CN1966495A - Method for preparing 5-(4- fluobenzene sulphonyloxy) benzimidazole-2-amido methyl formate - Google Patents
Method for preparing 5-(4- fluobenzene sulphonyloxy) benzimidazole-2-amido methyl formate Download PDFInfo
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Abstract
The invention relates to a preparation method for 5-(4-fluorophenyl-sulfonyl)-benzimidazole-2-methyl carbamate. The method includes (1) using p-aminophenol as raw materials, and preparing a number of new 3-nitro-4-substituted aminophenol intermediates through acylation and denitrification; (2) carrying out a condensation reaction of 3-nitro-4-substituted aminophenol intermediates with the 4-fluorophenylsulfonyl chloride in the alkaline solution, and hydrolyzing to obtain 2-nitro-4-(4-fluorophenyl-sulfonyl)-aniline intermediates; (3) carrying out a reduction reaction of 2-nitro-4-(4-fluorophenyl-sulfonyl)-aniline intermediates to obtain 4-(4-fluorophenyl-sulfonyl)-o-phenylenediamine intermediates; and (4) carrying out a closed loop reaction of closed-loop agents and 4-(4-fluorophenyl-sulfonyl)-o-phenylenediamine to obtain 5-(4-fluorophenyl-sulfonyl)-benzimidazole-2-methyl carbamate. This invention has the advantages of high yield, small unit consumption, and low cost. The raw materials are cheap and the method is easy for industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of benzimidazoles dehelminthization chemical synthetic drug 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane.
Background technology
5-(4-fluorobenzene sulfonyloxy) but benzimidazolyl-2 radicals-Urethylane beastly dual-purpose broad-spectrum de-worming medicine that is a kind of people has another name called luxabendazole, English luxabendazole by name belongs to the benzimidazole type chemical synthetic drug.
The structural formula of 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane is:
At present, the benzimidazole type chemical synthetic drug is as the broad-spectrum anti-parasite medicine, efficient, the safe anti-intestinal nematodes medicine of a class especially, and its use is very wide.Being extensive use of of this class medicine makes parasiticide commonly used at present become to subtracting with medicament categories and quantity, and shorten the anti-parasitic-infectious course of treatment, and methods of treatment is further simplified.
At present, have only U.S.Patent 4,639,463 have reported the synthetic method of 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane.In the patent, the author has reported three full chemical synthesis routes of 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane, is respectively:
(1) synthetic route of " first condensation restores, last closed loop ".Promptly will obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline to fluorobenzene SULPHURYL CHLORIDE and 3-nitro-4-amino-phenol condensation earlier, select for use Raney nickel catalytic hydrogenating reduction to obtain 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine then, adopting N at last, two (methylthio group) methylene radical of two (methoxycarbonyl)-S-methyl-isothioureas of N-or N-[] carbamate carries out ring-closure reaction and obtains 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane.
(2) synthetic route of " reduction earlier, closed loop again, last condensation ".Promptly earlier 3-nitro-4-amino-phenol is obtained 4-hydroxyl O-Phenylene Diamine with Raney nickel hydrogenating reduction, use N again, two (the methoxycarbonyl)-S-methyl-isothioureas of N-carry out ring-closure reaction and obtain 5-hydroxy benzo imidazoles-2-Urethylane, and condensation obtains 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane at last and to the fluorobenzene SULPHURYL CHLORIDE.
(3) synthetic route of " first condensation restores, closed loop and amination again, last esterification ".Promptly will obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline to fluorobenzene SULPHURYL CHLORIDE and 3-nitro-4-amino-phenol condensation earlier, select for use Raney nickel hydrogenating reduction to obtain 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine then, carry out ring-closure reaction with cyanogen bromide again and obtain 2-amino-5-(4-fluorobenzene sulfonyloxy) benzoglyoxaline, use dimethyl carbonate (DMC) esterification to obtain 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane at last.
But U.S.Patent 4,639, the reaction yield of 463 reported method is low, 3-nitro-4-amino-phenol of selecting for use, Raney nickel catalyzator and closed loop agent N, raw material unit price height such as two (the methoxycarbonyl)-S-methyl-isothioureas of N-, post-reaction treatment is more loaded down with trivial details, is unfavorable for industrial production.
