CN100482629C - Para-(2-methoxyl) ethylphenol synthesis method - Google Patents
Para-(2-methoxyl) ethylphenol synthesis method Download PDFInfo
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- CN100482629C CN100482629C CNB2006100234368A CN200610023436A CN100482629C CN 100482629 C CN100482629 C CN 100482629C CN B2006100234368 A CNB2006100234368 A CN B2006100234368A CN 200610023436 A CN200610023436 A CN 200610023436A CN 100482629 C CN100482629 C CN 100482629C
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- phenolic hydroxyl
- hydroxyl group
- ethylphenol
- ether
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- IXQGCWUGDFDQMF-UHFFFAOYSA-N o-Hydroxyethylbenzene Natural products CCC1=CC=CC=C1O IXQGCWUGDFDQMF-UHFFFAOYSA-N 0.000 title claims description 48
- 238000001308 synthesis method Methods 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 15
- YCCILVSKPBXVIP-UHFFFAOYSA-N 2-(4-hydroxyphenyl)ethanol Chemical compound OCCC1=CC=C(O)C=C1 YCCILVSKPBXVIP-UHFFFAOYSA-N 0.000 claims abstract description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 13
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 10
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 10
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 9
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 9
- 239000011777 magnesium Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 54
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 claims description 18
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 claims description 14
- 229960003742 phenol Drugs 0.000 claims description 14
- 229940090668 parachlorophenol Drugs 0.000 claims description 12
- 238000010189 synthetic method Methods 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 9
- 238000003747 Grignard reaction Methods 0.000 claims description 8
- 230000000977 initiatory effect Effects 0.000 claims description 8
- 230000000903 blocking effect Effects 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- JDZJVWAHZYIHFA-UHFFFAOYSA-N [Br].C1(=CC=CC=C1)O Chemical compound [Br].C1(=CC=CC=C1)O JDZJVWAHZYIHFA-UHFFFAOYSA-N 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 5
- 238000006266 etherification reaction Methods 0.000 claims description 5
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 3
- DBLDQZASZZMNSL-QMMMGPOBSA-N L-tyrosinol Natural products OC[C@@H](N)CC1=CC=C(O)C=C1 DBLDQZASZZMNSL-QMMMGPOBSA-N 0.000 abstract 3
- 235000004330 tyrosol Nutrition 0.000 abstract 3
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 abstract 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 abstract 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 11
- 229940067107 phenylethyl alcohol Drugs 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 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 description 7
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- JJHQOWSIVWOGGU-UHFFFAOYSA-N 1-chloro-2-phenylmethoxybenzene Chemical compound ClC1=CC=CC=C1OCC1=CC=CC=C1 JJHQOWSIVWOGGU-UHFFFAOYSA-N 0.000 description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- JBSSNSQYEIJWJT-UHFFFAOYSA-N 1-bromo-2-[(2-methylpropan-2-yl)oxy]benzene Chemical compound CC(C)(C)OC1=CC=CC=C1Br JBSSNSQYEIJWJT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- -1 bromophenyl tertbutyl ether toluene Chemical compound 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 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
- 229960002237 metoprolol Drugs 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- KLOHRGVQRCCZIF-UHFFFAOYSA-N 2-(2-methoxyethyl)phenol Chemical compound COCCC1=CC=CC=C1O KLOHRGVQRCCZIF-UHFFFAOYSA-N 0.000 description 1
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical class OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 description 1
- FAYGEALAEQKPDI-UHFFFAOYSA-N 4-(2-methoxyethyl)phenol Chemical compound COCCC1=CC=C(O)C=C1 FAYGEALAEQKPDI-UHFFFAOYSA-N 0.000 description 1
- ZPTVNYMJQHSSEA-UHFFFAOYSA-N 4-nitrotoluene Chemical compound CC1=CC=C([N+]([O-])=O)C=C1 ZPTVNYMJQHSSEA-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 150000005451 methyl sulfates Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 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 invention discloses a method for synthesizing phenetyl, which uses p-chlorophehol or p-bromophenol as starting reaction raw material. It first uses methyl, benzyl or tert-butyl to protect the phenolic hydroxyl, the parivis which is protected by the phenolic hydroxyl reacts with the magnesium in the ether, tetrahydrofuran, tert-butyl methyl ether, isopropyl ether and its mixing solution to obtain the Grignard reagent, the Grignard reagent directly reacted with the etox to obtain the tyrosol which is protected by the phenolic hydroxyl, the tyrosol reacts with the dimethyl sulfate, dimethyl carbonate, trimethyl orthoformate to obtain the tyrosol ether which is protected by phenolic hydroxyl, which obtains the product in acid or hydrogenation protection.
