CN1300079C - New technology of synthesizing 4-[2-(cyclo propyl methoxy] ethyl] phenol - Google Patents
New technology of synthesizing 4-[2-(cyclo propyl methoxy] ethyl] phenol Download PDFInfo
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- CN1300079C CN1300079C CNB2004100654168A CN200410065416A CN1300079C CN 1300079 C CN1300079 C CN 1300079C CN B2004100654168 A CNB2004100654168 A CN B2004100654168A CN 200410065416 A CN200410065416 A CN 200410065416A CN 1300079 C CN1300079 C CN 1300079C
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- ethyl
- cyclo propyl
- propyl methoxy
- tert
- butoxy
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- WNEQFDSWDCYKOE-UHFFFAOYSA-N 4-[2-(cyclopropylmethoxy)ethyl]phenol Chemical compound C1=CC(O)=CC=C1CCOCC1CC1 WNEQFDSWDCYKOE-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 50
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 21
- -1 2-cyclo propyl methoxy Chemical group 0.000 claims description 19
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 14
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-Phenylethanol Natural products OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 14
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 14
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims description 14
- 229940067107 phenylethyl alcohol Drugs 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 229940090668 parachlorophenol Drugs 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 7
- 239000011707 mineral Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical group BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- ZVTQWXCKQTUVPY-UHFFFAOYSA-N chloromethylcyclopropane Chemical compound ClCC1CC1 ZVTQWXCKQTUVPY-UHFFFAOYSA-N 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 238000005273 aeration Methods 0.000 claims description 2
- 239000003456 ion exchange resin Substances 0.000 claims description 2
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 230000018044 dehydration Effects 0.000 abstract 1
- 238000006297 dehydration reaction Methods 0.000 abstract 1
- 238000006266 etherification reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- 238000009423 ventilation Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 2
- YCCILVSKPBXVIP-UHFFFAOYSA-N 2-(4-hydroxyphenyl)ethanol Chemical compound OCCC1=CC=C(O)C=C1 YCCILVSKPBXVIP-UHFFFAOYSA-N 0.000 description 2
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960002274 atenolol Drugs 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229960002237 metoprolol Drugs 0.000 description 2
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 2
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- 229960004347 betaxolol hydrochloride Drugs 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000008422 chlorobenzenes Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses technology for preparing the target product of 4-[2-(cyclopropyl methoxy) ethyl] phenol through phenohydroxy protection, Grignard reaction, etherification, dehydration protection and other reactions by using p-chlorophenol as an initial raw material. The raw material used by the technology can be easily obtained and has low cost, the whole reaction process has the characteristics of short steps, mild conditions, high yield, convenient operation, etc., and the technology is suitable for industrial production. A compound 4-[2-(cyclopropyl methoxy) ethyl] phenol has a structure as shown in the following formula.
Description
Technical field
The present invention relates to prepare 4-[2-(cyclo propyl methoxy) ethyl] novel method of phenol, specifically, belong to the organic synthesis category.
Background technology
Betaxolol hydrochloride is a heart selectivity B-adrenergic receptor retarding agent, the endogenous sympatheticomimetic action, effect is strong, and the pharmacological action of human oral is 4 times of Propranololum, 5 times of atenolol USP 23, selectivity ratios metoprolol height to acceptor, the oral absorption rate is than atenolol USP 23 height, and first pass effect is lower than metoprolol, thereby bioavailability is than the two equal height, reach 90%, its transformation period reaches 20 hours.This medicine also can be used for the treatment of glaucoma with its eye drop of 0.5% except can being used for the treatment of hypertension and stenocardia, be an extremely rising medicine.
