CN1962603A - Method for preparing 2-(2,2,2-trifluoroethoxy)phenol - Google Patents
Method for preparing 2-(2,2,2-trifluoroethoxy)phenol Download PDFInfo
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- CN1962603A CN1962603A CN 200610098100 CN200610098100A CN1962603A CN 1962603 A CN1962603 A CN 1962603A CN 200610098100 CN200610098100 CN 200610098100 CN 200610098100 A CN200610098100 A CN 200610098100A CN 1962603 A CN1962603 A CN 1962603A
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- trifluoro ethoxy
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Abstract
The invention discloses a preparing method of 2-(2,2,2-trifluoro ethoxy) phenol (I) (the structural formula as follows), which comprises the following steps: adopting o-nitrochlorobenzene as raw material; etherifying 2,2,2-trifluoro ethoxy; reducing through hydrogen; diazotizing; proceeding hydroxy decomposition to obtain the product.
Description
Technical field
The preparation method of 2-(2,2, the 2-trifluoro ethoxy) phenol.
Background technology
(KMD-3213, KAD-3213) structural formula is as follows, is the α by the common exploitation of Japanese Kissei and Daiichi company for Silodosin
1-adrenoceptor antagonists is used for the treatment of benign prostatic hyperplasia clinically.This product in 2006 in Japanese Initial Public Offering, at present domestic still do not have a synthetic bibliographical information.2-(2,2, the 2-trifluoro ethoxy) phenol is synthetic Silodosin (structural formula is as follows) important intermediate.Its synthetic method has only the synthetic route of report in Japanese Kissei (tangerine gives birth to) house journal (EP600675), and its route is as follows:
This route shortcoming is:
1) reaction a needs price extremely expensive and need the reagent 2,2 of import, 2-trifluoro iodoethane, and its character instability is easily decomposed, and is difficult for storing transportation, and reaction conditions needs anhydrous, is not suitable for producing;
2) reactions steps b needs expensive reagent boron tribromide equally, boron tribromide character instability, and chance light, water, air decompose rapidly, and corrodibility is strong, pungency is big, and reaction conditions is extremely harsh, is difficult to suitability for industrialized production.
Summary of the invention
The objective of the invention is deficiency, provide a kind of preparation 2-(2,2, the 2-trifluoro ethoxy) variation route of phenol (I), novel method at above route.The synthetic route that the present invention relates to 2-(2,2, the 2-trifluoro ethoxy) phenol (I) is as follows:
The invention has the advantages that and use source abundance and cheap o-Nitrochlorobenzene (II) to be raw material, obtain product 2-(2,2, the 2-trifluoro ethoxy) phenol (I) through separating reaction with 2,2,2 tfifluoroethyl alcohol etherificate, reduction, diazotization and hydroxyl.Starting raw material also comprises adjacent nitro bromobenzene, adjacent nitro fluorobenzene and adjacent nitro iodobenzene, utilize the activation of nitro, under alkaline condition, thereby add the phase-transfer catalyst four butyl bromation amine smoothly with 2 to the ortho position halogen, 2,2-trifluoroethanol generation etherification reaction, high yield obtain intermediate 2-(2,2, the 2-trifluoro ethoxy) oil of mirbane (III), but do not need purifying direct hydrogenation reduction preparation 2-(2,2, the 2-trifluoro ethoxy) aniline (IV), yield is higher, need not separate the sour hydroxyl of direct usefulness after 2-(2,2, the 2-trifluoro ethoxy) aniline (IV) diazotization separates and makes 2-(2,2, the 2-trifluoro ethoxy) phenol (I).
