CN101973971A - Method for preparing 5-halogenated ethyl-2,3-dihydrobenzofuran - Google Patents
Method for preparing 5-halogenated ethyl-2,3-dihydrobenzofuran Download PDFInfo
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- CN101973971A CN101973971A CN2010102910658A CN201010291065A CN101973971A CN 101973971 A CN101973971 A CN 101973971A CN 2010102910658 A CN2010102910658 A CN 2010102910658A CN 201010291065 A CN201010291065 A CN 201010291065A CN 101973971 A CN101973971 A CN 101973971A
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- dihydrobenzofuranes
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- 0 *C(CC1C=C(CCO2)C2=CC1)=O Chemical compound *C(CC1C=C(CCO2)C2=CC1)=O 0.000 description 2
- JRKZQRRYNCMSCB-UHFFFAOYSA-N BrCCc1ccc2OCCc2c1 Chemical compound BrCCc1ccc2OCCc2c1 JRKZQRRYNCMSCB-UHFFFAOYSA-N 0.000 description 1
- RICJBTNKVBHIEN-UHFFFAOYSA-N O=NCCC1C=C(CCO2)C2=CC1 Chemical compound O=NCCC1C=C(CCO2)C2=CC1 RICJBTNKVBHIEN-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to the technical field of chemical synthesis methods and particularly relates to a preparation method of a darifenacin hydrobro intermediate, namely, 5-halogenated ethyl-2,3-dihydrobenzofuran. In the technical scheme of the invention, the method for preparing the 5-halogenated ethyl-2,3-dihydrobenzofuran is characterized by comprising the following steps of: 1) performing Friedel-Crafts acylation reaction and halogenated acetyl halogenating reaction on 2,3-dihydrobenzofuran so as to obtain 5-halogenated acetyl-2,3-dihydrobenzofuran shown as formula II, wherein a halogen element is Cl, Br or I; and 2) performing carbonyl reduction reaction on the 5-halogenated acetyl-2,3-dihydrobenzofuran so as to obtain the 5-halogenated ethyl-2,3-dihydrobenzofuran shown as formula I. The method has the advantages of simple and convenient process, low-price and readily available raw materials, high yield and high safety and is suitable for industrial production.
Description
Technical field
The invention belongs to the chemical synthesis process technical field, relate in particular to that new intermediate of Hydrogen bromide Tamiflu 5-halogenated ethyl-2, the preparation method of 3-Dihydrobenzofuranes.
Background technology
That new (Darifenacin of Tamiflu, (S)-[1-[2-(2,3-dihydro-5-benzofuryl) ethyl]-α, α-phenylbenzene]-the 3-pyrrolidine acetamide) be a kind of potent muscarine M3 receptor blocking agent, the M3 acceptor of regulating detrusor contractions be can optionally block, maincenter and cardiovascular systems M1, M2 acceptor do not influenced.This product was buied from Pfizer in 2003 by Switzerland Novartis Co.,Ltd.In December, 2003, drugs approved by FDA this product be used for overactive bladder; In December, 2004, that new slow releasing tablet of Hydrogen bromide Tamiflu is approved for bladder hyperactivity hyperkinesia diseases such as the treatment urinary incontinence, urgent urination and frequent micturition again.That new M3 of Tamiflu acts in all medicines has uniqueness, and slow releasing tablet can reduce the incidence of nervus centralis and cardiovascular adverse effects, and treatment bladder hyperactivity hyperkinesia disease is very effective, and therefore, tool plays a very important role.
That new structural formula of Hydrogen bromide Tamiflu is:
That new synthetic method of Tamiflu is a lot, and as U.S. Pat 5089505, US5096890 all adopts 5-bromotrifluoromethane-2; 3-Dihydrobenzofuranes (formula 1) is a key intermediate; this intermediate synthetic method is: with 2, the 3-Dihydrobenzofuranes is a raw material, makes 5-ethanoyl-2 through acetylize; the 3-Dihydrobenzofuranes; through 2,3-Dihydrobenzofuranes-5-acetate makes 2 through lithium aluminium hydride reduction again; 3-Dihydrobenzofuranes-5-ethanol, last bromination obtains target product.This technology shortcoming is: step is long, needs the reaction of 5 steps, and need use the hazardous agents lithium aluminum hydride, and the cost height amplifies and produces difficulty, is not easy to realize industrialization.Its synthetic route is as follows:
Chinese patent 200810114484 discloses with 2, and the 3-Dihydrobenzofuranes is a raw material, through bromination, make 5-bromo-2, the 3-Dihydrobenzofuranes is again through grignard reaction and feed oxyethane and make 2,3-Dihydrobenzofuranes-5-ethanol is after halo makes target compound.The shortcoming of this technology is: there is higher danger in grignard reaction in the big production of industry.Its synthetic route is as follows:
Summary of the invention
The objective of the invention is to, overcome the deficiencies in the prior art, a kind of that new intermediate of Hydrogen bromide Tamiflu 5-halogenated ethyl-2 is provided, the preparation method of 3-Dihydrobenzofuranes, this method technology is easy, and raw material is cheap and easy to get, the yield height, safe, be fit to industrial production.
