CN1966495B - Method for preparing 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate methyl ester - Google Patents

Abstract

The invention relates to a method for preparing methyl 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate. The preparation steps are as follows: using p-aminophenol as a raw material, first using a variety of acylating agents to carry out Acylation protection, and then nitration to prepare a variety of new 3-nitro-4-substituted aminophenol intermediates; 3-nitro-4-substituted aminophenol intermediates are condensed with p-fluorobenzenesulfonyl chloride in alkaline solution, Hydrolysis to obtain 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline intermediate; Reduction, obtains 4-(4-fluorobenzenesulfonyloxy group)-o-phenylenediamine intermediate; Select ring-closing agent and 4-(4-fluorobenzenesulfonyloxy)-o-phenylenediamine intermediate to carry out ring-closing reaction, Prepare 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate methyl ester product. The invention has the advantages of high product yield, low unit consumption, low production cost, cheap and easy-to-obtain raw materials, and is convenient for industrial production.

Description

Method for preparing 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate methyl ester

technical field

The invention relates to a preparation method of 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate methyl ester, a benzimidazole anthelmintic chemical synthesis drug.

Background technique

Methyl 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate is a broad-spectrum anthelmintic that can be used both in humans and animals. It is also known as lubendazole, and its English name is luxabendazole. Benzimidazole chemical synthesis drug.

The structural formula of 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate methyl ester is:

At present, benzimidazole chemical synthetic drugs are widely used as broad-spectrum antiparasitic drugs, especially a class of efficient and safe anti-intestinal nematode drugs. The widespread use of such drugs has reduced the types and quantities of commonly used anti-parasitic drugs, shortened the course of treatment for anti-parasitic infections, and further simplified the treatment methods.

At present, only U.S. Patent 4,639,463 reports the synthetic method of 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate methyl ester. In the patent, the author reported three total chemical synthesis routes of methyl 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate, which are:

(1) The synthetic route of "condensation first, then reduction, and finally ring closure". That is, first condense p-fluorobenzenesulfonyl chloride and 3-nitro-4-aminophenol to obtain 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline, and then use Raney nickel to catalyze hydrogenation reduction to obtain 4 -(4-Fluorobenzenesulfonyloxy)-o-phenylenediamine, finally N,N-bis(carbomethoxy)-S-methylisothiourea or N-[bis(methylthio)methylene ] carbamate to carry out ring closure reaction to obtain 5-(4-fluorobenzenesulfonyloxy) benzimidazole-2-methyl carbamate.

(2) The synthetic route of "first reduction, then ring closure, and final condensation". That is, first hydrogenate 3-nitro-4-aminophenol with Raney nickel to obtain 4-hydroxy-o-phenylenediamine, and then use N,N-bis(methoxycarboxy)-S-methylisothiourea for ring closure reaction Obtain 5-hydroxybenzimidazole-2-carbamate methyl ester, and finally condense with p-fluorobenzenesulfonyl chloride to obtain 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate methyl ester.

(3) The synthesis route of "first condensation, then reduction, then ring closure and amination, and finally methyl esterification". That is, first condense p-fluorobenzenesulfonyl chloride and 3-nitro-4-aminophenol to obtain 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline, and then select Raney nickel hydrogenation reduction to obtain 4- (4-fluorobenzenesulfonyloxy)-o-phenylenediamine, and then use cyanogen bromide to carry out ring-closure reaction to obtain 2-amino-5-(4-fluorobenzenesulfonyloxy) benzimidazole, and finally use dimethyl carbonate Methyl esterification of base ester [DMC] gives methyl 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate.

But, the reaction yield of the method of U.S.Patent 4,639,463 report is low, and the selected 3-nitro-4-aminophenol, Raney nickel catalyst and ring-closing agent N, N-bis(methoxycarboxy)-S-methyl isothiourea The unit price of such raw materials is high, and the post-reaction treatment is more loaded down with trivial details, which is unfavorable for industrial production.

Contents of the invention

The purpose of this invention is to provide a kind of yield height, and production cost is low, and aftertreatment is simple, is convenient to the preparation method of the 5-(4-fluorobenzenesulfonyloxy group) benzimidazole-2-methyl carbamate of industrial production.

