CN102086147B - Preparation method of substituted phenol - Google Patents

Preparation method of substituted phenol Download PDF

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CN102086147B
CN102086147B CN200910199912.5A CN200910199912A CN102086147B CN 102086147 B CN102086147 B CN 102086147B CN 200910199912 A CN200910199912 A CN 200910199912A CN 102086147 B CN102086147 B CN 102086147B
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aqueous solution
compound
preparation
reaction
acid
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CN102086147A (en
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王萍
潘强彪
邹本立
彭烨城
周小峰
杨伟
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Lianhe Chemical Technology Co Ltd
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Lianhe Chemical Technology Co Ltd
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Abstract

The invention discloses a preparation method of a substituted phenol as shown in formula 1, and the preparation method includes the following steps: compound 3 is reacted with water for substitution of the nitro-group by hydroxyl in a strong acid solution; and compound 3 and a reducing agent undergo diazo salt reduction reaction and the compound 1 is obtained, wherein X- is Cl-, Br-, HSO4-, or NO3-, X1 and X2 are each independently H, Br, Cl, F, I or C1-C5 alkyl. The preparation method in the present invention possesses low cost, easy availability of raw materials, convenient operation, easy purification of product and easy amplification of production, and a higher yield can be achieved.

Description

A kind of preparation method of fortified phenol
Technical field
The present invention relates to a kind of preparation method of organic synthesis intermediate, be specifically related to a kind of preparation method of fortified phenol.
Background technology
Halogenated phenol compound is as the important organic synthesis intermediate of a class, it is the key intermediate of a lot of medicines, for example compd A is used to prepare the medicine of the disease that a kind for the treatment of causes by immunodeficiency virus in patent US2006025462, patent 2007078128 has been described and has been used it for a kind of non-nucleoside reverse transcriptase inhibitor of preparation, and patent WO2007145569 has described a kind of medicine of using it for preparation treatment alzheimer's disease mild cognition impairment disease.
Compd B is used to prepare antiarrhythmic drug in patent WO03101956, and patent US2004198736 has described to use it for and prepared anti-AIDS drug, and patent US2003199511 has described to use it for and prepared kinases inhibitor.WO2008008059 has described to use it for and has prepared anticarcinogen.
Compound C is used to prepare antianaphylaxis or suppressing panting calming medicine in patent WO2004084898, and patent WO2004043904 has described to use it for and prepared anti-depression drug, and patent US2003139390 has described to use it for and prepared antidiabetic medicine.US2002107272 has described to use it for and has prepared anti-AIDS drug.
Compound D is for the preparation of lipid lowerers SMP-797 in addition, cardiovascular protector ARD-353, and compd E is applied to prepare medicine for central nervous system CERM-3726.Prepare antitumor drug SB-743921.
This class 5-substituted phenol compounds market demand potential is very large, but its synthetic method all has some limitations.Prior synthesizing method needs polystep reaction to prepare.To industrialization, bring certain difficulty.
Summary of the invention
Technical problem to be solved by this invention is that in existing fortified phenol synthetic route, cost is higher, side reaction is more in order to overcome, complicated operation, power consumption is higher, raw material is not easy to obtain and yield is lower defect, the preparation method of the diverse fortified phenol of a kind of and existing method is provided, preparation method's cost of the present invention is lower, raw material is easy to get, easy to operate, the easy purifying of product and easily amplify and produce, and can also reach higher productive rate.
The preparation method who the present invention relates to a kind of fortified phenol as shown in Equation 1, it comprises the following step: in strong acid solution, by compound 3 and water carry out reaction that hydroxyl replaces nitro and and reductive agent carry out the reduction reaction of diazonium salt, can make compound 1;
Wherein, X -for Cl -, Br -, HSO 4 -or NO 3 -, X 1and X 2be independently H, Br, Cl, F, I or C 1~C 5alkyl.Described C 1~C 5the preferred C of alkyl 1~C 3alkyl, better is methyl.
In the present invention, described hydroxyl replaces the reaction of nitro and the reduction reaction of diazonium salt can proceed step by step, also can carry out simultaneously.When proceed step by step, first carry out the reaction that hydroxyl replaces nitro, then carry out the reduction reaction of diazonium salt.