4-[2-(cyclo propyl methoxy) ethyl] phenol is the important intermediate of synthetic hydrochloric acid betaxolol, get up to have following several method its synthetic end: 1. be raw material with the p bromophenol, through prepared in reaction such as benzyl protection, grignard reaction, esterification, reduction, chloro, cyano group displacement, hydrolysis, one-tenth ester, reduction; 2. with the 4-hydroxyphenylacetic acid ethyl ether raw material, through prepared in reaction (referring to U.S. Pat 4342783 and US4252984) such as benzyl protection, reduction, Cyclopropylmetyl bromide etherificate, catalytic hydrogenolysiss; 3. with the p-hydroxyphenylethanol raw material, direct and cyclopropyl methyl chloride prepared in reaction (referring to U.S. Pat 5731463) under the alkali effect.All there is deficiency in above method, and method 1 synthetic route is longer, and total yield is not high; Method 2 routes are also longer, and cost is also very high; Though method 3 synthetic routes are short, the price height of starting raw material p-hydroxyphenylethanol, the productive rate that should react is also low simultaneously, and selectivity is not fine.
In sum, synthetic at present 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, or longer because of cost of material height, synthetic route, or, cost more high shortcoming lower because of product yield is difficult to industrialization.
Summary of the invention
The object of the present invention is to provide a kind of simple to operate, yield is high, easy industrialization and the lower-cost 4-[2-of preparation (cyclo propyl methoxy) ethyl] method of phenol.Be that para-chlorophenol gets the rubigan tertbutyl ether with isobutene reaction under acid catalysis; Rubigan tertbutyl ether and magnesium and oxyethane carry out grignard reaction and obtain 4-tert.-butoxy phenylethyl alcohol; 4-tert.-butoxy phenylethyl alcohol under certain temperature and alkali effect with the cyclopropyl halomethane react 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] benzene; 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] benzene takes off the tertiary butyl through acidolysis and obtains 4-[2-(cyclo propyl methoxy) ethyl] phenol.The raw material of this method is easy to get and is cheap, and the entire reaction course step is short, productive rate is high.Reaction formula is as follows:
The present invention is achieved by the following scheme, with the para-chlorophenol is starting raw material, in organic solvents such as benzene, toluene, chlorobenzene or methylene dichloride, in temperature is under 15-50 ℃, in the presence of acid such as tosic acid, methylsulfonic acid, dilute sulphuric acid or strong-acid ion exchange resin, feed iso-butylene and react, synthetic rubigan tertbutyl ether.Wherein the mol ratio of para-chlorophenol and iso-butylene is 1: 1-3; Aeration time is 0.5-50 hour.
The rubigan tertbutyl ether slowly joins in anhydrous tetrahydro furan in the solution that contains magnesium and tetrahydrofuran (THF), and temperature is 40 ℃ and arrives reflux temperature, makes Grignard reagent, oxyethane is splashed into obtain 4-tert.-butoxy phenylethyl alcohol in the above-mentioned Grignard reagent.Wherein the mol ratio of rubigan tertbutyl ether and magnesium is 1: 1-2; The mol ratio of rubigan tertbutyl ether and oxyethane is 1: 1-3.
Adopt method of the present invention, by the synthetic 1-tert.-butoxy of 4-tert.-butoxy phenylethyl alcohol-4-[(2-cyclo propyl methoxy) ethyl] used alkali is sodium hydride, potassium tert.-butoxide or sodium alkoxide during benzene, used alkylating agent is the cyclopropyl halomethane.Wherein the mol ratio of 4-tert.-butoxy phenylethyl alcohol and alkali is 1: 1-5, the mol ratio of 4-tert.-butoxy phenylethyl alcohol and cyclopropyl halomethane is 1: 1-3.
Take off tertiary butyl method with known mineral acid acidolysis in the inventive method, ℃ react with 4-tert.-butoxy styroyl alkyl oxide down in room temperature to 100 with mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid or their aqueous solution usually and promptly obtained final product in 0.5-5 hour.The mol ratio of 4-tert.-butoxy styroyl alkyl oxide and mineral acid is 1: 1-100.Adopting more, the mineral acid of volume does not have influence to this reaction yet.
Following examples help to understand the present invention, but are not limited to content of the present invention.
