CN102086147A - Preparation method of substituted phenol - Google Patents
Preparation method of substituted phenol Download PDFInfo
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- CN102086147A CN102086147A CN2009101999125A CN200910199912A CN102086147A CN 102086147 A CN102086147 A CN 102086147A CN 2009101999125 A CN2009101999125 A CN 2009101999125A CN 200910199912 A CN200910199912 A CN 200910199912A CN 102086147 A CN102086147 A CN 102086147A
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- reaction
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- NPCIWMOFULRTDX-UHFFFAOYSA-N Nc(c([N+]([O-])=O)cc(Cl)c1)c1Br Chemical compound Nc(c([N+]([O-])=O)cc(Cl)c1)c1Br NPCIWMOFULRTDX-UHFFFAOYSA-N 0.000 description 2
- GMGWXLPFRHYWAS-UHFFFAOYSA-N Oc1cc(Br)cc(Cl)c1 Chemical compound Oc1cc(Br)cc(Cl)c1 GMGWXLPFRHYWAS-UHFFFAOYSA-N 0.000 description 2
- 0 [*-]Nc(c(Br)cc(Cl)c1)c1[N+]([O-])=O Chemical compound [*-]Nc(c(Br)cc(Cl)c1)c1[N+]([O-])=O 0.000 description 1
- FHDZLLWGSFAZSE-UHFFFAOYSA-N [O-][N+](c1cc(Cl)cc(Br)c1N[Br-])=O Chemical compound [O-][N+](c1cc(Cl)cc(Br)c1N[Br-])=O FHDZLLWGSFAZSE-UHFFFAOYSA-N 0.000 description 1
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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
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 of treatment 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 cognitive dysfunction disease.
Compd B is used to prepare antiarrhythmic drug in patent WO03101956, patent US2004198736 has described and used it for the preparation anti-AIDS drug, and patent US2003199511 has described and used it for the preparation kinases inhibitor.WO2008008059 has described and has used it for the preparation anticarcinogen.
Compound C is used to prepare antianaphylaxis or suppressing panting calming medicine in patent WO2004084898, patent WO2004043904 has described and used it for the preparation anti-depression drug, and patent US2003139390 has described and used it for the preparation antidiabetic medicine.US2002107272 has described and has used it for the preparation anti-AIDS drug.
Compound D is used to prepare lipid lowerers SMP-797 in addition, and cardiovascular protector ARD-353, compd E are applied to prepare medicine for central nervous system CERM-3726.Preparation antitumor drug SB-743921.
This class 5-substituted phenol compounds market demand potential is very big, but all there is certain limitation in its synthetic method.Prior synthesizing method needs polystep reaction to prepare.Bring certain difficulty to industrialization.
Summary of the invention
Technical problem to be solved by this invention is that cost is higher in the existing fortified phenol synthetic route, 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 defective, 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 than higher productive rate.
The present invention relates to a kind of preparation method of fortified phenol as shown in Equation 1, it comprises the following step: in the strong acid solution, with 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
-Be Cl
-, Br
-, HSO
4 -Or NO
3 -, X
1And X
2Independently be 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.
Among the present invention, but described hydroxyl replaces the reaction of nitro and the reduction reaction proceed step by step of diazonium salt, also can carry out simultaneously.When proceed step by step, carry out the reaction that hydroxyl replaces nitro earlier, carry out the reduction reaction of diazonium salt again.
Among the present invention, the strong acid in the described strong acid solution is preferable is in hydrochloric acid, Hydrogen bromide, nitric acid and the sulfuric acid one or more, and the consumption of strong acid is preferable is 3～50 times of molar weight of compound 3, and better is 3～20 times.What described strong acid solution was preferable is the mixing solutions of strong acid aqueous solution or strong acid aqueous solution and organic inert solvent, and wherein, what the massfraction of described strong acid aqueous solution was preferable is 10%～98%; Described organic inert solvent is preferable is 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, the volume mass of described organic inert solvent and compound 3 than preferable be 3～25ml/g.
Among the present invention, described reductive agent can be the reductive agent commonly used that the diazonium salt reduction reaction is carried out in this area, the preferred especially C of the present invention
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 preferable is 5～100 times of molar weight of compound 3.