In the present invention, the strong acid in described strong acid solution is preferably one or more in hydrochloric acid, Hydrogen bromide, nitric acid and sulfuric acid, and the consumption of strong acid is preferably 3~50 times of molar weight of compound 3, and better is 3~20 times.Described strong acid solution is preferably the mixing solutions of strong acid aqueous solution or strong acid aqueous solution and organic inert solvent, and wherein, the massfraction of described strong acid aqueous solution is preferably 10%~98%; Described organic inert solvent is preferably selected from C 1-C 7alcohol and/or C 4-C 7ether; When strong acid solution is the mixing solutions of strong acid aqueous solution and organic inert solvent, described organic inert solvent is 3~25ml/g with the volume mass of compound 3 than preferably.
In the present invention, described reductive agent can be the conventional reductive agent that diazonium salt reduction reaction is carried out in this area, and the present invention is C particularly preferably 1-C 7alcohol, C 4-C 7the alkali aqueous solution of ether, the Hypophosporous Acid, 50 aqueous solution and formaldehyde in one or more; The consumption of described reductive agent is preferably 5~100 times of molar weight of compound 3.
Wherein, described C 1-C 7alcohol preferred alcohol, propyl alcohol, Virahol and propyl carbinol in one or more, when reductive agent is C 1-C 7alcohol time, C 1-C 7the consumption of alcohol be preferably 10~100 times of compound 3 molar weights.
Described C 4-C 7the preferred tetrahydrofuran (THF) of ether and/or Isosorbide-5-Nitrae-dioxane, when reductive agent is C 4-C 7ether time, the consumption of described ether is preferably 10~100 times of compound 3 molar weights.
The mass percent of the described Hypophosporous Acid, 50 aqueous solution is preferably 30%~50%, and when reductive agent is the Hypophosporous Acid, 50 aqueous solution, the consumption of described Hypophosporous Acid, 50 is preferably 5~15 times of compound 3 molar weights.
The alkali aqueous solution of described formaldehyde is the mixing solutions of the aqueous solution of formalin and alkali.The massfraction of wherein said formalin is preferably 20%~80%, and better is 50%~80%.The aqueous solution of described alkali is preferably aqueous sodium hydroxide solution and/or potassium hydroxide aqueous solution, and the massfraction of the aqueous solution of alkali is preferably 5%~30%.When alkali aqueous solution that reductive agent is formaldehyde, the consumption of formaldehyde is preferably 5~20 times of molar weight of compound 3.
Preferably, the reduction reaction of described diazonium salt also can be carried out under the effect of the catalyzer of this area diazonium salt reduction reaction, and described catalyzer is preferably copper salt catalyst, preferably sulfuric acid copper and/or Red copper oxide.The consumption of catalyzer be preferably compound 3 molar weight 5%~40%, better is 10%~20%.
In the present invention, when described hydroxyl replaces the reaction of nitro and the reduction reaction proceed step by step of diazonium salt, the temperature that described hydroxyl replaces the reaction of nitro is preferably 10 ℃~50 ℃, and better is 20 ℃~30 ℃; Hydroxyl replace nitro reaction time preferably with detection reaction completely till, till ruing out of with HPLC detecting reactant.The temperature of the reduction reaction of described diazonium salt is preferably 0~100 ℃, when reductive agent is C 1-C 7alcohol and/or C 4-C 7ether time, the temperature of the reduction reaction of described diazonium salt is preferably 30~100 ℃, better is 50~90 ℃; When reductive agent is the alkali aqueous solution of the Hypophosporous Acid, 50 aqueous solution and/or formaldehyde, the temperature of the reduction reaction of diazonium salt is preferably 0~30 ℃; The time of the reduction reaction of diazonium salt preferably with detection reaction completely till, till preferably HPLC detecting reactant runs out of.
Described hydroxyl replace the reaction of nitro and the reduction reaction of diazonium salt completely after, only need simple aftertreatment as extraction, concentrated, filter, the method such as dry can obtain pure compound 1.
In the present invention, compound 3 is diazols compounds, according to this area routine operation method, generally not separation and purification and directly using afterwards in preparation, therefore in the preparation method of above-claimed cpd 1, the consumption of the reagent relevant to compound 3, the amount obtaining after all transforming completely with the raw material of preparing it is calculated, in the present invention, the raw material of preparing compound 3 is preferably following compound 2.
In the present invention, described compound 3 can be made by following method: compound 2 is carried out to diazotization reaction;
Wherein, X -for Cl -, Br -, HSO 4 -or NO 3 -, X 1and X 2be independently H, Br, Cl, F, I or C 1~C 5alkyl.
