CN102827174A - Preparation method for aldose reductase inhibitor fidarestat - Google Patents

Abstract

The invention provides a preparation method for aldose reductase inhibitor fidarestat. Fluorophenol and maleimide serve as initial reaction raw materials, and an addition reaction, a hydrolysis reaction, a chiral resolution, a hydrolysis reaction, a cyclization reaction, a Bucherer reaction and an amidate reaction are carried out to obtain a target product. In a process for preparing 1-phenyl-3-(4-fluorophenoxy)-2,5-pyrrolidine diketone, acetone is used for serving as a solvent, and damage of toxic substances to human bodies in an industrialization productive process is reduced. In a resolution process of 2-(4-fluorophenoxy)-1,4 succinic acid, selective tests are repeatedly carried out, chiral optical reagent (S)-alpha-phenylethylamine containing amino serves as a resolution reagent, salifying and crystallization are carried out to separate out a diastereoisomeric compound VI, and the compound VI with a high optical purity can be obtained through carbinol recrystallization. The preparation method is low in cost, high in yield, relatively mild in reaction condition, relatively friendly in reaction environment, simple and convenient to process and operate after synthesizing and is suitable for mass preparation.

Description

A kind of preparation method of aldose reductase inhibitor fidarestat

Technical field

The present invention relates to organic chemistry and pharmaceutical chemistry technical field, be specifically related to a kind of preparation method of aldose reductase inhibitor fidarestat.

Background technology

Compound (2S; 4S)-and 6-fluoro-2,3-dihydro-2 ', 5 '-dioxy spiral shell (4H-1-chromene-4; 4 '-imidazolyl)-the 2-acid amides; Medicine name is a fidarestat, is the s-generation glycolylurea class aldose reductase inhibitor that is total to company's research and development by Japan three, is mainly used in the neurological complication that treatment glycosuria pathology causes.Compare with similar medicine epalrestat, this medical instrument has active high, characteristics such as selectivity is strong, long action time, and long-term prescription is had more advantage.Fidarestat is strong and single-minded to the restraining effect of aldose reductase, and untoward reaction is few, is the active drug of treatment diabetic complication.

The general names of the diabetic neuropathy multiple disease that to be mellitus take place in neural system are the highest a kind of of sickness rate in the chronic complicating diseases of diabetes.Because patient's blood sugar increasing, the local anoxic that diabetic microvascular complication causes is added in neural system generation sex change, finally causes neurocyte and nerve fiber to be destroyed, so diabetic neuropathy forms.The pathogeny of diabetic neuropathy is not still come to a conclusion, and its treatment is also very thorny, stresses the early stage controlling blood sugar elimination cause of disease.Some nervous symptoms can progressively alleviate, alleviate through treatment, until recovery from illness.The method of control of diabetes DPN comprises: controlling blood sugar, heavy dose of use VITAMINs, use aldose reductase inhibitor, improvement circulation increase oxygen supply.Since the nineties in last century, existing 2 aldose reductase inhibitors listing is used for the neurological complication due to the control of diabetes, and has obtained original achievement.Fidarestat is compared with the aldose reductase inhibitor that uses clinically at present, and it is stronger to have selectivity, active higher characteristics.Research of Animal Model for Study shows: its neural conduction of mouse of suffering from mellitus can be slowed down 10% (10 week) and 23% (26 week), and what fidarestat can histokinesis's nerve transmission speed slows down, and the prevention rate is in 93% (26 week).The effect that fidarestat improves diabetes model rat nerves symptom significantly is better than epalrestat and zenarestat, and last longer than the back both.According to the part clinical study result of announcement in 2000,279 patients that participate in clinical trials, through double blind controls (139/140) test in 52 weeks, every day, oral 1mg assessed individual symptom simultaneously.The test-results demonstration, in entire test, 8 electrophysiological indexs being estimated, the treatment group has 5 indexs obviously to improve, and all the other indexs are not seen deterioration.The more individual symptom of treatment group and control group (comprise numbness, autonomous pain, tension force is high excessively) obviously improve.The patient has good compliance to used dosage, and finding spinoff and control group do not have significant difference.Fidarestat can improve the individual symptom and the nerve conduction of diabetic neuropathy.To 52 weeks, to compare with placebo, fidarestat group median nerve F wave speed significantly improved with minimum latent period.Fidarestat group patient subjective symptom like numbness, spontaneous pain, tetanic sensation, sole paresthesia, have leaden feet and insensitively also be significantly improved.The researchist thinks that the fidarestat treatment is measured equally effective with other neural kinetic energy to the effect of subjective symptom, and the safety spectrum proves that fidarestat maybe be effectively to the basic treatment of diabetic peripheral neuropathy too simultaneously.

One of cause of disease of diabetic complication is the hyperfunction osmotic pressure theory of polyvalent alcohol metabolic activity; Based on above-mentioned principle; State such as Japan and the United States, English competitively develops the AR suppressor factor, and what gone on the market has Ah department it orders (alrestatin), epalrestat (epalrestat), Pa Nasita (ponalrestat), sorbinil (sorbinil) and tolrestatin (tolrestat).The aldose reductase inhibitor that begins one's study from the seventies was got permission listing by the tolrestatin of Wyeth's exploitation in 89 years, become first and be used for clinical aldose reductase inhibitor.The epalrestat that 92 years Japan has ratified the exploitation of little wild pharmaceutical industries company is used to treat diabetic neuropathy, and sea, Shenzhen king drops into 4,980 ten thousand these kinds of exploitation, has declared production at present.Estimate 14,000 ten thousand yuan of annual sales revenue, 2359.03 ten thousand yuan of profit after taxs.Other occupy the majority such medicine in the kind of the kind of grinding with Japanese enterprises.Compare with similar medicine, fidarestat has the characteristics of active height, long action time as the optical activity medicine, and synthesis technique has higher technology content.Have the potentiality that form high value added product.

At present, the method that domestic and international known report adopted, most of is starting raw material with maleic anhydride and 4-fluoroanisole.Like US5447946, EP0595183, US4861792, US4978758 etc.

Zhou Yanlis etc. (Chinese Journal of Pharmaceuticals, 2005,36 (12), 725) have been reported a kind of compound method of fidarestat, and it obtains 6-fluoro-3 with maleic anhydride (2) and 4-fluoroanisole through condensation, closed loop, 4-dihydro-4-oxo-2 H-1-chromene-2-carboxylic acid (4).

(4) and SOCl ₂The reaction, product with ( S)-(-)-the 1-phenylethylamine carries out condensation, obtains isomer mixture (5), and ethanol is to its recrystallization, splits, hydrolysis obtains single enantiomer (2 S)-6-fluoro-3,4-dihydro-4-oxo-2 H-1-chromene-2-carboxylic acid (6).