Wherein, described C
1-C
7Pure preferred alcohol, propyl alcohol, Virahol and propyl carbinol in one or more, when reductive agent is C
1-C
7Pure the time, C
1-C
7The consumption of alcohol preferable be 10～100 times of compound 3 molar weights.
Described C
4-C
7The preferred tetrahydrofuran (THF) of ether and/or 1, the 4-dioxane is when reductive agent is C
4-C
7Ether the time, the consumption of described ether is preferable is 10～100 times of compound 3 molar weights.
What the mass percent of the described Hypophosporous Acid, 50 aqueous solution was preferable is 30%～50%, and when reductive agent was the Hypophosporous Acid, 50 aqueous solution, the consumption of described Hypophosporous Acid, 50 is preferable was 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.What the massfraction of wherein said formalin was preferable is 20%～80%, and better is 50%～80%.What the aqueous solution of described alkali was preferable is aqueous sodium hydroxide solution and/or potassium hydroxide aqueous solution, and what the massfraction of the aqueous solution of alkali was preferable is 5%～30%.When reductive agent was the alkali aqueous solution of formaldehyde, the consumption of formaldehyde is preferable was 5～20 times of molar weight of compound 3.
Preferable, 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 what described catalyzer was preferable is copper salt catalyst, preferably sulfuric acid copper and/or Red copper oxide.Catalyst consumption is preferable be compound 3 molar weight 5%～40%, better is 10%～20%.
Among the present invention, when described hydroxyl replaces the reduction reaction proceed step by step of the reaction of nitro and diazonium salt, described hydroxyl replace the temperature of reaction of nitro preferable be 10 ℃～50 ℃, better is 20 ℃～30 ℃; Hydroxyl replace time of reaction of nitro preferable with detection reaction fully till, till ruing out of with the HPLC detecting reactant.What the temperature of the reduction reaction of described diazonium salt was preferable is 0～100 ℃, when reductive agent is C
1-C
7Alcohol and/or C
4-C
7Ether the time, what the temperature of the reduction reaction of described diazonium salt was preferable is 30～100 ℃, better is 50～90 ℃; When reductive agent was the alkali aqueous solution of the Hypophosporous Acid, 50 aqueous solution and/or formaldehyde, what the temperature of the reduction reaction of diazonium salt was preferable was 0～30 ℃; The time of the reduction reaction of diazonium salt preferable with detection reaction fully till, till preferred HPLC detecting reactant runs out of.
Reduction reaction that described hydroxyl replaces the reaction of nitro and diazonium salt fully after, only need simple aftertreatment as extraction, concentrate, methods such as filtration, drying can obtain pure compound 1.
Among the present invention, compound 3 is diazols compounds, according to this area routine operation method, generally do not separate purifying and directly use after preparation, therefore in the preparation method of above-claimed cpd 1, the consumption of the reagent relevant with compound 3, the amount that obtains after all transforming fully with the raw material for preparing it is calculated, what in the present invention, the raw material of preparation compound 3 was preferable is following compound 2.
Among the present invention, described compound 3 can be made by following method: compound 2 is carried out diazotization reaction get final product;
Wherein, X
-Be Cl
-, Br
-, HSO
4 -Or NO
3 -, X
1And X
2Independently be H, Br, Cl, F, I or C
1～C
5Alkyl.
Wherein, the method for described diazotization reaction and condition all can be the ordinary method and the condition of this area diazotization reaction.Preferable methods and condition are as follows:
In strong acid solution, compound 2 and inorganic nitrite are carried out diazotization reaction, can make diazenium compound 3.Wherein, described inorganic nitrite is preferable is in Sodium Nitrite, potassium nitrite and the cesium nitrite one or more, preferred Sodium Nitrite.When inorganic nitrite was Sodium Nitrite, what the mol ratio of compound 2 and Sodium Nitrite was preferable was 1: 1～1: 3, and better is 1: 1～1: 2.
What described strong acid solution was preferable is the mixing solutions of strong acid aqueous solution or strong acid aqueous solution and organic inert solvent, and described organic inert solvent is preferable is selected from C
1-C
7Alcohol and/or C
4-C
7Ether, described C
1-C
7Pure preferred alcohol, propyl alcohol, Virahol and propyl carbinol in one or more, described C
4-C
7The preferred tetrahydrofuran (THF) of ether and/or 1, the 4-dioxane; What the massfraction of strong acid aqueous solution was preferable is 10%～98%; Described strong acid is preferable is in hydrochloric acid, Hydrogen bromide, nitric acid and the sulfuric acid one or more, preferably sulfuric acid; When strong acid was sulfuric acid, the vitriolic consumption is preferable was 3～50 times of molar weight of compound 2, and better is 8～20 times.Diazotization reaction helps carrying out that reacts and the stability that guarantees diazonium salt under the strong acid acidic conditions.
