CN102311319A - Method for preparing 2-(2,2,2-trifluoroethyl) anisole - Google Patents
Method for preparing 2-(2,2,2-trifluoroethyl) anisole Download PDFInfo
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- CN102311319A CN102311319A CN201010218796XA CN201010218796A CN102311319A CN 102311319 A CN102311319 A CN 102311319A CN 201010218796X A CN201010218796X A CN 201010218796XA CN 201010218796 A CN201010218796 A CN 201010218796A CN 102311319 A CN102311319 A CN 102311319A
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- methyl
- trifluoroethyl
- phenoxide
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Abstract
The invention relates to a method for preparing 2-(2,2,2-trifluoroethyl) anisole which is shown as a structural formula (1). In the method, 2-methoxyphenol (shown as a formula II) is used as a starting raw material and reacts with a compound shown as a formula (III) in a solvent in the presence of an alkali to prepare the 2-(2,2,2-trifluoroethyl) anisole, wherein L in the formula (III) represents an acryl group. The compound is used for preparing silodosin, and the use of 2,2,2-trifluoro iodoethane, serving as an expensive imported reagent, is eliminated, so that the cost is greatly lowered.
Description
Technical field
The present invention relates generally to the preparation of 2-(2,2, the 2-trifluoroethyl) methyl-phenoxide.
Background technology
Silodosin shown in the formula A (silodosin) is the α that is given birth to company (Kissei) exploitation by Japanese tachibana
1A--adrenoceptor antagonists.This product is the active drug of treatment benign prostatic hyperplasia.It went on the market in Japan in 2006 first, and went on the market in the U.S. through drugs approved by FDA in October, 2008.
Formula (A)
The reaction scheme of the synthetic silodosin of reporting among the patent EP600675 that the Japanese tachibana company of giving birth to applies for is following:
Wherein, the used reaction reagent of step a is CF
3CH
2I, DMF, K
2CO
3, the used reaction reagent of step b is BBr
3, the used reaction reagent of step c is BrCH
2CH
2Br, the used reaction reagent of steps d is C1CH
2CH
2OH, the used reaction reagent of step e is MsCl.
The main drawback that this reaction process exists is, when step a synthetic intermediate 2-(2,2, the 2-trifluoroethyl) methyl-phenoxide, used to cost an arm and a leg and need 2,2 of import, and 2-trifluoro iodoethane, thus improved production cost.In addition, 2,2, also there is unstable chemcial property in 2-trifluoro iodoethane itself, be difficult for to store transportation and be not suitable for many shortcomings such as suitability for industrialized production.
Chinese patent ZL200610098100.8 has reported the method for a kind of Synthetic 2-(2,2, the 2-trifluoroethyl) phenol, and is specific as follows:
Wherein, the used chemical reagent of step a is CF
3CH
2OH and 50%NaOH, the used chemical reagent of step b is 10%Pd/C and EtOH, the used chemical reagent of step c is 20%H
2SO
4And NaNO
2
This method advantage is to have avoided the use of expensive reagent 2,2,2-trifluoro iodoethane, but have but in step c reaction (diazotization reaction) that yield is low, a diazo reagent explosive and be not suitable for many shortcomings such as industrialized production.
US20090012112 has reported the preparation of 2-(2,2,2-three fluoro-1-2D-oxyethyl groups) methyl-phenoxide, but this compound can't be applied to the synthetic of silodosin.
In a word, prior art synthetic intermediate 2-(2,2, the 2-trifluoroethyl) methyl-phenoxide still exists production cost high, and the reagent unstable chemcial property of being selected for use is difficult for many shortcomings such as transportation.
Summary of the invention
The object of the present invention is to provide a kind of brand-new synthetic intermediate 2-(2; 2; The 2-trifluoroethyl) method of methyl-phenoxide, midbody compound method of the present invention is synthesized required cost through selecting suitable reaction reagent for use and designing suitable reaction scheme thereby can reduce midbody greatly; And the reaction reagent chemical property that the present invention selected for use is stable, is easy to large-scale industrial production.
The present invention realizes through following technical scheme:
The method of a kind of preparation suc as formula the 2-shown in (I) (2,2, the 2-trifluoroethyl) methyl-phenoxide is provided, and it comprises the steps:
With the 2-methoxyphenol is starting raw material, makes it in the presence of alkali, reacts in solvent with the compound shown in the formula (III), prepares 2-(2,2, the 2-trifluoroethyl) methyl-phenoxide, and wherein, the L in the formula (III) represents acyl group, and the reaction formula of said reaction is following:
The method of synthetic intermediate 2-of the present invention (2,2, the 2-trifluoroethyl) methyl-phenoxide comprises following concrete steps:
1) in the 2-methoxyphenol, add alkali and formula (III) compound, fully react generation 2-(2,2, the 2-trifluoroethyl) methyl-phenoxide down at 80-150 ℃, wherein, the L in the formula (III) represents acyl group.