(6) step such as separate through closed loop, esterification and ammonia and make fidarestat (1), total recovery 20%.

The shortcoming of above-mentioned compound method is:

One, adopting maleic anhydride is raw material; After Fu Ke acylation reaction, Oxo-Michel addition; The raceme (4) that obtains utilizes the DCC condensation, and the diastereomer that forms with (S)-α-Ben Yian is through repeatedly obtain optical activity high (6) with the sour water hydrolysis behind the recrystallization again.This split process yield is lower, is merely 26%.

When two, adopting this legal system to be equipped with, initial step adopts aluminum chloride to make catalyzer, and usage quantity is bigger, and pollutes comparatively serious.

Three, in the molecule inner ring condensation reaction process, in order not make the intermolecular condensation of carrying out, adopted rarer acid solution, cause yield on the low side.

Four, the non-corresponding isomery acid amides that forms must just can reach higher optical purity, so this step yield be also on the low side through crystallization purifying repeatedly.

Five, amidate action adopts sulfuric acid, and reaction conditions is comparatively violent, and the easy racemization of product causes its optical purity just low.

Patent reports such as document US 5447946, EP0595183, US4861792, US4978758, CN101531651 (2S; 4S)-6-fluoro-2; 3-dihydro-2 ', a kind of key intermediate (2 in 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolyl)-2-amide compound building-up process S)-6-fluoro-3,4-dihydro-4-oxo-2 HThe preparation of-1-chromene-2-carboxylic acid.These compound methods adopt 3,4-dihydro-4-oxo-2 H-1-chromene-2-carboxylic acid and Chiral Amine are reacted, and form the ammonium salt of diastereomer, utilize the principle of diastereomer different solubility in solvent, adopt a kind of comparatively suitable solvent that it is carried out repeatedly recrystallization and obtain optically pure (4a).These methods are summarized as follows:

The shortcoming of above-mentioned method for splitting is:

One, used SOCl in the fractionation ₂, this reagent pungency is strong and environmental pollution is bigger, should evade its use.

Two, the non-corresponding isomery acid amides that forms must just can reach higher optical purity, so yield be on the low side through crystallization purifying repeatedly.

Three, splitting back gained amide compound need hydrolysis under acidity or alkaline condition, just can obtain the higher 4a of optical purity, and hydrolytic process can cause its racemization, and optical purity reduces.

Four, method two utilizes the direct and carboxylic acid salify of Chiral Amine, has avoided method one SOCl ₂Use, and avoided the comparatively violent acid or the hydrolysising condition of alkali, but the recrystallization number of times of diastereomer ammonium salt is more, causes yield also on the low side.

In sum, and disclosed preparation in the prior art (2S, 4S)-6-fluoro-2; 3-dihydro-2 ', the method for 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolyl)-2-amide compound; Exist production cost higher, the preparation manipulation complex steps, a large amount of preparations are restricted; And environmental pollution is serious, problems such as complex operation.

Summary of the invention

Technical problem to be solved by this invention is the deficiency to existing compound method; Provide that a kind of cost is low, yield is higher, reaction conditions is comparatively gentle, comparatively friendly, the synthetic post-processing operation of reaction environment is easy and safe, is fit to the preparation method of the aldose reductase inhibitor fidarestat of mass preparation.

Technical problem to be solved by this invention is to realize through following technical scheme.The present invention is a kind of preparation method of aldose reductase inhibitor fidarestat, is characterized in, its step is following:

(1) be initial feed with the compound N-phenyl maleimide shown in compound p-fluorophenol shown in the formula II and the formula III; In organic solvent through base catalysis Oxo-Michael addition reaction; Get the compound 1-phenyl-3-(4-fluorophenoxy)-2 shown in the formula IV, the 5-pyrrolidine-diones; Described organic solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: trichloromethane, methylene dichloride, ETHYLE ACETATE, toluene, benzene, acetone, acetonitrile, methyl alcohol, ethanol, acetone; Described alkali is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: TERTIARY BUTYL AMINE, tert-Octylamine, NSC 32389, dodecyl dimethyl tertiary amine, hexadecyldimethyl benzyl ammonium tertiary amine, cocoyl dimethyl tertiary amine, TMAH, pyridine, triethylamine, yellow soda ash, sodium hydrogencarbonate, sodium hydroxide;

(2) compound IV temperature rising reflux in acidic solution stirs, and hydrolysis is fully after aftertreatment gets the compound 2-shown in the formula V (4-fluorophenoxy)-1,4 Succinic Acid compound; Described acidic solution is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: hydrochloric acid, sulfuric acid, Glacial acetic acid min. 99.5, formic acid, propionic acid, butyric acid, pimelic acid, propanedioic acid;

(3) the compound V is split; It is resolution reagent that employing contains amino chirality optical agents; Through salify; Perhaps (S) 2-(4-fluorophenoxy)-1 of compound (R) that diastereoisomeric formula VI representes is separated out in crystallization; 4 Succinic Acid ammonium salts obtain higher (S)-2-(4-fluorophenoxy)-1, the 4 Succinic Acid ammonium salt of optical purity through recrystallization; Described chiral selectors is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: (S)-N, N-alpha-alpha-dimethyl phenylethylamine, (R)-N, N-alpha-alpha-dimethyl phenylethylamine, (S)-α-Ben Yian, (R)-α-Ben Yian; Described reaction solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: methyl alcohol, ethanol, water, methylene dichloride, trichloromethane, ETHYLE ACETATE, toluene, benzene, 1,2-ethylene dichloride; Described recrystallization solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: methyl alcohol, ethanol, Virahol, ETHYLE ACETATE;

(4) the compound VI is dissolved in the organic solvent,, gets compound (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid shown in the formula VII through the acidic solution acidifying; Described organic solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: methyl alcohol, ethanol, water, methylene dichloride, trichloromethane, ETHYLE ACETATE, toluene, benzene, 1,2-ethylene dichloride; Described acidic solution is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: Hydrogen chloride, dilute sulphuric acid, phosphoric acid, nitric acid;

(5) the compound VII is through the effect of acidylate cyclization reagent, the compound shown in the production VIII (S)-6-fluoro-3,4-dihydro-4-2-H-1-chromene-2-carboxylic acid; Described acidylate cyclizing agent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: boron trifluoride ether solution, the vitriol oil, polyphosphoric acid, pyrophosphoryl chloride;

(6) the compound VIII through Bu Keer react the compound shown in the formula IX (2S, 4S)-6 fluoro-2,3-dihydro-2 ', 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolidine)-2-carboxylic acid;

(7) the compound IX in organic solvent through acylation reaction get the compound shown in the formula I (2S, 4S) the 6-fluoro-2,3-dihydro-2 ', 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolyl)-2-amide compound;