For solving the problems of the technologies described above, technical scheme of the present invention is: a kind of preparation 5-halogenated ethyl-2, and the method for 3-Dihydrobenzofuranes is characterized in that comprising step:
1) with 2, the 3-Dihydrobenzofuranes is through paying the 5-halo ethanoyl-2 that the reaction of gram acylation reaction and halo acetyl halide makes formula 2,3-Dihydrobenzofuranes; Described haloid element is Cl, Br or I.
2) with the 5-halo ethanoyl-2 that makes, the reaction of 3-Dihydrobenzofuranes reducing carbonyl makes the 5-halogenated ethyl-2 of formula 1,3-Dihydrobenzofuranes.
Halo acetyl halide of the present invention is chloroacetyl chloride, bromoacetyl chloride, monoiodo-acetic chloride, chloro-acetyl bromide, bromoacetyl bromide or iodo-acetic bromide.
The used pair gram acylation reaction catalyst of the present invention is one or more mixtures in iron trichloride, aluminum chloride, boron trichloride and the boron trifluoride.
The trialkyl silane that reducing carbonyl of the present invention adopts is selected from trimethyl silane, triethyl silicane, tripropyl silane or tri isopropyl silane.
The used organic acid of reducing carbonyl of the present invention is selected from trifluoromethanesulfonic acid, methylsulfonic acid, tosic acid, trifluoroacetic acid or trichoroacetic acid(TCA).
Haloid element of the present invention is Cl or Br.
The of the present invention pair of gram solvent that acylation reaction adopted is dithiocarbonic anhydride, methylene dichloride, and chloroform, tetracol phenixin, the mixture of one or more in 1,2 ethylene dichloride, the temperature of acylation reaction is the reflux temperature of-30 ℃-solvent.The temperature of described pair of gram acylation reaction is a room temperature.
The reaction solvent of described reducing carbonyl is an acetate, formic acid, trifluoroacetic acid, trifluoromethanesulfonic acid one or more mixture wherein, and the temperature of reduction reaction is the reflux temperature of 0 ℃-solvent.
React in the road formula (following formula) in the present invention, reaction A represents to pay the gram acylation reaction, can select chloroacetyl chloride for use, bromoacetyl chloride, monoiodo-acetic chloride, chloro-acetyl bromide, bromoacetyl bromide, the acylating reagent that iodo-acetic bromide etc. are commonly used.According to selected acylating reagent difference, the solvent of selecting for use is also different, can select dithiocarbonic anhydride for use, one or more mixture wherein such as methylene dichloride, chloroform, tetracol phenixin, 1,2 ethylene dichloride etc.According to the difference of solvent for use, temperature of reaction also changes thereupon, can be-30 ℃-reflux temperature.
React Lu Shizhong in the present invention, reaction B is a reduction reaction, the trialkyl silane that adopts is trimethyl silane, triethyl silicane, tripropyl silane, tri isopropyl silane etc., used organic acid comprises trifluoromethanesulfonic acid, methylsulfonic acid, tosic acid, trifluoroacetic acid, trichoroacetic acid(TCA) one or more mixture wherein.The temperature of reduction reaction is 0 a ℃-reflux temperature, and products therefrom is 5-halogenated ethyl-2, the 3-Dihydrobenzofuranes.
The invention has the beneficial effects as follows: the present invention 2, and the 3-Dihydrobenzofuranes makes 5-halogenated ethyl-2, the 3-Dihydrobenzofuranes by paying gram acylation reaction and reduction reaction two-step reaction.Operational path novelty of the present invention, processing condition are reasonable, and reactions steps is short, and is simple to operate, the reaction yield height, production cost is low, does not have the three wastes substantially, has bigger implementary value and economic results in society.
Embodiment
Embodiment 1:
(1) 5-chloro ethanoyl-2,3-Dihydrobenzofuranes synthetic
With 12g (0.1mol) 2, the 3-Dihydrobenzofuranes is dissolved in the 240mL dithiocarbonic anhydride, adds aluminum trichloride (anhydrous) 12g (0.09mol), stirring at room 30 minutes.Be cooled to-10 ℃ again, drip 11g (0.097mol) chloroacetyl chloride.Drip to finish-10 ℃ of reactions in back 30 minutes, return to room temperature after, reacted again 2 hours.Add dilute hydrochloric acid 500mL, layering, organic layer washs with saturated nacl aqueous solution, and anhydrous sodium sulfate drying concentrates and does, and obtains yellow solid 5-chloro ethanoyl-2,3-Dihydrobenzofuranes 17.6g, yield 90%.