Summary of the invention
The purpose of this invention is to provide a kind of yield height, production cost is low, and aftertreatment is simple, is convenient to the preparation method of industrial 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane.
The technical scheme that realizes above-mentioned purpose is: the method for a kind of 5-of preparation (4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane, and preparation process is as follows:
A, be raw material, utilize acylating agent to carry out the acidylate protection earlier, again through the nitrated 3-nitro 4-substituted-amino phenol intermediate that makes with the p-aminophenol;
B, 3-nitro 4-substituted-amino phenol intermediate are in alkaline solution and to the condensation of fluorobenzene SULPHURYL CHLORIDE, and hydrolysis obtains 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline intermediate;
C, 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline intermediate is reduced, obtain 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate with reduction method;
D, select for use closed loop agent and 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate to carry out ring-closure reaction, make 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product.
The synthetic route of 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane is as follows:
In 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane was synthetic, the selected substituted-amino phenol intermediate of the present invention comprised 3-nitro-4-formamido group phenol, 3-nitro-4-acetoamidophenol, 3-nitro-4-propionamido phenol, 3-nitro-4-acylamino phenol, 3-nitro-4-benzoyl amino-phenol, 3-nitro-4-benzamido phenol, 3-nitro-4-trifluoroacetamido phenol and 3-nitro-4-chloro acetylamino phenol.In condensation reaction, the present invention selects the HCl that produces in multiple organic bases and mineral alkali and the aqueous solution absorption reaction process thereof for use, and reaction is moved to positive dirction.Wherein organic bases comprises organic amine compound, ammoniacal liquor, pyridine and derivative thereof, morpholine and derivative thereof, DMF, DBU, and mineral alkali comprises oxyhydroxide, carbonate, the supercarbonate of sodium and potassium.The mole dosage of alkali (comprising organic bases and mineral alkali) is for to 0.9～1.2 times of fluorobenzene SULPHURYL CHLORIDE (or substituted-amino phenol), preferably 1.0～1.1 times.
Based on dissolving characteristics to fluorobenzene SULPHURYL CHLORIDE and substituted-amino phenol raw material, the present invention selects for use among alcoholic solvent, acetone, methylene dichloride, ethylene dichloride, THF, the DMF such as methyl alcohol, ethanol one or more as solvent, raw material is fully dissolved, thereby realize homogeneous reaction.In addition, determine two more excellent reinforced order in condensation reaction, the first adds organic bases or mineral alkali and substituted-amino phenol raw material earlier, stirs to drip down the fluorobenzene chloride solution is reacted; It two is to add earlier substituted-amino phenol and to the fluorobenzene SULPHURYL CHLORIDE, stir and drip organic bases or mineral alkali and reactant aqueous solution thereof down.
The present invention mainly adopts three kinds of method reductase 12-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline intermediate, makes 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate.These three kinds of methods are respectively:
The active metal reduction method: the present invention selects for use zinc powder and acetate to form reductive agent nitro is reduced.
The sulfocompound reduction method: the present invention selects for use sodium sulphite and Sodium sulfhydrate reductase 12-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline to make 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate respectively.Wherein, the mole dosage of sodium sulphite is 1～8 times of 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline, and preferably 4～6 times, the mole dosage of Sodium sulfhydrate is 2～6 times of 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline.
The catalytic hydrogenating reduction method: it is catalyzer that the present invention adopts the cotton-shaped nickel of homemade porous, and hydrogenating reduction 2-nitro-4-under 1～10atm (4-fluorobenzene sulfonyloxy)-aniline makes 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate.The cotton-shaped nickel catalyzator of porous that adopts prepares by the following method: in the mashed prod of Zn powder, 30% acidic silicasol furnishing, add nickel chloride solution rapidly; After several minutes, use the deionized water wash sludge; Add 20% acetum again, stirring reaction 0.5h; Leave standstill the cotton-shaped nickel of porous is sunk; The supernatant liquid that inclines washes with water to neutrality; Use the 50ml absolute ethanol washing again 3 times, in ethanol, preserve standby.
The present invention selects three kinds of new closed loop agent and 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate reaction for use, makes 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product.These three kinds of closed loop agent are respectively Methyl cyanocarbamate, O-methyl-isourea methyl-formiate or S-methyl-isourea methyl-formiate.