What the temperature of described diazotization reaction was preferable is-5 ℃～30 ℃, and better is 0 ℃～10 ℃; The time of described diazotization reaction preferable with detection reaction fully till, till preferably ruing out of with the HPLC detecting reactant.
Each optimum condition among the above-mentioned preparation method can be to carry out arbitrary combination on the basis of foundation in the conventional knowledge with this area, promptly gets each preferred embodiments of the present invention.
Except that specified otherwise, reagent that the present invention relates to and raw material are all commercially available to be got.
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 cost, and raw material is easy to get, working method is simple and convenient, the easy purifying of product, not only is fit to the laboratory and prepares on a small quantity, also is fit to large-scale industrialization production; It can also reach higher productive rate and purity.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
The preparation of embodiment 13-bromo-5-chlorophenol
6-bromo-4-chloro-2-N-methyl-p-nitroaniline (12.57g, 0.05mol) be dissolved in the 50mL methyl alcohol, adding 100 mL, 50% Hydrogen bromide is warming up to 100 ℃ and is stirred to dissolving, be cooled to 0 ℃, controlled temperature is below 10 ℃, add in batches the Sodium Nitrite solid (3.45g, 0.05mol),-5 ℃ are continued to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is 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, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried, and the 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
6-bromo-4-chloro-2-N-methyl-p-nitroaniline (12.57g, 0.05mol) adding 100mL 50% nitric acid is warming up to 100 ℃ and is stirred to dissolving, is cooled to 0 ℃, controlled temperature is below 10 ℃, add in batches the Sodium Nitrite solid (6.90g, 0.10mol), 10 ℃ are continued to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained is at 10 ℃ of insulation 28h, splashes in 70 ℃ the 80mL aqueous isopropanol, and 70 ℃ are stirred 12h, concentrating under reduced pressure falls most of Virahol, add methylene dichloride 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and be about 4 to pH with the 4N hcl acidifying, with 3 * 50mL dichloromethane extraction, the organic layer drying is concentrated into dried, the normal heptane recrystallization gets 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
6-chloro-4-bromo-2-N-methyl-p-nitroaniline (12.57g, 0.05mol) be dissolved in the 80mL ethanol, add 10mL 98% sulfuric acid and be stirred to dissolving, be cooled to 0 ℃, controlled temperature is below 10 ℃, slowly drip the Sodium Nitrite solid (6.90g, 0.10mol) and the solution of 20g water, 10 ℃ are continued to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is 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, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried, and the normal heptane recrystallization gets 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-two chloro-2-N-methyl-p-nitroaniline (10.35g, 0.05mol) add 100mL 35% hydrochloric acid and be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, controlled temperature is below 10 ℃, add in batches the Sodium Nitrite solid (10.35g, 0.15mol), 10 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is warmed up to 50 ℃ of insulation 24h, be cooled to 0 ℃, the Hypophosporous Acid, 50 aqueous solution 100mL of adding 50%, 0 ℃ was stirred 30 minutes down, be incubated 6h after being warmed up to room temperature, add toluene 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, extract with 3 * 50mL toluene, the organic layer drying is concentrated into dried, and the sherwood oil recrystallization gets white solid, yield 68%.
HPLC：99.4％
The preparation of embodiment 5 m-Chlorophenols
4-chloro-2-N-methyl-p-nitroaniline (8.63g, 0.05mol) be dissolved in the 80mL tetrahydrofuran (THF), add 10mL98% sulfuric acid and be stirred to dissolving fully, be cooled to 0 ℃, controlled temperature is below 10 ℃, slowly drip the Sodium Nitrite solid (6.9g, 0.105mol) and the solution of 30g water, 10 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is 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, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried product, yield 65%.