Description
Technical field
The present invention relates to a kind of synthetic method that has at least a hydroxyl or O-metal group to be connected the compound on the six-membered aromatic ring carbon atom, relate in particular a kind of right-synthetic method of (2-methoxyl group) ethylphenol.
Background technology
(4-(2-methoxyethyl) phenol) is the key intermediate of synthetic drugs metoprolol to (2-methoxyl group) ethylphenol, and structural formula is as follows:
Generally adopt phenylethyl alcohol as starting raw material to (2-methoxyl group) ethylphenol, obtain through polystep reactions such as methyl-etherified, nitrated, reduction, diazotization hydrolysis and purification.Synthetic lower by this method, and three wastes quantity is big to the yield of (2-methoxyl group) ethylphenol, to produce higherly to the cost of (2-methoxyl group) ethylphenol, its building-up process can be represented with following chemical equation:
Also the someone to adopt para-nitrotoluene be that starting raw material synthesizes (2-methoxyl group) ethylphenol, but this reaction scheme exists synthesis of selective poor equally, produces heavy-polluted problem, its building-up process can be represented with following chemical equation:
Summary of the invention
Technical problem to be solved by this invention provides a kind of synthetic method of right-(2-methoxyl group) ethylphenol newly, and this method synthetic route is simple, the yield height, and the three wastes quantity of generation is few, and cost is lower.
The technical solution used in the present invention: a kind of right-synthetic method of (2-methoxyl group) ethylphenol, comprise the following steps: a. with para-chlorophenol or p bromophenol as initial action raw material and methyl, benzyl or tertiary butyl reaction protection phenolic hydroxyl group, obtain the P-Chlorophenol of phenolic hydroxyl group protection or to bromine phenol; B. the P-Chlorophenol of phenolic hydroxyl group protection or bromine phenol carried out grignard reaction with magnesium in solvent ether, tetrahydrofuran (THF), t-butyl methyl ether or isopropyl ether or in its mixed solvent obtains corresponding Grignard reagent; C. the Grignard reagent and the reacting ethylene oxide of step b preparation obtain the p-hydroxyphenylethanol that phenolic hydroxyl group is protected; D. p-hydroxyphenylethanol and methyl-sulfate, methylcarbonate or the trimethyl orthoformate of phenolic hydroxyl group protection carry out etherification reaction, obtain the para hydroxybenzene ethyl methyl ether of phenolic hydroxyl group protection; E. para hydroxybenzene ethyl methyl ether deprotection under acidity or hydrogenation conditions of phenolic hydroxyl group protection, obtain target product right-(2-methoxyl group) ethylphenol.The chemical equation of synthetic right-(2-methoxyl group) ethylphenol step a～e is as follows:
Wherein R is a blocking group, and R is selected from a kind of in methyl, the tertiary butyl or the benzyl.
Among the step a with para-chlorophenol or p bromophenol as the initial action raw material preferably with benzyl or tertiary butyl reaction protection phenolic hydroxyl group, the P-Chlorophenol that is protected or to bromine phenol.
The para-chlorophenol or the p bromophenol of phenolic hydroxyl group protection carry out grignard reaction with magnesium among the step b in solvent ether, t-butyl methyl ether, tetrahydrofuran (THF) or its mixed solvent, obtain corresponding Grignard reagent.
The p-hydroxyphenylethanol of protecting in the steps d preferably carries out etherification reaction with methyl-sulfate, the para hydroxybenzene ethyl methyl ether that is protected.
Described in the step e under the acidic conditions deprotection be meant with the protection the hydrolysis under sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid condition of para hydroxybenzene ethyl methyl ether slough blocking group.
Described in the step e under the hydrogenation conditions deprotection be meant and para hydroxybenzene ethyl methyl ether catalytic hydrogenation under catalyzer Raney's nickel, palladium carbon or rhodium carbon condition of protection sloughed blocking group, preferred catalyst Raney's nickel wherein.
Beneficial effect of the present invention: it is that starting raw material synthesizes (2-methoxyl group) ethylphenol that the present invention adopts para-chlorophenol or p bromophenol, therefore selected simpler reaction scheme, the three wastes that reaction process produces are less, the product yield height, the synthetic product stability is good, purity is high, can be used for the synthetic of metoprolol.