The technical solution for achieving the above object is: a method for preparing methyl 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate, the preparation steps of which are as follows:

a. Using p-aminophenol as a raw material, first use an acylating agent to carry out acylation protection, and then obtain a 3-nitro-4-substituted aminophenol intermediate through nitration;

B. The 3-nitro-4-substituted aminophenol intermediate is condensed with p-fluorobenzenesulfonyl chloride in an alkaline solution, and hydrolyzed to obtain a 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline intermediate;

c, 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline intermediate is reduced by reduction method to obtain 4-(4-fluorobenzenesulfonyloxy)-o-phenylenediamine intermediate ;

D, select ring-closing agent and 4-(4-fluorobenzenesulfonyloxy)-o-phenylenediamine intermediate to carry out ring-closing reaction, make 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-amino Methyl formate products.

The synthetic route of 5-(4-fluorobenzenesulfonyloxy) benzimidazole-2-carbamate methyl ester is as follows:

In the synthesis of 5-(4-fluorobenzenesulfonyloxy) benzimidazole-2-methyl carbamate, the selected substituted aminophenol intermediates of the present invention include 3-nitro-4-formylaminophenol, 3 -Nitro-4-acetamidophenol, 3-nitro-4-propionylaminophenol, 3-nitro-4-butyrylaminophenol, 3-nitro-4-phenamidophenol, 3-nitro -4-Benzoylaminophenol, 3-nitro-4-trifluoroacetamidophenol and 3-nitro-4-chloroacetamidophenol. In the condensation reaction process, the present invention selects various organic bases and inorganic bases and their aqueous solutions to absorb the HCl produced in the reaction process to make the reaction move in the positive direction. The organic bases include organic amine compounds, ammonia water, pyridine and its derivatives, morpholine and its derivatives, DMF, DBU, and the inorganic bases include sodium and potassium hydroxides, carbonates, and bicarbonates. The molar dosage of base (including organic base and inorganic base) is 0.9 to 1.2 times that of p-fluorobenzenesulfonyl chloride [or substituted aminophenol], preferably 1.0 to 1.1 times.

Based on the dissolution characteristics of p-fluorobenzenesulfonyl chloride and substituted aminophenol raw materials, the present invention selects one or more of alcohol solvents such as methanol and ethanol, acetone, methylene dichloride, ethylene dichloride, THF, and DMF as solvents, The raw materials are fully dissolved to achieve a homogeneous reaction. In addition, during the condensation reaction, two optimal feeding sequences are determined. One is to add organic base or inorganic base and substituted aminophenol raw materials first, and then add p-fluorobenzenesulfonyl chloride solution dropwise under stirring; the other is to add substituted aminophenol first. Aminophenol and p-fluorobenzenesulfonyl chloride are added dropwise with organic base or inorganic base and its aqueous solution under stirring.

The present invention mainly adopts three methods to reduce 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline intermediate to obtain 4-(4-fluorobenzenesulfonyloxy)-o-phenylenediamine intermediate body. The three methods are:

Active metal reduction method: the present invention uses zinc powder and acetic acid to form a reducing agent to reduce nitro groups.

Sulfur-containing compound reduction method: the present invention selects sodium sulfide and sodium hydrosulfide to reduce 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline to obtain 4-(4-fluorobenzenesulfonyloxy) - O-phenylenediamine intermediate. Wherein, the molar dosage of sodium sulfide is 1～8 times of 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline, preferably 4～6 times, and the molar dosage of sodium hydrosulfide is 2- 2 to 6 times that of nitro-4-(4-fluorobenzenesulfonyloxy)-aniline.

Catalyzed hydrogenation reduction method: the present invention adopts self-made porous flocculent nickel as a catalyst, and hydrogenates 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline at 1 to 10 atm to obtain 4-( 4-fluorobenzenesulfonyloxy)-o-phenylenediamine intermediate. The porous flocculated nickel catalyst that adopts is prepared by the following method: in the paste that Zn powder, 30% acidic silica sol are transferred, add nickel chloride solution rapidly; After several minutes, wash muddy precipitate with deionized water; Add 20% acetic acid solution, stir and react for 0.5h; let the porous flocculent nickel sink; pour off the supernatant, wash with water until neutral; then wash with 50ml of absolute ethanol for 3 times, and store in ethanol for later use.