。

Above-described preparation method of the present invention, its preferred concrete steps are following:

(1) Oxo-Michael addition reaction: in reaction vessel, drop into p-fluorophenol and N-phenylmaleimide, abundant stirring and evenly mixing under 20 ~ 30 ℃ of conditions treats that solid all after the dissolving, adds the proper amount of sodium hydroxide solid; Temperature rising reflux stirs 3 ~ 8h, and TLC detects, DCM: methyl alcohol=10:1, and reaction finishes; Reaction solution is reduced to 20 ~ 25 ℃, decompress filter, filter cake is used distilled water wash; The gained solid is used the chloroform recrystallization, and 10 ~ 15 ℃ leave standstill 3 ~ 5h, suction filtration; 40 ~ 45 ℃ of decompression oven dry promptly get the compound 1-phenyl-3-(4-fluorophenoxy)-2 shown in the white powder solid type IV, the 5-pyrrolidine-diones; Described p-fluorophenol and N-phenylmaleimide molar ratio are 1.2 ~ 1.8:1.0;

(2) hydrolysis reaction: the compound IV is mixed with hydrolysis reaction liquid in the input reactor drum, and described hydrolysis reaction liquid is formic acid and concentrated hydrochloric acid, in 20 ~ 30 ℃ of stirring and evenly mixings, is warming up to backflow; Reaction 4 ~ 8h, TLC detects, DCM: methyl alcohol=10:1; Reaction finishes, concentrating under reduced pressure solvent evaporated, residual adding dissolved in distilled water salts substances; Add the extracted with diethyl ether layering, anhydrous sodium sulfate drying 2 ~ 4h removes solvent under reduced pressure; The residual chloroform recrystallization of using gets compound 2-(4-fluorophenoxy)-1,4 Succinic Acid shown in the white powder solid type V; The mass volume ratio of compound IV and hydrolysis reaction liquid is 1:3 ~ 3.5g/ml;

(3) chiral separation and hydrolysis reaction: drop into compound V, zero(ppm) water, chiral selectors (S)-α phenylethylamine in the reaction flask successively, the mol ratio of chiral selectors and compound V is 1.0 ~ 1.5:1.0; In 20 ~ 30 ℃ of stirring and evenly mixings, be warming up to backflow, solid continues stirring reaction 1 ~ 2h after all dissolving; TLC, ETHYLE ACETATE: sherwood oil=3:7, reaction finishes, and reaction solution is reduced to 40 ~ 50 ℃, adds a little crystal seed, and 0 ~ 5 ℃ leaves standstill crystallization 5 ~ 12h; Decompress filter, filter cake water washed twice promptly gets perhaps (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid ammonium salt of the compound (R) shown in the white solid formula VI;

(4) the compound VI is dissolved in the dichloromethane solution, with the hydrochloric acid soln neutralization reaction liquid of 3 ~ 6mol/L to strongly-acid, standing demix; Water layer is with twice of dichloromethane extraction; Merge organic layer, anhydrous sodium sulfate drying 2 ~ 4h is evaporated to dried; Promptly get the compound shown in the formula VII (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid;

(5) ring-closure reaction: with reaction flask in 110 ℃ of forced air dryings; Sealing is fallen reaction flask and is reduced to room temperature; Add the compound VII, slowly be added dropwise to pyrophosphoryl chloride under the agitation condition, the mol ratio of compound VII and acidylate cyclization reagent pyrophosphoryl chloride is 1.0 ~ 1.5:3.0 ~ 4.0; Whipping temp is 15 ~ 40 ℃, and the dropping time is 10 ~ 30min; Be warming up to 60 ~ 62 ℃ of stirring reaction 1h, finish, ice-water bath is cooled to 0 ~ 5 ℃; In the slow impouring trash ice of reaction solution, magnetic agitation adds dichloromethane extraction three times; Anhydrous sodium sulfate drying organic layer 2 ~ 4h; Remove solvent under reduced pressure, promptly get white powder solid (S)-6-fluoro-3,4-dihydro-4-2-H-1-chromene-2-carboxylic acid; Compound (S)-6-fluoro-3 shown in the formula VIII that optical purity is higher behind the recrystallization, 4-dihydro-4-2-H-1-chromene-2-carboxylic acid; Recrystallization reagent is methyl alcohol, ethanol, acetone, Virahol, ETHYLE ACETATE, normal hexane, ETHYLE ACETATE/normal hexane, Virahol/normal hexane, 50% ethanol, perhaps the mixing solutions of arbitrary proportion wherein;

(6) Bu Keer reaction: join compound VIII, volatile salt, Potssium Cyanide and zero(ppm) water in the reaction flask successively; 20 ~ 30 ℃ stir, and are warming up to 50 ~ 55 ℃ of reaction 22 ~ 26h, continue to be warming up to 90 ~ 92 ℃ of reaction 2 ~ 3h; Reaction finishes; System is reduced to 20 ~ 25 ℃, and concentrated hydrochloric acid is transferred PH to 2 ~ 3, separates out a large amount of solids; Stir energetically, suction filtration, filter cake with water washing repeatedly, vacuum-drying promptly get the compound shown in the white solid formula IX (2S, 4S)-6 fluoro-2,3-dihydro-2 ', 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolidine)-2-carboxylic acid; The mol ratio of KCN and volatile salt is 1.0 ~ 1.2:3.5 ~ 5.0;

(7) acylation reaction: compound IX and mass concentration are that 10% ~ 50% ammonia soln mixes to the solid dissolving, add DMT-MM reagent, and the mol ratio of DMT-MM and compound IX is 1.0 ~ 1.5:0.5 ~ 0.8; 20 ~ 30 ℃ of stirring reaction 12 ~ 24h, reaction finishes, suction filtration; Filter cake is used distilled water wash, drying, and solid is with twice of recrystallizing methanol; After the oven dry the white granular solid type be the compound shown in the I (2S, 4S) the 6-fluoro-2,3-dihydro-2 '; 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolyl)-2-acid amides.

In the above-described preparing method's of the present invention step (7), the mass concentration of preferred ammonia soln is: 10%, 15%, 17%, 20%, 23%, 25%, 30%, 35% or 40%.

Synthetic route of the present invention is:

As do not have specified otherwise, except that preferable amount, the consumption of each reaction raw materials is thrown in by theoretical value and is got final product among the present invention.

Compared with prior art, preparation method of the present invention has following advantage:

(1) p-fluorophenol that process using of the present invention is comparatively cheap and maleimide are as initial feed; With caustic soda as catalyzer; And the compound method of domestic report is synthesized under the katalysis of aluminum chloride all to be initial feed to fluoroanisole and maleic anhydride.Compare with the compound method of bibliographical information, the present invention has evaded a large amount of uses of aluminum chloride, has certain environment friendly.