2-(2,2, the 2-trifluoro ethoxy) preparation method of phenol (I), it is characterized in that intermediate 2-(2,2,2-trifluoro ethoxy) preparation of oil of mirbane (III) is to be raw material with o-Nitrochlorobenzene (II), has used phase-transfer catalyst and 2 under alkaline condition, 2, the preparation of 2-trifluoroethanol etherification reaction.Wherein raw material also comprises adjacent nitro fluorobenzene, adjacent nitro iodobenzene and adjacent nitro bromobenzene; Catalyzer comprises four butyl bromation amine, benzyltriethylammoinium chloride, tetrabutylammonium iodide, tetramethyl ammonium chloride, cetyl trimethylammonium bromide, hexaoxacyclooctadecane-6-6; Mol ratio is an o-Nitrochlorobenzene: 2,2,2 tfifluoroethyl alcohol: four butyl bromation amine=1: 0.5～10: 0.001～10; Employed alkali comprises sodium hydroxide, potassium hydroxide, calcium hydroxide, hydrated barta, lithium hydroxide; Temperature of reaction is 0～100 ℃.
2-(2,2, the 2-trifluoro ethoxy) preparation method of phenol (I), it is characterized in that intermediate 2-(2,2, the 2-trifluoro ethoxy) preparation of aniline (IV) is by intermediate 2-(2,2, the 2-trifluoro ethoxy) oil of mirbane (III) makes through hydro-reduction, catalyzer is selected palladium carbon, Ruan Shi nickel, platinum oxide for use, also can be made by reductive agent iron powder, zinc powder, sodium sulphite, sodium disulfide, S-WAT, sodium bisulfite, ammonium bisulfite, ammonium sulphite, V-Brite B, vat powder, hydrazine hydrate reduction; Employed solvent is selected water, C for use
1～C
8Alcohols, DMF; 0～150 ℃ of temperature of reaction.
2-(2,2, the 2-trifluoro ethoxy) preparation method of phenol (I), it is characterized in that 2-(2,2,2-trifluoro ethoxy) phenol (I) is by intermediate 2-(2,2, the 2-trifluoro ethoxy) aniline (IV) is separated reaction through diazotization and hydroxyl and is made, and the selected acid of diazotization reaction comprises sulfuric acid, hydrochloric acid, boric acid, nitric acid, sodium pyrosulfate, sal enixum, monoammonium sulfate; Temperature of reaction is-20～50 ℃; The temperature of reaction that hydroxyl is separated is 0～100 ℃.
The invention has the advantages that the synthetic route that has designed a new 2-(2,2, the 2-trifluoro ethoxy) phenol (I) in a word, all reagent that use abundance of all originating, cheap, avoided using expensive 2,2,2-trifluoro iodoethane and boron tribromide, optimize reaction conditions, simplified operation, reduced cost, compare with the preparation method of bibliographical information, be more suitable for suitability for industrialized production.
Embodiment
Embodiment:
Embodiment 1, the preparation of 2-(2,2, the 2-trifluoro ethoxy) oil of mirbane (III):
Add o-Nitrochlorobenzene (II) 100g, 50% sodium hydroxide 260g, phase-transfer catalyst four butyl bromation amine 8g in the reaction flask, stir, be warming up to 60 ℃, drip 2,2,2-trifluoroethanol 68g drips and finishes, 70 ℃ of stirring reactions 6 hours, cooling, suction filtration, washing, dry orange solid (III) 124g, mp53～5 ℃, yield 88.4%.
1HNMR(CDCL
3)δ：4.50(q，2H，-CH
2CF
3)，7.13-7.90(m，4H，Ar-H)
Embodiment 2, the preparation of 2-(2,2, the 2-trifluoro ethoxy) aniline (IV):
Add 2-(2,2, the 2-trifluoro ethoxy) oil of mirbane (III) 120g, dehydrated alcohol 1.5L in the hydrogenation still, 10% palladium carbon 10g, normal pressure hydrogenation, stirring at room reaction 12 hours, suction filtration, filtrate decompression concentrate faint yellow solid (IV) 95g, mp58～60 ℃, yield 91.6%.