Embodiment
Embodiment 1: add 128.0 gram (1 mole) para-chlorophenol, 200 milliliters of toluene and several methylsulfonic acids in four-necked bottle, feed iso-butylene down at 35 ℃, keep certain ventilation speed, ventilation is after 10 hours under steady temperature, make the amount of substance of iso-butylene be controlled at 1.30 moles, under 45 ℃, reacted again 15 hours, and took off and weigh.Add less water, heating is weighed behind the separatory with the unnecessary iso-butylene of rushing, and adds twice of neutralizing treatment to remove unreacted phenol, weighs after washing.Again with washing 3-4 time, boil off behind the solvent to such an extent that crude product be 153.0 grams, rectification under vacuum gets rubigan tertbutyl ether 141.0 and restrains.Yield is 76.4%, and content is 99.5% (GC).
IR(KBr)：2980，1890，1590，1480，1390，1360，1240，1080，1155，1055，890，850
1H-NMR(CDCl
3/TMS)：δ1.34(9H，s)，6.90(2H，d)，7.20(2H，d)
Embodiment 2: add 128.0 gram (1 mole) para-chlorophenol, 200 milliliters of chlorobenzenes and several dilute sulphuric acids in four-necked bottle, feed iso-butylene down at 15 ℃, keep certain ventilation speed, ventilation is after 10 hours under steady temperature, make the amount of substance of iso-butylene be controlled at 1.30 moles, under 25 ℃, reacted again 15 hours, and took off and weigh.All the other operation biconditional operation embodiment 1, the yield of rubigan tertbutyl ether is 68.8%, content is 99.5% (GC).
Embodiment 3: add 128.0 gram (1 mole) para-chlorophenol, 200 milliliters of methylene dichloride and several dilute sulphuric acids in four-necked bottle, feed iso-butylene down at 25 ℃, keep certain ventilation speed, ventilation is after 10 hours under steady temperature, make the amount of substance of iso-butylene be controlled at 1.30 moles, under 30 ℃, reacted again 15 hours, and took off and weigh.All the other operation biconditional operation embodiment 1, the yield of rubigan tertbutyl ether is 69.5%, content is 99.2% (GC).
Embodiment 4: tosic acid 0.2 gram that adds 128.0 gram (1 mole) para-chlorophenols, 200 milliliters of toluene and 30% in four-necked bottle, feed iso-butylene down at 20 ℃, keep certain ventilation speed, ventilation is after 10 hours under steady temperature, make the amount of substance of iso-butylene be controlled at 1.30 moles, under 25 ℃, reacted again 15 hours, and took off and weigh.All the other operation biconditional operation embodiment 1, the yield of rubigan tertbutyl ether is 72.2%, content is 99.2% (GC).
Embodiment 5: add 30.0 gram magnesium rod and 80 milliliters of anhydrous tetrahydro furans in 1000 milliliters of four-necked bottles, stir and add 2-3 milliliter monobromethane down, slowly heating, reaction is caused, add and under reflux temperature, drip rubigan tertbutyl ether 184.6 grams (1 mole) and 500 milliliters of mixing solutionss that tetrahydrofuran (THF) is formed, added in about 2 hours, dropwise, continue to reflux 6 hours, cooling begins to drip 60 milliliters of oxyethane, the control rate of addition, make about 10 ℃ of temperature controls, after dropwising, continue reaction 2 hours.
Above-mentioned solution is poured in the aqueous solution of 500 milliliters of saturated ammonium chlorides, stir, add 500 milliliters of toluene simultaneously, tell organic phase, organic phase with the saturated common salt water washing several times, drying, rotary evaporation are removed and are desolvated to such an extent that crude product 196.0 restrains, and underpressure distillation gets product 4-tert.-butoxy phenylethyl alcohol (II) 176.0 grams.Yield is 90.7%, and content is 99.5% (GC).
