grade, it is standby to keep supernatant liquid, bleeds off lower floor's extracting solution;

F, reacting kettle jacketing feed icy salt solution, and making reactor temperature is about 5 ℃, add the sulfur oxychloride 1195kg of technical grade in the reactor, after dropwising, are warming up to about 20 ℃, are incubated 3.5 hours; The logical hot water of reacting kettle jacketing makes the temperature in the reactor arrive 45 ℃, is decompressed to vacuum tightness 0.08MPa and reclaims sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; After adding dehydrated alcohol 475kg, add the ethyl acetate 995kg of technical grade again, be warming up to about 50 ℃, stir down and kept 0.5 hour, logical cooling water temperature to 0 ℃ gets rid of filter, gets filter cake;

G, add 95% ethanol 1795kg in the reactor, stirs 10 minutes to even; 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline the 495kg that adds technical grade; Be warming up to 50 ℃, be incubated 20 minutes, disposable input filter cake 495kg is warming up to 55 ℃, treats stable back insulation 1.5 hours; Be decompressed to vacuum tightness 0.08MPa and reclaim ethanol; Add about water 2495kg, logical water of condensation is cooled to about 10 ℃, filters, and dries, and vacuum tightness 0.04MPa, 102 ℃ of oven dry are namely.

Embodiment 3: methyl a kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl)] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps:

A, in reactor, add water 1400kg, the solid-state sodium hydroxide 200kg that adds technical grade is stirred to dissolving, after the voitol 500kg that adds technical grade again is stirred to dissolving, add the methyl-sulfate 900kg of technical grade, dropwise, be warming up to 60 ℃, be incubated 2 hours, be cooled to below 25 ℃, the methylene dichloride 2000L that adds technical grade extracts, methylene dichloride is reclaimed in 85 ℃ of distillations of extracting solution normal pressure, does not stop distillation to there being the methylene dichloride overhead product;

B, in still behind the methylene dichloride is reclaimed in distillation, add water 400kg, add concentration and be 28% ammoniacal liquor 1300kg, slowly be warming up to 85 ℃, be incubated 1 hour, be warming up to 90 ℃ again, be incubated 2 hours; Be decompressed to vacuum tightness 0.09MPa, behind the ammonia in the removal still, feed liquid slowly imported single-effect evaporator, pressure in the vaporizer is reduced to vacuum tightness 0.09MPa, steam water to moisture and be about at 35% o'clock, feed liquid is imported bipyramid while hot, be decompressed to vacuum tightness 0.09MPa oven dry under 90 ℃;

C, with in the bipyramid baker oven dry material put into reactor, the methylene dichloride 1800kg that adds technical grade again in the still, the phosphorus oxychloride 2100L that adds technical grade, dropwise, with steam reactor slowly is warming up to 60 ℃, start stirring, treat the material dissolution in the still, after being warming up to 85 ℃, will expect that temperature remains on 85 ℃, be incubated 7 hours; Insulation finishes, and is decompressed to vacuum tightness 0.09MPa, reclaims phosphorus oxychloride, be decompressed to terminal point after, logical slightly water coolant will expect to close vacuum and open emptying about temperature drop to 70 ℃; Concentrated solution in the still is put into lower floor while hot 3000kg water still is housed, stir hydrolysis, blowing finishes and continues to be stirred to 2 hours, and is abundant to the whole hydrolysis of material; Continue logical water coolant and will expect below the temperature drop to 25 ℃, slowly drip concentration in the still and be 28% ammoniacal liquor, adjusting PH=8; Stop stirring and left standstill 2 hours, layer oily matter is separated, and layer oily matter is put into strainer filter;

D, the strainer filtrate filtered is imported in the reactor, add the phospho-wolframic acid 180L of technical grade again in the still, be warming up to 80 ℃, be incubated after 30 minutes, begin to drip concentration and be 30%0 hydrogen peroxide 8500L, dropwise, 85 ℃ are incubated 6 hours; Logical icy salt solution is cooled to below 25 ℃, is 30% sodium hydroxide lye adjusting PH=8 with concentration; Add the dichloromethane extraction of technical grade, lower floor's extracting solution stirred 20 minutes in reactor;