(1) selecting for use Methyl cyanocarbamate to carry out in the process of ring-closure reaction, the concentration of Methyl cyanocarbamate is between 97g/l～200g/l, preferably between 170g/l～180g/l.If concentration is on the low side, the moisture that Methyl cyanocarbamate self brings can reduce reactive behavior; If concentration is higher, the easy crystallization of Methyl cyanocarbamate, inconvenient operation is simultaneously because the reaction solution volume is little and a large amount of solid inorganic salts are arranged, 4-(4-fluorobenzene the sulfonyloxy)-O-Phenylene Diamine intermediate that causes adding can not dissolve fully, thereby reaction is incomplete, yield reduces.The ratio (mol ratio) of consumption of mineral acid (in H+) and 4-in the reaction (4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate is 1.5～3: 1.If acid very little, can not guarantee reaction and carry out fully; Hyper acid, then makes 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane further generate salt, causes product yield to descend.
(2) selecting for use O-methyl-isourea methyl-formiate or S-methyl-isourea methyl-formiate to carry out in the process of ring-closure reaction, the mole dosage of closed loop agent is 1.1～1.4 times of 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine reduzate intermediate.The acid that ring-closure reaction is used can be selected mineral acid and organic acid for use.
Embodiment
The present invention is further detailed explanation below in conjunction with embodiment.
1 substituted-amino phenol preparation process
Embodiment one
Step 1
Have in the four-hole boiling flask of whipping appts and thermometer at 150ml, add 10.0g (0.092mol) p-aminophenol, 10ml (0.120mol) aceticanhydride successively, heated and stirred, back flow reaction 2h.Temperature constantly raises in the reaction process.After reaction finishes, reaction solution is poured in a small amount of frozen water, promptly had crystal to separate out, suction filtration, product alcohol recrystallization obtains acamol 13.2g, yield 94.9%, 170 ℃ of fusing points.
Step 2
Have in the four-hole boiling flask of whipping appts and thermometer at 150ml, add 80ml 98% sulfuric acid, be cooled to below 10 ℃ under stirring, add acamol 9.4g (0.062mol), be cooled to below 10 ℃, drip the mixed acid solution of 3.7ml98% sulfuric acid and 3.8ml96% nitric acid, add afterreaction 2h.The reaction stop after, under strong mixing, reaction solution is poured in a large amount of trash ices, separate out yellow crystals, suction filtration, dry 3-nitro-4-acetoamidophenol 9.2g, yield 75.6%, 162 ℃ of fusing points.
Embodiment two
With reference to embodiment one reactions steps, first formylation, the nitrated 3-nitro-4-formamido group phenol that obtains again.
Embodiment three
With reference to embodiment one reactions steps, first propionylization, the nitrated 3-nitro-4-propionamido phenol that obtains again.
Embodiment four
With reference to embodiment one reactions steps, first Butyrylation, the nitrated 3-nitro-4-acylamino phenol that obtains again.
Embodiment five
With reference to embodiment one reactions steps, first benzoylation, the nitrated 3-nitro-4-benzoyl amino-phenol that obtains again.
Embodiment six
With reference to embodiment one reactions steps, first benzoylation, the nitrated 3-nitro-4-benzamido phenol that obtains again.
Embodiment seven
With reference to embodiment one reactions steps, first trifluoroacetylation, the nitrated 3-nitro-4-trifluoroacetamido phenol that obtains again.
Embodiment eight
With reference to embodiment one reactions steps, first chloroacetylation, the nitrated 3-nitro-4-chloro acetylamino phenol that obtains again.
2 condensation reactions
Embodiment nine
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add 100mlDMF, 14ml (0.1mol) triethylamine, 19.6g (0.1mol) 3-nitro-4-acetoamidophenol successively, stirring is all dissolved raw material.Other takes by weighing 19.5g (0.1mol) the fluorobenzene SULPHURYL CHLORIDE is dissolved among the 30mlDMF, after treating to dissolve fully, is added drop-wise in the reaction system.After dropwising, reaction 5h.After reaction finishes, suction filtration, filter cake is with a small amount of DMF washed twice.Merging filtrate moves in the 500ml reaction flask hydrolysis reaction 1h.After reaction finished, concentrating under reduced pressure added small amount of methanol and deionized water more successively, stirred 1.5h, suction filtration, filter cake deionized water wash, dry condenses 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline 26.4g, yield 84.5%, 161 ℃ of the fusing points of getting.