The present invention selects three kinds of new ring-closing agents and 4-(4-fluorobenzenesulfonyloxy)-o-phenylenediamine intermediate reaction, makes 5-(4-fluorobenzenesulfonyloxy) benzimidazole-2 - Methyl carbamate products. The three ring-closing agents are methyl cyanocarbamate, methyl O-methylisoureaformate or methyl S-methylisoureaformate, respectively.

(1) In the process of selecting methyl cyanocarbamate for ring-closing reaction, the concentration of methyl cyanocarbamate is between 97g/l and 200g/l, preferably between 170g/l and 180g/l. If concentration is on the low side, the moisture that methyl cyanocarbamate self brings can reduce reactivity; If concentration is high, methyl cyanocarbamate is easy to crystallize, and operation is inconvenient, simultaneously because reaction solution volume is little and has a large amount of solid inorganic salts, As a result, the added 4-(4-fluorobenzenesulfonyloxy)-o-phenylenediamine intermediate cannot be completely dissolved, resulting in incomplete reaction and reduced yield. In the reaction, the ratio (molar ratio) of the amount of inorganic acid used (calculated as H+) to the 4-(4-fluorobenzenesulfonyloxy)-o-phenylenediamine intermediate is 1.5-3:1. If the acid is too little, the reaction cannot be guaranteed to be carried out completely; if the acid is too much, the 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate methyl ester is further generated into a salt, resulting in a decline in product yield.

(2) In the process of selecting O-methylisoureaformate or S-methylisoureaformate to carry out the ring-closing reaction, the molar amount of the ring-closing agent is 4-(4-fluorobenzenesulfonyloxy)- 1.1 to 1.4 times that of the intermediate of o-phenylenediamine reduction. The acid used for the ring-closing reaction can be selected from inorganic acid and organic acid.

Detailed ways

Below in conjunction with embodiment the present invention is described in further detail.

1 Preparation process of substituted aminophenol

Embodiment one

step 1

In a 150ml four-neck flask equipped with a stirring device and a thermometer, add 10.0g (0.092mol) of p-aminophenol and 10ml (0.120mol) of acetic anhydride in sequence, heat and stir, and reflux for 2 hours. The temperature continued to rise during the reaction. After the reaction was completed, the reaction solution was poured into a small amount of ice water, and crystals were precipitated. After suction filtration, the product was recrystallized with alcohol to obtain 13.2 g of paracetamol, with a yield of 94.9% and a melting point of 170°C.

step 2

In a 150ml four-neck flask with a stirring device and a thermometer, add 80ml of 98% sulfuric acid, stir and cool down to below 10°C, add 9.4g (0.062mol) of paracetamol, cool down to below 10°C, dropwise add 3.7ml98 % sulfuric acid and 3.8ml 96% nitric acid mixed acid solution, after adding, react for 2h. After the reaction stopped, under strong stirring, pour the reaction solution into a large amount of crushed ice, and yellow crystals were precipitated, filtered by suction, and dried to obtain 9.2 g of 3-nitro-4-acetamidophenol, with a yield of 75.6% and a melting point of 162°C .

Embodiment two

Referring to the first reaction step of Example, first formylate and then nitrate to obtain 3-nitro-4-formylaminophenol.

Embodiment three

Referring to the first reaction step of Example, propionylation and then nitration were carried out to obtain 3-nitro4-propionylaminophenol.

Embodiment four

Referring to the first reaction step of Example, first butylation, then nitration to obtain 3-nitro-4-butyrylaminophenol.

Embodiment five

Referring to the first reaction step of Example, first benzoylation and then nitration to obtain 3-nitro-4-benzoylaminophenol.

Embodiment six

Referring to the first reaction step of Example, first benzoylation, then nitration to obtain 3-nitro-4-benzamidophenol.

Embodiment seven

Referring to the reaction step of Example 1, trifluoroacetylation was performed first, followed by nitration to obtain 3-nitro-4-trifluoroacetamidophenol.

Embodiment eight

Referring to the first reaction step of Example, first chloroacetylation, then nitration to obtain 3-nitro-4-chloroacetamidophenol.