E, in the reacting kettle jacketing logical 90 ℃ of hot water, be warming up to 80 ℃ of left and right sides distilled dichloromethanes under the first normal pressure, 80 ℃ are decompressed to vacuum tightness 00.09MPa distilled dichloromethane again, the distillation end point phenomenon is that material all solidifies in the still; Add the Glacial acetic acid 3500kg of technical grade, return-flow system is opened, and starts to stir, and after stirring is normal, keeps stirring; Be warming up to 90 ℃, allow solid dissolving, slowly add the acetic anhydride 15000L of technical grade, after dropwising, kept 85 ℃ of temperature in the kettle 4 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim Glacial acetic acid and acetic anhydride, to feed concentration greater than 80% o'clock; Concentrated solution is cooled to about 25 ℃, adds the methyl alcohol 400kg of technical grade, stir about 20 minutes is to evenly; Be that 30% sodium hydroxide lye is regulated PH=12 with concentration, 25 ℃ of insulations 4 hours; Be decompressed to vacuum tightness 0.09MPa, kept 2 hours, utilize the methyl alcohol in the vacuum removal feed liquid; Be that aqueous acetic acid more than 90% is regulated PH=7 with concentration again; With the dichloromethane extraction of technical grade, it is standby to keep supernatant liquid, bleeds off lower floor's extracting solution;

F, reacting kettle jacketing feed icy salt solution, and making reactor temperature is about 10 ℃, add the sulfur oxychloride 12000kg of technical grade in the reactor, after dropwising, are warming up to about 25 ℃, are incubated 4 hours; The logical hot water of reacting kettle jacketing makes the temperature in the reactor arrive 50 ℃, is decompressed to vacuum tightness 00.09MPa and reclaims sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; After adding dehydrated alcohol 4800kg, add the ethyl acetate 10000kg of technical grade again, be warming up to about 55 ℃, stir down and kept 1 hour, logical cooling water temperature to 5 ℃ gets rid of filter, gets filter cake;

G, add 95% ethanol 1800kg in the reactor, stirs 20 minutes to even; 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline the 500kg that adds technical grade; Be warming up to 55 ℃, be incubated 30 minutes, disposable input filter cake 500kg is warming up to 60 ℃, treats stable back insulation 2 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim ethanol; Add about water 2500kg, logical water of condensation is cooled to about 15 ℃, filters, and dries, and vacuum tightness 0.04,5 ℃ of oven dry are namely.

Embodiment 4: methyl a kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl)] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps:

A, in reactor, add water 1405kg, the solid-state sodium hydroxide 205kg that adds technical grade is stirred to dissolving, after the voitol 505kg that adds technical grade again is stirred to dissolving, add the methyl-sulfate 905kg of technical grade, dropwise, be warming up to 65 ℃, be incubated 2.5 hours, be cooled to below 25 ℃, the methylene dichloride 2005L that adds technical grade extracts, methylene dichloride is reclaimed in 90 ℃ of distillations of extracting solution normal pressure, does not stop distillation to there being the methylene dichloride overhead product;

B, in still behind the methylene dichloride is reclaimed in distillation, add water 405kg, add concentration and be 28% ammoniacal liquor 1305kg, slowly be warming up to 90 ℃, be incubated 1.5 hours, be warming up to 95 ℃ again, be incubated 2.5 hours; Be decompressed to vacuum tightness 0.09MPa, behind the ammonia in the removal still, feed liquid slowly imported single-effect evaporator, pressure in the vaporizer is reduced to vacuum tightness 0.09MPa, steam water to moisture and be about at 35% o'clock, feed liquid is imported bipyramid while hot, be decompressed to vacuum tightness 0.09MPa oven dry under 90 ℃;

C, with in the bipyramid baker oven dry material put into reactor, the methylene dichloride 1805kg that adds technical grade again in the still, the phosphorus oxychloride 2105L that adds technical grade, dropwise, with steam reactor slowly is warming up to 65 ℃, start stirring, treat the material dissolution in the still, after being warming up to 90 ℃, will expect that temperature remains on 90 ℃, be incubated 7.5 hours; Insulation finishes, and is decompressed to vacuum tightness 0.09MPa, reclaims phosphorus oxychloride, be decompressed to terminal point after, logical slightly water coolant will expect to close vacuum and open emptying about temperature drop to 75 ℃; Concentrated solution in the still is put into lower floor while hot 3005kg water still is housed, stir hydrolysis, blowing finishes and continues to be stirred to 2.5 hours, and is abundant to the whole hydrolysis of material; Continue logical water coolant and will expect below the temperature drop to 25 ℃, slowly drip concentration in the still and be about 28% ammoniacal liquor, adjusting PH=9; Stop stirring and left standstill 2.5 hours, layer oily matter is separated, and layer oily matter is put into strainer filter;