HPLC：99％
The preparation of embodiment 6 m-Chlorophenols
4-chloro-2-N-methyl-p-nitroaniline (8.63g, 0.05mol) be dissolved in 120mL 1, in the 4-dioxane, add 10mL 98% sulfuric acid and be stirred to dissolving fully, be cooled to 0 ℃, controlled temperature is below 10 ℃, add Sodium Nitrite solid (6.9g in batches, 0.19mol), 10 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is 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, the 4-dioxane, add vinyl acetic monomer 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and be about 4 to pH with the 4N hcl acidifying, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried, the sherwood oil recrystallization gets product, yield 72%.
HPLC：99.3％
The preparation of 7 bromophenols of embodiment
4-bromo-2-N-methyl-p-nitroaniline (10.85g, 0.05mol) adding 100mL 35% hydrochloric acid is warming up to 100 ℃ and is stirred to dissolving, is cooled to 0 ℃, controlled temperature is below 10 ℃, add in batches the Sodium Nitrite solid (6.9g, 0.10mol), 10 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution
The yellow diazonium salt solution of gained slowly is warmed up to 20～30 ℃ of insulation 12h, is added drop-wise to fast then in the mixing solutions of formalin of the aqueous sodium hydroxide solution of 800mL 10% and 50mL 37%.20 ℃ continue to be stirred 2h, add tetracol phenixin 200mL, leave standstill separatory, boil off organic layer after, steam distillation is collected the oily matter in the distillate, dry 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-two chloro-2-N-methyl-p-nitroaniline (10.35g, 0.05mol) be dissolved in the 80mL ethanol, add 100mL 35% hydrochloric acid, 1g copper sulfate successively, be stirred to dissolving fully, be cooled to 0 ℃, controlled temperature is below 10 ℃, add in batches the Sodium Nitrite solid (10.35g, 0.15mol) and the solution of 30mL water, 5 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is warmed up to 20～25 ℃ of insulation 8h, be incubated 6h after continuing to be warmed up to 70 ℃, add vinyl acetic monomer 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried product.Yield 70%.
HPLC：99.1％
Embodiment 83, the preparation of 4-chlorophenesic acid
4,5-two chloro-2-N-methyl-p-nitroaniline (10.35g, 0.05mol) be dissolved in the 80mL propyl carbinol, add 100mL 35% hydrochloric acid, 2g copper sulfate successively, be stirred to dissolving fully, be cooled to 0 ℃, controlled temperature is below 10 ℃, add in batches the Sodium Nitrite solid (10.35g, 0.15mol) and the solution of 30mL water, 5 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is warmed up to 20～25 ℃ of insulation 8h, be incubated 6h after continuing to be warmed up to 70 ℃, add vinyl acetic monomer 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried product.Yield 65%.
HPLC：99％
The preparation of 9 iodophenols of embodiment
4-iodo-2-N-methyl-p-nitroaniline (13.20g, 0.05mol) be dissolved in the 80mL butanols, add 20g98% sulfuric acid, 1g Red copper oxide successively, be stirred to dissolving fully, be cooled to 0 ℃, controlled temperature is below 10 ℃, add Sodium Nitrite solid (10.35g in batches, 0.15mol) and the solution of 30mL water, 5 ℃ are continued down to stir 30 minutes, yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is warmed up to 20～25 ℃ of insulation 8h, is incubated 3h after continuing to be warmed up to 70 ℃.Add vinyl acetic monomer 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and be about 4 to pH with the 4N hcl acidifying, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried product.Yield 65%.
HPLC：99.1％
The preparation of embodiment 10 p-fluorophenols
(7.81g 0.05mol) is dissolved in the 80mL ethanol 5-fluoro-2-N-methyl-p-nitroaniline, adds 15g successively
98% sulfuric acid, 1g copper sulfate are stirred to dissolving fully, are cooled to 0 ℃, and controlled temperature is below 10 ℃, add in batches the Sodium Nitrite solid (10.35g, 0.15mol) and the solution of 25mL water, 5 ℃ are continued down to stir 30 minutes, yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is warmed up to 20～25 ℃ of insulation 8h, is incubated 3h after continuing to be warmed up to 70 ℃.Add vinyl acetic monomer 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and be about 4 to pH with the 4N hcl acidifying, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried 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
6-chloro-4-bromo-2-N-methyl-p-nitroaniline (14.80g, 0.05mol) be dissolved in the 80mL ethanol, add 10mL 98% sulfuric acid and be stirred to dissolving, be cooled to 0 ℃, controlled temperature is below 10 ℃, slowly drip the Sodium Nitrite solid (6.90g, 0.10mol) and the solution of 20g water, 10 ℃ are continued to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is 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, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried, and the normal heptane recrystallization gets 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-N-methyl-p-nitroaniline (7.61g, 0.05mol) be dissolved in the 80mL ethanol, add 10mL 98% sulfuric acid and be stirred to dissolving fully, be cooled to 0 ℃, controlled temperature is below 10 ℃, slowly drip the Sodium Nitrite solid (6.9g, 0.105mol) and the solution of 30g water, 10 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is 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, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried product, yield 41%.