Embodiment
By embodiment the present invention being described in further detail, is the initial action raw material with para-chlorophenol or p bromophenol, at first with methyl, benzyl or the tertiary butyl phenolic hydroxyl group is implemented protection, wherein better with the effect of benzyl and tertiary butyl protection.The para-chlorophenol or the p bromophenol of protection carry out grignard reaction with magnesium in ether, tetrahydrofuran (THF), t-butyl methyl ether, isopropyl ether and basic mixed solvent, get Grignard reagent, and wherein solvent ether or tetrahydrofuran (THF) effect are better.Grignard reagent directly obtains the p-hydroxyphenylethanol that phenolic hydroxyl group is protected with reacting ethylene oxide.The p-hydroxyphenylethanol of phenolic hydroxyl group protection can carry out etherificate with methyl-sulfate, methylcarbonate or trimethyl orthoformate reaction, obtains the para hydroxybenzene ethyl methyl ether of phenolic hydroxyl group protection, and wherein the methyl-sulfate effect is better.The para hydroxybenzene ethyl methyl ether of phenolic hydroxyl group protection obtains target product in acidity or hydrogenation deprotection.Deprotection is meant blocking group is sloughed in para hydroxybenzene ethyl methyl ether hydrolysis under sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid condition of phenolic hydroxyl group protection under the described acidic conditions.Deprotection is meant para hydroxybenzene ethyl methyl ether catalytic hydrogenation under catalyzer Raney's nickel, palladium carbon or rhodium carbon condition of phenolic hydroxyl group protection is sloughed blocking group under the described hydrogenation conditions, wherein preferred Raney's nickel.
Embodiment 1
In the 1000ml there-necked flask, add 128 gram (1.0mol) para-chlorophenols, 500ml toluene, the 2 gram vitriol oils feed isobutene reaction under the water-bath cooling conditions, be converted into the rubigan tertbutyl ether to 90% above para-chlorophenol after, stop to feed iso-butylene.Be cooled to lesser temps with 30% aqueous sodium hydroxide solution termination reaction and wash, remove unreacted para-chlorophenol, be washed with water to nearly neutrality again.Resulting rubigan tertbutyl ether toluene solution concentrates, and it is on probation for the next steps to obtain containing the rubigan tertbutyl ether and be about 40% about 420 grams of toluene solution.
Embodiment 2
In the 1000ml there-necked flask, add 172 gram (1.0mol) p bromophenols, 500ml toluene, the 2 gram vitriol oils feed isobutene reaction under the water-bath cooling conditions, be converted into behind the bromophenyl tertbutyl ether to 90% above p bromophenol, stop to feed iso-butylene.Be cooled to lesser temps with 30% aqueous sodium hydroxide solution termination reaction and wash, remove unreacted p bromophenol, be washed with water to nearly neutrality again.Resulting bromophenyl tertbutyl ether toluene solution is concentrated, obtaining containing to the bromophenyl tertbutyl ether is that about 40% about 420 grams of toluene solution are on probation for the next steps.
Embodiment 3:
In the 2000ml there-necked flask, add the 500ml tetrahydrofuran (THF), 24 gram (1.0mol) magnesium, under refluxad once add and go up the about 5-10% initiation reaction of step reaction solution, control under refluxad drips and goes up the rubigan tertbutyl ether toluene solution that the step reaction obtains then, after dropwising, back flow reaction to rubigan tertbutyl ether reaction obtains grignard reaction liquid substantially fully again.Under cooling conditions, slowly add oxyethane 48.4 gram (1.1mol) reactions and obtain then the tert.-butoxy phenylethyl alcohol.Reaction solution is washed with water, and layering obtains organic phase, and with organic phase concentrate carry out rectifying can be to about 125 grams of tert.-butoxy phenylethyl alcohol (purity〉95%).
Embodiment 4
In the 2000ml there-necked flask, add the 500ml ether, 24 gram (1.0mol) magnesium, under refluxad once add and go up the about 5-10% initiation reaction of step reaction solution, control under refluxad drips and goes up the rubigan tertbutyl ether toluene solution that the step reaction obtains then, after dropwising, back flow reaction to rubigan tertbutyl ether reaction obtains grignard reaction liquid substantially fully again.Under cooling conditions, slowly add oxyethane 48.4 gram (1.1mol) reactions and obtain then the tert.-butoxy phenylethyl alcohol.Reaction solution is washed with water, and layering obtains organic phase, and with organic phase concentrate carry out rectifying can be to about 125 grams of tert.-butoxy phenylethyl alcohol (purity〉95%).
