CN102276550B - The synthetic method of 2-aryl nitrile thiazole derivative and intermediate thereof - Google Patents
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Abstract
The present invention relates to technical field of organic chemistry, be specially the synthetic method of 2-aryl nitrile thiazole derivative and intermediate thereof.In view of in prior art, starting raw material is expensive, agents useful for same is poisoned large, serious to equipment corrosion, separation and purification difficulty, not easily the shortcoming such as industrialization, the invention provides the synthetic method of a kind of new 2-aryl nitrile thiazole derivative, above-mentioned preparation method be with p-HBN be that raw material is substituted, is hydrolyzed, electrophilic substitution, nucleophilic substitution, sulphur oxygen exchange, ring and, the simple types reaction such as hydrolysis, can obtain 2-aryl nitrile thiazole derivative, total recovery can reach 30% ~ 42%.
Description
Technical field
The present invention relates to technical field of organic chemistry, particularly relate to heterocyclic chemistry and vitochemical general method technical field.
Background technology
Febuxostat (Febuxostat) in 2-aryl nitrile thiazole derivative, chemistry is by name: 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid, be the novel non-purines selectivity xanthine oxidase inhibitor of one developed by Japanese Teijin company, be mainly used in the too high disease for the treatment of uric acid clinically.
About the preparation of 2-aryl nitrile thiazole derivative, carry out a lot of research work at present.In existing synthetic route, every bar route also all has some shortcomings while having one's own knack, and synthetic route common both at home and abroad at present mainly contains following several.
Route one: disclosed in Japanese Patent JP10139770, synthetic route is as follows:
Wherein X is halogen.
Obtain in the reaction of 3-bromo-4-isobutoxy thiobenzamide under thioacetamide effect by 3-bromo-4-isobutoxy phenyl nitrile in this route, thio reagents thioacetamide used, there is strong carcinogenesis, and can cause damage to liver, have very strong pungency; After adding dilute hydrochloric acid during this post-reaction treatment, a large amount of hydrogen sulfide can be produced, poison very large.Carried out with cupric cyanide being obtained by reacting in the reaction of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-thiazole-5-ethyl formate under 80 DEG C of conditions by 2-(the bromo-4-isobutoxy phenyl of 3-)-4-methyl-thiazole-5-ethyl formate, 2-(the bromo-4-isobutoxy phenyl of 3-)-4-methyl-thiazole-5-ethyl formate is unstable, and at high temperature thiazole ring is easy to open loop; And almost often step reaction all needed post to purify, cause cost intensive.
Route two: the synthetic route reported in Chinese patent CN101386604A is as follows:
This route uses the sodium cyanide of severe toxicity when being prepared 3-itrile group-4-isobutoxy ethyl benzoate by 4-nitro-benzoic acid ethyl ester, unfavorable factor is difficult to control, and is unfavorable for labour protection, is difficult to carry out industrialization.
Route three: the route announced in Japanese Patent JP1944329647 is as follows:
This technique is industrial selection process route, but starting raw material 4-hydroxythiobenzamide in this route is valuable and be not easy preparation, prepare 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl-thiazole-5-formic acid acetoacetic ester by 2-(4-hydroxy phenyl)-4-methyl-thiazole-5-ethyl formate to make to use the trifluoracetic acid with strong and stimulating, trifluoracetic acid also has strong corrodibility, very easily corrosion reaction container, and also will will use when preparing 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-thiazole-5-ethyl formate by 2-(3-formyl radical-4-isobutoxy)-4-methyl-thiazole-5-formic acid acetoacetic ester there is strong and stimulating and corrosive formic acid equally, therefore, this route also can run into many problems when industrialization.
In view of the medicine prospect that Febuxostat is good, therefore need to develop a kind of cheaper starting materials and be easy to get, reaction safety is high, and cost is low, is easy to industrialized operational path.
Summary of the invention
The object of the invention is to overcome starting raw material in above-mentioned prior art expensive, agents useful for same is poisoned large, serious to equipment corrosion, separation and purification difficulty, and not easily the shortcoming such as industrialization, provides the synthetic method of a kind of new 2-aryl nitrile thiazole derivative.
To achieve these goals, the present invention adopts following technical scheme:
A synthetic method for 2-aryl nitrile thiazole derivative, is expressed as follows by chemical equation:
Wherein: R
1, R
2, R
3be respectively alkyl, X
1, X
2, X
3be respectively halogen.