IR(KBr)：3350，2980，1890，1595，1486，1392，1365，1100，1055
1H-NMR(CDCl
3/TMS)：δ1.30(9H，s)，2.74(2H，t)，3.10(1H，s)，3.68(2H，t)，6.88(2H，d)，7.18(2H，d)
Embodiment 6: in 500 milliliters four-necked bottle, add 40 milliliters of N, dinethylformamide and 5.2 gram sodium hydrides, stir the N that adds 4-tert.-butoxy phenylethyl alcohol down, (wherein 4-tert.-butoxy phenylethyl alcohol 19.4 grams (0.1 mole) dissolve in 60 milliliters N to dinethylformamide solution, the solution of dinethylformamide gained), be heated to 70 ℃, add N, 140 milliliters of N-dimethyl imines, be cooled to 30 ℃, drip the N of Cyclopropylmetyl bromide, (wherein Cyclopropylmetyl bromide 17.5 grams dissolve in 40 milliliters of N to dinethylformamide solution, dinethylformamide), dropwise, elevated temperature reaches 60 ℃, continues reaction 8 hours under this temperature.Reaction finishes, and cooling, frozen water cooling add the entry dilution down, use ether extraction, and drying desolventizes, and gets crude product 25.6 grams, and underpressure distillation gets product 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] benzene (III) 21.8 grams.Yield is 87.9%, and content is 99.5% (GC).
IR(KBr)：2930，2980，1890，1595，1486，1360，1230，1160，1110，895
1H-NMR(CDCl
3/TMS)：δ0.22(2H，m)，0.55(2H，m)，1.03(1H，m)，1.35(9H，s)，2.88(2H，t)，3.34(2H，d)，3.66(2H，t)，6.92(2H，d)，7.20(2H，d)
Embodiment 7: in 500 milliliters four-necked bottle, add 40 milliliters of methyl-sulphoxides and 8.7 gram sodium methylates, stir the dimethyl sulfoxide solution (wherein 4-tert.-butoxy phenylethyl alcohol 19.4 grams (0.05 mole) are dissolved in the solution of 60 milliliters methyl-sulphoxide gained) that adds 4-tert.-butoxy phenylethyl alcohol down, be heated to 70 ℃, add 140 milliliters of methyl-sulphoxides, be cooled to 30 ℃, drip the dimethyl sulfoxide solution (wherein cyclopropyl methyl chloride 11.9 grams dissolve in 40 milliliters of methyl-sulphoxides) of cyclopropyl methyl chloride, dropwise, elevated temperature reaches 60 ℃, continues reaction 8 hours under this temperature.All the other operations are with embodiment 6,1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] yield of benzene is 72.5%, content is 99.5% (GC).
Embodiment 8: add 1-tert.-butoxy-4-[(2-cyclo propyl methoxy in reaction flask) ethyl] benzene 24.8 grams (0.1 mole), stir and about 25-30 ℃, drip 25 milliliters of concentrated hydrochloric acids down, finish, under this temperature, continue reaction 2 hours, cooling, add saturated sodium hydrogen carbonate solution neutralization, divide three extractions with ethyl acetate, organic phase saturated common salt water washing, dry, removal of solvent under reduced pressure gets thick product 22.5 grams, and underpressure distillation gets product 4-[2-(cyclo propyl methoxy) ethyl] phenol (IV) 17.7 grams.Yield is 92.2%, and content is 99.5% (GC).
IR(KBr)：3300，2900，1890，1595，1440，1392，1220，1100，1095，890，850
1H-NMR(CDCl
3/TMS)：δ0.24(2H，m)，0.56(2H，m)，1.08(1H，m)，2.88(2H，t)，3.34(2H，d)，3.66(2H，t)，5.35(1H，s)，6.92(2H，d)，7.20(2H，d)
Claims (8)
- One kind to adopt para-chlorophenol be raw material, make and obtain 4-[2-(cyclo propyl methoxy) ethyl] novel process of phenol; It is characterized in that with the para-chlorophenol being raw material, under acid catalysis, obtain the rubigan tertbutyl ether with isobutene reaction; Rubigan tertbutyl ether and magnesium and oxyethane carry out grignard reaction and obtain 4-tert.-butoxy phenylethyl alcohol; 4-tert.-butoxy phenylethyl alcohol obtains 1-tert.-butoxy-4-[(2-cyclo propyl methoxy with the reaction of cyclopropyl halomethane under the alkali effect) ethyl] benzene; 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] benzene frees the tertiary butyl through mineral acid and obtains 4-[2-(cyclo propyl methoxy) ethyl] phenol.