Embodiment 5
In the 1000ml there-necked flask, add toluene 400ml, 194 grams (1.0mol) are to the tert.-butoxy phenylethyl alcohol, sodium hydroxide 48 grams (1.2mol), temperature is lower than dropping methyl-sulfate 139 grams (1.1mol) under 60 ℃ of conditions in the control then, dropwises the back and continues stirring reaction to the tert.-butoxy phenylethyl alcohol all is converted into tert.-butoxy styroyl methyl ether.After reaction finishes, add entry 100ml, and be heated to more than 60 ℃ stirring reaction 1 hour to destroy excessive methyl-sulfate.Add a small amount of sulfuric acid then and make system be acid, and stirring reaction makes the hydrolysis of tert.-butoxy ether generate (2-methoxyl group) ethylphenol.Tell water, and with less water washing organic phase once.The gained organic phase concentrates can get (2-methoxyl group) ethylphenol first product, and first product can obtain purity at the finished product more than 99.5% through rectifying.
Embodiment 6:
In the 1000ml there-necked flask, add toluene 400ml, 194 grams (1.0mol) are to the tert.-butoxy phenylethyl alcohol, sodium hydroxide 48 grams (1.2mol), temperature is lower than dropping methylcarbonate 99 grams (1.1mol) under 60 ℃ of conditions in the control then, dropwises the back and continues stirring reaction to the tert.-butoxy phenylethyl alcohol all is converted into tert.-butoxy styroyl methyl ether.After reaction finishes, add entry 100ml, and be heated to more than 60 ℃ stirring reaction 1 hour to destroy excessive methyl-sulfate.Add a small amount of sulfuric acid then and make system be acid, and stirring reaction makes the hydrolysis of tert.-butoxy ether generate (2-methoxyl group) ethylphenol.Tell water, and with less water washing organic phase once.The gained organic phase concentrates can get (2-methoxyl group) ethylphenol first product, and first product can obtain purity at the finished product more than 99.5% through rectifying.
Embodiment 7:
In the 1000ml there-necked flask, add 128 gram (1.0mol) para-chlorophenols, 500ml methyl alcohol, 137 gram (1.2mol) yellow soda ash under refluxad drip Benzyl Chloride 140 grams (1.1mol).After dropwising, continue back flow reaction, after reacting completely to para-chlorophenol, remove by filter the salt of generation, and use methanol wash salt.The gained solution concentration must be to benzyloxy chlorobenzene first product, and first product can get pure product to benzyloxy chlorobenzene 194 grams, yield 89% through the methanol-water crystallization.
Embodiment 8:
In the 2000ml there-necked flask, add the 500ml t-butyl methyl ether, 24 gram (1.0mol) magnesium, under refluxad once adding 30ml restrains benzyloxy chlorobenzene and the initiation reaction of 300ml t-butyl methyl ether solution by 218, control under refluxad drips the t-butyl methyl ether solution solution to the benzyloxy chlorobenzene then, after dropwising, back flow reaction obtains grignard reaction liquid to the benzyloxy chlorobenzene is reacted completely again.Under cooling conditions, slowly add oxyethane 48.4 gram (1.1mol) reactions and obtain then benzyloxy phenylethyl alcohol solution.In this solution, add 40 gram sodium hydroxide, under cooling, drip 140 gram methyl-sulfates then and carry out etherification reaction.After reaction finishes, add entry 200ml, and be heated to more than 60 ℃ stirring reaction 1 hour to destroy excessive methyl-sulfate.Tell water, and washing obtains once to benzyloxy styroyl methyl ether solution.After concentrating also crystallization, obtain 177 grams to benzyloxy styroyl methyl ether, yield 75%, purity 98.5% (HPLC).
Embodiment 9:
Add 242 grams to benzyloxy styroyl methyl ether in the 2L autoclave, 800ml toluene and 10 gram Raney's nickels ventilate behind the secondary with nitrogen system, feed hydrogen to 10 normal atmosphere, maintain then to carry out hydrogenation under 10 atmospheric pressure and slough benzyl.Reaction removes by filter catalyzer after finishing, and the concentrated solvent toluene of removing, and product can be to (2-methoxy ethyl) phenol 118 grams, yield 78%, purity 99.6% through rectifying.
Above said content only is the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.