Described alkyl is preferably C
1~ C
20straight or branched alkyl, be more preferably C
1~ C
8straight or branched alkyl; Described halogen is, F, Cl, Br or I.
Described alkyl specifically can be methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-; Described halogen specifically can be Cl or Br.
Concrete reaction process is made up of following steps:
A), can with reference to method disclosed in Japanese Patent JP10139770, be specially formula (Ⅸ) compound p-HBN and there is lower and formula (Ⅹ) compound halohydrocarbon in the basic conditions with catalyzer and carry out substitution reaction and obtain formula (VIII) compound palkoxy benzene nitrile.
B), formula (VIII) compound palkoxy benzene nitrile is hydrolyzed with superoxol the formula that is obtained by reacting (VIII) compound palkoxy benzene methane amide in dilute alkaline aqueous solution.
C), formula (VII) compound palkoxy benzene methane amide obtains formula VI compound 3-halogen-4-alkoxy benzamides under Louis acid catalysis with halogen generation electrophilic substitution reaction.
D), formula VI compound 3-halogen-4-alkoxy benzamides and prussiate generation nucleophilic substitution reaction, obtain formula (V) chemical compound 3-cyano-4-alkoxy benzamides.
Synthesize formula I compound 2-aryl nitrile thiazole derivative by formula (V) chemical compound 3-cyano-4-alkoxy benzamides with reference to the method in US Patent No. 5614520, to be specially:
E), formula (V) chemical compound 3-cyano-4-alkoxy benzamides and sulfiding reagent carry out sulphur oxygen exchange reaction, obtain formula III chemical compound 3-cyano-4-alkoxy benzamide.
F), formula III chemical compound 3-cyano-4-alkoxy benzamide and formula IV compound 2-halogen-3-oxo alkanoic acid ester carry out ring-closure reaction, obtain formula II compound 2-(3-cyano group-4-alkoxyl group)-4-alkyl-thiazole-5-manthanoate.
G), formula II compound 2-(3-cyano group-4-alkoxyl group)-4-alkyl-thiazole-5-manthanoate is hydrolyzed in the basic conditions, obtains formula I compound 2-aryl nitrile thiazole derivative.
In described step (a), the alkali forming alkaline condition is preferably mineral alkali, is more preferably alkali-metal carbonate or alkali-metal supercarbonate, is specifically as follows sodium carbonate, salt of wormwood, saleratus or sodium bicarbonate; Described catalyzer is preferably alkali-metal halide salts, is more preferably alkali-metal iodide salt, is specifically as follows sodium iodide or potassiumiodide.
In described step (a), the mole dosage ratio of formula (Ⅸ) compound p-HBN and formula (Ⅹ) compound halohydrocarbon is 1: (1.0 ~ 5.0); Formula (Ⅸ) compound p-HBN is 1 with the alkali mole dosage ratio of formation alkaline condition: (1.0 ~ 6.0); The amount ratio of formula (Ⅸ) compound para hydroxybenzene nitrile and catalyzer is 1: (0.01 ~ 0.05).
In described step (a), reaction solvent for use is polar aprotic solvent, is preferably DMF, N-Methyl pyrrolidone, N,N-dimethylacetamide.Described solvent load is 5 ~ 50 times of formula (Ⅸ) compound p-HBN, is preferably 10 ~ 30 times.
In described step (a), temperature of reaction is 0 ~ 200 DEG C, is preferably 60 ~ 90 DEG C; Reaction times is 2 ~ 30 hours, is preferably 4 ~ 15 hours.
In described step (b), the alkali forming alkaline condition is alkali metal base, is preferably sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide; Be more preferably sodium hydroxide, potassium hydroxide.
In described step (b), described dilute alkaline aqueous solution concentration is 1% ~ 30%, and formula (VIII) compound palkoxy benzene nitrile is 1 with the mole dosage ratio of dilute alkaline aqueous solution: (0.1 ~ 5.0); Described superoxol concentration is 1% ~ 50%, and formula (VIII) compound palkoxy benzene nitrile is 1 with the mole dosage ratio of described hydrogen peroxide: (1 ~ 3.0).
In described step (b), reaction solvent for use is alcohols, is preferably C
1~ C
6alcohols, be more preferably methyl alcohol, ethanol, Virahol.Described solvent load is 5 ~ 60 times of described formula (VIII) compound palkoxy benzene nitrile, is preferably 20 ~ 30 times.