Embodiment ten
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add 19.6g (0.1mol) 3-nitro-4-acetoamidophenol, 19.5g (0.1mol) successively to fluorobenzene SULPHURYL CHLORIDE, 100mlDMF, heated and stirred is all dissolved raw material.Drip the NaOH aqueous solution in reaction system.Add back temperature reaction 5h.Hydrolysis reaction 1h again.React and finish back adding deionized water, suction filtration behind the stirring 1.0h, filter cake deionized water wash, dry condenses 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline 26.8g, yield 85.8%, 161 ℃ of the fusing points of getting.
Embodiment 11
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-formamido group phenol and alkali reaction, again through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points.
Embodiment 12
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-propionamido phenol and alkali reaction, again through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points.
Embodiment 13
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-acylamino phenol and alkali reaction, again through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points.
Embodiment 14
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-benzoyl amino-phenol and alkali reaction, again through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points.
Embodiment 15
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-benzamido phenol and alkali reaction, through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points again.
Embodiment 16
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-trifluoroacetamido phenol and alkali reaction, through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points again.
Embodiment 17
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-chloro acetylamino phenol and alkali reaction, through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points again.
3 reduction reaction processes
Embodiment 18
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add 10.9g (0.195mol) zinc powder successively, 5ml acetate and 50ml deionized water stir and make the raw material thorough mixing.After the heated and boiled, cooling slightly.Other takes by weighing 15.6g (0.05mol) 2-nitro 4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate and dissolves with DMF, moves into constant pressure funnel.Stir down, be added drop-wise in the reaction system and react.Finish heating reflux reaction 6h.Reaction can adopt following two kinds of methods to handle after finishing:
(1), pressure reducing and steaming water and DMF, after crystallization is separated out, leave standstill 1h, suction filtration, the filter cake deionized water wash, drying obtains 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine reduzate intermediate.But the crude product recrystallization obtains crystal, but the present invention does not adopt the recrystallization operation, is directly used in the next step.
(2), add deionized water, benzene stirs the 0.5h after-filtration, filtrate is told upper strata (organic layer) with separating funnel.The benzene organic layer that contains 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine reduzate intermediate that obtains is directly used in down the step ring-closure reaction.
Embodiment 19
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add 31.2g (0.1mol) 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 100ml ethanol successively, heated and stirred adds 46.8g (0.6mol) sodium sulphite, heating reflux reaction 4h in batches.Reaction finishes, and cooling is poured reaction solution in the separating funnel into, divides and falls down layer, and the upper strata moves in the reaction flask, and normal pressure concentrates and reclaims ethanol, and raffinate can adopt following two kinds of methods to handle:
(1) stir and to add the deionized water crystallization down, leave standstill suction filtration behind the 1h, the filter cake deionized water wash, drying obtains 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine reduzate intermediate.But the reduzate intermediate recrystallization that obtains obtains crystal, but the present invention does not adopt the recrystallization operation, is directly used in the next step.
(2) add deionized water, benzene stirs the 0.5h after-filtration, and filtrate is told upper strata (organic layer) with separating funnel.The benzene organic layer that contains 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine reduzate intermediate that obtains is directly used in down the step ring-closure reaction.
Embodiment 20
Have in the four-hole boiling flask of whipping appts and thermometer at 500ml, add 31.2g (0.1mol) 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 100ml ethanol successively, heated and stirred.Other takes by weighing in 22.4g (0.4mol) the Sodium sulfhydrate adding reaction system, finishes heating reflux reaction 4h, and reaction finishes, cooling is poured reaction solution in the separating funnel into, divides and falls down layer, the upper strata moves in the reaction flask, and normal pressure concentrates and reclaims ethanol, and it is consistent that subsequent operations and embodiment 19 are adopted.