Wherein, the method for described diazotization reaction and condition all can be ordinary method and the condition of this area diazotization reaction.Preferred method and condition are as follows:
In strong acid solution, compound 2 and inorganic nitrite are carried out to diazotization reaction, can make diazenium compound 3.Wherein, described inorganic nitrite is preferably one or more in Sodium Nitrite, potassium nitrite and cesium nitrite, preferably Sodium Nitrite.When inorganic nitrite is Sodium Nitrite, compound 2 is preferably 1: 1~1: 3 with the mol ratio of Sodium Nitrite, and better is 1: 1~1: 2.
Described strong acid solution is preferably the mixing solutions of strong acid aqueous solution or strong acid aqueous solution and organic inert solvent, and described organic inert solvent is preferably selected from C 1-C 7alcohol and/or C 4-C 7ether, described C 1-C 7alcohol preferred alcohol, propyl alcohol, Virahol and propyl carbinol in one or more, described C 4-C 7the preferred tetrahydrofuran (THF) of ether and/or Isosorbide-5-Nitrae-dioxane; The massfraction of strong acid aqueous solution is preferably 10%~98%; Described strong acid is preferably one or more in hydrochloric acid, Hydrogen bromide, nitric acid and sulfuric acid, preferably sulfuric acid; When strong acid is sulfuric acid, the consumption of sulfuric acid is preferably 3~50 times of molar weight of compound 2, and better is 8~20 times.Diazotization reaction is conducive to the carrying out of reaction and guarantees the stability of diazonium salt under strong acid acidic conditions.
The temperature of described diazotization reaction is preferably-5 ℃~30 ℃, and better is 0 ℃~10 ℃; The time of described diazotization reaction preferably with detection reaction completely till, till preferably ruing out of with HPLC detecting reactant.
Each optimum condition in above-mentioned preparation method can carry out arbitrary combination take on the basis that the conventional knowledge of this area is foundation, obtains each preferred embodiments of the present invention.
Except specified otherwise, the reagent the present invention relates to and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is: the preparation method who the invention provides the diverse fortified phenol of a kind of and existing method.And preparation method of the present invention can avoid expensive reagent or raw material, thereby reduces costs, and raw material is easy to get, working method is simple and convenient, the easy purifying of product, is not only applicable to laboratory and prepares on a small quantity, is also applicable to large-scale industrialization and produces; It can also reach higher productive rate and purity.
Embodiment
With embodiment, further illustrate the present invention below, but the present invention is not limited.
The preparation of embodiment 13-bromo-5-chlorophenol
The bromo-4-chloro-2-nitroaniline of 6-(12.57g, 0.05mol) be dissolved in 50mL methyl alcohol, add 100 mL 50% Hydrogen bromides to be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (3.45g, 0.05mol) in batches,-5 ℃ are continued to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~25 ℃ of insulation 12h, be warmed up to 60 ℃ and stir 12h, concentrating under reduced pressure falls most of methyl alcohol, adds ethyl acetate 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL ethyl acetate, extract, organic layer is dry to be concentrated into dryly, and normal heptane recrystallization obtains white solid, yield 85%.
1H?NMR(300MHz,CDCl 3)δ:5.16(br,1H),6.82(t,J=1.46Hz,1H),6.93(t,J=1.46Hz,1H),7.12(t,J=1.46Hz,1H).
HPLC:99.1%
The preparation of embodiment 23-bromo-5-chlorophenol
The bromo-4-chloro-2-nitroaniline of 6-(12.57g, 0.05mol) add 100mL 50% nitric acid to be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (6.90g in batches, 0.10mol), 10 ℃ are continued to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is at 10 ℃ of insulation 28h, splashes in the 80mL aqueous isopropanol of 70 ℃, and 70 ℃ are stirred 12h, concentrating under reduced pressure falls most of Virahol, add methylene dichloride 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL dichloromethane extraction, organic layer is dry be concentrated into dry, normal heptane recrystallization obtains white solid, yield 80%.。
1H?NMR(300MHz,CDCl 3)δ:5.16(br,1H),6.82(t,J=1.46Hz,1H),6.93(t,J=1.46Hz,1H),7.12(t,J=1.46Hz,1H).