D, the strainer filtrate filtered is imported in the reactor, add the phospho-wolframic acid 185L of technical grade again in the still, be warming up to 85 ℃, be incubated after 40 minutes, begin to drip concentration and be 30% hydrogen peroxide 855L, dropwise, 90 ℃ are incubated 6.5 hours; Logical icy salt solution is cooled to below 25 ℃, is that 30% sodium hydroxide lye is regulated PH=9 with concentration; Add the dichloromethane extraction of technical grade, lower floor's extracting solution stirred 30 minutes in reactor;

E, in the reacting kettle jacketing logical 90 ℃ of hot water, be warming up to 85 ℃ of left and right sides distilled dichloromethanes under the first normal pressure, 85 ℃ are decompressed to vacuum tightness 0.09MPa distilled dichloromethane again, the distillation end point phenomenon is that material all solidifies in the still; Add the Glacial acetic acid 355kg of technical grade, return-flow system is opened, and starts to stir, and after stirring is normal, keeps stirring; Be warming up to 95 ℃, allow solid dissolving, slowly add the acetic anhydride 1505L of technical grade, after dropwising, kept 90 ℃ of temperature in the kettle 4.5 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim Glacial acetic acid and acetic anhydride, to feed concentration greater than 80% o'clock; Concentrated solution is cooled to about 30 ℃, adds the methyl alcohol 405kg of technical grade, stir about 30 minutes is to evenly; Be that 30% sodium hydroxide lye is regulated PH=13 with concentration, 30 ℃ of insulations 4.5 hours; Be decompressed to vacuum tightness 0.09MPa, kept 2.5 hours, utilize the methyl alcohol in the vacuum removal feed liquid; Be that aqueous acetic acid more than 90% is regulated PH=8 with concentration again; With the dichloromethane extraction of technical grade, it is standby to keep supernatant liquid, bleeds off lower floor's extracting solution;

F, reacting kettle jacketing feed icy salt solution, and making reactor temperature is about 15 ℃, add the sulfur oxychloride 1205kg of technical grade in the reactor, after dropwising, are warming up to about 30 ℃, are incubated 4.5 hours; The logical hot water of reacting kettle jacketing makes the temperature in the reactor arrive 55 ℃, is decompressed to vacuum tightness 0.09MPa and reclaims sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; After adding dehydrated alcohol 485kg, add the ethyl acetate 1005kg of technical grade again, be warming up to about 60 ℃, stir down and kept 1.5 hours, logical cooling water temperature to 10 ℃ gets rid of filter, gets filter cake;

G, add 95% ethanol 1805kg in the reactor, stirs 30 minutes to even; 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline the 505kg that adds technical grade; Be warming up to 60 ℃, be incubated 40 minutes, disposable input filter cake 505kg is warming up to 65 ℃, treats stable back insulation 2.5 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim ethanol; Add about water 2505kg, logical water of condensation is cooled to about 20 ℃, filters, and dries, and vacuum tightness 0.05MPa, 107 ℃ of oven dry are namely.

Embodiment 5: methyl a kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl)] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps:

A, in reactor, add water 1400kg, the solid-state sodium hydroxide 202kg that adds technical grade is stirred to dissolving, after the voitol 500kg that adds technical grade again is stirred to dissolving, add the methyl-sulfate 900kg of technical grade, dropwise, be warming up to 58 ℃, be incubated 2 hours, be cooled to below 25 ℃, the methylene dichloride 2000L that adds technical grade extracts, methylene dichloride is reclaimed in 83 ℃ of distillations of extracting solution normal pressure, does not stop distillation to there being the methylene dichloride overhead product;