In described step (b), temperature of reaction is 25 ~ 75 DEG C, is preferably 45 ~ 60 DEG C; Reaction times is 3 ~ 24 hours, is preferably 5 ~ 15 hours.
In described step (c), described Lewis acid is metal halide, is preferably the metallide of bromine, is more preferably aluminum bromide or zinc bromide; Described halogen is for being preferably bromine or iodine element.
In described step (c), described formula (VII) compound palkoxy benzene methane amide is 1 with lewis acidic mole dosage ratio; (0.005 ~ 0.05); Described formula (VII) compound palkoxy benzene methane amide is 1 with the mole dosage ratio of described halogen: (1 ~ 2.5).
In described step (c), reaction solvent for use is alcohols, halogenated hydrocarbon or aromatic halohydrocarbon class.Be preferably methyl alcohol, ethanol, Virahol; Methylene dichloride, chloroform, 1,1-ethylene dichloride; Chlorobenzene, bromobenzene.Be more preferably methyl alcohol, ethanol, methylene dichloride, ethylene dichloride, chlorobenzene.Described solvent load is 10 ~ 50 times of described formula (VII) compound palkoxy benzene methane amide.
In described step (c), temperature of reaction is 25 ~ 140 DEG C, is preferably 65 ~ 85 DEG C; Reaction times is 20 ~ 50 hours, is preferably 24 ~ 30 hours.
In described step (d), described prussiate is the cyanate of basic metal or transiting state metal; Be preferably sodium cyanide, potassium cyanide, cupric cyanide, cuprous cyanide; Be more preferably cuprous cyanide.
In described step (d), described formula VI compound 3-halogen-4-alkoxy benzamides is 1 with the mole dosage ratio of prussiate: (1 ~ 20) times; Be preferably 1: (1.5 ~ 10.0) times.
In described step (d), reaction solvent for use is polar aprotic solvent; Be preferably DMF, N-Methyl pyrrolidone, N,N-dimethylacetamide; Solvent for use consumption is 5 ~ 60 times of described formula VI compound 3-halogen-4-alkoxy benzamides, is preferably 10 ~ 30 times.
In described step (d), temperature of reaction is 25 ~ 150 DEG C, is preferably 80 ~ 120 DEG C; Reaction times is 2 ~ 24 hours, is preferably 5 ~ 15 hours.
In described step (e), described sulfiding reagent can be thiophosphoric anhydride or Lloyd's's reagent.
In described step (e), described formula (V) chemical compound 3-cyano-4-alkoxy benzamides is 1 with the mole dosage ratio of sulfiding reagent: (0.2 ~ 2.0).
In described step (e), reaction solvent for use is ethers or arene, is preferably tetrahydrofuran (THF), 2-methyltetrahydrofuran, benzene, toluene, dimethylbenzene; Described solvent load is 10 ~ 60 times of described formula (V) chemical compound 3-cyano-4-alkoxy benzamides, is preferably 25 ~ 40 times.
In described step (e), temperature of reaction is 20 ~ 150 DEG C, is preferably 70 ~ 90 DEG C; Reaction times is 3 ~ 24 hours, is preferably 5 ~ 10 hours.
In described step (f), described formula III chemical compound 3-cyano-4-alkoxy benzamide is 1 with the mole dosage ratio of described formula IV compound 2-halogen-3-oxo alkanoic acid ester: (1 ~ 2.5).
In described step (f), the required solvent of reaction is alcoholic solvent, is preferably C
1~ C
6alcohols, be more preferably methyl alcohol, ethanol, Virahol; Reaction solvent is 4 ~ 60 times of described formula III chemical compound 3-cyano-4-alkoxy benzamide, is preferably 5 ~ 20 times.
In described step (f), temperature of reaction is 25 ~ 100 DEG C, is preferably 50 ~ 90 DEG C; Reaction times is 3 ~ 24 hours, is preferably 5 ~ 10 hours.
In described step (g), the alkali of described formation alkaline condition is alkali-metal alkali, is preferably saleratus, salt of wormwood, sodium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide.
In described step (g), described formula II compound 2-(3-cyano group-4-alkoxyl group)-4-alkyl-thiazole-5-manthanoate is 1 with the mole dosage ratio of described alkali: (1.0 ~ 6.0), is preferably 1: (1.0 ~ 2.5).