HPLC：98％
The preparation of embodiment 133-bromo-5-chlorophenol
6-bromo-4-chloro-2-N-methyl-p-nitroaniline (12.57g, 0.05mol) be dissolved in the 50mL methyl alcohol, adding 120mL10% Hydrogen bromide is warming up to 100 ℃ and is stirred to dissolving, be cooled to 0 ℃, controlled temperature is below 10 ℃, add potassium nitrite solid 4.26g (0.05mol), 30 ℃ are continued to stir 30 minutes, get yellow diazonium salt solution in batches.
The yellow diazonium salt solution of gained slowly is 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, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried, and the 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-N-methyl-p-nitroaniline (7.61g, 0.05mol) be dissolved in the 37.6mL propyl alcohol, add 8.2mL98% sulfuric acid and be stirred to dissolving fully, be cooled to 0 ℃, controlled temperature is below 10 ℃, slowly drip the Sodium Nitrite solid (6.9g, 0.15mol) and the solution of 30g water, 10 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is 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, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried 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 the 291mL ethanol, add 136mL 98% sulfuric acid, 0.4g copper sulfate successively, be stirred to dissolving fully, be cooled to 0 ℃, controlled temperature is below 10 ℃, add Sodium Nitrite solid (10.35g in batches, 0.15mol) and the solution of 25mL water, 5 ℃ are continued down to stir 30 minutes, yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is warmed up to 20～25 ℃ of insulation 8h, is incubated 3h after continuing to be warmed up to 70 ℃.Add toluene 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and be about 4 to pH with the 4N hcl acidifying, with 3 * 50mL toluene extraction, the organic layer drying is concentrated into dried product.Yield 53%.
HPLC：99.0％
The preparation of 16 bromophenols of embodiment
4-bromo-2-N-methyl-p-nitroaniline (10.85g, 0.05mol) adding 100mL 35% hydrochloric acid is warming up to 100 ℃ and is stirred to dissolving, is cooled to 0 ℃, controlled temperature is below 10 ℃, add in batches the Sodium Nitrite solid (6.9g, 0.10mol), 10 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution
The yellow diazonium salt solution of gained slowly is warmed up to 20～30 ℃ of insulation 12h, is added drop-wise to fast then in the mixing solutions of formalin of the potassium hydroxide aqueous solution of 800mL 5% and 37.5g 20%.30 ℃ continue to be stirred 2h, add tetracol phenixin 200mL, leave standstill separatory, boil off organic layer after, steam distillation is collected the oily matter in the distillate, dry 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
4-bromo-2-N-methyl-p-nitroaniline (10.85g, 0.05mol) adding 100mL 35% hydrochloric acid is warming up to 100 ℃ and is stirred to dissolving, is cooled to 0 ℃, controlled temperature is below 10 ℃, add in batches the Sodium Nitrite solid (6.9 g, 0.10mol), 10 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution
The yellow diazonium salt solution of gained slowly is warmed up to 20～30 ℃ of insulation 12h, is added drop-wise to fast then in the mixing solutions of formalin of the potassium hydroxide aqueous solution of 800mL 30% and 37.5g 80%.30 ℃ continue to be stirred 2h, add tetracol phenixin 200mL, leave standstill separatory, boil off organic layer after, steam distillation is collected the oily matter in the distillate, dry 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-N-methyl-p-nitroaniline (12.14g, 0.05mol) be dissolved in 240mL1, in the 4-dioxane, add 10mL 98% sulfuric acid and be stirred to dissolving fully, be cooled to 0 ℃, controlled temperature is below 10 ℃, add Sodium Nitrite solid (6.9g in batches, 0.19mol), 10 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is 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, the 4-dioxane, add vinyl acetic monomer 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and be about 4 to pH with the 4N hcl acidifying, with 3 * 50mL ethyl acetate extraction, the organic layer drying is concentrated into dried, the sherwood oil recrystallization gets product, yield 44%.
