CN101648851B - Clean preparation method of (E)-3,5-dyhydroxy-4-isopropyl toluylene - Google Patents
Clean preparation method of (E)-3,5-dyhydroxy-4-isopropyl toluylene Download PDFInfo
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Abstract
The invention discloses a clean preparation method of (E)-3,5-dyhydroxy-4-isopropyl toluylene. In the preparation method, 3,5-dimethoxy-4- isopropylbenzyl alcohol is prepared by methylating and isopropylating (or isopropylating and methylating) 3,5-dihydroxy-benzoic acid, and then synthesizing the (E)-3,5-dyhydroxy-4-isopropyl toluylene through the steps of reduction, halogenation, Witting-Horner condensation, deprotection, and the like. The invention has low-cost and easily-obtained materials, mild condition and simple operation, avoids using fluoride reductant and thionyl chloride causing acidic sulfur-containing tail gas, has less pollution to environment and is suitable for industrial clean production of medicament of benzene alkene mohammad with antifungal activity, i.e. compound of (E)-3,5-dyhydroxy-4-isopropyl toluylene.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate to a kind of preparation method of compound, specifically a kind of medicine benzene alkene not moral is (E)-3, the clean method for preparing of 5-dihydroxyl-4-isopropyl toluylene.
Background technology
Medicine benzene alkene is moral not, chemical name (E)-3,5-dihydroxyl-4-isopropyl toluylene belongs to stilbenes compound, be from large intestine parasitic nematode symbiotic bacterium the verivate of extract.Show that after deliberation (E)-3,5-dihydroxyl-4-isopropyl toluylene comprises that to relevant disease of neutrophil or the disorder relevant with the protein kinase inflammation, tetter, psoriasis, tumour etc. have physiologically active.(E)-3, the structural formula of 5-dihydroxyl-4-isopropyl toluylene is following:
(E)-3 of existing report; 5-dihydroxyl-4-isopropyl toluylene synthetic route; Can adopt Heck reaction, Perkin reaction, Knoevenagel reaction, grignard reaction, aldol reaction and Wittig-Horner condensation reaction etc. to synthesize; Comprehensive yield and configuration are considered, are the best with Wittig-Horner condensation route.
But the reagent toxicity that relates in the Wittig-Horner condensation reaction is big, as has adopted the malicious reagent BF of high-risk height
3Et
2O, SOCl
2Deng, dangerous high during operation in addition, can produce toxic gases such as borine, sulfurous gas, hydrogenchloride in the reaction process, can discharge a large amount of fluoride wastes simultaneously, contaminate environment causes when carrying out suitability for industrialized production the harm to environment bigger.
Summary of the invention
The technical problem that the present invention will solve; Provide a kind of (E)-3; The clean method for preparing of 5-dihydroxyl-4-isopropyl toluylene, by 3, the 5-resorcylic acid be raw material through methylate, isopropylation (or isopropylation, methylate) preparation 3; 5-dimethoxy-4 '-isopropyl benzene methyl alcohol is again through the synthetic title product of steps such as the reduction of non-fluorochemicals, hydrochloric acid chloro, Wittig-Horner condensation, deprotection.This clean method for preparing is raw materials used cheap and easy to get, mild condition, simple to operate, and the use of having abandoned fluorine-containing reductive agent and the sulfur oxychloride that causes acid sulfur-bearing tail gas to produce, environmental pollution is little.
The present invention will solve above-mentioned technical problem, is to realize through following technical scheme:
A kind of (E)-3; The clean method for preparing of 5-dihydroxyl-4-isopropyl toluylene, it is with 3, and the 5-resorcylic acid is a feedstock production 3; 5-dimethoxy-4 '-isopropyl benzene methyl alcohol; Prepare (E)-3 through steps such as hydrochloric acid chloro, Wittig-Horner condensation, deprotections then, 5-dihydroxyl-4-isopropyl toluylene, its preparation technology is following:
3; 5-resorcylic acid------------→ 3; 5-dimethoxy-4 '-isopropyl benzene methyl alcohol----→ 3,5-dimethoxy-4 '-sec.-propyl benzyl chloro----→ 3,5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate----→ (E)-3; 5-dimethoxy-4 '-isopropyl toluylene----→ (E)-3,5-dihydroxyl-4-isopropyl toluylene.