In described step (g), the required solvent of reaction is the mixture of water and alcoholic solvent or ether solvent; Described alcoholic solvent is preferably as C
1~ C
6alcohols, described ether solvent is preferably tetrahydrofuran (THF), 2-methyltetrahydrofuran.
In described step (g), temperature of reaction is 25 ~ 100 DEG C, is preferably 40 ~ 70 DEG C; Reaction times is 3 ~ 20 hours, is preferably 5 ~ 10 hours.
The method of what the present invention provided prepare 2-aryl nitrile thiazole derivative, reaction raw materials p-HBN is the most cheap in industrial preparation 2-aryl nitrile thiazole derivative raw material, present invention, avoiding the sodium cyanide of thioacetamide and the severe toxicity using strong carcinogenesis, the present invention it also avoid use simultaneously and has strong and stimulating and corrosive trifluoroacetic acid and formic acid, in addition, in the present invention, each step all without column purification, can obtain highly purified product, and total recovery can reach 30% ~ 42%.Therefore, the present invention, in preparation 2-aryl nitrile thiazole derivative, can effectively reduce reaction cost, and it is simple to have reaction type, reacts completely, reaction conditions relaxes, acquisition product yield is high, is easy to the feature of technology, has very high industrial application and economic worth.
Embodiment
Content for a better understanding of the present invention, is described further below in conjunction with specific embodiment, but concrete embodiment is not the restriction done content of the present invention.
The preparation of embodiment 1:4-isobutoxy cyanophenyl
Para hydroxybenzene nitrile (119.0g is added successively in 1000ml tetra-neck round-bottomed flask, 1.0mol) with 400mL DMF, under 20 ~ 25 DEG C of conditions, drop into Anhydrous potassium carbonate (207.0g, 1.5mol), sodium iodide (5.0g, 0.03mol) with isobutane bromide (274.0g, 2.0mol), be slowly warming up to 80 ~ 85 DEG C, stable reaction at this temperature, follow the tracks of with TLC between the reaction period, until raw material transforms completely, approximately need 20 hours.After completion of the reaction, suction filtration, filter cake 30mLN, dinethylformamide drip washing, adds normal hexane in gained solid, extracts with the aqueous sodium hydroxide solution of 5%, merge organic phase, obtain the 4-isobutoxy cyanophenyl 172.0g of orange oily after concentrated, yield is 98.28%, HPLC purity is 98.67%.
1H NMR(400 MHz，DMSO)δ 0.99(d，J＝5.2 Hz，6H)，1.99-2.07(m，1H)，3.83(d，J＝5.2 Hz，2H)，7.09-7.11(m，2H)，7.74-7.77(m，2H).
The preparation of embodiment 2:4-isobutoxy benzamide
4-isobutoxy cyanophenyl (105.0g is added successively in 2000ml tetra-neck round-bottomed flask, 0.6mol), methyl alcohol 600mL and the 240.0g5%NaOH aqueous solution, be warming up to backflow, under reflux state, slowly drip 10% hydrogen peroxide 408.0g, dropwise, continue reaction 8 hours at this temperature.Reaction is finished, suction filtration when reaction system is cooled to 20 ~ 25 DEG C, and filter cake, with after 300.0g water wash, is dried, and final white, needle-shaped crystals thing 4-isobutoxy benzamide 106.5g, yield is 92.00%, HPLC purity 99.87%.
1H NMR(400 MHz，DMSO)δ 0.98(d，J＝5.2 Hz，6H)，1.98-2.06(m，1H)，3.80(d，J＝5.2 Hz，2H)，6.95-6.98(m，2H)，7.1 8(br,1 H)，7.82-7.85(m，3H).
The preparation of embodiment 3:3-bromo-4-isobutoxy benzamide
4-isobutoxy benzamide (96.5g is added successively in 1000ml tetra-neck round-bottomed flask, 0.5mol),, 600mL ethylene dichloride and zinc bromide (1.75g, 0.008mol), in 20 ~ 25 DEG C of instillation bromine (88.0g, 0.55mol), drip after finishing and be warming up to 65 DEG C of continuation reactions 20 hours, absorb tail gas with the 30%NaOH aqueous solution.Reaction is finished, with saturated aqueous solution of sodium bisulfite cancellation reaction, stratification, organic phase concentrates, add 250mL dehydrated alcohol in enriched material, carry out recrystallization, separate out a large amount of white, needle-shaped crystals thing 3-bromo-4-isobutoxy benzamide 124.58g, yield is 91.60%, HPLC purity is 95.71%.