HPLC：99.2％
Embodiment 193, the preparation of 5-chlorophenesic acid
4,6-two chloro-2-N-methyl-p-nitroaniline (10.35g, 0.05mol) add 100mL 35% hydrochloric acid and be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, controlled temperature is below 10 ℃, add in batches the Sodium Nitrite solid (10.35g, 0.15mol), 10 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is warmed up to 50 ℃ of insulation 24h, be cooled to 0 ℃, the Hypophosporous Acid, 50 aqueous solution that adds 70mL30%, 0 ℃ was stirred 30 minutes down, be incubated 6h after being warmed up to room temperature, add toluene 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, extract with 3 * 50mL toluene, the organic layer drying is concentrated into dried, and the sherwood oil recrystallization gets white solid, yield 67%.
HPLC：99.4％
Embodiment 203, the preparation of 5-chlorophenesic acid
4,6-two chloro-2-N-methyl-p-nitroaniline (10.35g, 0.05mol) add 100mL 35% hydrochloric acid and be warming up to 100 ℃ and be stirred to dissolving, be cooled to 0 ℃, controlled temperature is below 10 ℃, add in batches the Sodium Nitrite solid (10.35g, 0.15mol), 10 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is warmed up to 50 ℃ of insulation 24h, is cooled to 0 ℃, adds the Hypophosporous Acid, 50 aqueous solution of 99g50%, 0 ℃ was stirred 30 minutes down, was incubated 6h after being warmed up to room temperature, added toluene 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and with the 4N hcl acidifying to pH be about 4, extract with 3 * 50mL toluene, the organic layer drying is concentrated into dried, and the sherwood oil recrystallization gets white solid, yield 60%.
HPLC：99.4％
The preparation of embodiment 21 p-fluorophenols
5-fluoro-2-N-methyl-p-nitroaniline (7.81g, 0.05mol) be dissolved in the 150mL ethanol, add 147.8mL98% sulfuric acid, 3.2g copper sulfate successively, be stirred to dissolving fully, be cooled to 0 ℃, controlled temperature adds the solution of 26.8g cesium nitrite solid and 25mL water below 10 ℃ in batches, 5 ℃ are continued down to stir 30 minutes, get yellow diazonium salt solution.
The yellow diazonium salt solution of gained slowly is warmed up to 20～25 ℃ of insulation 8h, is incubated 3h after continuing to be warmed up to 70 ℃.Add toluene 200mL, leave standstill separatory, organic layer adds 50mL 4N sodium hydroxide and stirred 10 minutes, separatory and with 50mL water washing organic layer, combining water layer and be about 4 to pH with the 4N hcl acidifying, with 3 * 50mL toluene extraction, the organic layer drying is concentrated into dried 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 (13)
1. the preparation method of a fortified phenol as shown in Equation 1 is characterized in that comprising the following step: in the strong acid solution, with 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
-Be Cl
-, Br
-, HSO
4 -Or NO
3 -, X
1And X
2Independently be H, Br, Cl, F, I or C
1～C
5Alkyl.
2. the preparation method of fortified phenol as claimed in claim 1, it is characterized in that: described step is: in the strong acid solution, compound 3 and water are carried out the reaction that hydroxyl replaces nitro earlier, carry out the reduction reaction of diazonium salt again with reductive agent, get final product.
3. the preparation method of fortified phenol as claimed in claim 1 or 2, it is characterized in that: the strong acid in the described strong acid solution is one or more in hydrochloric acid, Hydrogen bromide, nitric acid and the sulfuric acid, the consumption of strong acid is 3～100 times of molar weight of compound 3; Described strong acid solution is the mixing solutions of strong acid aqueous solution or strong acid aqueous solution and organic inert solvent.
4. the preparation method of fortified phenol as claimed in claim 3 is characterized in that: the consumption of described strong acid is 3～50 times of molar weight of compound 3.
5. the preparation method of fortified phenol as claimed in claim 3, it 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%.
6. the preparation method of fortified phenol as claimed in claim 1 or 2, it is characterized in that: 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, the consumption of reductive agent is 5～100 times of compound 3 molar weights.