Said preparing method's preparation method one comprises 3, step such as the 5-resorcylic acid methylates, the reduction of isopropylation, non-fluorochemicals, hydrochloric acid chloro, Wittig-Horner condensation, deprotection; Its technological process is following:
3,5-resorcylic acid----→ 3,5-dimethoxybenzoic acid ester----→ 3; 5-dimethoxy-4 '-isopropyl acid----→ 3; 5-dimethoxy-4 '-isopropyl benzene methyl alcohol----→ 3,5-dimethoxy-4 '-sec.-propyl benzyl chloro----→ 3,5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate----→ (E)-3; 5-dimethoxy-4 '-isopropyl toluylene----→ (E)-3,5-dihydroxyl-4-isopropyl toluylene.
Said preparing method's preparation method two comprises 3,5-resorcylic acid isopropylation, methylate, step such as reduction of non-fluorochemicals, hydrochloric acid chloro, Wittig-Horner condensation, deprotection; Its technological process is following:
3,5-resorcylic acid----→ 3,5-dihydroxyl-4-isopropyl acid----→ 3; 5-dimethoxy-4 '-isopropyl acid ester----→ 3; 5-dimethoxy-4 '-isopropyl benzene methyl alcohol----→ 3,5-dimethoxy-4 '-sec.-propyl benzyl chloro----→ 3,5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate----→ (E)-3; 5-dimethoxy-4 '-isopropyl toluylene----→ (E)-3,5-dihydroxyl-4-isopropyl toluylene.
Among the preparation method one and two, the hydrochloric acid chloro be adopt hydrochloric acid with the immiscible organic solvent of water in the presence of carry out.
The reduction of non-fluorochemicals among the preparation method one is to adopt boracic an alkali metal salt Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN, reduces with the iodine acting in conjunction.
The reduction of non-fluorochemicals among the preparation method two can be to adopt boracic an alkali metal salt Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN to reduce with the acting in conjunction of organic alcohols compound, and wherein the organic alcohols compound is a kind of in Fatty Alcohol(C12-C14 and C12-C18) methyl alcohol, ethanol or the Virahol.
The reduction of non-fluorochemicals among the preparation method two can also be to adopt boracic an alkali metal salt Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN, reduces with the aluminum trihalide acting in conjunction.
Preparing method one reaction scheme is suc as formula (I):
Formula (I)
And carry out according to the following steps order:
A1.3, the 5-resorcylic acid methylates: 3, the preparation of 5-dimethoxybenzoic acid ester A1
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone, methyl-sulfate mix, and add water behind the 2～18h that refluxes, and filter, the dry product A 1 that gets;
B1. isopropylation: 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B1
A1 mixes with 60～80% vitriol oils, drips Virahol, and 30～90 ℃ of reaction 5～12h add water filtration, the dry pearl product B 1 that gets;
C1. the reduction of non-fluorochemicals: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C
Peng Qinghuana, THF mix the back and add B1 and I
2, add water behind reaction 12～80h, extraction, desolventizing gets white solid product C;
D. hydrochloric acid chloro: 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D
C and hydrochloric acid and normal hexane hybrid reaction; Layering, the organic phase desolventizing gets yellow oil D;
The e.Wittig-Horner condensation: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E
D mix with triethyl-phosphite reduce pressure behind the 3～20h that refluxes product E;
F. (E)-3, the preparation of 5-dimethoxy-4 '-isopropyl toluylene F
E mixes with THF, N
2Protection adds NaH and phenyl aldehyde in the time of-20～20 ℃, in the impouring frozen water, cross and filter F behind the 2～8h that refluxes;
G. deprotection: (E)-3, the preparation of 5-dihydroxyl-4-isopropyl toluylene
F adds water mix the 2～20h that refluxes with pyridine hydrochloride after, extraction, and desolventizing, recrystallization gets (E)-3,5-dihydroxyl-4-isopropyl toluylene.