B, in still behind the methylene dichloride is reclaimed in distillation, add water 400kg, add concentration and be 28% ammoniacal liquor 1302kg, slowly be warming up to 83 ℃, be incubated 1.5 hours, be warming up to 90 ℃ again, be incubated 2 hours; Be decompressed to vacuum tightness 0.09MPa, behind the ammonia in the removal still, feed liquid slowly imported single-effect evaporator, pressure in the vaporizer is reduced to vacuum tightness 0.09MPa, steam water to moisture and be about at 35% o'clock, feed liquid is imported bipyramid while hot, be decompressed to vacuum tightness 0.09MPa oven dry under 90 ℃;

C, with in the bipyramid baker oven dry material put into reactor, the methylene dichloride 1801kg that adds technical grade again in the still, the phosphorus oxychloride 2103L that adds technical grade, dropwise, with steam reactor slowly is warming up to 62 ℃, start stirring, treat the material dissolution in the still, after being warming up to 86 ℃, will expect that temperature remains on 86 ℃, be incubated 6.5 hours; Insulation finishes, and is decompressed to vacuum tightness 0.09MPa, reclaims phosphorus oxychloride, be decompressed to terminal point after, logical slightly water coolant will expect to close vacuum and open emptying about temperature drop to 68 ℃; Concentrated solution in the still is put into lower floor while hot 3000kg water still is housed, stir hydrolysis, blowing finishes and continues to be stirred to 2.5 hours, and is abundant to the whole hydrolysis of material; Continue logical water coolant and will expect below the temperature drop to 25 ℃, slowly drip concentration in the still and be 28% ammoniacal liquor, adjusting PH=8; Stop stirring and left standstill 2 hours, layer oily matter is separated, and layer oily matter is put into strainer filter;

D, the strainer filtrate filtered is imported in the reactor, add the phospho-wolframic acid 182L of technical grade again in the still, be warming up to 78 ℃, be incubated after 30 minutes, begin to drip concentration and be 30% hydrogen peroxide 854L, dropwise, 85 ℃ are incubated 5.5 hours; Logical icy salt solution is cooled to below 25 ℃, is 30% sodium hydroxide lye adjusting PH=8 with concentration; Add the dichloromethane extraction of technical grade, lower floor's extracting solution stirred 30 minutes in reactor;

E, in the reacting kettle jacketing logical 90 ℃ of hot water, be warming up to 85 ℃ of left and right sides distilled dichloromethanes under the first normal pressure, 85 ℃ are decompressed to vacuum tightness 0.09MPa distilled dichloromethane again, the distillation end point phenomenon is that material all solidifies in the still; Add the Glacial acetic acid 355kg of technical grade, return-flow system is opened, and starts to stir, and after stirring is normal, keeps stirring; Be warming up to 90 ℃, allow solid dissolving, slowly add the acetic anhydride 1501L of technical grade, after dropwising, kept 85 ℃ of temperature in the kettle 4.5 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim Glacial acetic acid and acetic anhydride, to feed concentration greater than 80% o'clock; Concentrated solution is cooled to about 25 ℃, adds the methyl alcohol 400kg of technical grade, stir about 20 minutes is to evenly; Be that 30% sodium hydroxide lye is regulated PH=12 with concentration, 25 ℃ of insulations 4 hours; Be decompressed to vacuum tightness 0.09MPa, kept 1.5 hours, utilize the methyl alcohol in the vacuum removal feed liquid; Be that aqueous acetic acid more than 90% is regulated PH=7 with concentration again; With the dichloromethane extraction of technical grade, it is standby to keep supernatant liquid, bleeds off lower floor's extracting solution;

F, reacting kettle jacketing feed icy salt solution, and making reactor temperature is about 10 ℃, add the sulfur oxychloride 1203kg of technical grade in the reactor, after dropwising, are warming up to about 25 ℃, are incubated 3.5 hours; The logical hot water of reacting kettle jacketing makes the temperature in the reactor arrive 52 ℃, is decompressed to vacuum tightness 0.09MPa and reclaims sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; After adding dehydrated alcohol 480kg, add the ethyl acetate 1000kg of technical grade again, be warming up to about 50 ℃, stir down and kept 1.5 hours, about logical cooling water temperature to 5 ℃, get rid of filter, get filter cake;

G, add 95% ethanol 1805kg in the reactor, stirs 30 minutes to even; 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline the 500kg that adds technical grade; Be warming up to 50 ℃, be incubated 30 minutes, disposable input filter cake 500kg is warming up to 61 ℃, treats stable back insulation 2 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim ethanol; Add about water 2502kg, logical water of condensation is cooled to about 15 ℃, filters, and dries, and vacuum tightness .05MPa, 105 ℃ of oven dry are namely.