(2) at 1-phenyl-3-(4-fluorophenoxy)-2; The 5-pyrrolidine-diones prepares in the process, avoid existing patent documentation report with 1, the 2-ethylene dichloride is as the compound method of solvent; Adopt acetone as solvent, reduced in the commercial process toxic substance the harm of human body.

(3) to midbody (V) 2-(4-fluorophenoxy)-1; 4 Succinic Acid carry out repeatedly selectivity test of warp in the split process, and it is resolution reagent that the present invention adopts chirality optical agents (the S)-α-Ben Yian that contains amino, through salify; Crystallization is separated out diastereoisomeric (R) perhaps (S) 2-(4-fluorophenoxy)-1; 4 Succinic Acid ammonium salts (VI), wherein (S)-2-(4-fluorophenoxy)-1,4 Succinic Acid ammonium salt (VI) through obtaining higher optical purity after the recrystallizing methanol.

Compound method cost of the present invention is low, yield is higher, reaction conditions is comparatively gentle, comparatively friendly, the synthetic easy and safety of post-processing operation of reaction environment, is fit to mass preparation.

Embodiment

Below further describe concrete technical scheme of the present invention,, and do not constitute restriction its right so that those skilled in the art understands the present invention further.

Embodiment 1, a kind of preparation method of aldose reductase inhibitor fidarestat, and its step is following:

(1) be initial feed with the compound N-phenyl maleimide shown in compound p-fluorophenol shown in the formula II and the formula III; In organic solvent through base catalysis Oxo-Michael addition reaction; Get the compound 1-phenyl-3-(4-fluorophenoxy)-2 shown in the formula IV, the 5-pyrrolidine-diones; Described organic solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: trichloromethane, methylene dichloride, ETHYLE ACETATE, toluene, benzene, acetone, acetonitrile, methyl alcohol, ethanol, acetone; Described alkali is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: TERTIARY BUTYL AMINE, tert-Octylamine, NSC 32389, dodecyl dimethyl tertiary amine, hexadecyldimethyl benzyl ammonium tertiary amine, cocoyl dimethyl tertiary amine, TMAH, pyridine, triethylamine, yellow soda ash, sodium hydrogencarbonate, sodium hydroxide;

(2) compound IV temperature rising reflux in acidic solution stirs, and hydrolysis is fully after aftertreatment gets the compound 2-shown in the formula V (4-fluorophenoxy)-1,4 Succinic Acid compound; Described acidic solution is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: hydrochloric acid, sulfuric acid, Glacial acetic acid min. 99.5, formic acid, propionic acid, butyric acid, pimelic acid, propanedioic acid;

(3) the compound V is split; It is resolution reagent that employing contains amino chirality optical agents; Through salify; Perhaps (S) 2-(4-fluorophenoxy)-1 of compound (R) that diastereoisomeric formula VI representes is separated out in crystallization; 4 Succinic Acid ammonium salts obtain higher (S)-2-(4-fluorophenoxy)-1, the 4 Succinic Acid ammonium salt of optical purity through recrystallization; Described chiral selectors is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: (S)-N, N-alpha-alpha-dimethyl phenylethylamine, (R)-N, N-alpha-alpha-dimethyl phenylethylamine, (S)-α-Ben Yian, (R)-α-Ben Yian; Described reaction solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: methyl alcohol, ethanol, water, methylene dichloride, trichloromethane, ETHYLE ACETATE, toluene, benzene, 1,2-ethylene dichloride; Described recrystallization solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: methyl alcohol, ethanol, Virahol, ETHYLE ACETATE;

(4) the compound VI is dissolved in the organic solvent,, gets compound (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid shown in the formula VII through the acidic solution acidifying; Described organic solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: methyl alcohol, ethanol, water, methylene dichloride, trichloromethane, ETHYLE ACETATE, toluene, benzene, 1,2-ethylene dichloride; Described acidic solution is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: Hydrogen chloride, dilute sulphuric acid, phosphoric acid, nitric acid;

(5) the compound VII is through the effect of acidylate cyclization reagent, the compound shown in the production VIII (S)-6-fluoro-3,4-dihydro-4-2-H-1-chromene-2-carboxylic acid; Described acidylate cyclizing agent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: boron trifluoride ether solution, the vitriol oil, polyphosphoric acid, pyrophosphoryl chloride;

(6) the compound VIII through Bu Keer react the compound shown in the formula IX (2S, 4S)-6 fluoro-2,3-dihydro-2 ', 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolidine)-2-carboxylic acid;

(7) the compound IX in organic solvent through acylation reaction get the compound shown in the formula I (2S, 4S) the 6-fluoro-2,3-dihydro-2 ', 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolyl)-2-amide compound;

Embodiment 2, a kind of preparation method of aldose reductase inhibitor fidarestat, and its concrete steps are following:

(1) Oxo-Michael addition reaction: in reaction vessel, drop into p-fluorophenol and N-phenylmaleimide, abundant stirring and evenly mixing under 20 ~ 30 ℃ of conditions treats that solid all after the dissolving, adds the proper amount of sodium hydroxide solid; Temperature rising reflux stirs 3 ~ 8h, and TLC detects, DCM: methyl alcohol=10:1, and reaction finishes; Reaction solution is reduced to 20 ~ 25 ℃, decompress filter, filter cake is used distilled water wash; The gained solid is used the chloroform recrystallization, and 10 ~ 15 ℃ leave standstill 3 ~ 5h, suction filtration; 40 ~ 45 ℃ of decompression oven dry promptly get the compound 1-phenyl-3-(4-fluorophenoxy)-2 shown in the white powder solid type IV, the 5-pyrrolidine-diones; Described p-fluorophenol and N-phenylmaleimide molar ratio are 1.2 ~ 1.8:1.0;

(2) hydrolysis reaction: the compound IV is mixed with hydrolysis reaction liquid in the input reactor drum, and described hydrolysis reaction liquid is formic acid and concentrated hydrochloric acid, in 20 ~ 30 ℃ of stirring and evenly mixings, is warming up to backflow; Reaction 4 ~ 8h, TLC detects, DCM: methyl alcohol=10:1; Reaction finishes, concentrating under reduced pressure solvent evaporated, residual adding dissolved in distilled water salts substances; Add the extracted with diethyl ether layering, anhydrous sodium sulfate drying 2 ~ 4h removes solvent under reduced pressure; The residual chloroform recrystallization of using gets compound 2-(4-fluorophenoxy)-1,4 Succinic Acid shown in the white powder solid type V; The mass volume ratio of compound IV and hydrolysis reaction liquid is 1:3 ~ 3.5g/ml;