Embodiment 21
Step 1
Taking by weighing the 10.0g Nickel dichloride hexahydrate is dissolved in the 10mL water.Take by weighing the 12.6gZn powder again, add 30% acidic silicasol furnishing pasty state, stir down, nickel chloride solution is added rapidly in the zinc powder, react fierce heat release, have hydrogen to emit.After several minutes, use 50ml deionized water wash sludge 3 times.Add the 180ml20% acetum in precipitation, behind 40～50 ℃ of following stirring reaction 0.5h, the speed that hydrogen produces significantly slows down.By stirring, the cotton-shaped nickel of the porous of floating on liquid level is sunk.The supernatant liquid that inclines washes with water to neutrality, uses the 50ml absolute ethanol washing again 3 times, the cotton-shaped nickel catalyzator of porous, be stored in the ethanol standby.
Step 2
Have at 250ml on the four-hole boiling flask of whipping appts and thermometer, connect the hydrogen airway, inflated with nitrogen inspection units resistance to air loss.The laggard line replacement of passed examination, add 15.6g2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, the cotton-shaped nickel catalyzator of porous of preparation, 100ml ethanol subsequently successively, heated and stirred, after temperature rises to 40 ℃, with the hydrogen gas in the steel cylinder, through importing in the reaction flask behind the aerometer buret.Through after the inducing of certain hour, inhale the speed of hydrogen and accelerate.Treat that hydrogen-absorption speed reduces to 0.1～0.2ml/min, when total hydrogen is about 1100ml, stop to feed hydrogen and stirring, a moment is left standstill in cooling, allow catalyzer be sunken to bottle at the bottom of, the sucking-off supernatant liquid.Normal pressure concentrate to reclaim ethanol, and it is consistent that subsequent operations and embodiment 19 are adopted.
The ring-closure reaction process
Embodiment 22
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add solid reduction thing 4-(4-fluorobenzene the sulfonyloxy)-O-Phenylene Diamine 27.6g (0.098mol), the 100ml benzene that adopt treatment process (1) operation to obtain among the embodiment of reduction reaction process successively, add after the stirring and dissolving and contain 10.8g (0.108mol) the Methyl cyanocarbamate aqueous solution (concentration of Methyl cyanocarbamate is 97g/l).Other measures 29.4ml (0.294mol) concentrated hydrochloric acid, is added drop-wise in the system and reacts.Dropwise, heating reflux reaction 3h, cooling, suction filtration, the filter cake deionized water wash is used methyl alcohol/DMF solution weight crystallization again, dry 5-(the 4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product 27.0g that gets, yield 74.0% (so that 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline is reference), 236 ℃ of fusing points.
Embodiment 23
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add solid reduction thing 4-(4-fluorobenzene the sulfonyloxy)-O-Phenylene Diamine 27.6g (0.098mol), the 100ml benzene that adopt treatment process (1) operation to obtain among the embodiment of reduction reaction process successively, add after the stirring and dissolving and contain 10.8g (0.108mol) the Methyl cyanocarbamate aqueous solution (concentration of Methyl cyanocarbamate is 200g/l).Other measures 15ml (0.15mol) concentrated hydrochloric acid, is added drop-wise in the system and reacts.Dropwise, heating reflux reaction 3h, cooling, suction filtration, the filter cake deionized water wash is used methyl alcohol/DMF solution weight crystallization again, dry 5-(the 4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product 27.4g that gets, yield 75.0% (so that 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline is reference), 236 ℃ of fusing points.
Embodiment 24
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add solid reduction thing 4-(4-fluorobenzene the sulfonyloxy)-O-Phenylene Diamine 27.6g (0.098mol) that adopts treatment process (1) operation to obtain among the embodiment of reduction reaction process successively, 100ml benzene, add 15.0g (0.113mol) O-methyl-isourea methyl-formiate and small amount of acid after the stirring and dissolving, heated and stirred, react 4h down at 60 ℃, suction filtration, the filter cake deionized water wash, use methyl alcohol/DMF solution weight crystallization again, dry 5-(the 4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product 28.5g that gets, yield 78.0% (so that 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline is reference), 236 ℃ of fusing points.
Embodiment 25
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add the reduzate benzole soln (4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine 27.6g (0.098mol) that adopts treatment process (2) operation to obtain among the embodiment of reduction reaction process, 100ml benzene, add 18.1g (0.137mol) O-methyl-isourea methyl-formiate and small amount of acid after the stirring and dissolving, heated and stirred, 60 ℃ are reacted 4h down, suction filtration, the filter cake deionized water wash, use methyl alcohol/DMF solution weight crystallization again, dry 5-(the 4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product 28.5g that gets, yield 78.8% (so that 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline is reference), 236 ℃ of fusing points.