Embodiment 6: methyl a kind of 5-difluoro-methoxy of the present invention-2-[[(4-chloro-3-methoxyl group-2-pyridyl)] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps:

A, in reactor, add water 1402kg, the solid-state sodium hydroxide 201kg that adds technical grade is stirred to dissolving, after the voitol 498kg of reprocessing industry level is stirred to dissolving, add the methyl-sulfate 899kg of technical grade, dropwise, be warming up to 58 ℃, be incubated 2.5 hours, be cooled to below 25 ℃, the methylene dichloride 2002L of processing industry level extracts, methylene dichloride is reclaimed in 85 ℃ of distillations of extracting solution normal pressure, does not stop distillation to there being the methylene dichloride overhead product;

B, in still behind the methylene dichloride is reclaimed in distillation, add water 397kg, add concentration and be 28% ammoniacal liquor 1304kg, slowly be warming up to 85 ℃, be incubated 1.5 hours, be warming up to 88 ℃ again, be incubated 2 hours; Be decompressed to vacuum tightness 0.09MPa, behind the ammonia in the removal still, feed liquid slowly imported single-effect evaporator, pressure in the vaporizer is reduced to vacuum tightness 0.09MPa, steaming water to moisture is 35% o'clock, feed liquid is led while hot entering the bipyramid baker, is decompressed to vacuum tightness 0.09MPa oven dry under 90 ℃;

C, with in the bipyramid baker oven dry material put into reactor, the methylene dichloride 1802kg that adds technical grade again in the still, the phosphorus oxychloride 2097L of processing industry level, dropwise, with steam reactor slowly is warming up to 58 ℃, start stirring, treat the material dissolution in the still, after being warming up to 85 ℃, will expect that temperature remains on 85 ℃, be incubated 6 hours; Insulation finishes, and is decompressed to vacuum tightness 0.09MPa, reclaims phosphorus oxychloride, be decompressed to terminal point after, logical slightly water coolant will be expected temperature drop to 70 ℃, close vacuum and open emptying; Concentrated solution in the still is put into the still that 3000kg water is equipped with in lower floor while hot, stir hydrolysis, blowing finishes and continues to stir 2 hours, and is abundant to the whole hydrolysis of material; Continue logical water coolant and will expect below the temperature drop to 25 ℃, slowly drip concentration in the still and be 28% ammoniacal liquor, adjusting PH=8; Stop stirring and left standstill 2 hours, layer oily matter is isolated, and layer oily matter is put into strainer filter;

D, the strainer filtrate filtered is imported in the reactor, the phospho-wolframic acid 184L of processing industry level in the still is warming up to 82 ℃ again, be incubated after 30 minutes, begins to drip concentration and be 30% hydrogen peroxide 8499L, dropwises, and 85 ℃ are incubated 5.5 hours; Logical icy salt solution is cooled to below 25 ℃, is that 30% sodium hydroxide lye is regulated PH=8 with concentration; Add the dichloromethane extraction of technical grade, lower floor's extracting solution joins in the reactor, stirs 30 minutes;

E, in the reacting kettle jacketing logical 90 ℃ of hot water, be warming up to 85 ℃ of distilled dichloromethanes under the first normal pressure, be decompressed to vacuum tightness 0.09MPa distilled dichloromethane under 85 ℃ again, the distillation end point phenomenon is that material all solidifies in the still; Add the Glacial acetic acid 352kg of technical grade, return-flow system is opened, and starts to stir, and after stirring is normal, keeps stirring; Be warming up to 90 ℃, allow solid dissolve, slowly add the acetic anhydride 1500L of technical grade, after dropwising, keep 85 ℃ of temperature in the kettle, 3.5 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim Glacial acetic acid and acetic anhydride, to feed concentration greater than 80% o'clock; Concentrated solution is cooled to 25 ℃, adds the methyl alcohol 400kg of technical grade, stir 30 minutes to even; Be that 30% sodium hydroxide lye is regulated PH=12 with concentration, 25 ℃ of insulations 4 hours down; Be decompressed to vacuum tightness 0.09MPa, kept 2 hours, utilize the methyl alcohol in the vacuum removal feed liquid; Be that aqueous acetic acid more than 90% is regulated PH=7 with concentration again; With the dichloromethane extraction of technical grade, it is standby to keep supernatant liquid, bleeds off lower floor's extracting solution;