1H NMR(400 MHz，DMSO)δ1.02(d，J＝5.2 Hz，6H)，2.02-2.09(m，1H)，3.90(d，J＝5.2 Hz，2H)，7.15(d，J＝7.2 Hz，1H)，7.30(br，1H)，7.86-7.88(m，1H)，7.93(br，1H)，8.10(d，J＝1.6 Hz，1H).
The preparation of embodiment 4:3-cyano-4-isobutoxy benzamide
3-bromo-4-isobutoxy benzamide (108.8g is added successively in 1000ml mono-neck round-bottomed flask; 0.4mol), cuprous cyanide (43.2g; 0.48mol) with 600mL N; dinethylformamide; under nitrogen protection; be warming up to 130 DEG C, continue reaction 5 ~ 6 hours at this temperature.After completion of the reaction, 85 ~ 95 DEG C are cooled to.Underpressure distillation, reclaims DMF.Add 500mL ethyl acetate in residue, extraction, merge organic phase, organic phase 200mL10%NaCl solution washing, underpressure distillation, reclaim ethyl acetate.Add 60mL ethyl acetate and 250mL normal hexane recrystallization in residue, suction filtration, obtain white powdery solids 3-cyano group-4-(2-methyl propoxy-) benzamide 80.12g, yield is 91.88%, HPLC purity 92.31%.
The preparation of embodiment 5:3-cyano-4-isobutoxy thiobenzamide
Add 3-cyano-4-isobutoxy benzamide (76.3g, 0.35mol) and 600mL2-methyltetrahydrofuran successively in the mono-neck round-bottomed flask of 1000ml, connect device for absorbing tail gas.Under nitrogen protection, add thiophosphoric anhydride (39.8g, 0.179mol) in 15 ~ 20 DEG C in batches.Reaction 7 ~ 12 hours is continued at this temperature after completing.Reaction is finished, and 2-methyltetrahydrofuran is reclaimed in underpressure distillation.Add 450mL ethyl acetate in residue, add 5% aqueous sodium hydroxide solution, regulation system PH=8, extraction, merge organic phase, concentrated, suction filtration, obtain yellow powdery solid 3-cyano-4-isobutoxy thiobenzamide 73.46g, yield is 89.69%, HPLC purity is 95.81%.
1H NMR(400 MHz，CDCl
3)δ 1.08(d，J＝5.2 Hz，6H)，2.15-2.24(m，1H)，3.90(d，J＝5.2 Hz，2H)，6.96(d，J＝7.2 Hz，1H)，7.19(br，1H)，7.58(br，1H)，8.11(d，J＝2.0 Hz，1H)，8.15-8.17(m，1H).
The preparation of embodiment 6:2-(3-cyano-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, ethyl ester
Add 3-cyano-4-isobutoxy thiobenzamide (60.84g, 0.26mol), 300mL dehydrated alcohol and 2-chloroacetyl acetacetic ester (64.19g, 0.39mol) successively in the mono-neck round-bottomed flask of 1000ml, connect device for absorbing tail gas.Slowly be warming up to 75 DEG C under nitrogen protection and continue reaction 3 ~ 5 hours.React complete, be cooled to 15 ~ 20 DEG C.Suction filtration, filter cake is with after the drip washing of about 120.0g dehydrated alcohol, and normal pressure is dried, and obtain 78.96g pale yellow powder shape solid 2-(3-cyano-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, ethyl ester, yield is 80.18%, HPLC purity 99.25%.
1H NMR(400 MHz，CDCl
3)δ 1.09(d，J＝5.2 Hz，6H)，1.39(t，J＝5.6 Hz，3H)，2.17-2.24(m，1H)，2.77(s，3H)，3.90(d，J＝5.2 Hz，2H)，4.36(q，J＝5.6 Hz，2H)，7.01(d，J=7.2 Hz，1H)，8.08-8.10(m，1H)，8.18(d，J＝1.6 Hz，1H).