7. the preparation method of fortified phenol as claimed in claim 6 is characterized in that: described C
1-C
7Alcohol be in ethanol, propyl alcohol, Virahol and the propyl carbinol one or more; Described C
4-C
7Ether be tetrahydrofuran (THF) and/or 1, the 4-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%.
8. the preparation method of fortified phenol as claimed in claim 6 is characterized in that: when reductive agent is C
1-C
7Pure the 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 the time, described C
4-C
7The consumption of ether be 10～100 times of compound 3 molar weights; When reductive agent was the Hypophosporous Acid, 50 aqueous solution, the consumption of described Hypophosporous Acid, 50 was 5～15 times of compound 3 molar weights; When reductive agent was the alkali aqueous solution of formaldehyde, the consumption of described formaldehyde was 5～20 times of molar weight of compound 3.
9. the preparation method of fortified phenol as claimed in claim 1 or 2, it is characterized in that: the reduction reaction of described diazonium salt is carried out under the effect of copper salt catalyst; Catalyst consumption be compound 3 molar weight 5%～40%.
10. the preparation method of fortified phenol as claimed in claim 2 is characterized in that: the temperature that described hydroxyl replaces the reaction of nitro is 10 ℃～50 ℃; Described hydroxyl replace nitro reaction time with detection reaction fully till; When reductive agent is C
1-C
7Alcohol and/or C
4-C
7Ether the time, the temperature of the reduction reaction of described diazonium salt is 30～100 ℃; When reductive agent was the alkali aqueous solution of the Hypophosporous Acid, 50 aqueous solution and/or formaldehyde, the temperature of the reduction reaction of diazonium salt was 0～30 ℃; The time of the reduction reaction of described diazonium salt with detection reaction fully till.
11. the preparation method of fortified phenol as claimed in claim 10 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 the time, the temperature of the reduction reaction of described diazonium salt is 50～90 ℃.
12. the preparation method of fortified phenol as claimed in claim 1 or 2 is characterized in that: described compound 3 is made by following method: compound 2 is carried out diazotization reaction, get final product;
Wherein, X
-Be Cl
-, Br
-, HSO
4 -Or NO
3 -, X
1And X
2Independently be H, Br, Cl, F, I or C
1～C
5Alkyl.
13. the preparation method of fortified phenol as claimed in claim 12 is characterized in that: described compound 3 is made by following method: in strong acid solution, compound 2 and inorganic nitrite are carried out diazotization reaction, can make diazenium compound 3;
Wherein, described inorganic nitrite is one or more in Sodium Nitrite, potassium nitrite and the cesium nitrite; When inorganic nitrite was Sodium Nitrite, compound 2 was 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 the sulfuric acid; When strong acid was sulfuric acid, the vitriolic consumption was 3～50 times of molar weight of compound 2; The temperature of described reaction is-5 ℃～30 ℃; The time of described reaction with detection reaction fully till.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103086817A (en) * | 2013-02-04 | 2013-05-08 | 清华大学 | Poly-substituted phenol preparation method |
| CN107935858A (en) * | 2016-10-12 | 2018-04-20 | 利尔化学股份有限公司 | The preparation method of 5 fluorine, 2 nitrophenol |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1861554A (en) * | 2005-05-09 | 2006-11-15 | 临海市永太化工有限公司 | Production tech, of 3,4,5 trifluorophenol |
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2009
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1861554A (en) * | 2005-05-09 | 2006-11-15 | 临海市永太化工有限公司 | Production tech, of 3,4,5 trifluorophenol |
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| Title |
|---|
| 张付利等: "3,4-二氯苯酚的合成研究", 《河南化工》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103086817A (en) * | 2013-02-04 | 2013-05-08 | 清华大学 | Poly-substituted phenol preparation method |
| CN103086817B (en) * | 2013-02-04 | 2015-09-23 | 清华大学 | A kind of preparation method of polysubstituted phenol |
| CN107935858A (en) * | 2016-10-12 | 2018-04-20 | 利尔化学股份有限公司 | The preparation method of 5 fluorine, 2 nitrophenol |
| CN107935858B (en) * | 2016-10-12 | 2020-09-08 | 利尔化学股份有限公司 | Preparation method of 5-fluoro-2-nitrophenol |
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