F, reacting kettle jacketing feed icy salt solution, and making reactor temperature is 10 ℃, add the sulfur oxychloride 1198kg of technical grade in the reactor; After dropwising, be warming up to 23 ℃, be incubated 4 hours; The logical hot water of reacting kettle jacketing makes the temperature of reactor the inside reach 50 ℃, is decompressed to vacuum tightness 0.09MPa and reclaims sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; After adding dehydrated alcohol 480kg, add the ethyl acetate 1000kg of technical grade again, be warming up to 55 ℃, stir down and kept 1 hour, logical cooling water temperature to 5 ℃ gets rid of filter, gets filter cake;

G, add 95% ethanol 1802kg in the reactor, stirred 20 minutes; 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline the 500kg that adds technical grade; Be warming up to 55 ℃, be incubated 30 minutes, disposable input filter cake 500kg is warming up to 60 ℃, treats stable back insulation 2 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim ethanol; Add water 2500kg, logical water of condensation is cooled to 14 ℃, filters, and dries, and vacuum tightness 0.05MPa, 105 ℃ of following oven dry are namely.

Claims (3)

1. methyl 5-difluoro-methoxy-2-[[(4-chloro-3-methoxyl group-2-pyridyl)] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps: a, in reactor, add sodium hydroxide solution, after adding voitol and being stirred to dissolving, add methyl-sulfate again, temperature reaction, cooling adds methylene chloride and extracts, and methylene dichloride is reclaimed in the extracting solution distillation;

B, in reclaiming still behind the methylene dichloride, distillation adds water and ammoniacal liquor temperature reaction; Decompression is slowly dried feed liquid after removing the interior ammonia of still;

C, will dry material and put into reactor, in still, add methylene dichloride and phosphorus oxychloride, the intensification stirring and dissolving again; The reclaim under reduced pressure phosphorus oxychloride is put into the still that water is equipped with in lower floor with concentrated solution in the still, stirs hydrolysis; Cooling adds ammoniacal liquor in still; Standing separation is filtered;

D, filtrate is imported in the reactor, add phospho-wolframic acid again in still, heating up adds hydrogen peroxide, regulates PH=8; Add dichloromethane extraction, lower floor's extracting solution joins in the reactor;

Material all solidifies in e, the intensification distilled dichloromethane, still kettle; Add Glacial acetic acid and stir rising temperature for dissolving, add acetic anhydride, keep 85 ℃ of temperature in the kettle, 3.5 hours; Reclaim under reduced pressure Glacial acetic acid and acetic anhydride; Concentrated solution is cooled to 25 ℃, adds methyl alcohol and stir; Regulate PH=12,25 ℃ are incubated 4 hours down; Decompression is except the methyl alcohol in the feed liquid; Re-adjustment PH=7; Use dichloromethane extraction, it is standby to keep supernatant liquid;

F, reactor temperature are cooled to 10 ℃, add sulfur oxychloride in reactor; Reclaim under reduced pressure sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; Add dehydrated alcohol, add the ethyl acetate intensification again and stir, filter is got rid of in cooling, gets filter cake;

G, in reactor, add ethanol; Add 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline; Be warming up to 55 ℃, be incubated 30 minutes, drop into filter cake, be warming up to 60 ℃; Decompression recycling ethanol; Add water for cooling to 14 ℃, filter, dry, vacuum drying namely.

2. according to the described a kind of 5-difluoro-methoxy of claim 1-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps: a, in reactor, add water, add solid-state sodium hydroxide and be stirred to dissolving, after adding voitol again and being stirred to dissolving, add methyl-sulfate, be warming up to 58 ℃, be incubated 2.5 hours, be cooled to below 25 ℃, add methylene chloride and extract, methylene dichloride is reclaimed in 85 ℃ of distillations of extracting solution normal pressure;

B, in still behind the methylene dichloride is reclaimed in distillation, add water, add ammoniacal liquor, slowly be warming up to 85 ℃, be incubated 1.5 hours, be warming up to 88 ℃ again, be incubated 2 hours; Decompression slowly imports single-effect evaporator with feed liquid after removing the interior ammonia of still, and steaming water to moisture is 35% o'clock, feed liquid is led while hot entering the oven dry of bipyramid baker.