(3) chiral separation and hydrolysis reaction: drop into compound V, zero(ppm) water, chiral selectors (S)-α phenylethylamine in the reaction flask successively, the mol ratio of chiral selectors and compound V is 1.0 ~ 1.5:1.0; In 20 ~ 30 ℃ of stirring and evenly mixings, be warming up to backflow, solid continues stirring reaction 1 ~ 2h after all dissolving; TLC, ETHYLE ACETATE: sherwood oil=3:7, reaction finishes, and reaction solution is reduced to 40 ~ 50 ℃, adds a little crystal seed, and 0 ~ 5 ℃ leaves standstill crystallization 5 ~ 12h; Decompress filter, filter cake water washed twice promptly gets perhaps (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid ammonium salt of the compound (R) shown in the white solid formula VI;

(4) the compound VI is dissolved in the dichloromethane solution, with the hydrochloric acid soln neutralization reaction liquid of 3 ~ 6mol/L to strongly-acid, standing demix; Water layer is with twice of dichloromethane extraction; Merge organic layer, anhydrous sodium sulfate drying 2 ~ 4h is evaporated to dried; Promptly get the compound shown in the formula VII (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid;

(5) ring-closure reaction: with reaction flask in 110 ℃ of forced air dryings; Sealing is fallen reaction flask and is reduced to room temperature; Add the compound VII, slowly be added dropwise to pyrophosphoryl chloride under the agitation condition, the mol ratio of compound VII and acidylate cyclization reagent pyrophosphoryl chloride is 1.0 ~ 1.5:3.0 ~ 4.0; Whipping temp is 15 ~ 40 ℃, and the dropping time is 10 ~ 30min; Be warming up to 60 ~ 62 ℃ of stirring reaction 1h, finish, ice-water bath is cooled to 0 ~ 5 ℃; In the slow impouring trash ice of reaction solution, magnetic agitation adds dichloromethane extraction three times; Anhydrous sodium sulfate drying organic layer 2 ~ 4h; Remove solvent under reduced pressure, promptly get white powder solid (S)-6-fluoro-3,4-dihydro-4-2-H-1-chromene-2-carboxylic acid; Compound (S)-6-fluoro-3 shown in the formula VIII that optical purity is higher behind the recrystallization, 4-dihydro-4-2-H-1-chromene-2-carboxylic acid; Recrystallization reagent is methyl alcohol, ethanol, acetone, Virahol, ETHYLE ACETATE, normal hexane, ETHYLE ACETATE/normal hexane, Virahol/normal hexane, 50% ethanol, perhaps the mixing solutions of arbitrary proportion wherein;

(6) Bu Keer reaction: join compound VIII, volatile salt, Potssium Cyanide and zero(ppm) water in the reaction flask successively; 20 ~ 30 ℃ stir, and are warming up to 50 ~ 55 ℃ of reaction 22 ~ 26h, continue to be warming up to 90 ~ 92 ℃ of reaction 2 ~ 3h; Reaction finishes; System is reduced to 20 ~ 25 ℃, and concentrated hydrochloric acid is transferred PH to 2 ~ 3, separates out a large amount of solids; Stir energetically, suction filtration, filter cake with water washing repeatedly, vacuum-drying promptly get the compound shown in the white solid formula IX (2S, 4S)-6 fluoro-2,3-dihydro-2 ', 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolidine)-2-carboxylic acid; The mol ratio of KCN and volatile salt is 1.0 ~ 1.2:3.5 ~ 5.0;

(7) acylation reaction: compound IX and mass concentration are that 10% ~ 50% ammonia soln mixes to the solid dissolving, add DMT-MM reagent, and the mol ratio of DMT-MM and compound IX is 1.0 ~ 1.5:0.5 ~ 0.8; 20 ~ 30 ℃ of stirring reaction 12 ~ 24h, reaction finishes, suction filtration; Filter cake is used distilled water wash, drying, and solid is with twice of recrystallizing methanol; After the oven dry the white granular solid type be the compound shown in the I (2S, 4S) the 6-fluoro-2,3-dihydro-2 '; 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolyl)-2-acid amides.

Embodiment 3, and in embodiment 2 described preparing methods' the step (7), the mass concentration of described ammonia soln is: 10%, 15%, 17%, 20%, 23%, 25%, 30%, 35% or 40%.

Embodiment 4, a kind of preparing method's experiment of aldose reductase inhibitor fidarestat.

Experiment one: 1-phenyl-3-(4-fluorophenoxy)-2, the preparation of 5-pyrrolidine-diones

In three mouthfuls of reaction flasks of 250ml, drop into p-fluorophenol 10.6g (II) and N-phenylmaleimide (III) 18.1g, add organic solvent dichloromethane 120ml, abundant stirring and evenly mixing under 20 ~ 30 ℃ of conditions; After treating that solid all dissolves, add sodium hydrate solid 1.2g, temperature rising reflux stirs 3 ~ 8h; (TLC detects, DCM: methyl alcohol=10:1), reaction solution is reduced to 20 ~ 25 ℃ to the reaction end; Decompress filter, filter cake is used distilled water wash, and the gained solid is used the chloroform recrystallization.40 ~ 45 decompression oven dry, get final product white powder solid 1-phenyl-3-(4-fluorophenoxy)-2,5-pyrrolidine-diones (IV) 21.3g.Mp:197 ℃ ~ 199 ℃, HPLC detects purity 98.5%.

Experiment two: operation steps only replaces with the yellow soda ash solid with sodium hydrate solid with experiment one, gets white powder solid 1-phenyl-3-(4-fluorophenoxy)-2,5-pyrrolidine-diones (IV) 18.7g, and HPLC detects purity 98.7%.

Experiment three: operation steps only replaces with sodium bicarbonate solid with sodium hydrate solid with experiment one, gets white powder solid 1-phenyl-3-(4-fluorophenoxy)-2,5-pyrrolidine-diones (IV) 16.2g.HPLC detects purity 97.2%.

Experiment four: operation steps is with experiment one; Only sodium hydrate solid is replaced with organic bases reagent pyridine; Wherein drop into p-fluorophenol 10.6g (II) and N-phenylmaleimide (III) 18.1g, pyridine solution 21ml gets pale yellow powder shape solid 1-phenyl-3-(4-fluorophenoxy)-2; 5-pyrrolidine-diones (IV) 14.3g, HPLC detects purity 96.8%.

Experiment five: operation steps only replaces with organic bases reagent triethylamine with sodium hydrate solid with experiment one, four, gets yellow powder shape solid 1-phenyl-3-(4-fluorophenoxy)-2,5-pyrrolidine-diones (IV) 15.1g, and HPLC detects purity 95.5%.