The preparation of example 7:2-(3-cyano-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid
2-(3-cyano-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, ethyl ester (65.436g is added successively in 1000ml tetra-neck round-bottomed flask, 0.19mol), 250mL dehydrated alcohol and the 228g 5%NaOH aqueous solution, be warming up to 60 ~ 65 DEG C, continue reaction 10 hours at this temperature, react complete, be warming up to backflow.The concentrated hydrochloric acid of 31% is dripped, regulation system PH=2 ~ 2.5 under reflux state.Slow cooling to 15 ~ 20 DEG C.Suction filtration, filter cake is with after the drip washing of about 150.0g pure water, and normal pressure is dried.Obtain 58.52g off-white powder shape solid 2-(3-cyano-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, yield is 97.34%, HPLC purity 98.13%.
1H NMR(400 MHz，Acetone)δ 1.09(d，J＝5.2 Hz，6H)，2.14-2.21(m，1H)，2.71(s，3H)，4.05(d，J＝5.2 Hz，2H)，7.36(d，J＝7.2 Hz，1H)，8.23-8.25(m，1H)，8.28(d，J＝1.6 Hz，1H).
The preparation of embodiment 8:4-ethoxy benzamide
Operate with method according to the method for embodiment 2, get 4-oxyethyl group cyanophenyl (100g, 0.68mol), obtain 4-ethoxy benzamide 103.0g, yield is 91.83%, HPLC purity is 98.38%.
The preparation of the bromo-4-ethoxy benzamide of embodiment 9:3-
Operate with method according to the method for embodiment 3, get 4-ethoxy benzamide (80g, 0.48mol), obtain 3-bromo-4-ethoxy benzamide 161.94g, yield is 97.61%, HPLC purity is 99.52%.
The preparation of embodiment 10:3-cyano group-4-ethoxy benzamide
Operate with method according to the method for embodiment 4, get the bromo-4-ethoxy benzamide (60g, 0.25mol) of 3-, obtain 3-cyano group-4-ethoxy benzamide 42.61g, yield is 89.63%, HPLC purity is 91.87%.
In sum, the present invention relates to the preparation method of 2-aryl nitrile thiazole derivative, above-mentioned preparation method be with p-HBN be that raw material is substituted, is hydrolyzed, electrophilic substitution, nucleophilic substitution, sulphur oxygen exchange, ring and, the simple types reaction such as hydrolysis, the 2-aryl nitrile thiazole derivative that applicable technology is produced can be obtained.
It should be noted that all documents mentioned in the present invention are quoted as a reference in this application, just quoted separately as a reference as each section of document.In addition should understand, the above-described know-why being specific embodiments of the invention and using, after having read foregoing of the present invention, those skilled in the art can make various changes or modifications the present invention and not deviate from spirit of the present invention and scope, and these equivalent form of values fall within the scope of the invention equally.
Claims (3)
1. there is the preparation method as shown in the formula (VI) compound, it is characterized in that, comprise step:
C formula (VII) compound that () is following, in halo alkanes reaction solvent, prepares formula (VI) compound with bromine generation electrophilic substitution reaction under Louis acid catalysis,
Wherein R
1for isobutyl-, X
1for Br;
Described Lewis acid is zinc bromide;
Described formula (VII) compound is 1 with the mole dosage ratio of described bromine: (1 ~ 2.5).
2. there is a preparation method for following formula V compound, comprise step:
C formula (VII) compound that () is following, in halo alkanes reaction solvent, prepares formula (VI) compound with bromine generation electrophilic substitution reaction under Louis acid catalysis,
D () formula (VI) compound and cuprous cyanide generation nucleophilic substitution reaction prepare formula (V) compound,
Wherein R
1, X
1definition identical with the definition of claim 1;
In step (c), described Lewis acid is zinc bromide; Described formula (VII) compound is 1 with the mole dosage ratio of described bromine: (1 ~ 2.5);
In step (d), described (VI) compound is 1 with the mole dosage ratio of cuprous cyanide: (1.2-1.5).
3. there is the preparation method as shown in the formula (VI) compound, comprise step:
B () formula (VIII) compound is hydrolyzed with superoxol the formula that is obtained by reacting (VII) compound in dilute alkaline aqueous solution,
C formula (VII) compound that () is following, in halo alkanes reaction solvent, prepares formula (VI) compound with bromine generation electrophilic substitution reaction under Louis acid catalysis,
Wherein R
1, X
1definition identical with the definition of claim 1;
In step (b), the alkali of described dilute alkaline aqueous solution is sodium hydroxide or potassium hydroxide;
In step (c), described Lewis acid is zinc bromide; Described formula (VII) compound is 1 with the mole dosage ratio of described bromine: (1 ~ 2.5).
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