2 Condensation reaction process

Embodiment nine

In a 250ml four-neck flask equipped with a stirring device and a thermometer, add 100ml of DMF, 14ml (0.1mol) of triethylamine, and 19.6g (0.1mol) of 3-nitro-4-acetamidophenol in sequence, and stir to dissolve all the raw materials. Another weighed 19.5g (0.1mol) of p-fluorobenzenesulfonyl chloride was dissolved in 30ml of DMF, and after it was completely dissolved, it was added dropwise into the reaction system. After the dropwise addition, react for 5h. After the reaction was finished, it was filtered with suction, and the filter cake was washed twice with a small amount of DMF. The filtrates were combined, transferred into a 500ml reaction bottle, and hydrolyzed for 1h. After the reaction was completed, concentrate under reduced pressure, then add a small amount of methanol and deionized water in turn, stir for 1.5 h, filter with suction, wash the filter cake with deionized water, and dry to obtain the condensate 2-nitro-4-(4-fluorobenzenesulfonate Acyloxy)-aniline 26.4g, yield 84.5%, melting point 161°C.

Embodiment ten

In a 250ml four-necked flask with a stirring device and a thermometer, add 19.6g (0.1mol) 3-nitro-4-acetamidophenol, 19.5g (0.1mol) p-fluorobenzenesulfonyl chloride, 100mlDMF successively, heat and stir, Allow all ingredients to dissolve. NaOH aqueous solution was added dropwise to the reaction system. After the addition, the temperature was raised for 5 hours. Then hydrolysis reaction 1h. After the reaction was completed, deionized water was added, stirred for 1.0 h, and suction filtered. The filter cake was washed with deionized water, and dried to obtain 26.8 g of condensate 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline. The yield is 85.8%, and the melting point is 161°C.

Embodiment Eleven

With reference to the reaction steps of Example 9 and Example 10, equimolar equivalents of p-fluorobenzenesulfonyl chloride, 3-nitro-4-formylaminophenol and alkali were used to react, and then hydrolyzed to obtain 2-nitro-4-( 4-fluorobenzenesulfonyloxy)-aniline condensate intermediate, melting point 161°C.

Embodiment 12

With reference to the reaction steps of Example 9 and Example 10, equimolar equivalents of p-fluorobenzenesulfonyl chloride, 3-nitro-4-propionylaminophenol and alkali were used to react, and then hydrolyzed to obtain 2-nitro-4-( 4-fluorobenzenesulfonyloxy)-aniline condensate intermediate, melting point 161°C.

Embodiment Thirteen

With reference to the reaction steps of Example 9 and Example 10, equimolar equivalents of p-fluorobenzenesulfonyl chloride, 3-nitro-4-butyrylaminophenol and alkali were used to react, and then hydrolyzed to obtain 2-nitro-4-( 4-fluorobenzenesulfonyloxy)-aniline condensate intermediate, melting point 161°C.

Embodiment Fourteen

With reference to the reaction steps of Example 9 and Example 10, equimolar equivalents of p-fluorobenzenesulfonyl chloride, 3-nitro-4-benzoylaminophenol and alkali were used to react, and then hydrolyzed to obtain 2-nitro-4-( 4-fluorobenzenesulfonyloxy)-aniline condensate intermediate, melting point 161°C.

Embodiment 15

With reference to the reaction steps of Example 9 and Example 10, equimolar equivalents of p-fluorobenzenesulfonyl chloride, 3-nitro-4-benzamidophenol and alkali were used to react, and then hydrolyzed to obtain 2-nitro-4- (4-Fluorobenzenesulfonyloxy)-aniline condensate intermediate, melting point 161°C.

Embodiment sixteen

With reference to the reaction steps of Example 9 and Example 10, equimolar equivalents of p-fluorobenzenesulfonyl chloride, 3-nitro-4-trifluoroacetamidophenol and alkali are used to react, and then hydrolyzed to obtain 2-nitro-4- (4-Fluorobenzenesulfonyloxy)-aniline condensate intermediate, melting point 161°C.

Embodiment 17

With reference to the reaction steps of Example 9 and Example 10, equimolar equivalents of p-fluorobenzenesulfonyl chloride, 3-nitro-4-chloroacetamidophenol and alkali were used to react, and then hydrolyzed to obtain 2-nitro-4-( 4-fluorobenzenesulfonyloxy)-aniline condensate intermediate, melting point 161°C.