Preparing method two reaction scheme is suc as formula (II):
Formula (II)
Preparing method two carries out according to the following steps order:
A2. isopropylation: 3, the preparation of 5-dihydroxyl-4-isopropyl acid A2
3, the 5-resorcylic acid mixes with 70～90% vitriol oils, drips Virahol, and 30～90 ℃ of reaction 5～12h add water filtration, the dry green product A2 that gets;
B2. methylate: 3, the preparation of 5-dimethoxy-4 '-isopropyl acid ester B2
A2, Anhydrous potassium carbonate, acetone, methyl-sulfate mix, and add water behind the 2～18h that refluxes, and extraction gets product B 2 after desolventizing;
C2. the reduction of non-fluorochemicals: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C
B2 mixes with Peng Qinghuana and THF, and heating drips methyl alcohol, adds water behind the 12～80h that refluxes, extraction, desolventize white solid product C;
D. the hydrochloric acid chloro 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D
C and hydrochloric acid and normal hexane hybrid reaction; Layering, the organic phase desolventizing gets yellow oil D;
The e.Wittig-Horner condensation: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E
D, triethyl-phosphite mix reduce pressure behind the 3～20h that refluxes product E;
F. (E)-3, the preparation of 5-dimethoxy-4 '-isopropyl toluylene F
E mixes with THF, N
2Protection adds NaH and phenyl aldehyde in the time of-20～20 ℃, in the impouring frozen water, cross and filter F behind the 2～8h that refluxes;
G. deprotection: (E)-3, the preparation of 5-dihydroxyl-4-isopropyl toluylene
F adds water mix the 2～20h that refluxes with pyridine hydrochloride after, extraction, and desolventizing, recrystallization gets (E)-3,5-dihydroxyl-4-isopropyl toluylene.
Among the above-mentioned preparation method two, said step c2 substitutes with following step c3:
C3. the reduction of non-fluorochemicals: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C
B2 mixes with Peng Qinghuana and THF, adds aluminum trihalide, and 5～10h refluxes; Add water, the extraction, desolventize white solid product C.
Above-mentioned (E)-3 provided by the present invention, the clean method for preparing of 5-dihydroxyl-4-isopropyl toluylene, raw materials used cheap and easy to get; Reaction conditions is gentle, simple to operate; Do not use fluorine-containing reductive agent and the sulfur oxychloride that causes SO 2 tail gas to produce, environmental pollution is little, is suitable for and carries out not moral of industriallization cleaner production medicine benzene alkene; I.e. (E)-3,5-dihydroxyl-4-isopropyl toluylene.
The present invention below will combine specific embodiment to do further explain.
Embodiment
Following examples only are used to explain the present invention, do not limit the present invention.