Experiment six: the preparation of 2-(4-fluorophenoxy)-1,4 Succinic Acid

With midbody IV 13.5g, formic acid 52ml and concentrated hydrochloric acid 52ml, drop in three mouthfuls of reaction flasks of reaction flask 250ml, in 20 ~ 30 ℃ of stirring and evenly mixings, be warming up to backflow; Reaction 6 ~ 8h, and the question response end (TLC detects, DCM: methyl alcohol=10:1), the concentrating under reduced pressure solvent evaporated; Residual adding dissolved in distilled water salts substances adds the extracted with diethyl ether layering, anhydrous sodium sulfate drying 2 ~ 4h; Remove solvent under reduced pressure, the residual chloroform recrystallization of using gets white powder solid 2-(4-fluorophenoxy)-1; 4 Succinic Acid (V) 9.2g, Mp:132 ~ 135 ℃, HPLC detects purity 99.6%.

Experiment seven: operation steps only replaces with glacial acetic acid solution with formic acid solution with experiment six, and reaction conditions is constant.White powder solid 2-(4-fluorophenoxy)-1,4 Succinic Acid (V) 8.1g, Mp:130 ~ 132 ℃, HPLC detects purity 98.7%.

Experiment eight: operation steps only replaces with propanedioic acid solution with formic acid solution with experiment six, and reaction conditions is constant.White powder solid 2-(4-fluorophenoxy)-1,4 Succinic Acid (V) 7.6g, Mp:129 ~ 131 ℃, HPLC detects purity 97.5%.

Experiment nine: operation steps only replaces with concentrated sulfuric acid solution with concentrated hydrochloric acid solution with experiment six, and reaction conditions is constant.Yellow powder shape solid 2-(4-fluorophenoxy)-1,4 Succinic Acid (V) 2.1g, Mp:120 ~ 121 ℃, HPLC detects purity 76.1%.

Experiment ten: operation steps only replaces with the 2N dilution heat of sulfuric acid with concentrated hydrochloric acid solution with experiment six, and reaction conditions is constant.Pale powder shape solid 2-(4-fluorophenoxy)-1,4 Succinic Acid (V) 6.6g, Mp:125 ~ 128 ℃, HPLC detects purity 81.6%.

Test 11: (S)-preparation of 2-(4-fluorophenoxy)-1,4 Succinic Acid

Drop into (V) 10.49g, zero(ppm) water 58ml, chiral selectors (S)-α phenylethylamine 12g in the reaction flask successively, in 20 ~ 30 ℃ of stirring and evenly mixings, be warming up to backflow, solid continues stirring reaction 1 ~ 2h after all dissolving.The reaction finish (TLC, ETHYLE ACETATE: sherwood oil=3:7), reaction solution is reduced to 40 ~ 50 ℃, add a little crystal seed, 0 ~ 5 ℃, refrigerator leaves standstill crystallization 5 ~ 12h.Decompress filter, filter cake water washed twice promptly gets perhaps (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid ammonium salt (VI) 5.7g of white solid (R).(VI) is dissolved in the dichloromethane solution, with the hydrochloric acid soln neutralization reaction liquid of 3 ~ 6mol/L to strongly-acid, standing demix; Water layer merges organic layer, anhydrous sodium sulfate drying 2 ~ 4h with dichloromethane extraction twice; Be evaporated to dried; Promptly get the higher chiral intermediate of optical activity (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid (VII) 2.3g, [α] _D ²⁵=-21.9 ° (c1.1, MeOH).Mp:94 ~ 96 ℃, HPLC detects purity 98.7%.

Test 12: operation steps only replaces with (S)-N with chiral selectors (S)-α phenylethylamine with experiment 11, N-alpha-alpha-dimethyl phenylethylamine, and reaction conditions is constant.White powder solid (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid (VII) 1.2g, Mp:112 ~ 116 ℃, HPLC detects purity 86.1%, [α] _D ²⁵=-11.9 ° (c1.1, MeOH).

Test 13: operation steps only replaces with (R)-α-Ben Yian with chiral selectors (S)-α phenylethylamine with experiment 11, and reaction conditions is constant.Pale powder shape solid (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid (VII) 1.2g, Mp:98 ~ 105 ℃, HPLC detects purity 74.3%, [α] _D ²⁵=-1.9 ° (c1.1, MeOH).

Test 14: (S)-6-fluoro-3, the preparation of 4-dihydro-4-2-H-1-chromene-2-carboxylic acid.

In 110 ℃ of forced air dryings, sealing is fallen reaction flask and is reduced to room temperature, adds highly purified chiral intermediate (VII) 2.5g with reaction flask, slowly is added dropwise to pyrophosphoryl chloride 14ml under the agitation condition; Be warming up to 60 ~ 62 ℃ of stirring reaction 1h, finish, ice-water bath is cooled to 0 ~ 5 ℃; In the slow impouring trash ice of reaction solution, magnetic agitation adds dichloromethane extraction three times fast; Anhydrous sodium sulfate drying organic layer 2 ~ 4h removes solvent under reduced pressure, promptly gets white powder solid (S)-6-fluoro-3; 4-dihydro-4-2-H-1-chromene-2-carboxylic acid (VIII) 1.2g, Mp:172 ~ 175 ℃, [α] _D ²⁵=+61.9 °, HPLC detects purity 99.4%.

Test 15: operation steps only replaces with polyphosphoric acid with the cyclization reagent pyrophosphoryl chloride with experiment 14, white powder solid (S)-6-fluoro-3,4-dihydro-4-2-H-1-chromene-2-carboxylic acid (VIII) 0.7g, Mp:170 ~ 172 ℃, [α] _D ²⁵=+52.1 °, HPLC detects purity 97.2%.

Test 16: operation steps only replaces with the vitriol oil with the cyclization reagent pyrophosphoryl chloride with experiment 14, yellow powder shape solid (S)-6-fluoro-3,4-dihydro-4-2-H-1-chromene-2-carboxylic acid (VIII) 0.2g, Mp:150 ~ 158 ℃, [α] _D ²⁵=+12.3 °, HPLC detects purity 67.7%.

Test 17: operation steps only replaces with chlorsulfonic acid with the cyclization reagent pyrophosphoryl chloride with experiment 14, white powder solid (S)-6-fluoro-3,4-dihydro-4-2-H-1-chromene-2-carboxylic acid (VIII) 0.8g, Mp:165 ~ 170 ℃, [α] _D ²⁵=+42.7 °, HPLC detects purity 90.5%.

Test 18: (2S, 4S)-6 fluoro-2,3-dihydro-2 ', the preparation of 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolidine)-2-carboxylic acid.

