CN101857581A - Method for preparing darifenacin intermediate 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran - Google Patents
Method for preparing darifenacin intermediate 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran Download PDFInfo
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- CN101857581A CN101857581A CN 201010207209 CN201010207209A CN101857581A CN 101857581 A CN101857581 A CN 101857581A CN 201010207209 CN201010207209 CN 201010207209 CN 201010207209 A CN201010207209 A CN 201010207209A CN 101857581 A CN101857581 A CN 101857581A
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Abstract
The invention provides a method for preparing darifenacin intermediate 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran. The method comprises the following steps of: directly reducing 2,3-dihydro benzofuran-5-acetic acid serving as a raw material into 2,3-dihydro benzofuran-5-ethanol in the presence of an ether solvent; and performing bromination on the 2,3-dihydro benzofuran-5-ethanol to obtain 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran. The method has the advantages of simple and convenient operation, readily available raw material, high yield, low production cost and suitability for industrial production.
Description
Technical field
The present invention relates to a kind of preparation darifenacin intermediate 5-(2-bromotrifluoromethane)-2, the method for 3-dihydro-1-cumarone belongs to chemical industry and chemical field of medicaments.
Technical background
Darifenacin (DariFenacin), (S)-2-[1-[2-(2,3-Dihydrobenzofuranes-5-yl) ethyl]-the 3-pyrrolidyl]-2,2-phenylbenzene ethanamide, selectivity muscarine antagonist by the Pfizer exploitation, be mainly used in the treatment urinary incontinence, and by Novartis Co.,Ltd (Novartis) with 2.25 hundred million dollars successfully acceptance of the bid buy, in Nikkei FDA approval December 22 in 2004 in the U.S. with Enablex
The trade(brand)name listing.Its structural formula is as follows:
The synthetic document of darifenacin is a lot; as U.S. Pat 5096890; European patent EP 0388054 all adopts 5-(2-bromotrifluoromethane)-2; 3-dihydro-1-cumarone is a key intermediate; this intermediate synthetic method is: with 2; the 3-Dihydrobenzofuranes is a raw material; make 5-ethanoyl-2 through acetylize; the 3-Dihydrobenzofuranes; make 2 through two steps again, 3-Dihydrobenzofuranes-5-acetate, lithium aluminium hydride reduction makes 2 then; 3-Dihydrobenzofuranes-5-ethanol, bromination obtains target product under carbon tetrachloride solvent at last.This technology exists step long, need be through the reaction of 5 steps, and the lithium aluminum hydride that need use danger and costliness is a reductive agent, bromination alcohol easily produces inferior phosphide ester by product in halohydrocarbon, yield is low, needs just can carry out next step reaction after the column chromatography purification, so the cost height, be unfavorable for commercial scale production, its synthetic route is as follows:
Summary of the invention
For solving 5-(2-bromotrifluoromethane)-2, need to use danger and expensive reagent among 3-dihydro-1-cumarone preparation method, yield is low, the cost height is unsuitable for and realizes industrialized shortcoming, the invention provides a kind of new preparation method, this method technology is easy, raw material is easy to get, and the yield height, is suitable for suitability for industrialized production.
Darifenacin intermediate 5-of the present invention (2-bromotrifluoromethane)-2,3-dihydro-1-cumarone structural formula is shown in formula I:
For realizing goal of the invention, the technical solution used in the present invention is:
A kind of preparation 5-(2-bromotrifluoromethane)-2,3-dihydro-1-cumarone (formula I) method comprises the steps:
(1) with 2,3-Dihydrobenzofuranes-5-acetate (formula III) is a raw material, in the presence of ether solvent, directly is reduced to 2 with reductive agent, 3-Dihydrobenzofuranes-5-ethanol (formula II);
(2) to 2 of gained, 3-Dihydrobenzofuranes-5-ethanol (formula II) carries out bromo-reaction and obtains 5-(2-bromotrifluoromethane)-2,3-dihydro-1-cumarone (formula I).
Reaction formula is:
In the reduction reaction of step (1):
Described reductive agent is NaBH
4/ KBH
4And I
2, NaBH
4/ KBH
4And H
2SO
4
Described ether solvent is a tetrahydrofuran (THF), 1,4-dioxane or diethylene glycol dimethyl ether.
Described reduction reaction temperature is 5～65 ℃.
The advantage of this reduction reaction is I
2And H
2SO
4Can improve NaBH
4/ KBH
4Reducing power, ether solvent and tetrahydrofuran (THF) are to NaBH in addition
4/ KBH
4And carboxylic acid all has solvability preferably, and aftertreatment is also very convenient.