2) add entry to the 2-(2,2, the 2-trifluoroethyl) of gained methyl-phenoxide, use SX, obtain oily matter, vacuum fractionation obtains target product 2-(2,2, the 2-trifluoroethyl) methyl-phenoxide solid.
Above-mentioned steps 1) acyl group of L representative can be alkylsulfonyl, replacement or unsubstituted benzenesulfonyl, chlorosulfonyl or alkyloyl in.Further L can be selected from methyl sulphonyl, trifluoromethyl sulfonyl or trichloromethyl alkylsulfonyl; Replacement or unsubstituted benzenesulfonyl can be benzenesulfonyl, Methyl benzenesulfonyl base or oil of mirbane alkylsulfonyl; Alkyloyl can be a trifluoroacetyl group.
According to the present invention one preferred embodiment, above-mentioned benzenesulfonyl can be 4-Methyl benzenesulfonyl base or 4-oil of mirbane alkylsulfonyl.
The employed alkali of this method is highly basic, and said highly basic can be KOH, NaOH, NaH, KH, potassium tert.-butoxide, salt of wormwood or yellow soda ash; Further preferred highly basic can be NaH or salt of wormwood or yellow soda ash.
The said solvent of step 1) of the present invention is dipole solvent such as N-Methyl pyrrolidone (NMP), N, dinethylformamide (DMF), HMPA (HMPT) or methyl-sulphoxide (DMSO).Said solvent further is selected from N, dinethylformamide (DMF) or N-Methyl pyrrolidone.
The temperature of reaction of the reaction of compound shown in 2-methoxyphenol of the present invention and the structural formula (III) is 80-150 ℃, is preferably 120-150 ℃.
Embodiment
Embodiment 1: the preparation of compound (I)
2-methoxyphenol 12.4 grams, N-Methyl pyrrolidone 100ml places reaction flask, slowly adds NaH4.4g, when treating that hydrogen stops to produce, is warming up to 130 ℃, reaction 1h; Add 2,2,2-trifluoroethyl 4-tolylsulfonyl ester 28 grams are warming up to 130 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, NaHCO
3Saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 15.5 grams.
1NMR composes (DMSO-d6): and δ ppm3.8-4.0 (3H, s); 4.3-4.5 (2H, dd), 6.9-7.2 (4H, m)
Embodiment 2: the preparation of compound (I)
2-methoxyphenol 12.4 gram, N-Methyl pyrrolidone) 100ml places reaction flask, slowly adds the NaH4.4 gram, when treating that hydrogen stops to produce, is warming up to 130 ℃, reaction 1h; Add 2,2,2-trifluoroethyl 4-oil of mirbane sulfonyl ester 32 grams are warming up to 130 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, the NaHCO3 saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 14.5 grams.
Embodiment 3: the preparation of compound (I)
2-methoxyphenol 12.4 grams, N-Methyl pyrrolidone 100ml places reaction flask, slowly adds the NaH4.4 gram, when treating that hydrogen stops to produce, is warming up to 130 ℃, reaction 1h; Add 2,2,2-trifluoroethyl trichloromethyl sulfonyl ester 31 grams are warming up to 130 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, NaHCO
3Saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 9.3 grams.
Embodiment 4: the preparation of compound (I)
2-methoxyphenol 12.4 grams, N-Methyl pyrrolidone 100ml places reaction flask, slowly adds the NaH4.4 gram, when treating that hydrogen stops to produce, is warming up to 130 ℃, reaction 1h; Add 2,2,2-trifluoroethyl 2,2,2-trifluoro ethyl ester 21.5 grams are warming up to 130 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, NaHCO
3Saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 7 grams.
Embodiment 5: the preparation of compound (I)
2-methoxyphenol 12.4 grams, N-Methyl pyrrolidone 100ml places reaction flask, slowly adds NaOH 4 grams, when treating that hydrogen stops to produce, is warming up to 130 ℃, reaction 1h; Add 2,2,2-trifluoroethyl 4-tolylsulfonyl ester 28 grams are warming up to 130 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, NaHCO
3Saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 14.4 grams.