C, with in the bipyramid baker oven dry material put into reactor, in still, add methylene dichloride again, add phosphorus oxychloride, be warming up to 58 ℃ of stirring and dissolving, be warming up to 85 ℃ after, will expect that temperature remains on 85 ℃, be incubated 6 hours; Insulation finishes, and the reclaim under reduced pressure phosphorus oxychloride is cooled to 70 ℃; Concentrated solution in the still is put into the still that water is equipped with in lower floor, stir hydrolysis; Be cooled to below 25 ℃, in still, add ammoniacal liquor, regulate PH=8; Left standstill 2 hours, layer oily matter is isolated, and layer oily matter is put into strainer filter;

D, the strainer filtrate filtered is imported in the reactor, add phospho-wolframic acid again in still, be warming up to 82 ℃, be incubated after 30 minutes, add hydrogen peroxide, 85 ℃ are incubated 5.5 hours; Be cooled to below 25 ℃, regulate PH=8 with sodium hydroxide lye; Add dichloromethane extraction, lower floor's extracting solution joins in the reactor, stirs 30 minutes;

E, normal pressure are warming up to 85 ℃ of distilled dichloromethanes, 85 ℃ of following underpressure distillation methylene dichloride again, and material all solidifies in the still kettle; Add the Glacial acetic acid stirring and be warming up to 90 ℃, allow solid dissolve, add acetic anhydride, keep 85 ℃ of temperature in the kettle, 3.5 hours; Reclaim under reduced pressure Glacial acetic acid and acetic anhydride, to feed concentration greater than 80% o'clock; Concentrated solution is cooled to 25 ℃, adds methyl alcohol and stir; Regulate PH=12 with sodium hydroxide lye, 25 ℃ are incubated 4 hours down; Decompression kept 2 hours, utilized the methyl alcohol in the vacuum removal feed liquid; Regulate PH=7 with aqueous acetic acid again; Use dichloromethane extraction, it is standby to keep supernatant liquid, bleeds off lower floor's extracting solution;

F, reactor temperature are cooled to 10 ℃, add sulfur oxychloride in reactor; Be warming up to 23 ℃, be incubated 4 hours; Intensification degree to 50 ℃, reclaim under reduced pressure sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; Add dehydrated alcohol, add ethyl acetate again and be warming up to 55 ℃, stir maintenance down 1 hour, be cooled to 5 ℃, get rid of filter, get filter cake;

G, in reactor, add ethanol; Add 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline; Be warming up to 55 ℃, be incubated 30 minutes, disposable input filter cake is warming up to 60 ℃, treats stable back insulation 2 hours; Decompression recycling ethanol; Add water for cooling to 14 ℃, filter, dry, vacuum drying namely.

3. according to the described a kind of 5-difluoro-methoxy of claim 1-2-[[(4-chloro-3-methoxyl group-2-pyridyl) methyl] sulfo-]-preparation method of 1H-benzoglyoxaline monohydrate, it is characterized in that containing following steps: a, in reactor, add water 1402kg, the solid-state sodium hydroxide 201kg that adds technical grade is stirred to dissolving, after the voitol 498kg of reprocessing industry level is stirred to dissolving, the methyl-sulfate 899kg that adds technical grade, dropwise, be warming up to 58 ℃, be incubated 2.5 hours, be cooled to below 25 ℃, the methylene dichloride 2002L of processing industry level extracts, methylene dichloride is reclaimed in 85 ℃ of distillations of extracting solution normal pressure, does not stop distillation to there being the methylene dichloride overhead product;

B, in still behind the methylene dichloride is reclaimed in distillation, add water 397kg, add concentration and be 28% ammoniacal liquor 1304kg, slowly be warming up to 85 ℃, be incubated 1.5 hours, be warming up to 88 ℃ again, be incubated 2 hours; Be decompressed to vacuum tightness 0.09MPa, behind the ammonia in the removal still, feed liquid slowly imported single-effect evaporator, pressure in the vaporizer is reduced to vacuum tightness 0.09MPa, steaming water to moisture is 35% o'clock, feed liquid is led while hot entering the bipyramid baker, is decompressed to vacuum tightness 0.09MPa oven dry under 90 ℃;