In the bromo-reaction of step (2):
When bromizating agent is PBr
3, selected solvent and catalyzer are N, dinethylformamide (DMF), and described temperature of reaction is-20-100 ℃.
Here we select for use DMF to do the bromo solvent and the catalyzer of alcoholic extract hydroxyl group, and the phosphorous acid ester impurity of generation is lacking of solvent than chloroform, and yield can reach more than 85%, and patent US 2009005431 usefulness chloroforms are made solvent, and yield is 62%.
With this prepared 5-(2-bromotrifluoromethane)-2,3-dihydro-1-cumarone, easy and simple to handle, raw material is easy to get, the yield height, production cost is low, is suitable for suitability for industrialized production.
Embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Example 1.5-(2-bromotrifluoromethane)-2,3-dihydro-1-cumarone synthetic
Add tetrahydrofuran (THF) 250ml in the 5-10 ℃ of downhill reaction bottle, sodium borohydride 52.9g, 2,150 milliliters of THF solution of 3-Dihydrobenzofuranes-5-acetate 71.2 grams.Ice bath stirs, and temperature is lower than under 20 ℃, slowly drips vitriol oil 37.3ml, drips complete stirring at room 2 hours, after reaction finishes, add the methyl alcohol cancellation, reaction solution is evaporated to dried, adds entry 100ml, methylene dichloride 300ml, the 10%NaOH300ml standing demix, organic layer washes with water.Methylene dichloride continuous extraction water layer merges organic layer, anhydrous magnesium sulfate drying, and organic layer is evaporated to dried, adds DMF150ml and stirs molten clear.Ice bath slowly drips phosphorus tribromide 120g down for 25 ℃ in temperature, and 45～50 ℃ were reacted 1 hour, after the end, and ice bath, t＜40 ℃ drip water 600ml, drip and finish stirring at room 1 hour, filter, filter cake water 100ml is respectively washed, and ice methyl alcohol 100ml washes, t＜50 ℃ dry white solid 83.6 grams that get.Yield 92%.
Example 2.2,3-Dihydrobenzofuranes-5-alcoholic acid is synthetic
Add 1 in the 5-10 ℃ of downhill reaction bottle, 4-dioxane 250ml, POTASSIUM BOROHYDRIDE 80.7g, 2,150 milliliters of THF solution of 3-Dihydrobenzofuranes-5-acetate 71.2 grams.Ice bath stirs, temperature is lower than under 20 ℃, slowly drips the 200mlTHF solution of 127g iodine, drips complete stirring at room 2 hours, 60 ℃ were reacted 2 hours, after reaction finishes, add the dilute hydrochloric acid cancellation, reaction solution is evaporated to dried, add entry 100ml, methylene dichloride 300ml, the 20%NaOH300ml standing demix, organic layer washes with water.Methylene dichloride continuous extraction water layer merges organic layer, anhydrous magnesium sulfate drying, and organic layer is evaporated to dried, gets white solid 64.3 grams.Yield 98%.
Example 3.2,3-Dihydrobenzofuranes-5-alcoholic acid is synthetic
Add diethylene glycol dimethyl ether 250ml in the 5-10 ℃ of downhill reaction bottle, POTASSIUM BOROHYDRIDE 75.4g, 2,150 milliliters of THF solution of 3-Dihydrobenzofuranes-5-acetate 71.2 grams.Ice bath stirs, temperature is lower than under 20 ℃, slowly drips vitriol oil 37.3ml, drips complete stirring at room 2 hours, 5 ℃ were reacted 2 hours, after reaction finishes, add the dilute hydrochloric acid cancellation, reaction solution is evaporated to dried, add entry 100ml, methylene dichloride 300ml, the 20%NaOH300ml standing demix, organic layer washes with water.Methylene dichloride continuous extraction water layer merges organic layer, anhydrous magnesium sulfate drying, and organic layer is evaporated to dried, gets white solid 64.9 grams.Yield 99%.
Example 4.5-(2-bromotrifluoromethane)-2,3-dihydro-1-cumarone
2,3-Dihydrobenzofuranes-5-ethanol 0.4mol adds DMF150ml and stirs molten clear.Add phosphorus tribromide 60g, 90～100 ℃ of reactions 1 hour, after the end, ice bath, t＜40 ℃ drip water 600ml, drip and finish, stirring at room 1 hour is filtered, filter cake water 100ml is respectively washed, ice methyl alcohol 100ml washes, t＜50 ℃ dry a white solid 79 grams.Yield 87%.
