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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- CN101648851B CN101648851B CN200910075295A CN200910075295A CN101648851B CN 101648851 B CN101648851 B CN 101648851B CN 200910075295 A CN200910075295 A CN 200910075295A CN 200910075295 A CN200910075295 A CN 200910075295A CN 101648851 B CN101648851 B CN 101648851B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 72
- -1 3,5-dimethoxy-4- isopropylbenzyl Chemical group 0.000 claims abstract description 44
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000009833 condensation Methods 0.000 claims abstract description 17
- 230000005494 condensation Effects 0.000 claims abstract description 17
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 34
- 238000010992 reflux Methods 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000000605 extraction Methods 0.000 claims description 20
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 claims description 19
- 239000000047 product Substances 0.000 claims description 19
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 239000003921 oil Substances 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000012265 solid product Substances 0.000 claims description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- IWPZKOJSYQZABD-UHFFFAOYSA-N 3,5-dimethoxybenzoic acid Chemical compound COC1=CC(OC)=CC(C(O)=O)=C1 IWPZKOJSYQZABD-UHFFFAOYSA-N 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 abstract description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 abstract description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 229910052717 sulfur Inorganic materials 0.000 abstract description 2
- 239000011593 sulfur Substances 0.000 abstract description 2
- UYEMGAFJOZZIFP-UHFFFAOYSA-N 3,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC(O)=C1 UYEMGAFJOZZIFP-UHFFFAOYSA-N 0.000 abstract 2
- 230000001035 methylating effect Effects 0.000 abstract 2
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 230000000843 anti-fungal effect Effects 0.000 abstract 1
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- 230000026030 halogenation Effects 0.000 abstract 1
- 238000005658 halogenation reaction Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 12
- 229910052782 aluminium Inorganic materials 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000007789 gas Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000003684 Perkin reaction Methods 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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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