C, with in the bipyramid baker oven dry material put into reactor, the methylene dichloride 1802kg that adds technical grade again in the still, the phosphorus oxychloride 2097L of processing industry level, dropwise, with steam reactor slowly is warming up to 58 ℃, start stirring, treat the material dissolution in the still, after being warming up to 85 ℃, will expect that temperature remains on 85 ℃, be incubated 6 hours; Insulation finishes, and is decompressed to vacuum tightness 0.09MPa, reclaims phosphorus oxychloride, be decompressed to terminal point after, logical slightly water coolant will be expected temperature drop to 70 ℃, close vacuum and open emptying; Concentrated solution in the still is put into the still that 3000kg water is equipped with in lower floor while hot, stir hydrolysis, blowing finishes and continues to stir 2 hours, and is abundant to the whole hydrolysis of material; Continue logical water coolant and will expect below the temperature drop to 25 ℃, slowly drip concentration in the still and be 28% ammoniacal liquor, adjusting PH=8; Stop stirring and left standstill 2 hours, layer oily matter is isolated, and layer oily matter is put into strainer filter;

D, the strainer filtrate filtered is imported in the reactor, the phospho-wolframic acid 184L of processing industry level in the still is warming up to 82 ℃ again, be incubated after 30 minutes, begins to drip concentration and be 30% hydrogen peroxide 8499L, dropwises, and 85 ℃ are incubated 5.5 hours; Logical icy salt solution is cooled to below 25 ℃, is that 30% sodium hydroxide lye is regulated PH=8 with concentration; Add the dichloromethane extraction of technical grade, lower floor's extracting solution joins in the reactor, stirs 30 minutes;

E, in the reacting kettle jacketing logical 90 ℃ of hot water, be warming up to 85 ℃ of distilled dichloromethanes under the first normal pressure, be decompressed to vacuum tightness 0.09MPa distilled dichloromethane under 85 ℃ again, the distillation end point phenomenon is that material all solidifies in the still; Add the Glacial acetic acid 352kg of technical grade, return-flow system is opened, and starts to stir, and after stirring is normal, keeps stirring; Be warming up to 90 ℃, allow solid dissolve, slowly add the acetic anhydride 1500L of technical grade, after dropwising, keep 85 ℃ of temperature in the kettle, 3.5 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim Glacial acetic acid and acetic anhydride, to feed concentration greater than 80% o'clock; Concentrated solution is cooled to 25 ℃, adds the methyl alcohol 400kg of technical grade, stir 30 minutes to even; Be that 30% sodium hydroxide lye is regulated PH=12 with concentration, 25 ℃ of insulations 4 hours down; Be decompressed to vacuum tightness 0.09MPa, kept 2 hours, utilize the methyl alcohol in the vacuum removal feed liquid; Be that aqueous acetic acid more than 90% is regulated PH=7 with concentration again; With the dichloromethane extraction of technical grade, it is standby to keep supernatant liquid, bleeds off lower floor's extracting solution;

F, reacting kettle jacketing feed icy salt solution, and making reactor temperature is 10 ℃, add the sulfur oxychloride 1198kg of technical grade in the reactor; After dropwising, be warming up to 23 ℃, be incubated 4 hours; The logical hot water of reacting kettle jacketing makes the temperature of reactor the inside reach 50 ℃, is decompressed to vacuum tightness 0.09MPa and reclaims sulfur oxychloride and the methylene dichloride whole evaporates to dryness of liquid material to the still; After adding dehydrated alcohol 480kg, add the ethyl acetate 1000kg of technical grade again, be warming up to 55 ℃, stir down and kept 1 hour, logical cooling water temperature to 5 ℃ gets rid of filter, gets filter cake;

G, add 95% ethanol 1802kg in the reactor, stirred 20 minutes; 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline the 500kg that adds technical grade; Be warming up to 55 ℃, be incubated 30 minutes, disposable input filter cake 500kg is warming up to 60 ℃, treats stable back insulation 2 hours; Be decompressed to vacuum tightness 0.09MPa and reclaim ethanol; Add water 2500kg, logical water of condensation is cooled to 14 ℃, filters, and dries, and vacuum tightness 0.05MPa, 105 ℃ of following oven dry are namely.