1H?NMR(300MHz，CDCl
3)δ：7.82(m，2H)，6.83(d，J＝8.4Hz，1H)，4.68(t，J＝8.8Hz，2H)，4.64(S，2H)，3.27(t，J＝8.8Hz，2H)
(2) 5-chloro ethyl 2,3-Dihydrobenzofuranes synthetic
With 2g (10mmol) 5-chloro ethanoyl-2, the 3-Dihydrobenzofuranes is dissolved in the 20mL trifluoroacetic acid, adds triethyl silicane under the room temperature, finishes the back and refluxes 3 hours.Evaporate to dryness on Rotary Evaporators, adding 20mL ethyl acetate, the sodium bicarbonate washing is to neutral, and saturated sodium-chloride washs, saturated dried over sodium sulfate, evaporate to dryness gets yellow solid 1.5g, yield 82%.
1H?NMR(300MHz，CDCl
3)δ：7.07(s，1H)，6.97(d，J＝1.2，8.0Hz，1H)，6.75(d，J＝8.4Hz，1H)，4.58(t，J＝8.8Hz，2H)，3.69(t，J＝7.6Hz，2H)，3.21(t，J＝8.8Hz，2H)，3.01(t，J＝7.2Hz，2H)
Embodiment 2:
(1) 5-chloro ethanoyl-2,3-Dihydrobenzofuranes synthetic
With 12g (0.1mol) 2, the 3-Dihydrobenzofuranes is dissolved in the 240mL methylene dichloride, adds aluminum trichloride (anhydrous) 12g (0.09mol), stirring at room 30 minutes.Be cooled to-10 ℃ again, drip 11g (0.097mol) chloroacetyl chloride.Drip to finish-10 ℃ of reactions in back 30 minutes, return to room temperature after, reacted again 2 hours.Add dilute hydrochloric acid 500mL, layering, organic layer washs with saturated nacl aqueous solution, and anhydrous sodium sulfate drying concentrates and does, and obtains yellow solid 5-chloro ethanoyl-2,3-Dihydrobenzofuranes 16.6g, yield 84.7%.
Step (2) is with the step (2) of embodiment 1.
Embodiment 3:
(1) 5-bromo ethanoyl-2,3-Dihydrobenzofuranes synthetic
With 12g (0.1mol) 2, the 3-Dihydrobenzofuranes is dissolved in the 240mL methylene dichloride, adds aluminum trichloride (anhydrous) 12g (0.09mol), stirring at room 30 minutes.Be cooled to-10 ℃ again, drip 20g (0.13mol) bromoacetyl chloride.Drip and finish-10 ℃ of reactions in back 30 minutes, heating reflux reaction 2 hours.Add dilute hydrochloric acid 500mL after being cooled to room temperature, layering, organic layer washs with saturated nacl aqueous solution, and anhydrous sodium sulfate drying concentrates and does, and obtains yellow solid 5-bromo ethanoyl-2,3-Dihydrobenzofuranes 22g, yield 91.3%.
1H?NMR(300MHz，CDCl
3)δ：7.98-6.81(m，3H)，4.73-4.65(2H，m)，4.39(2H，s)，3.32-3.34(2H，m)，3.27(t，J＝8.8Hz，2H).
(2) the 5-bromoethyl 2,3-Dihydrobenzofuranes synthetic
With 2.4g (10mmol) 5-bromo ethanoyl-2, the 3-Dihydrobenzofuranes is dissolved in the 20mL trifluoroacetic acid, adds triethyl silicane under the room temperature, finishes the back and refluxes 3 hours.Evaporate to dryness on Rotary Evaporators, adding 20mL ethyl acetate, the sodium bicarbonate washing is to neutral, and saturated sodium-chloride washs, saturated dried over sodium sulfate, evaporate to dryness gets yellow solid 2.1g, yield 93%.
1H?NMR(300MHz，CDCl
3)δ：7.04(s，1H)，6.95-6.93(d，1H)，6.74-6.72(d，1H)，4.58-4.54(t，2H)，3.54-3.50(t，2H)，3.22-3.18(t，2H)，3.10-3.06(t，2H).