1NMR composes (DMSO-d6): and δ ppm3.8-4.0 (3H, s); 4.3-4.5 (2H, dd), 6.9-7.2 (4H, m)
Embodiment 6: the preparation of compound (I)
2-methoxyphenol 12.4 grams, HMPA (HMPT) 100ml places reaction flask, slowly adds NaOH 4 grams, when treating that hydrogen stops to produce, is warming up to 130 ℃, reaction 1h; Add 2,2,2-trifluoroethyl 4-oil of mirbane sulfonyl ester 32 grams are warming up to 130 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, NaHCO
3Saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 14 grams.
Embodiment 7: the preparation of compound (I)
2-methoxyphenol 12.4 grams, N-Methyl pyrrolidone 100ml places reaction flask, slowly adds the KOH5.6 gram, when treating that hydrogen stops to produce, is warming up to 130 ℃, reaction 1h; Add 2,2,2-trifluoroethyl trichloromethyl sulfonyl ester 31 grams are warming up to 130 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, NaHCO
3Saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 8 grams.
Embodiment 8: the preparation of compound (I)
2-methoxyphenol 12.4 grams, HMPA 100ml places reaction flask, slowly adds KOH 5.6 grams, when treating that hydrogen stops to produce, is warming up to 130 ℃, reaction 1h; Add 2,2,2-trifluoroethyl 2,2,2-trifluoro ethyl ester 21.5 grams are warming up to 130 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, NaHCO
3Saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 4 grams.
Embodiment 9: the preparation of compound (I)
2-methoxyphenol 12.4 grams, N-Methyl pyrrolidone 80ml places reaction flask, slowly adds the KOH5.6 gram, when treating that hydrogen stops to produce, is warming up to 130 ℃, reaction 1h; Add 2,2,2-trifluoroethyl methylsulfonyl ester 20 grams are warming up to 130 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, NaHCO
3Saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 7 grams.
Embodiment 10: the preparation of compound (I)
2-methoxyphenol 12.4 grams, DMSO 99.8MIN. 80ml places reaction flask, slowly adds NaH 4.4 grams, when treating that hydrogen stops to produce, is warming up to 120 ℃, reaction 1h; Add 2,2,2-trifluoroethyl methylsulfonyl ester 20 grams are warming up to 120 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, NaHCO
3Saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 5 grams.
Embodiment 10: the preparation of compound (I)
2-methoxyphenol 12.4 grams, N, dinethylformamide 180ml places reaction flask, adds salt of wormwood 27.6 grams, and 2,2,2-trifluoroethyl 4-tolylsulfonyl ester 28 grams are warming up to 140 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, NaHCO
3Saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 16 grams.
Embodiment 11: the preparation of compound (I)
2-methoxyphenol 12.4 grams, N, dinethylformamide 180ml places reaction flask, adds yellow soda ash 21.6 grams, and 2,2,2-trifluoroethyl 4-tolylsulfonyl ester 28 grams are warming up to 140 ℃, reaction 5h.Add entry, ethyl acetate extraction, organic layer is water successively, 1mol/L HCl, NaHCO
3Saturated aqueous solution, the washing of NaCl saturated aqueous solution, drying, concentrating under reduced pressure obtains oily matter, and vacuum fractionation goes out product again, obtains white solid 12 grams.
Embodiment 12: the preparation of compound (I)
2-methoxyphenol 12.4 grams, N, dinethylformamide 180ml places reaction flask, adds yellow soda ash 21.6 grams, and 2,2,2-trifluoroethyl 4-tolylsulfonyl ester 28 grams are warming up to 90 ℃, reaction 5h, raw material reaction is incomplete.Add entry, aftertreatments such as ethyl acetate extraction obtain oily matter, and vacuum fractionation goes out product again, obtain white solid 2 grams.
Claims (10)
1. method for preparing suc as formula the 2-shown in (I) (2,2, the 2-trifluoroethyl) methyl-phenoxide, it comprises the steps:
With the 2-methoxyphenol is starting raw material, makes it in the presence of alkali, reacts in solvent with the compound shown in the formula (III), prepares 2-(2,2, the 2-trifluoroethyl) methyl-phenoxide, and wherein, the L in the formula (III) represents acyl group.
2. the method for claim 1 is characterized by and comprises the steps:
1) in the 2-methoxyphenol, adds alkali and formula (III) compound, fully react generation 2-(2,2, the 2-trifluoroethyl) methyl-phenoxide down at 80-150 ℃;
2) add entry to the 2-(2,2, the 2-trifluoroethyl) of gained methyl-phenoxide, use SX, obtain oily matter, vacuum fractionation obtains target product 2-(2,2, the 2-trifluoroethyl) methyl-phenoxide solid.
3. according to claim 1 or claim 2 method is characterized in that, the acyl group of L representative is alkylsulfonyl, replacement or unsubstituted benzenesulfonyl, chlorosulfonyl or alkyloyl.