HPLC:99.2%
The preparation of embodiment 33-bromo-5-chlorophenol
The bromo-2-N-methyl-p-nitroaniline of the chloro-4-of 6-(12.57g, 0.05mol) be dissolved in 80mL ethanol, add 10mL 98% sulfuric acid to be stirred to dissolving, be cooled to 0 ℃, control temperature below 10 ℃, slowly drip the solution of Sodium Nitrite solid (6.90g, 0.10mol) and 20g water, 10 ℃ are continued to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 30 ℃ of insulation 12h, continue to be warmed up to 70 ℃ and stir 12h, pressurization concentrates most of ethanol, adds ethyl acetate 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL ethyl acetate, extract, organic layer is dry to be concentrated into dryly, and normal heptane recrystallization obtains white solid, yield 80%.。
1H?NMR(300MHz,CDCl 3)δ:5.16(br,1H),6.82(t,J=1.46Hz,1H),6.93(t,J=1.46Hz,1H),7.12(t,J=1.46Hz,1H).
HPLC:99.2%
Embodiment 43, the preparation of 5-chlorophenesic acid
4,6-bis-chloro-2-nitroaniline (10.35g, 0.05mol) add 100mL 35% hydrochloric acid to be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (10.35g, 0.15mol) in batches, at 10 ℃, continue to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 50 ℃ of insulation 24h, be cooled to 0 ℃, add 50% Hypophosporous Acid, 50 aqueous solution 100mL, at 0 ℃, stir 30 minutes, after being warmed up to room temperature, be incubated 6h, add toluene 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL toluene, extract, organic layer is dry to be concentrated into dryly, and sherwood oil recrystallization obtains white solid, yield 68%.
HPLC:99.4%
The preparation of embodiment 5 m-Chlorophenols
4-chloro-2-nitroaniline (8.63g, 0.05mol) be dissolved in 80mL tetrahydrofuran (THF), add 10mL98% sulfuric acid to be stirred to and dissolve completely, be cooled to 0 ℃, control temperature below 10 ℃, slowly drip the solution of Sodium Nitrite solid (6.9g, 0.105mol) and 30g water, at 10 ℃, continue to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~30 ℃ of insulation 12h, is warmed up to 40~50 ℃ and continues reaction 12h.Concentrating under reduced pressure falls most of tetrahydrofuran (THF), add vinyl acetic monomer 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL ethyl acetate extraction, organic layer is dry is concentrated into dry product, yield 65%.
HPLC:99%
The preparation of embodiment 6 m-Chlorophenols
4-chloro-2-nitroaniline (8.63g, 0.05mol) be dissolved in 120mL 1, in 4-dioxane, add 10mL 98% sulfuric acid to be stirred to and dissolve completely, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (6.9g in batches, 0.19mol), continue at 10 ℃ to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~30 ℃ of insulation 12h, is warmed up to 70~80 ℃ and continues reaction 6h.Concentrating under reduced pressure falls most of 1,4-dioxane, add vinyl acetic monomer 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL ethyl acetate extraction, organic layer is dry be concentrated into dry, sherwood oil recrystallization obtains product, yield 72%.
HPLC:99.3%
The preparation of 7 bromophenols of embodiment
The bromo-2-N-methyl-p-nitroaniline of 4-(10.85g, 0.05mol) add 100mL 35% hydrochloric acid to be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (6.9g in batches, 0.10mol), continue at 10 ℃ to stir 30 minutes, obtain yellow diazonium salt solution
The yellow diazonium salt solution of gained is slowly warmed up to 20~30 ℃ of insulation 12h, is then added drop-wise to fast in the mixing solutions of the aqueous sodium hydroxide solution of 800mL 10% and the formalin of 50mL 37%.20 ℃ are continued to stir 2h, add tetracol phenixin 200mL, and standing separatory, boils off after organic layer, and steam distillation is collected the oily matter in distillate, is dried to obtain product, yield 65%.
1H?NMR(300MHz,CDCl 3)δ:6.12(s,1H),6.77-6.81(m,1H),7.04(d,J=1.8Hz,1H),7.09-7.14(m,2H).