Claims (6)
1. the synthetic method of right-(2-methoxyl group) ethylphenol comprises the following steps:
A. with para-chlorophenol or p bromophenol as initial action raw material and methyl, benzyl or tertiary butyl reaction protection phenolic hydroxyl group, the P-Chlorophenol that is protected or to bromine phenol;
B. Bao Hu P-Chlorophenol or bromine phenol carried out grignard reaction with magnesium in solvent ether, tetrahydrofuran (THF), t-butyl methyl ether or isopropyl ether obtains corresponding Grignard reagent;
C. the Grignard reagent and the reacting ethylene oxide of step b preparation obtain the p-hydroxyphenylethanol that phenolic hydroxyl group is protected;
D. p-hydroxyphenylethanol and methyl-sulfate, methylcarbonate or the trimethyl orthoformate of phenolic hydroxyl group protection carry out etherification reaction, the para hydroxybenzene ethyl methyl ether that is protected;
E. para hydroxybenzene ethyl methyl ether deprotection under acidity or hydrogenation conditions of phenolic hydroxyl group protection, obtain target product right-(2-methoxyl group) ethylphenol.
2. according to claim 1 right-synthetic method of (2-methoxyl group) ethylphenol; it is characterized in that: adopt para-chlorophenol or p bromophenol as initial action raw material and benzyl or tertiary butyl reaction protection phenolic hydroxyl group among the step a, obtain P-Chlorophenol that phenolic hydroxyl group protects or bromine phenol.
3. according to claim 1 right-synthetic method of (2-methoxyl group) ethylphenol; it is characterized in that: the para-chlorophenol or the p bromophenol of phenolic hydroxyl group protection carry out grignard reaction with magnesium among the step b in solvent ether, t-butyl methyl ether, tetrahydrofuran (THF) or its mixed solvent, obtain corresponding Grignard reagent.
4. according to claim 1 right-synthetic method of (2-methoxyl group) ethylphenol, it is characterized in that: p-hydroxyphenylethanol and the methyl-sulfate of phenolic hydroxyl group protection carry out etherification reaction in the steps d, obtain the para hydroxybenzene ethyl methyl ether that phenolic hydroxyl group is protected.
5. according to claim 1 right-synthetic method of (2-methoxyl group) ethylphenol, it is characterized in that: described in the step e under the acidic conditions deprotection be meant blocking group sloughed in para hydroxybenzene ethyl methyl ether hydrolysis under sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid condition of phenolic hydroxyl group protection.
6. according to claim 1 right-synthetic method of (2-methoxyl group) ethylphenol, it is characterized in that: described in the step e under the hydrogenation conditions deprotection be meant para hydroxybenzene ethyl methyl ether catalytic hydrogenation under catalyzer Raney's nickel, palladium carbon or rhodium carbon condition of phenolic hydroxyl group protection sloughed blocking group.
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| CN102898289B (en) * | 2012-10-11 | 2014-09-03 | 江苏德峰药业有限公司 | Method for synthesizing 2-(4-benzylmethoxyphenyl)ethanol medical intermediate |
| CN105906482B (en) * | 2016-05-19 | 2019-02-12 | 江苏优嘉植物保护有限公司 | A method of 2,5- chlorophenesic acid is prepared using 2,5- dichloro phenolic ether |
| CN107382683A (en) * | 2017-07-18 | 2017-11-24 | 荆门医药工业技术研究院 | A kind of synthetic method for preparing Metoprolol intermediate |
| CN108689810A (en) * | 2018-06-13 | 2018-10-23 | 连云港市工投集团利海化工有限公司 | To the synthetic method of methoxy ethyl phenol |
| CN109651094B (en) * | 2018-12-29 | 2021-09-28 | 浙江永太科技股份有限公司 | Preparation method of p- (2-methoxy) ethylphenol |
| CN111116328A (en) * | 2019-12-27 | 2020-05-08 | 江西美晶科技有限公司 | Preparation method of metoprolol intermediate |
| CN114409511B (en) * | 2022-03-04 | 2023-05-23 | 浙江博聚新材料有限公司 | Preparation method of propylene glycol |
| CN114702372B (en) * | 2022-03-25 | 2022-12-16 | 台州市前进化工有限公司 | Method for preparing 4- (2-methoxyl) ethylphenol |
| CN116020438A (en) * | 2022-12-23 | 2023-04-28 | 山东普洛汉兴医药有限公司 | Solid acid catalyst, preparation method thereof and application of solid acid catalyst in deprotection reaction of p-tert-butoxyphenethyl methyl ether |
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