Midbody (VIII) 13.9g, volatile salt 38.1g, Potssium Cyanide 9g and zero(ppm) water 100ml are joined in the 250ml reaction flask successively; 20 ~ 30 ℃ stir, and are warming up to 50 ~ 55 ℃ of reaction 22 ~ 26h, continue to be warming up to 90 ~ 92 ℃ of reaction 2 ~ 3h; Reaction finishes; System is reduced to 20 ~ 25 ℃, and concentrated hydrochloric acid is transferred PH to 2 ~ 3, separates out a large amount of solids.Stir energetically, suction filtration, filter cake with water washing repeatedly, vacuum-drying promptly gets white solid, and (2S, 4S)-6 fluoro-2,3-dihydro-2 ', 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolidine)-2-carboxylic acid (IX) 12.8g, Mp:146 ~ 149 ℃, [α] _D ²⁵=+192.7 °, HPLC detects purity 97.9%.

Test 19: operation steps is with experiment 18, and 4g compound (IX) adopts ETHYLE ACETATE/normal hexane (1:1) recrystallization once, white solid (IX) 3.2g, Mp:147 ~ 149 ℃, [α] _D ²⁵=+198.7 °, HPLC detects purity 98.2%.

Test 20: operation steps is with experiment 19, and 3.2g compound (IX) adopts ETHYLE ACETATE/normal hexane (1:1) recrystallization secondary, white solid (IX) 2.7g, Mp:149 ~ 150 ℃, [α] _D ²⁵=+210.7 °, HPLC detects purity 99.8%.

Test 21: operation steps is with experiment 19, and 4g compound (IX) adopts ethyl alcohol recrystallization once, white solid (IX) 3.5g, Mp:149 ~ 151 ℃, [α] _D ²⁵=+214.7 °, HPLC detects purity 99.86%.

Test 22: operation steps is with experiment 19, and 4g compound (IX) adopts the Virahol recrystallization once, white solid (IX) 3.6g, Mp:148 ~ 149 ℃, [α] _D ²⁵=+197.5 °, HPLC detects purity 98.7%.

Test 23: operation steps is with experiment 19, and 3.6g compound (IX) adopts Virahol recrystallization secondary, white solid (IX) 3.1g, Mp:149 ~ 151 ℃, [α] _D ²⁵=+211.8 °, HPLC detects purity 99.6%.

Test 24: (2S, 4S) the 6-fluoro-2,3-dihydro-2 ', the preparation of 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolyl)-2-amide compound.

Midbody (IX) 3.5g and 20% ammoniacal liquor 15ml mix to the solid dissolving, add DMT-MM reagent 4.7g, 20 ~ 30 ℃ of stirring reaction 12 ~ 16h; Reaction finishes, suction filtration, and filter cake is used distilled water wash, drying; Solid is with recrystallizing methanol twice, get final product after the oven dry the white granular solid (2S, 4S) the 6-fluoro-2,3-dihydro-2 '; 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolyl)-2-amide compound (I) 2.9g, Mp:290 ~ 295 ℃, [α] _D ²⁵=+167.8 °, HPLC detects purity 99.2%.

Test 25: operation steps only replaces with 15% ammonia soln with 20% ammonia soln with experiment 24, and reaction conditions and post-treating method are constant.White granular solid 2.2g, Mp:253 ~ 260 ℃, [α] _D ²⁵=+152.1 °, HPLC detects purity 97.2%.

Test 26: operation steps only replaces with 25% ammonia soln with 20% ammonia soln with experiment 24, and reaction conditions and post-treating method are constant.White granular solid 2.7g, Mp:286 ~ 290 ℃, [α] _D ²⁵=+162.1 °, HPLC detects purity 98.7%.

Test 27: operation steps only replaces with 30% ammonia soln with 20% ammonia soln with experiment 24, and reaction conditions and post-treating method are constant.White granular solid 1.8g, Mp:246 ~ 250 ℃, [α] _D ²⁵=+110.1 °, HPLC detects purity 91.4%.

Claims (3)

1. the preparation method of an aldose reductase inhibitor fidarestat is characterized in that, its step is following:

(1) be initial feed with the compound N-phenyl maleimide shown in compound p-fluorophenol shown in the formula II and the formula III; In organic solvent through base catalysis Oxo-Michael addition reaction; Get the compound 1-phenyl-3-(4-fluorophenoxy)-2 shown in the formula IV, the 5-pyrrolidine-diones; Described organic solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: trichloromethane, methylene dichloride, ETHYLE ACETATE, toluene, benzene, acetone, acetonitrile, methyl alcohol, ethanol, acetone; Described alkali is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: TERTIARY BUTYL AMINE, tert-Octylamine, NSC 32389, dodecyl dimethyl tertiary amine, hexadecyldimethyl benzyl ammonium tertiary amine, cocoyl dimethyl tertiary amine, TMAH, pyridine, triethylamine, yellow soda ash, sodium hydrogencarbonate, sodium hydroxide;

(2) compound IV temperature rising reflux in acidic solution stirs, and hydrolysis is fully after aftertreatment gets the compound 2-shown in the formula V (4-fluorophenoxy)-1,4 Succinic Acid compound; Described acidic solution is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: hydrochloric acid, sulfuric acid, Glacial acetic acid min. 99.5, formic acid, propionic acid, butyric acid, pimelic acid, propanedioic acid;

(3) the compound V is split; It is resolution reagent that employing contains amino chirality optical agents; Through salify; Perhaps (S) 2-(4-fluorophenoxy)-1 of compound (R) that diastereoisomeric formula VI representes is separated out in crystallization; 4 Succinic Acid ammonium salts obtain higher (S)-2-(4-fluorophenoxy)-1, the 4 Succinic Acid ammonium salt of optical purity through recrystallization; Described chiral selectors is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: (S)-N, N-alpha-alpha-dimethyl phenylethylamine, (R)-N, N-alpha-alpha-dimethyl phenylethylamine, (S)-α-Ben Yian, (R)-α-Ben Yian; Described reaction solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: methyl alcohol, ethanol, water, methylene dichloride, trichloromethane, ETHYLE ACETATE, toluene, benzene, 1,2-ethylene dichloride; Described recrystallization solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: methyl alcohol, ethanol, Virahol, ETHYLE ACETATE;

(4) the compound VI is dissolved in the organic solvent,, gets compound (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid shown in the formula VII through the acidic solution acidifying; Described organic solvent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: methyl alcohol, ethanol, water, methylene dichloride, trichloromethane, ETHYLE ACETATE, toluene, benzene, 1,2-ethylene dichloride; Described acidic solution is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: Hydrogen chloride, dilute sulphuric acid, phosphoric acid, nitric acid;

(5) the compound VII is through the effect of acidylate cyclization reagent, the compound shown in the production VIII (S)-6-fluoro-3,4-dihydro-4-2-H-1-chromene-2-carboxylic acid; Described acidylate cyclizing agent is selected from a kind of in the following reagent or appoints the mixture of several kinds arbitrary proportion: boron trifluoride ether solution, the vitriol oil, polyphosphoric acid, pyrophosphoryl chloride;