HPLC:99.5%
Embodiment 82, the preparation of 3-chlorophenesic acid
3,4-bis-chloro-2-nitroaniline (10.35g, 0.05mol) be dissolved in 80mL ethanol, add successively 100mL 35% hydrochloric acid, 1g copper sulfate, be stirred to and dissolve completely, be cooled to 0 ℃, control temperature below 10 ℃, add the solution of Sodium Nitrite solid (10.35g, 0.15mol) and 30mL water in batches, at 5 ℃, continue to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~25 ℃ of insulation 8h, after continuing to be warmed up to 70 ℃, be incubated 6h, add vinyl acetic monomer 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL ethyl acetate extraction, organic layer is dry is concentrated into dry product.Yield 70%.
HPLC:99.1%
Embodiment 83, the preparation of 4-chlorophenesic acid
4,5-bis-chloro-2-nitroaniline (10.35g, 0.05mol) be dissolved in 80mL propyl carbinol, add successively 100mL 35% hydrochloric acid, 2g copper sulfate, be stirred to and dissolve completely, be cooled to 0 ℃, control temperature below 10 ℃, add the solution of Sodium Nitrite solid (10.35g, 0.15mol) and 30mL water in batches, at 5 ℃, continue to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~25 ℃ of insulation 8h, after continuing to be warmed up to 70 ℃, be incubated 6h, add vinyl acetic monomer 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL ethyl acetate extraction, organic layer is dry is concentrated into dry product.Yield 65%.
HPLC:99%
The preparation of 9 iodophenols of embodiment
The iodo-2-N-methyl-p-nitroaniline of 4-(13.20g, 0.05mol) be dissolved in 80mL butanols, add successively 20g98% sulfuric acid, 1g Red copper oxide, be stirred to and dissolve completely, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (10.35g in batches, 0.15mol) and the solution of 30mL water, continue to stir 30 minutes at 5 ℃, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~25 ℃ of insulation 8h, is incubated 3h after continuing to be warmed up to 70 ℃.Add vinyl acetic monomer 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer the 4N hcl acidifying of take are 4 left and right to pH, and with 3 * 50mL ethyl acetate extraction, organic layer is dry is concentrated into dry product.Yield 65%.
HPLC:99.1%
The preparation of embodiment 10 p-fluorophenols
The fluoro-2-N-methyl-p-nitroaniline of 5-(7.81g, 0.05mol) is dissolved in 80mL ethanol, adds successively 15g
98% sulfuric acid, 1g copper sulfate, be stirred to and dissolve completely, is cooled to 0 ℃, controls temperature below 10 ℃, adds the solution of Sodium Nitrite solid (10.35g, 0.15mol) and 25mL water in batches, continues stirring 30 minutes at 5 ℃, obtains yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~25 ℃ of insulation 8h, is incubated 3h after continuing to be warmed up to 70 ℃.Add vinyl acetic monomer 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer the 4N hcl acidifying of take are 4 left and right to pH, and with 3 * 50mL ethyl acetate extraction, organic layer is dry is concentrated into dry product.Yield 65%.
1H?NMR(300MHz,CDCl 3)δ:5.98(s,1H),6.77-6.83(m,2H),6.90-6.96(m,2H).
HPLC:99.4%
Embodiment 113, the preparation of 5-bromophenol
The bromo-2-N-methyl-p-nitroaniline of the chloro-4-of 6-(14.80g, 0.05mol) be dissolved in 80mL ethanol, add 10mL 98% sulfuric acid to be stirred to dissolving, be cooled to 0 ℃, control temperature below 10 ℃, slowly drip the solution of Sodium Nitrite solid (6.90g, 0.10mol) and 20g water, 10 ℃ are continued to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 30 ℃ of insulation 12h, continue to be warmed up to 70 ℃ and stir 12h, concentrating under reduced pressure falls most of ethanol, adds ethyl acetate 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL ethyl acetate, extract, organic layer is dry to be concentrated into dryly, and normal heptane recrystallization obtains white solid, yield 80%.。
1H?NMR(300MHz,CDCl 3)δ:7.21(s,1H),6.97(s,2H),5.88(s,1H).
HPLC:99.2%
The preparation of embodiment 12 m-cresols
4-chloro-2-nitroaniline (7.61g, 0.05mol) be dissolved in 80mL ethanol, add 10mL 98% sulfuric acid to be stirred to and dissolve completely, be cooled to 0 ℃, control temperature below 10 ℃, slowly drip the solution of Sodium Nitrite solid (6.9g, 0.105mol) and 30g water, at 10 ℃, continue to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~30 ℃ of insulation 12h, is warmed up to 50~60 ℃ and continues reaction 12h.Concentrating under reduced pressure falls most of ethanol, add vinyl acetic monomer 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL ethyl acetate extraction, organic layer is dry is concentrated into dry product, yield 41%.