- 2. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, in synthetic rubigan tertbutyl ether, the mol ratio that it is characterized in that para-chlorophenol and iso-butylene is 1: 1-3, used catalyzer is dilute sulphuric acid, tosic acid, methylsulfonic acid or strong-acid ion exchange resin, used solvent is benzene, toluene, chlorobenzene or methylene dichloride, temperature of reaction is at 15-50 ℃, and aeration time is 0.5-50 hour.
- 3. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at synthetic 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] in the benzene, it is characterized in that alkali is sodium hydride, potassium tert.-butoxide or sodium alkoxide.
- 4. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at synthetic 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] in the benzene, the mol ratio that it is characterized in that described 4-tert.-butoxy phenylethyl alcohol and alkali is 1: 1-5.
- 5. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at synthetic 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] in the benzene, it is characterized in that solvent is methyl-sulphoxide or N, dinethylformamide.
- 6. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at synthetic 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] in the benzene, it is characterized in that used cyclopropyl halomethane is Cyclopropylmetyl bromide or cyclopropyl methyl chloride.
- 7. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at synthetic 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] in the benzene, the mol ratio that it is characterized in that 4-tert.-butoxy phenylethyl alcohol and cyclopropyl halomethane is 1: 1-3.
- 8. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] benzene frees the tertiary butyl through mineral acid and obtains 4-[2-(cyclo propyl methoxy) ethyl] and in the phenol, 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] mol ratio of benzene and mineral acid is 1: reaction is 0.5-5 hour when 1-100 and room temperature to 100 ℃.
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| CNB2004100654168A CN1300079C (en) | 2004-12-03 | 2004-12-03 | New technology of synthesizing 4-[2-(cyclo propyl methoxy] ethyl] phenol |
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| CN103214380B (en) * | 2013-04-22 | 2014-10-08 | 浙江大学 | Synthesis method for m-hydroxy-N,N-diethyl aniline |
| CN107814687B (en) * | 2017-11-27 | 2021-02-26 | 湖北朗昕生化药业有限公司 | Synthetic method of p-chlorophenylethanol |
| CN108640821B (en) * | 2018-04-10 | 2021-06-18 | 恒河材料科技股份有限公司 | Efficient and continuous p-chlorophenyl tert-butyl ether synthesis method and device |
| CN116239452A (en) * | 2022-12-20 | 2023-06-09 | 浙江圣效化学品有限公司 | Method for preparing tert-butyl phenyl ether compound |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4252984A (en) * | 1975-11-06 | 1981-02-24 | Synthelabo | Phenol ethers |
| US4342783A (en) * | 1980-06-30 | 1982-08-03 | Synthelabo | Anti-glaucoma agent |
| US4652563A (en) * | 1984-05-19 | 1987-03-24 | Smith Kline & French Laboratories Ltd. | Vasodilators and β-adrenoceptor antagonists |
| US4760182A (en) * | 1985-02-07 | 1988-07-26 | Torcan Chemical Ltd. | Process for preparing substituted phenol ethers via oxazolidine-structure intermediates |
| US5731463A (en) * | 1996-09-23 | 1998-03-24 | Abbott Laboratories | Selective alkylation of an alcohol substituted phenol compound |
-
2004
- 2004-12-03 CN CNB2004100654168A patent/CN1300079C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4252984A (en) * | 1975-11-06 | 1981-02-24 | Synthelabo | Phenol ethers |
| US4342783A (en) * | 1980-06-30 | 1982-08-03 | Synthelabo | Anti-glaucoma agent |
| US4652563A (en) * | 1984-05-19 | 1987-03-24 | Smith Kline & French Laboratories Ltd. | Vasodilators and β-adrenoceptor antagonists |
| US4760182A (en) * | 1985-02-07 | 1988-07-26 | Torcan Chemical Ltd. | Process for preparing substituted phenol ethers via oxazolidine-structure intermediates |
| US5731463A (en) * | 1996-09-23 | 1998-03-24 | Abbott Laboratories | Selective alkylation of an alcohol substituted phenol compound |
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