Embodiment 1-5 (E)-3, the clean method for preparing one of 5-dihydroxyl-4-isopropyl toluylene
Embodiment 1-5 utilizes method one preparation (E)-3,5-dihydroxyl-4-isopropyl toluylene, and the preparation process is following:
3,5-resorcylic acid----→ 3,5-dimethoxybenzoic acid ester----→ 3; 5-dimethoxy-4 '-isopropyl acid----→ 3; 5-dimethoxy-4 '-isopropyl benzene methyl alcohol----→ 3,5-dimethoxy-4 '-sec.-propyl benzyl chloro----→ 3,5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate----→ (E)-3; 5-dimethoxy-4 '-isopropyl toluylene----→ (E)-3,5-dihydroxyl-4-isopropyl toluylene (benzene alkene is moral not);
This method comprises 3, step such as the 5-resorcylic acid methylates, the reduction of isopropylation, non-fluorochemicals, hydrochloric acid chloro, Wittig-Horner condensation, deprotection, wherein the hydrochloric acid chloro with the immiscible organic solvent of water in the presence of carry out; The reduction of non-fluorochemicals is meant adopts Peng Qinghuana to make reductive agent, is equipped with the method for reducing of iodine.Its reaction scheme is suc as formula (I):
Formula (I)
Method one is carried out according to the following steps order:
A1.3, the 5-resorcylic acid methylates: 3, the preparation of 5-dimethoxybenzoic acid ester A1
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone, methyl-sulfate mix, and add water behind the backflow 2-18h, and extraction desolventizes, and gets product A 1; (3, the mol ratio of 5-resorcylic acid, Anhydrous potassium carbonate, acetone, methyl-sulfate is 1: 3～6: 10～50: 3～10)
B1. isopropylation: 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B1
A1 mixes with 60～80% vitriol oils, drips Virahol, and 30～90 ℃ of reaction 5～12h add water filtration, the dry pearl product B 1 that gets; (mol ratio of A1, the vitriol oil, Virahol is 1: 0.1～0.5: 1～3)
C1. the reduction of non-fluorochemicals: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C
Peng Qinghuana, THF mix the back and add B1 and I
2, add water behind reaction 12～80h, extraction, desolventizing gets white solid product C; (B1, Peng Qinghuana, THF, I
2Mol ratio be 1: 0.1～10: 10～50: 0.1～10)
D. hydrochloric acid chloro: 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D
C and hydrochloric acid and normal hexane join hybrid reaction in the four-hole boiling flask; Tell the organic phase desolventizing and get yellow oil D; (mol ratio of C, hydrochloric acid, normal hexane is 1: 1～20: 10～100)
The e.Wittig-Horner condensation: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E
Mol ratio be 1: 1～6 D mix with triethyl-phosphite reduce pressure behind the 3～20h that refluxes product E;
F. (E)-3, the preparation of 5-dimethoxy-4 '-isopropyl toluylene F
E mixes with THF, N
2Protection adds NaH and phenyl aldehyde in the time of-20～20 ℃, behind the backflow 2-8h in the impouring frozen water, extraction, desolventize F; (mol ratio of E, THF, NaH, phenyl aldehyde is 1: 20-100: 0.1-10: 0.5-10)
G. deprotection: (E)-3, the preparation of 5-dihydroxyl-4-isopropyl toluylene
Mol ratio is that 1: 2～60 F mixes with pyridine hydrochloride, is heated to 130--250 ℃, adds water behind the 2-20h, extraction, desolventizing, recrystallization, (E)-3,5-dihydroxyl-4-isopropyl toluylene.
The concrete parameter that the foregoing description 1-5 relates to is seen table one.
Table one (E)-3, the clean method for preparing one of 5-dihydroxyl-4-isopropyl toluylene
Embodiment 6-10 (E)-3, the clean method for preparing two of 5-dihydroxyl-4-isopropyl toluylene
Embodiment 6-10 utilizes method two preparation (E)-3,5-dihydroxyl-4-isopropyl toluylene, and process is following:
3,5-resorcylic acid----→ 3,5-dihydroxyl-4-isopropyl acid----→ 3; 5-dimethoxy-4 '-isopropyl acid ester----→ 3; 5-dimethoxy-4 '-isopropyl benzene methyl alcohol----→ 3,5-dimethoxy-4 '-sec.-propyl benzyl chloro----→ 3,5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate----→ (E)-3; 5-dimethoxy-4 '-isopropyl toluylene----→ (E)-3,5-dihydroxyl-4-isopropyl toluylene (benzene alkene is moral not);
This process comprises 3; 5-resorcylic acid isopropylation, methylate, steps such as the reduction of non-fluorochemicals, hydrochloric acid chloro, Wittig-Horner condensation, deprotection, wherein the hydrochloric acid chloro be adopt hydrochloric acid with the immiscible organic solvent of water in the presence of carry out; The reduction of non-fluorochemicals is meant adopts Peng Qinghuana to make reductive agent, is equipped with the method for reducing of methyl alcohol or aluminum trihalide.