HPLC:98%
The preparation of embodiment 133-bromo-5-chlorophenol
The bromo-4-chloro-2-nitroaniline of 6-(12.57g, 0.05mol) be dissolved in 50mL methyl alcohol, add 120mL10% Hydrogen bromide to be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, control temperature below 10 ℃, add potassium nitrite solid 4.26g (0.05mol), 30 ℃ are continued to stir 30 minutes, obtain yellow diazonium salt solution in batches.
The yellow diazonium salt solution of gained is slowly warmed up to 20~25 ℃ of insulation 12h, be warmed up to 30 ℃ and stir 12h, concentrating under reduced pressure falls most of methyl alcohol, adds ethyl acetate 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL ethyl acetate, extract, organic layer is dry to be concentrated into dryly, and normal heptane recrystallization obtains white solid, yield 75%.
1H?NMR(300MHz,CDCl 3)δ:5.16(br,1H),6.82(t,J=1.46Hz,1H),6.93(t,J=1.46Hz,1H),7.12(t,J=1.46Hz,1H).
HPLC:99%
The preparation of embodiment 14 m-cresols
4-chloro-2-nitroaniline (7.61g, 0.05mol) be dissolved in 37.6mL propyl alcohol, add 8.2mL98% sulfuric acid to be stirred to and dissolve completely, be cooled to 0 ℃, control temperature below 10 ℃, slowly drip the solution of Sodium Nitrite solid (6.9g, 0.15mol) and 30g water, at 10 ℃, continue to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~30 ℃ of insulation 12h, is warmed up to 50~60 ℃ and continues reaction 12h.Concentrating under reduced pressure falls most of propyl alcohol, add vinyl acetic monomer 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL ethyl acetate extraction, organic layer is dry is concentrated into dry product, yield 45%.
HPLC:98%
The preparation of embodiment 153-sec.-propyl-5-bromophenol
2-nitro-3-sec.-propyl-5-bromaniline (12.96g, 0.05mol) be dissolved in 291mL ethanol, add successively 136mL 98% sulfuric acid, 0.4g copper sulfate, be stirred to and dissolve completely, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (10.35g in batches, 0.15mol) and the solution of 25mL water, continue to stir 30 minutes at 5 ℃, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~25 ℃ of insulation 8h, is incubated 3h after continuing to be warmed up to 70 ℃.Add toluene 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer the 4N hcl acidifying of take are 4 left and right to pH, and with 3 * 50mL toluene extraction, organic layer is dry is concentrated into dry product.Yield 53%.
HPLC:99.0%
The preparation of 16 bromophenols of embodiment
The bromo-2-N-methyl-p-nitroaniline of 4-(10.85g, 0.05mol) add 100mL 35% hydrochloric acid to be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (6.9g in batches, 0.10mol), continue at 10 ℃ to stir 30 minutes, obtain yellow diazonium salt solution
The yellow diazonium salt solution of gained is slowly warmed up to 20~30 ℃ of insulation 12h, is then added drop-wise to fast in the mixing solutions of the potassium hydroxide aqueous solution of 800mL 5% and the formalin of 37.5g 20%.30 ℃ are continued to stir 2h, add tetracol phenixin 200mL, and standing separatory, boils off after organic layer, and steam distillation is collected the oily matter in distillate, is dried to obtain product, yield 66%.
1H?NMR(300MHz,CDCl 3)δ:6.12(s,1H),6.77-6.81(m,1H),7.04(d,J=1.8Hz,1H),7.09-7.14(m,2H).
HPLC:99.1%
The preparation of 17 bromophenols of embodiment
The bromo-2-N-methyl-p-nitroaniline of 4-(10.85g, 0.05mol) add 100mL 35% hydrochloric acid to be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (6.9 g in batches, 0.10mol), continue at 10 ℃ to stir 30 minutes, obtain yellow diazonium salt solution
The yellow diazonium salt solution of gained is slowly warmed up to 20~30 ℃ of insulation 12h, is then added drop-wise to fast in the mixing solutions of the potassium hydroxide aqueous solution of 800mL 30% and the formalin of 37.5g 80%.30 ℃ are continued to stir 2h, add tetracol phenixin 200mL, and standing separatory, boils off after organic layer, and steam distillation is collected the oily matter in distillate, is dried to obtain product, yield 52%.