4. method as claimed in claim 3; It is characterized in that; Said alkylsulfonyl is methyl sulphonyl, trifluoromethyl sulfonyl or trichloromethyl alkylsulfonyl, and said replacement or unsubstituted benzenesulfonyl are benzenesulfonyl, Methyl benzenesulfonyl base or oil of mirbane alkylsulfonyl, and said alkyloyl is a trifluoroacetyl group.
5. method as claimed in claim 4 is characterized in that, said benzenesulfonyl is 4-Methyl benzenesulfonyl base or 4-oil of mirbane alkylsulfonyl.
6. according to claim 1 or claim 2 method is characterized in that said alkali is KOH, NaOH, NaH, KH, potassium tert.-butoxide, salt of wormwood or yellow soda ash.
7. method as claimed in claim 6 is characterized in that, said alkali is NaH, salt of wormwood or yellow soda ash.
8. the method for claim 1 is characterized in that, said solvent is N-Methyl pyrrolidone, N, dinethylformamide/HMPA or DMSO 99.8MIN..
9. method as claimed in claim 8 is characterized in that, said solvent is DMF or N-Methyl pyrrolidone.
10. the method for claim 1 is characterized in that, temperature of reaction is 80-150 ℃, is preferably 120-150 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010218796XA CN102311319A (en) | 2010-07-05 | 2010-07-05 | Method for preparing 2-(2,2,2-trifluoroethyl) anisole |
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| CN201010218796XA CN102311319A (en) | 2010-07-05 | 2010-07-05 | Method for preparing 2-(2,2,2-trifluoroethyl) anisole |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109516933A (en) * | 2018-10-29 | 2019-03-26 | 安徽省庆云医药股份有限公司 | A kind of preparation method of Silodosin intermediate |
| US10421719B2 (en) | 2015-09-30 | 2019-09-24 | Urquima S.A. | Maleic acid salt of a silodosin intermediate |
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| US5387603A (en) * | 1992-12-02 | 1995-02-07 | Kissei Pharmaceutical Co., Ltd. | 1,5,7-trisubstituted indoline compounds and salts thereof |
| JP2006188470A (en) * | 2005-01-07 | 2006-07-20 | Kissei Pharmaceut Co Ltd | Indoline derivative and method for producing the same |
| CN1962603A (en) * | 2006-12-04 | 2007-05-16 | 中国药科大学 | Method for preparing 2-(2,2,2-trifluoroethoxy)phenol |
| CN101048376A (en) * | 2004-10-27 | 2007-10-03 | 橘生药品工业株式会社 | Indoline compound and process for producing the same |
| CN101768056A (en) * | 2010-01-19 | 2010-07-07 | 扬子江药业集团有限公司 | Preparation method of substituted phenyl methyl ether |
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2010
- 2010-07-05 CN CN201010218796XA patent/CN102311319A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4543425A (en) * | 1982-08-12 | 1985-09-24 | Wella Ag | 1,3-Diamino-4-(2',2',2',-trifluoroethoxy)-benzene, method of producing the same, and hair coloring composition containing the same |
| US5387603A (en) * | 1992-12-02 | 1995-02-07 | Kissei Pharmaceutical Co., Ltd. | 1,5,7-trisubstituted indoline compounds and salts thereof |
| EP0600675B1 (en) * | 1992-12-02 | 1998-07-08 | Kissei Pharmaceutical Co., Ltd. | Indoline compounds for the treatment of dysuria |
| CN101048376A (en) * | 2004-10-27 | 2007-10-03 | 橘生药品工业株式会社 | Indoline compound and process for producing the same |
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| CN101768056A (en) * | 2010-01-19 | 2010-07-07 | 扬子江药业集团有限公司 | Preparation method of substituted phenyl methyl ether |
Non-Patent Citations (1)
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| TODD R. ELWORTHY, 等: "N-Arylpiperazinyl-N’-propylamino Derivatives of Heteroaryl Amides as Functional Uroselective α1-Adrenoceptor Antagonists", 《J.MED.CHEM.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10421719B2 (en) | 2015-09-30 | 2019-09-24 | Urquima S.A. | Maleic acid salt of a silodosin intermediate |
| CN109516933A (en) * | 2018-10-29 | 2019-03-26 | 安徽省庆云医药股份有限公司 | A kind of preparation method of Silodosin intermediate |
| CN109516933B (en) * | 2018-10-29 | 2021-03-02 | 安徽省庆云医药股份有限公司 | Preparation method of silodosin intermediate |
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Application publication date: 20120111 |