1HNMR(CDCL
3)δ：3.84(brs，2H，-NH
2)，4.42(q，2H，-CH
2CF
3)，6.70-7.26(m，4H，Ar-H)
Embodiment 3, the preparation of 2-(2,2, the 2-trifluoro ethoxy) phenol (I):
Add 20% (W/W) sulfuric acid 210g in the reaction flask, the ice-water bath cooling is stirred, and adds 2-(2,2, the 2-trifluoro ethoxy) aniline (IV) 80g, reacted 30 minutes, drip the solution that is made into by Sodium Nitrite 30g and water 50g, drip and finish, 0～5 ℃ was reacted 2 hours, freezing standby.
Add 20% (W/W) sulfuric acid 200g, sodium sulfate 100g, toluene 500ml in the reaction flask, stir, be heated to 70 ℃, drip above-mentioned diazonium salt solution, drip and finish, continue reaction 2 hours, cooling, separatory, water extracts with toluene 200ml * 2, the combining methylbenzene layer, washing is concentrated into 1/3 volume, extracts with 30% (W/W) sodium hydroxide 200g * 3, combining water layer, the 2N hcl acidifying, extract toluene 200ml * 2, the combining methylbenzene layer, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, resistates gets white solid (I) 26g with the normal hexane recrystallization, mp52～54 ℃, yield 32.4%.
1HNMR(CDCL
3)δ：4.42(q，2H，-CH
2CF
3)，5.53(s，1H，-OH)，6.86-7.00(m，4H，Ar-H)
Claims (4)
- The preparation method of (1.2-2,2, the 2-trifluoro ethoxy) phenol (I).It is characterized in that: use o-Nitrochlorobenzene to obtain intermediate 2-(2 as raw material and 2,2,2 tfifluoroethyl alcohol etherification reaction, 2, the 2-trifluoro ethoxy) oil of mirbane (III), 2-(2,2,2-trifluoro ethoxy) oil of mirbane (III) hydro-reduction obtains 2-(2,2, the 2-trifluoro ethoxy) aniline (IV), 2-(2,2, the 2-trifluoro ethoxy) aniline (IV) is separated prepared in reaction 2-(2 through diazotization and hydroxyl at last, 2, the 2-trifluoro ethoxy) phenol (I).
- 2. 2-(2 according to claim 1,2, the 2-trifluoro ethoxy) preparation method of phenol (I), it is characterized in that intermediate 2-(2,2, the 2-trifluoro ethoxy) preparation of oil of mirbane (III) is to be that raw material has used the preparation of phase-transfer catalyst and 2,2,2 tfifluoroethyl alcohol etherification reaction under alkaline condition with o-Nitrochlorobenzene (II).Wherein raw material also comprises adjacent nitro fluorobenzene, adjacent nitro bromobenzene and adjacent nitro iodobenzene; Catalyzer comprises four butyl bromation amine, benzyltriethylammoinium chloride, tetrabutylammonium iodide, tetramethyl ammonium chloride, cetyl trimethylammonium bromide, hexaoxacyclooctadecane-6-6; Mol ratio is an o-Nitrochlorobenzene: 2,2,2 tfifluoroethyl alcohol: four butyl bromation amine=1: 0.5～10: 0.001～10; Employed alkali comprises sodium hydroxide, potassium hydroxide, calcium hydroxide, hydrated barta, lithium hydroxide; Temperature of reaction is 0～100 ℃.
- 3. 2-(2 according to claim 1,2, the 2-trifluoro ethoxy) preparation method of phenol (I), it is characterized in that intermediate 2-(2,2, the 2-trifluoro ethoxy) preparation of aniline (IV) is by intermediate 2-(2,2, the 2-trifluoro ethoxy) oil of mirbane (III) makes through hydro-reduction, catalyzer is selected palladium carbon, Ruan Shi nickel, platinum oxide for use, also can be made by reductive agent iron powder, zinc powder, sodium sulphite, sodium disulfide, S-WAT, sodium bisulfite, ammonium bisulfite, ammonium sulphite, V-Brite B, vat powder, hydrazine hydrate reduction; Employed solvent is selected water, C for use 1～C 8Alcohols, DMF; 0～150 ℃ of temperature of reaction.