1H?NMR(300MHz,CDCl 3)δ:6.12(s,1H),6.77-6.81(m,1H),7.04(d,J=1.8Hz,1H),7.09-7.14(m,2H).
The preparation of embodiment 183-Skellysolve A base-5-chlorophenol
4-Skellysolve A base-6-chloro-2-nitroaniline (12.14g, 0.05mol) be dissolved in 240mL1, in 4-dioxane, add 10mL 98% sulfuric acid to be stirred to and dissolve completely, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (6.9g in batches, 0.19mol), continue at 10 ℃ to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~30 ℃ of insulation 12h, is warmed up to 100 ℃ and continues reaction 6h.Concentrating under reduced pressure falls most of 1,4-dioxane, add vinyl acetic monomer 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL ethyl acetate extraction, organic layer is dry be concentrated into dry, sherwood oil recrystallization obtains product, yield 44%.
HPLC:99.2%
Embodiment 193, the preparation of 5-chlorophenesic acid
4,6-bis-chloro-2-nitroaniline (10.35g, 0.05mol) add 100mL 35% hydrochloric acid to be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (10.35g, 0.15mol) in batches, at 10 ℃, continue to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 50 ℃ of insulation 24h, be cooled to 0 ℃, the Hypophosporous Acid, 50 aqueous solution that adds 70mL30%, at 0 ℃, stir 30 minutes, after being warmed up to room temperature, be incubated 6h, add toluene 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL toluene, extract, organic layer is dry to be concentrated into dryly, and sherwood oil recrystallization obtains white solid, yield 67%.
HPLC:99.4%
Embodiment 203, the preparation of 5-chlorophenesic acid
4,6-bis-chloro-2-nitroaniline (10.35g, 0.05mol) add 100mL 35% hydrochloric acid to be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, control temperature below 10 ℃, add Sodium Nitrite solid (10.35g, 0.15mol) in batches, at 10 ℃, continue to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 50 ℃ of insulation 24h, is cooled to 0 ℃, adds the Hypophosporous Acid, 50 aqueous solution of 99g50%, at 0 ℃, stir 30 minutes, be incubated 6h after being warmed up to room temperature, add toluene 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer and take 4N hcl acidifying to pH be 4 left and right, with 3 * 50mL toluene, extract, organic layer is dry to be concentrated into dryly, and sherwood oil recrystallization obtains white solid, yield 60%.
HPLC:99.4%
The preparation of embodiment 21 p-fluorophenols
The fluoro-2-N-methyl-p-nitroaniline of 5-(7.81g, 0.05mol) be dissolved in 150mL ethanol, add successively 147.8mL98% sulfuric acid, 3.2g copper sulfate, be stirred to and dissolve completely, be cooled to 0 ℃, control temperature below 10 ℃, add the solution of 26.8g cesium nitrite solid and 25mL water in batches, at 5 ℃, continue to stir 30 minutes, obtain yellow diazonium salt solution.
The yellow diazonium salt solution of gained is slowly warmed up to 20~25 ℃ of insulation 8h, is incubated 3h after continuing to be warmed up to 70 ℃.Add toluene 200mL, standing separatory, organic layer adds 50mL 4N sodium hydroxide to stir 10 minutes, separatory with 50mL water washing organic layer, combining water layer the 4N hcl acidifying of take are 4 left and right to pH, and with 3 * 50mL toluene extraction, organic layer is dry is concentrated into dry product.Yield 62%.
1H?NMR(300MHz,CDCl 3)δ:5.98(s,1H),6.77-6.83(m,2H),6.90-6.96(m,2H).