Embodiment 26
With reference to embodiment 24,25 reactions steps and charging capacity, selecting S-methyl-isourea methyl-formiate for use is the closed loop agent, obtains 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product, 236 ℃ of fusing points.
Claims (10)
1, a kind of method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane is characterized in that preparation process is as follows:
A, be raw material, utilize acylating agent to carry out the acidylate protection earlier, again through the nitrated 3-nitro-4-substituted-amino phenol intermediate that makes with the p-aminophenol;
B, 3-nitro-4-substituted-amino phenol intermediate is in alkaline solution and to the condensation of fluorobenzene SULPHURYL CHLORIDE, and hydrolysis obtains 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline intermediate;
C, 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline intermediate is reduced, obtain 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate with reduction method;
D, select for use closed loop agent and 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate to carry out ring-closure reaction, make 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product;
Wherein said acylating agent is formic acid, acetate, trifluoroacetic acid, Mono Chloro Acetic Acid, propionic acid, butyric acid, phenylformic acid; First and second acid anhydrides, diacetyl oxide; Acetyl Chloride 98Min., chloroacetyl chloride, trifluoroacetyl chloride, propionyl chloride, butyryl chloride, Benzoyl chloride;
Wherein the alkali in the alkaline solution in the b step is organic bases or mineral alkali, organic bases is one or more among organic amine compound, ammoniacal liquor, pyridine and derivative thereof, morpholine and derivative thereof, DMF, the DBU, and mineral alkali is one or more in the oxyhydroxide, carbonate, supercarbonate of sodium and potassium; The mole dosage of alkali is 0.9～1.2 times to the fluorobenzene SULPHURYL CHLORIDE.
2, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 1, it is characterized in that: in the b step contract and process is selected alcoholic solvent methyl alcohol or ethanol for use, and in the acetone, methylene dichloride, ethylene dichloride, THF, DMF one or more are as solvent.
3, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 1, it is characterized in that: the reduction method of c step is selected any one in active metal reduction method, sulfocompound reduction method and the catalytic hydrogenating reduction method for use.
4, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 3 is characterized in that: the active metal reduction method adopts zinc powder and acetate to form reductive agent.
5, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 3, it is characterized in that: the sulfocompound reduction method adopts sodium sulphite and sodium bisulfide as reductive agent, the mole dosage of sodium sulphite is 1～8 times of 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline, and the mole dosage of sodium bisulfide is 2～6 times of 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline.
6, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 3 is characterized in that: the catalytic hydrogenating reduction method adopts the cotton-shaped nickel of porous as catalyzer.
7, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 6, it is characterized in that: the cotton-shaped nickel catalyzator of the porous of employing prepares by the following method: in the mashed prod of Zn powder, 30% acidic silicasol furnishing, add nickel chloride solution rapidly; After several minutes, use the deionized water wash sludge; Add 20% acetum again, stirring reaction 0.5h; Leave standstill the cotton-shaped nickel of porous is sunk; The supernatant liquid that inclines washes with water to neutrality; Use the 50ml absolute ethanol washing again 3 times, in ethanol, preserve standby.
8, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 1, it is characterized in that: the closed loop agent in the d step is any one in Methyl cyanocarbamate, O-methyl-isourea methyl-formiate, the S-methyl-isourea methyl-formiate.
9, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 8, it is characterized in that: the concentration of the closed loop agent Methyl cyanocarbamate in the d step is between 97g/l～200g/l, and the mole dosage of mineral acid (in H+) is 1.5～3 times of 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine in the reaction.
10, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 8 is characterized in that: the closed loop agent O-methyl-isourea methyl-formiate in the d step, the mole dosage in the S-methyl-isourea methyl-formiate are 1.1～1.4 times of 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE3247615A1 (en) * | 1982-12-23 | 1984-07-05 | Hoechst Ag, 6230 Frankfurt | SUBSTITUTED PHENYLSULFONYLOXYBENZIMIDAZOLE CARBAMINATES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
| CS277240B6 (en) * | 1990-08-31 | 1992-12-16 | Chemopharma | Process for preparing methyl/5-(4-fluorobenzenesulfonyloxy)benzimidazol-2-yl/carbamate |
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