Example 5.5-(2-bromotrifluoromethane)-2,3-dihydro-1-cumarone
2,3-Dihydrobenzofuranes-5-ethanol 0.4mol adds DMF150ml and stirs molten clear.Lower the temperature-20 ℃, drip phosphorus tribromide 80g ,-15～-20 ℃ drip 40% potassium hydroxide to PH be 4-6, after the end, rise to room temperature.Dropping water 500ml drips and finishes, and stirring at room 1 hour is filtered, and filter cake water 100ml is respectively washed, and ice methyl alcohol 100ml washes, t＜50 ℃ dry white solid 78 grams that get.Yield 86%.
Claims (7)
1. one kind prepares formula I 5-(2-bromotrifluoromethane)-2, and the method for 3-dihydro-1-cumarone is characterized in that comprising the steps:
(1) with 2,3-Dihydrobenzofuranes-5-acetate (formula III) is a raw material, in the presence of ether solvent, directly is reduced to 2 with reductive agent, 3-Dihydrobenzofuranes-5-ethanol (formula II);
(2) to 2 of gained, 3-Dihydrobenzofuranes-5-ethanol (formula II) carries out bromo-reaction and obtains 5-(2-bromotrifluoromethane)-2,3-dihydro-1-cumarone (formula I).
2. method according to claim 1 is characterized in that the reduction reaction of described step (1), and the reductive agent of using is NaBH
4/ KBH
4And I
2
3. method according to claim 1 is characterized in that the reduction reaction of described step (1), and the reductive agent of using is NaBH
4/ KBH
4And H
2SO
4
4. method according to claim 1 is characterized in that the reduction reaction of described step (1), and the ether solvent of using is a tetrahydrofuran (THF), 1,4-dioxane or diethylene glycol dimethyl ether.
5. method according to claim 1 is characterized in that the reduction reaction of described step (1), and also having temperature is 5～65 ℃.
6. method according to claim 1 is characterized in that the bromo-reaction of described step (2), and bromizating agent is PBr
3, solvent and catalyzer are N, dinethylformamide.
7. method according to claim 6 is characterized in that the bromo-reaction of described step (2), bromination temperature are-20-100 ℃.
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| CN 201010207209 CN101857581A (en) | 2010-06-22 | 2010-06-22 | Method for preparing darifenacin intermediate 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran |
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| CN 201010207209 CN101857581A (en) | 2010-06-22 | 2010-06-22 | Method for preparing darifenacin intermediate 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107721954A (en) * | 2016-11-30 | 2018-02-23 | 内蒙古京东药业有限公司 | The novel preparation method of the benzofuranacetic acid of 2,3 dihydro of darifenacin intermediate 5 |
| CN107721955A (en) * | 2016-11-30 | 2018-02-23 | 内蒙古京东药业有限公司 | The novel preparation method of the benzofuranacetic acid of 2,3 dihydro of darifenacin intermediate 5 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5096890A (en) * | 1989-03-17 | 1992-03-17 | Pfizer Inc. | Pyrrolidine derivatives |
-
2010
- 2010-06-22 CN CN 201010207209 patent/CN101857581A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5096890A (en) * | 1989-03-17 | 1992-03-17 | Pfizer Inc. | Pyrrolidine derivatives |
| US5096890B1 (en) * | 1989-03-17 | 1995-03-28 | Pfizer | Pyrrolidine derivatives |
Non-Patent Citations (2)
| Title |
|---|
| 《http://priorartdatabase.com/ipcom/000193899#》 20100312 Disclosed Anonymously PROCESS FOR THE PREPARATION OF MUSCARINIC RECEPTOR ANTAGONIST 第1－7页 , 2 * |
| 《药物合成化学》 19850630 朱淬砺 磷的卤化物对羟基的卤置换反应 化学工业出版社 第70-71页 , 1 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107721954A (en) * | 2016-11-30 | 2018-02-23 | 内蒙古京东药业有限公司 | The novel preparation method of the benzofuranacetic acid of 2,3 dihydro of darifenacin intermediate 5 |
| CN107721955A (en) * | 2016-11-30 | 2018-02-23 | 内蒙古京东药业有限公司 | The novel preparation method of the benzofuranacetic acid of 2,3 dihydro of darifenacin intermediate 5 |
| CN107721955B (en) * | 2016-11-30 | 2019-10-11 | 内蒙古京东药业有限公司 | Darifenacin intermediate 2, the novel preparation method of 3- dihydro -5- benzofuranacetic acid |
| CN107721954B (en) * | 2016-11-30 | 2020-02-14 | 内蒙古京东药业有限公司 | Novel preparation method of darifenacin intermediate 2, 3-dihydro-5-benzofuran acetic acid |
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Application publication date: 20101013 |