HPLC:99.0%?。

Claims (8)

1. a preparation method for fortified phenol as shown in Equation 1, is characterized in that comprising the following step: in strong acid solution, compound 3 and water first carried out to the reaction that hydroxyl replaces nitro, then carries out the reduction reaction of diazonium salt with reductive agent; Strong acid in described strong acid solution is one or more in hydrochloric acid, Hydrogen bromide, nitric acid and sulfuric acid, and the consumption of strong acid is 3~50 times of molar weight of compound 3; Described reductive agent is C 1-C 7alcohol, C 4-C 7the alkali aqueous solution of ether, the Hypophosporous Acid, 50 aqueous solution and formaldehyde in one or more; When reductive agent is C 1-C 7alcohol time, described C 1-C 7the consumption of alcohol be 10~100 times of compound 3 molar weights; When reductive agent is C 4-C 7ether time, described C 4-C 7the consumption of ether be 10~100 times of compound 3 molar weights; When reductive agent is the Hypophosporous Acid, 50 aqueous solution, the consumption of described Hypophosporous Acid, 50 is 5~15 times of compound 3 molar weights; When alkali aqueous solution that reductive agent is formaldehyde, the consumption of described formaldehyde is 5~20 times of molar weight of compound 3; The temperature that described hydroxyl replaces the reaction of nitro is 10 ℃~50 ℃; Described hydroxyl replace nitro reaction time with detection reaction completely till; When reductive agent is C 1-C 7alcohol and/or C 4-C 7ether time, the temperature of the reduction reaction of described diazonium salt is 30~100 ℃; When reductive agent is the alkali aqueous solution of the Hypophosporous Acid, 50 aqueous solution and/or formaldehyde, the temperature of the reduction reaction of diazonium salt is 0~30 ℃; Till the time of the reduction reaction of described diazonium salt is complete with detection reaction;
Wherein, X for Cl , Br , HSO 4 or NO 3 , X 1and X 2be independently H, Br, Cl, F, I or C 1~C 5alkyl.
2. the preparation method of fortified phenol as claimed in claim 1, is characterized in that: described strong acid solution is the mixing solutions of strong acid aqueous solution or strong acid aqueous solution and organic inert solvent.
3. the preparation method of fortified phenol as claimed in claim 2, is characterized in that: described organic inert solvent is selected from C 1-C 7alcohol and/or C 4-C 7ether; The massfraction of described strong acid aqueous solution is 10%~98%.
4. the preparation method of fortified phenol as claimed in claim 1, is characterized in that: described C 1-C 7alcohol be one or more in ethanol, propyl alcohol, Virahol and propyl carbinol; Described C 4-C 7ether be tetrahydrofuran (THF) and/or Isosorbide-5-Nitrae-dioxane; The mass percent of the described Hypophosporous Acid, 50 aqueous solution is 30%~50%; The alkali aqueous solution of described formaldehyde is the mixing solutions of the aqueous solution of formalin and alkali, and the massfraction of described formalin is 20%~80%; The aqueous solution of described alkali is aqueous sodium hydroxide solution and/or potassium hydroxide aqueous solution, and the massfraction of the aqueous solution of alkali is 5%~30%.
5. the preparation method of fortified phenol as claimed in claim 1, is characterized in that: the reduction reaction of described diazonium salt is carried out under the effect of copper salt catalyst; The consumption of catalyzer be compound 3 molar weight 5%~40%.
6. the preparation method of fortified phenol as claimed in claim 1, is characterized in that: the temperature that described hydroxyl replaces the reaction of nitro is 20 ℃~30 ℃; When reductive agent is C 1-C 7alcohol and/or C 4-C 7ether time, the temperature of the reduction reaction of described diazonium salt is 50~90 ℃.
7. the preparation method of fortified phenol as claimed in claim 1, is characterized in that: described compound 3 is made by following method: compound 2 is carried out to diazotization reaction;
Wherein, X for Cl , Br , HSO 4 or NO 3 , X 1and X 2be independently H, Br, Cl, F, I or C 1~C 5alkyl.
8. the preparation method of fortified phenol as claimed in claim 7, is characterized in that: described compound 3 is made by following method: in strong acid solution, compound 2 and inorganic nitrite are carried out to diazotization reaction, can make diazenium compound 3;
Wherein, described inorganic nitrite is one or more in Sodium Nitrite, potassium nitrite and cesium nitrite; When inorganic nitrite is Sodium Nitrite, compound 2 is 1:1~1:3 with the mol ratio of Sodium Nitrite; Described strong acid solution is the mixing solutions of strong acid aqueous solution or strong acid aqueous solution and organic inert solvent, and wherein said organic inert solvent is selected from C 1-C 7alcohol and/or C 4-C 7ether; The massfraction of described strong acid aqueous solution is 10%~98%; Described strong acid is one or more in hydrochloric acid, Hydrogen bromide, nitric acid and sulfuric acid; When strong acid is sulfuric acid, the consumption of sulfuric acid is 3~50 times of molar weight of compound 2; The temperature of described reaction is-5 ℃~30 ℃; Till the time of described reaction is complete with detection reaction.
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