Preparing method two reaction scheme is suc as formula (II):
Preparing method two carries out according to the following steps order:
A2. isopropylation: 3, the preparation of 5-dihydroxyl-4-isopropyl acid A2
3, the 5-resorcylic acid mixes with 70～90% vitriol oils, drips Virahol, and 30～90 ℃ of reaction 5～12h add water filtration, the dry green product A2 that gets; (3, the proportioning of 5-resorcylic acid, the vitriol oil, Virahol is 1mol: 300～600mL: 60～90mL)
B2. methylate: 3, the preparation of 5-dimethoxy-4 '-isopropyl acid ester B1
A2, Anhydrous potassium carbonate, acetone and methyl-sulfate mix, and add water behind the backflow 2-18h, and extraction gets product B 2 after desolventizing; (mol ratio of A2, Anhydrous potassium carbonate, acetone, methyl-sulfate is 1: 3～6: 10～50: 3～10)
C2. the reduction of non-fluorochemicals: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C
B2 mixes with Peng Qinghuana and THF, and heating drips methyl alcohol, adds water behind the 12～80h that refluxes, extraction, desolventize white solid product C; (mol ratio of B2, Peng Qinghuana, THF, methyl alcohol is 1: 1～40: 10～100: 10～100)
D. hydrochloric acid chloro: 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D
C and hydrochloric acid and normal hexane hybrid reaction; Layering, the organic phase desolventizing gets yellow oil D; (mol ratio of C, hydrochloric acid, normal hexane is 1: 1-20: 10-100)
The e.Wittig-Horner condensation: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E
Mol ratio is 1: the D of 1-6, triethyl-phosphite mix reduce pressure behind the 3～20h that refluxes product E;
F. (E)-3, the preparation of 5-dimethoxy-4 '-isopropyl toluylene F
E mixes with THF, N
2Protection adds NaH and phenyl aldehyde in the time of-20～20 ℃, in the impouring frozen water, extract behind the 2～8h that refluxes, and desolventizing gets F; (mol ratio of E, THF, NaH, phenyl aldehyde is 1: 20～100: 1～10: 1～10)
G. deprotection: (E)-3, the preparation of 5-dihydroxyl-4-isopropyl toluylene
F mixes with pyridine hydrochloride (mol ratio is 1: 2～60), adds water behind reflux 2～20h, extraction, and desolventizing, recrystallization gets (E)-3,5-dihydroxyl-4-isopropyl toluylene.
Step c2 among the embodiment 6-10 can substitute with c3, and concrete operations are following:
C3. the reduction of non-fluorochemicals: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C
B2 mixes with Peng Qinghuana and THF, adds aluminum chloride, and 5～10h refluxes; Add water, the extraction, desolventize white solid product C; (mol ratio of B2, Peng Qinghuana, THF, aluminum chloride is 1: 1～10: 1～40: 1～10)
The concrete parameter that the foregoing description 6-10 relates to is seen table two (step c2 and c3 select and only select one of which).
Table two (E)-3, the clean method for preparing two of 5-dihydroxyl-4-isopropyl toluylene
Embodiment of the present invention is not limited to above embodiment, and its characteristic can have the equivalent transformation of various ways, and example hydrochloric acid can also substitute by Hydrogen bromide, and correspondingly the Cl in the dependency structure formula can substitute with Br; Among the step c2 among organic alcohols compound and the c3 aluminum trihalide more more options etc. can also be arranged.In every case be the preparation (E)-3 that is realized by the said characteristic of claims of the present invention, the method for 5-dihydroxyl-4-isopropyl toluylene is all thought to fall within protection scope of the present invention.