Claims (9)
1. one kind prepares 5-halogenated ethyl-2, and the method for 3-Dihydrobenzofuranes is characterized in that comprising step:
1) with 2, the 3-Dihydrobenzofuranes makes 5-halo ethanoyl-2,3-Dihydrobenzofuranes through paying the reaction of gram acylation reaction and halo acetyl halide; Described haloid element is Cl, Br or I;
2) with the 5-halo ethanoyl-2 that makes, the 5-halogenated ethyl-2 that the reaction of 3-Dihydrobenzofuranes reducing carbonyl makes, 3-Dihydrobenzofuranes.
2. preparation 5-halogenated ethyl-2 according to claim 1, the method for 3-Dihydrobenzofuranes is characterized in that: described halo acetyl halide is chloroacetyl chloride, bromoacetyl chloride, monoiodo-acetic chloride, chloro-acetyl bromide, bromoacetyl bromide or iodo-acetic bromide.
3. preparation 5-halogenated ethyl-2 according to claim 1; the method of 3-Dihydrobenzofuranes is characterized in that: used pair gram acylation reaction catalyst is one or more mixtures in iron trichloride, aluminum chloride, boron trichloride and the boron trifluoride.
4. preparation 5-halogenated ethyl-2 according to claim 1, the method for 3-Dihydrobenzofuranes is characterized in that: the trialkyl silane that described reducing carbonyl adopts is selected from trimethyl silane, triethyl silicane, tripropyl silane or tri isopropyl silane.
5. preparation 5-halogenated ethyl-2 according to claim 1, the method for 3-Dihydrobenzofuranes is characterized in that: the used organic acid of described reducing carbonyl is selected from trifluoromethanesulfonic acid, methylsulfonic acid, tosic acid, trifluoroacetic acid or trichoroacetic acid(TCA).
6. preparation 5-halogenated ethyl-2 according to claim 1, the method for 3-Dihydrobenzofuranes is characterized in that: described haloid element is Cl or Br.
7. preparation 5-halogenated ethyl-2 according to claim 1; the method of 3-Dihydrobenzofuranes; it is characterized in that: the described pair of gram solvent that acylation reaction adopted is dithiocarbonic anhydride; methylene dichloride; chloroform, tetracol phenixin, 1; the mixture of one or more in 2 ethylene dichloride, the temperature of acylation reaction are the reflux temperatures of-30 ℃-solvent.
8. preparation 5-halogenated ethyl-2 according to claim 7, the method for 3-Dihydrobenzofuranes is characterized in that: the temperature of described pair of gram acylation reaction is a room temperature.
9. preparation 5-halogenated ethyl-2 according to claim 1, the method of 3-Dihydrobenzofuranes, it is characterized in that: the reaction solvent of described reducing carbonyl is an acetate, formic acid, trifluoroacetic acid, trifluoromethanesulfonic acid one or more mixture wherein, the temperature of reduction reaction is the reflux temperature of 0 ℃-solvent.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731449A (en) * | 2011-04-01 | 2012-10-17 | 浙江九洲药业股份有限公司 | Synthetic technology of darifenacin intermediate 5-(2-bromomethyl)-2,3-dihydro-1-coumarone |
| CN103360360A (en) * | 2012-04-10 | 2013-10-23 | 肖竹平 | Method for preparing (+)-gallocatechin on basis of dihydromyricetin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008100651A2 (en) * | 2007-01-05 | 2008-08-21 | Dr. Reddy's Laboratories Ltd. | Preparation of darifenacin and its salts |
| WO2008126106A2 (en) * | 2007-04-16 | 2008-10-23 | Manne Satyanarayana Reddy | Novel and improved processes for the preparation of intermediates of darifenacin, darifenacin and its pharmaceutically acceptable salts |
-
2010
- 2010-09-26 CN CN2010102910658A patent/CN101973971A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008100651A2 (en) * | 2007-01-05 | 2008-08-21 | Dr. Reddy's Laboratories Ltd. | Preparation of darifenacin and its salts |
| WO2008126106A2 (en) * | 2007-04-16 | 2008-10-23 | Manne Satyanarayana Reddy | Novel and improved processes for the preparation of intermediates of darifenacin, darifenacin and its pharmaceutically acceptable salts |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731449A (en) * | 2011-04-01 | 2012-10-17 | 浙江九洲药业股份有限公司 | Synthetic technology of darifenacin intermediate 5-(2-bromomethyl)-2,3-dihydro-1-coumarone |
| CN102731449B (en) * | 2011-04-01 | 2015-04-29 | 浙江九洲药业股份有限公司 | Synthetic technology of darifenacin intermediate 5-(2-bromomethyl)-2,3-dihydro-1-coumarone |
| CN103360360A (en) * | 2012-04-10 | 2013-10-23 | 肖竹平 | Method for preparing (+)-gallocatechin on basis of dihydromyricetin |
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Application publication date: 20110216 |