(6) the compound VIII through Bu Keer react the compound shown in the formula IX (2S, 4S)-6 fluoro-2,3-dihydro-2 ', 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolidine)-2-carboxylic acid;

(7) the compound IX in organic solvent through acylation reaction get the compound shown in the formula I (2S, 4S) the 6-fluoro-2,3-dihydro-2 ', 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolyl)-2-amide compound;

。

2. preparation method according to claim 1 is characterized in that, its concrete steps are following:

(1) Oxo-Michael addition reaction: in reaction vessel, drop into p-fluorophenol and N-phenylmaleimide, abundant stirring and evenly mixing under 20 ~ 30 ℃ of conditions treats that solid all after the dissolving, adds the proper amount of sodium hydroxide solid; Temperature rising reflux stirs 3 ~ 8h, and TLC detects, DCM: methyl alcohol=10:1, and reaction finishes; Reaction solution is reduced to 20 ~ 25 ℃, decompress filter, filter cake is used distilled water wash; The gained solid is used the chloroform recrystallization, and 10 ~ 15 ℃ leave standstill 3 ~ 5h, suction filtration; 40 ~ 45 ℃ of decompression oven dry promptly get the compound 1-phenyl-3-(4-fluorophenoxy)-2 shown in the white powder solid type IV, the 5-pyrrolidine-diones; Described p-fluorophenol and N-phenylmaleimide molar ratio are 1.2 ~ 1.8:1.0;

(2) hydrolysis reaction: the compound IV is mixed with hydrolysis reaction liquid in the input reactor drum, and described hydrolysis reaction liquid is formic acid and concentrated hydrochloric acid, in 20 ~ 30 ℃ of stirring and evenly mixings, is warming up to backflow; Reaction 4 ~ 8h, TLC detects, DCM: methyl alcohol=10:1; Reaction finishes, concentrating under reduced pressure solvent evaporated, residual adding dissolved in distilled water salts substances; Add the extracted with diethyl ether layering, anhydrous sodium sulfate drying 2 ~ 4h removes solvent under reduced pressure; The residual chloroform recrystallization of using gets compound 2-(4-fluorophenoxy)-1,4 Succinic Acid shown in the white powder solid type V; The mass volume ratio of compound IV and hydrolysis reaction liquid is 1:3 ~ 3.5g/ml;

(3) chiral separation and hydrolysis reaction: drop into compound V, zero(ppm) water, chiral selectors (S)-α phenylethylamine in the reaction flask successively, the mol ratio of chiral selectors and compound V is 1.0 ~ 1.5:1.0; In 20 ~ 30 ℃ of stirring and evenly mixings, be warming up to backflow, solid continues stirring reaction 1 ~ 2h after all dissolving; TLC, ETHYLE ACETATE: sherwood oil=3:7, reaction finishes, and reaction solution is reduced to 40 ~ 50 ℃, adds a little crystal seed, and 0 ~ 5 ℃ leaves standstill crystallization 5 ~ 12h; Decompress filter, filter cake water washed twice promptly gets perhaps (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid ammonium salt of the compound (R) shown in the white solid formula VI;

(4) the compound VI is dissolved in the dichloromethane solution, with the hydrochloric acid soln neutralization reaction liquid of 3 ~ 6mol/L to strongly-acid, standing demix; Water layer is with twice of dichloromethane extraction; Merge organic layer, anhydrous sodium sulfate drying 2 ~ 4h is evaporated to dried; Promptly get the compound shown in the formula VII (S) 2-(4-fluorophenoxy)-1,4 Succinic Acid;

(5) ring-closure reaction: with reaction flask in 110 ℃ of forced air dryings; Sealing is fallen reaction flask and is reduced to room temperature; Add the compound VII, slowly be added dropwise to pyrophosphoryl chloride under the agitation condition, the mol ratio of compound VII and acidylate cyclization reagent pyrophosphoryl chloride is 1.0 ~ 1.5:3.0 ~ 4.0; Whipping temp is 15 ~ 40 ℃, and the dropping time is 10 ~ 30min; Be warming up to 60 ~ 62 ℃ of stirring reaction 1h, finish, ice-water bath is cooled to 0 ~ 5 ℃; In the slow impouring trash ice of reaction solution, magnetic agitation adds dichloromethane extraction three times; Anhydrous sodium sulfate drying organic layer 2 ~ 4h; Remove solvent under reduced pressure, promptly get white powder solid (S)-6-fluoro-3,4-dihydro-4-2-H-1-chromene-2-carboxylic acid; Compound (S)-6-fluoro-3 shown in the formula VIII that optical purity is higher behind the recrystallization, 4-dihydro-4-2-H-1-chromene-2-carboxylic acid; Recrystallization reagent is methyl alcohol, ethanol, acetone, Virahol, ETHYLE ACETATE, normal hexane, ETHYLE ACETATE/normal hexane, Virahol/normal hexane, 50% ethanol, perhaps the mixing solutions of arbitrary proportion wherein;

(6) Bu Keer reaction: join compound VIII, volatile salt, Potssium Cyanide and zero(ppm) water in the reaction flask successively; 20 ~ 30 ℃ stir, and are warming up to 50 ~ 55 ℃ of reaction 22 ~ 26h, continue to be warming up to 90 ~ 92 ℃ of reaction 2 ~ 3h; Reaction finishes; System is reduced to 20 ~ 25 ℃, and concentrated hydrochloric acid is transferred PH to 2 ~ 3, separates out a large amount of solids; Stir energetically, suction filtration, filter cake with water washing repeatedly, vacuum-drying promptly get the compound shown in the white solid formula IX (2S, 4S)-6 fluoro-2,3-dihydro-2 ', 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolidine)-2-carboxylic acid; The mol ratio of KCN and volatile salt is 1.0 ~ 1.2:3.5 ~ 5.0;

(7) acylation reaction: compound IX and mass concentration are that 10% ~ 50% ammonia soln mixes to the solid dissolving, add DMT-MM reagent, and the mol ratio of DMT-MM and compound IX is 1.0 ~ 1.5:0.5 ~ 0.8; 20 ~ 30 ℃ of stirring reaction 12 ~ 24h, reaction finishes, suction filtration; Filter cake is used distilled water wash, drying, and solid is with twice of recrystallizing methanol; After the oven dry the white granular solid type be the compound shown in the I (2S, 4S) the 6-fluoro-2,3-dihydro-2 '; 5 '-dioxy spiral shell (4H-1-chromene-4,4 '-imidazolyl)-2-acid amides.

3. preparation method according to claim 2 is characterized in that: in the step (7), the mass concentration of described ammonia soln is: 10%, 15%, 17%, 20%, 23%, 25%, 30%, 35% or 40%.