Claims (8)
1. (E)-3; The clean method for preparing of 5-dihydroxyl-4-isopropyl toluylene is characterized in that it with 3, and the 5-resorcylic acid is a feedstock production 3; 5-dimethoxy-4 '-isopropyl benzene methyl alcohol; Prepare (E)-3 through hydrochloric acid chloro, Wittig-Horner condensation, deprotection then, 5-dihydroxyl-4-isopropyl toluylene, its preparation technology is following:
3; 5-resorcylic acid--------→ 3; 5-dimethoxy-4 '-isopropyl benzene methyl alcohol----→ 3,5-dimethoxy-4 '-sec.-propyl benzyl chloro----→ 3,5-dimethoxy-4 '-isopropyl benzyl phosphonic acid ester----→ (E)-3; 5-dimethoxy-4 '-isopropyl toluylene----→ (E)-3,5-dihydroxyl-4-isopropyl toluylene; This clean method for preparing is preparation method one or preparation method two, and wherein preparation method one comprises 3, and the 5-resorcylic acid methylates, isopropylation, the reduction of non-fluorochemicals, hydrochloric acid chloro, Wittig-Horner condensation, deprotection steps; Technological process is following:
3,5-resorcylic acid----→ 3,5-dimethoxybenzoic acid ester----→ 3; 5-dimethoxy-4 '-isopropyl acid----→ 3; 5-dimethoxy-4 '-isopropyl benzene methyl alcohol----→ 3,5-dimethoxy-4 '-sec.-propyl benzyl chloro----→ 3,5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate----→ (E)-3; 5-dimethoxy-4 '-isopropyl toluylene----→ (E)-3,5-dihydroxyl-4-isopropyl toluylene;
Preparing method two comprises 3,5-resorcylic acid isopropylation, methylate, the reduction of non-fluorochemicals, hydrochloric acid chloro, Wittig-Horner condensation, deprotection steps; Technological process is following:
3,5-resorcylic acid----→ 3,5-dihydroxyl-4-isopropyl acid----→ 3; 5-dimethoxy-4 '-isopropyl acid methyl esters----→ 3; 5-dimethoxy-4 '-isopropyl benzene methyl alcohol----→ 3,5-dimethoxy-4 '-sec.-propyl benzyl chloro----→ 3,5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate----→ (E)-3; 5-dimethoxy-4 '-isopropyl toluylene----→ (E)-3,5-dihydroxyl-4-isopropyl toluylene.
2. (E)-3 according to claim 1, the clean method for preparing of 5-dihydroxyl-4-isopropyl toluylene is characterized in that: said hydrochloric acid chloro be adopt hydrochloric acid with the immiscible organic solvent of water in the presence of carry out.
3. (E)-3 according to claim 1, the clean method for preparing of 5-dihydroxyl-4-isopropyl toluylene is characterized in that: the reduction of the non-fluorochemicals described in the preparation method one is to adopt Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN and iodine acting in conjunction reduction.
4. (E)-3 according to claim 1; The clean method for preparing of 5-dihydroxyl-4-isopropyl toluylene; It is characterized in that: the reduction of the non-fluorochemicals described in the preparation method two is a kind of acting in conjunction reduction of adopting in boracic an alkali metal salt Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN and methyl alcohol, ethanol or the Virahol.
5. (E)-3 according to claim 1; The clean method for preparing of 5-dihydroxyl-4-isopropyl toluylene; It is characterized in that: the reduction of the non-fluorochemicals described in the preparation method two is to adopt boracic an alkali metal salt Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN, reduces with the aluminum chloride acting in conjunction.