3 Reduction reaction process

Embodiment eighteen

In a 250ml four-necked flask equipped with a stirring device and a thermometer, 10.9g (0.195mol) of zinc powder, 5ml of acetic acid and 50ml of deionized water were successively added, and stirred to fully mix the raw materials. After heating and boiling, cool slightly. Another 15.6 g (0.05 mol) of 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline condensate intermediate was weighed and dissolved in DMF, and transferred into a constant pressure dropping funnel. Under stirring, dropwise added to the reaction system to react. After the addition, the reaction was heated to reflux for 6h. After the reaction is over, the following two methods can be used for processing:

(1), water and DMF were evaporated under reduced pressure, and when crystals were precipitated, let stand for 1h, filtered with suction, washed the filter cake with deionized water, and dried to obtain 4-(4-fluorobenzenesulfonyloxy)-o-phenylene Diamine reduction product intermediate. The crude product can be recrystallized to obtain crystals, but the present invention does not use recrystallization operation, and is directly used in the next reaction.

(2), add deionized water and benzene, stir for 0.5h and then filter, and the filtrate is separated from the upper layer [organic layer] with a separatory funnel. The obtained benzene organic layer containing 4-(4-fluorobenzenesulfonyloxy)-o-phenylenediamine reduction product intermediate was directly used for the next ring-closing reaction.

Embodiment nineteen

In a 250ml four-necked flask with a stirring device and a thermometer, add 31.2g (0.1mol) 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline condensate intermediate and 100ml ethanol in sequence, and heat Stir, add 46.8g (0.6mol) sodium sulfide in batches, and heat to reflux for 4h. After the reaction is completed and cooled, the reaction solution is poured into a separatory funnel, the lower layer is separated, the upper layer is moved into a reaction flask, concentrated at normal pressure to recover ethanol, and the raffinate can be processed in the following two ways:

(1) Add deionized water to crystallize under stirring, suction filter after standing for 1h, wash the filter cake with deionized water, and dry to obtain the intermediate of 4-(4-fluorobenzenesulfonyloxy)-o-phenylenediamine reduction . The obtained reduced product intermediate can be recrystallized to obtain crystals, but the present invention does not use recrystallization operation, and is directly used in the next step reaction.

(2) Add deionized water and benzene, stir for 0.5h, then filter, and separate the upper layer [organic layer] from the filtrate with a separatory funnel. The obtained benzene organic layer containing 4-(4-fluorobenzenesulfonyloxy)-o-phenylenediamine reduction product intermediate was directly used for the next ring-closing reaction.

Embodiment 20

In a 500ml four-necked flask with a stirring device and a thermometer, add 31.2g (0.1mol) 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline condensate intermediate and 100ml ethanol successively, and heat Stir. Another 22.4g (0.4mol) of sodium hydrosulfide was weighed and added to the reaction system, and the addition was heated and refluxed for 4 hours. After the reaction was completed, cooled, the reaction solution was poured into a separatory funnel, and the lower layer was separated, and the upper layer was moved into the reaction flask. Ethanol was recovered by concentration under pressure, and the follow-up operation was consistent with that used in Example 19.

Embodiment 21

step 1

Weigh 10.0g of nickel chloride hexahydrate and dissolve in 10mL of water. Weigh again 12.6g of Zn powder, add 30% acidic silica sol to make a paste, and under stirring, quickly add nickel chloride solution into the zinc powder, the reaction is intense and exothermic, and hydrogen gas is released. After a few minutes, the sludge was washed 3 times with 50 ml of deionized water. Add 180ml of 20% acetic acid solution to the precipitate, and stir and react at 40-50°C for 0.5h, the rate of hydrogen generation slows down significantly. By stirring, the porous nickel floating on the liquid surface sinks. Pour off the supernatant, wash with water until neutral, and then wash 3 times with 50ml of absolute ethanol to obtain a porous flocculent nickel catalyst, which is stored in ethanol for future use.

step 2

On a 250ml four-necked flask with a stirring device and a thermometer, connect a hydrogen gas guide tube, and fill it with nitrogen to check the airtightness of the device. After passing the inspection, replace, then add 15.6g 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline condensate intermediate, the prepared porous nickel catalyst, 100ml ethanol, heat and stir, when the temperature After rising to 40°C, the hydrogen gas in the steel cylinder is introduced into the reaction bottle after passing through the gas metering tube. After a certain period of induction, the rate of hydrogen absorption is accelerated. When the hydrogen absorption rate drops to 0.1-0.2ml/min and the total hydrogen absorption capacity is about 1100ml, stop feeding hydrogen and stirring, cool down, and let it stand for a while to let the catalyst sink to the bottom of the bottle, and suck out the supernatant. Concentrate and recover ethanol under normal pressure, and the follow-up operation is consistent with that used in Example 19.