- 4. 2-(2 according to claim 1,2, the 2-trifluoro ethoxy) preparation method of phenol (I), it is characterized in that 2-(2,2,2-trifluoro ethoxy) phenol (I) is by intermediate 2-(2,2, the 2-trifluoro ethoxy) aniline (IV) is separated reaction through diazotization and hydroxyl and is made, and the selected acid of diazotization reaction comprises sulfuric acid, hydrochloric acid, boric acid, nitric acid, sodium pyrosulfate, sal enixum, monoammonium sulfate; Temperature of reaction is-20～50 ℃; The temperature of reaction that hydroxyl is separated is 0～100 ℃.
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| CNB2006100981008A CN100534973C (en) | 2006-12-04 | 2006-12-04 | Method for preparing 2-(2,2,2-trifluoroethoxy)phenol |
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|---|---|---|---|
| CNB2006100981008A CN100534973C (en) | 2006-12-04 | 2006-12-04 | Method for preparing 2-(2,2,2-trifluoroethoxy)phenol |
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| CN100534973C CN100534973C (en) | 2009-09-02 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311319A (en) * | 2010-07-05 | 2012-01-11 | 浙江华海药业股份有限公司 | Method for preparing 2-(2,2,2-trifluoroethyl) anisole |
| CN101817751B (en) * | 2009-12-14 | 2012-02-29 | 浙江永太科技股份有限公司 | 3,5-difluoro-4-(2,2,2-trifluoroethoxy) nitrobenzene compound and preparation method thereof |
| CN102381985A (en) * | 2011-08-31 | 2012-03-21 | 常州市阳光药业有限公司 | Preparation method of bis(p aminophenoxyl) alkane |
| CN103709095A (en) * | 2014-01-14 | 2014-04-09 | 浙江永宁药业股份有限公司 | Preparation method of 4-cyclic lactam group aniline |
| CN105348048A (en) * | 2015-11-30 | 2016-02-24 | 东华大学 | Method for preparing aryl trifluoroethoxyl ether |
| CN106831460A (en) * | 2017-02-24 | 2017-06-13 | 青铜峡市嘉华化工有限公司 | The preparation method of the aminobenzoic acid of 3 methyl 4 |
-
2006
- 2006-12-04 CN CNB2006100981008A patent/CN100534973C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101817751B (en) * | 2009-12-14 | 2012-02-29 | 浙江永太科技股份有限公司 | 3,5-difluoro-4-(2,2,2-trifluoroethoxy) nitrobenzene compound and preparation method thereof |
| CN102311319A (en) * | 2010-07-05 | 2012-01-11 | 浙江华海药业股份有限公司 | Method for preparing 2-(2,2,2-trifluoroethyl) anisole |
| CN102381985A (en) * | 2011-08-31 | 2012-03-21 | 常州市阳光药业有限公司 | Preparation method of bis(p aminophenoxyl) alkane |
| CN102381985B (en) * | 2011-08-31 | 2014-03-26 | 常州市阳光药业有限公司 | Preparation method of bis(p aminophenoxyl) alkane |
| CN103709095A (en) * | 2014-01-14 | 2014-04-09 | 浙江永宁药业股份有限公司 | Preparation method of 4-cyclic lactam group aniline |
| CN103709095B (en) * | 2014-01-14 | 2016-06-22 | 浙江永宁药业股份有限公司 | The preparation method of 4-cyclic lactam base aniline |
| CN105348048A (en) * | 2015-11-30 | 2016-02-24 | 东华大学 | Method for preparing aryl trifluoroethoxyl ether |
| CN105348048B (en) * | 2015-11-30 | 2017-12-22 | 东华大学 | A kind of method for preparing aryl trifluoro ethoxy ether compound |
| CN106831460A (en) * | 2017-02-24 | 2017-06-13 | 青铜峡市嘉华化工有限公司 | The preparation method of the aminobenzoic acid of 3 methyl 4 |
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| CN100534973C (en) | 2009-09-02 |
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