6. according to claim 1 or 3 described (E)-3, the clean method for preparing of 5-dihydroxyl-4-isopropyl toluylene is characterized in that: preparation method one carries out according to the following steps order:
A1.3, the 5-resorcylic acid methylates: 3, the preparation of 5-dimethoxybenzoic acid ester A1
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone, methyl-sulfate mix, and add water behind the 2～18h that refluxes, and filter, the dry product A 1 that gets;
B1. isopropylation: 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B1
A1 mixes with 60～80% vitriol oils, drips Virahol, and 30～90 ℃ of reaction 5～12h add water filtration, the dry pearl product B 1 that gets;
C1. the reduction of non-fluorochemicals: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C
Peng Qinghuana, THF mix the back and add B1 and I
2, add water behind reaction 12～80h, extraction, desolventizing gets white solid product C;
D. hydrochloric acid chloro: 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D
C and hydrochloric acid and normal hexane hybrid reaction; Layering, the organic phase desolventizing gets yellow oil D;
The e.Wittig-Horner condensation: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E
D mixes the 3～20h that refluxes with triethyl-phosphite, reduce pressure product E;
F. (E)-3, the preparation of 5-dimethoxy-4 '-isopropyl toluylene F
E mixes with THF, N
2Protection adds NaH and phenyl aldehyde in the time of-20～20 ℃, 2～8h refluxes; In the impouring frozen water, cross and filter F after reaction finishes;
G. deprotection: (E)-3, the preparation of 5-dihydroxyl-4-isopropyl toluylene
F mixes with pyridine hydrochloride, adds water behind the 2～20h that refluxes, extraction, and desolventizing, recrystallization gets (E)-3,5-dihydroxyl-4-isopropyl toluylene.
7. according to each described (E)-3 in the claim 1,4 or 5, the clean method for preparing of 5-dihydroxyl-4-isopropyl toluylene is characterized in that: said preparation method two carries out according to the following steps order:
A2. isopropylation: 3, the preparation of 5-dihydroxyl-4-isopropyl acid A2
3, the 5-resorcylic acid mixes with 70～90% vitriol oils, drips Virahol, and 30～90 ℃ of reaction 5～12h add water filtration, the dry green product A2 that gets;
B2. methylate: 3, the preparation of 5-dimethoxy-4 '-isopropyl acid ester B2
A2, Anhydrous potassium carbonate, acetone, methyl-sulfate mix, and add water behind the 2～18h that refluxes, and extraction gets product B 2 after desolventizing;
C2. the reduction of non-fluorochemicals: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C
B2 mixes with Peng Qinghuana and THF, and heating drips methyl alcohol, adds water behind the 12～80h that refluxes, extraction, desolventize white solid product C;
D. hydrochloric acid oxo: 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D
C and hydrochloric acid and normal hexane hybrid reaction; Layering, the organic phase desolventizing gets yellow oil D;
The e.Wittig-Horner condensation: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E
D, triethyl-phosphite mix reduce pressure behind the 3～20h that refluxes product E;
F. (E)-3, the preparation of 5-dimethoxy-4 '-isopropyl toluylene F
E mixes with THF, N
2Protection adds NaH and phenyl aldehyde in the time of-20～20 ℃, in the impouring frozen water, cross and filter F behind the 2～8h that refluxes;
G. deprotection: (E)-3, the preparation of 5-dihydroxyl-4-isopropyl toluylene
F mixes with pyridine hydrochloride, adds water behind the 2～20h that refluxes, extraction, and desolventizing, recrystallization gets (E)-3,5-dihydroxyl-4-isopropyl toluylene.
8. (E)-3 according to claim 7, the clean method for preparing of 5-dihydroxyl 4-isopropyl toluylene is characterized in that among the said preparation method two, step c2 substitutes with following step c3:
C3. the reduction of non-fluorochemicals: 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C
B2 mixes with Peng Qinghuana and THF, adds aluminum chloride, and 5～10h refluxes; Add water, the extraction, desolventize white solid product C.
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| CN115536497A (en) * | 2022-11-23 | 2022-12-30 | 化学与精细化工广东省实验室 | Synthesis method of (E) -3,5-dihydroxy-4-isopropyl stilbene |
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