closed loop reaction process

Embodiment 22

In a 250ml four-necked flask with a stirring device and a thermometer, sequentially add the solid reduction product 4-(4-fluorobenzenesulfonyloxy)-o-phthalic acid obtained by using the treatment method (1) in the embodiment of the reduction reaction process. Diamine 27.6g (0.098mol), 100ml benzene, after stirring and dissolving, add the aqueous solution containing 10.8g (0.108mol) methyl cyanocarbamate [concentration of methyl cyanocarbamate is 97g/l]. Another 29.4ml (0.294mol) of concentrated hydrochloric acid was measured and added dropwise to the system for reaction. After completion of the dropwise addition, heat to reflux for 3 hours, cool, filter with suction, wash the filter cake with deionized water, recrystallize with methanol/DMF solution, and dry to obtain 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2 - 27.0 g of methyl carbamate product, yield 74.0% [with 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline as reference], melting point 236°C.

Embodiment 23

In a 250ml four-necked flask with a stirring device and a thermometer, sequentially add the solid reduction product 4-(4-fluorobenzenesulfonyloxy)-o-phthalic acid obtained by using the treatment method (1) in the embodiment of the reduction reaction process. Diamine 27.6g (0.098mol), 100ml benzene, after stirring and dissolving, add the aqueous solution containing 10.8g (0.108mol) methyl cyanocarbamate [concentration of methyl cyanocarbamate is 200g/l]. Another 15ml (0.15mol) of concentrated hydrochloric acid was measured and added dropwise to the system for reaction. After completion of the dropwise addition, heat to reflux for 3 hours, cool, filter with suction, wash the filter cake with deionized water, recrystallize with methanol/DMF solution, and dry to obtain 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2 - 27.4 g of methyl carbamate product, yield 75.0% [using 2-nitro-4-(4-fluorobenzenesulfonyloxy)-aniline as reference], melting point 236°C.

Embodiment 24

In a 250ml four-necked flask with a stirring device and a thermometer, sequentially add the solid reduction product 4-(4-fluorobenzenesulfonyloxy)-o-phthalic acid obtained by using the treatment method (1) in the embodiment of the reduction reaction process. 27.6g (0.098mol) of diamine, 100ml of benzene, stir to dissolve, add 15.0g (0.113mol) of O-methylisourea formate methyl ester and a small amount of acid, heat and stir, react at 60°C for 4h, suction filter, filter cake Wash with deionized water, recrystallize with methanol/DMF solution, and dry to obtain 28.5g of 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate methyl ester product, yield 78.0% [with 2 -nitro-4-(4-fluorobenzenesulfonyloxy)-aniline as reference], melting point 236°C.

Example 25

In a 250ml four-necked flask with a stirring device and a thermometer, add the reduced product benzene solution (4-(4-fluorobenzenesulfonyloxy)-o- 27.6g (0.098mol) of phenylenediamine, 100ml of benzene, stir to dissolve, add 18.1g (0.137mol) of O-methylisourea formate methyl ester and a small amount of acid, heat and stir, react at 60°C for 4h, suction filter, filter cake Wash with deionized water, recrystallize with methanol/DMF solution, and dry to obtain 28.5g of 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-carbamate methyl ester product, yield 78.8% [with 2 -nitro-4-(4-fluorobenzenesulfonyloxy)-aniline as reference], melting point 236°C.

Embodiment 26

With reference to the twenty-fourth and twenty-five reaction steps and the feeding amount of Example 2, S-methylisoureaformic acid methyl ester is selected as the ring-closing agent to obtain 5-(4-fluorobenzenesulfonyloxy)benzimidazole-2-amino Methyl formate product, melting point 236°C.

Claims (9)

1. 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, morpholine, DMF, the DBU, and mineral alkali is selected from 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;

Wherein 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.

2. the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 1, it is characterized in that: the condensation course in the b step 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 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 is 1.5～3 times of 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine in the reaction.

9. the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 1 is characterized in that: closed loop agent O-methyl-isourea methyl-formiate in the d step or the mole dosage in the S-methyl-isourea methyl-formiate are 1.1～1.4 times of 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine.