CN101134721A - Method for preparing 5-methoxy-1-(4-trifluoromethyl phenyl)pentanone - Google Patents
Method for preparing 5-methoxy-1-(4-trifluoromethyl phenyl)pentanone Download PDFInfo
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- CN101134721A CN101134721A CNA2006101045289A CN200610104528A CN101134721A CN 101134721 A CN101134721 A CN 101134721A CN A2006101045289 A CNA2006101045289 A CN A2006101045289A CN 200610104528 A CN200610104528 A CN 200610104528A CN 101134721 A CN101134721 A CN 101134721A
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Abstract
The present invention discloses process of preparing 5-methoxyl-1-(4-trifluoromehyl phenyl) pentanone as one key intermediate for preparing depression treating medicine fluvoxamine maleate with p-trifluoromethyl benzoyl chloride and magnesium 4-methoxyl butyl halide in the presence of catalyst. The process includes following four steps: 1. preparing p-trifluoromethyl benzoyl chloride with p-trifluoromethyl benzoic acid and thionyl chloride through chlorination; 2. preparing 1-halo-4-methoxyl butane; 3. preparing Grignard reagent through reaction of 1-halo-4-methoxyl butane and metal Mg; and 4. preparing 5-methoxyl-1-(4-trifluoromehyl phenyl) pentanone through reaction of p-trifluoromethyl benzoyl chloride and the Grignard reagent. The process has the features of facile material, low cost, short reaction period, high efficiency and environment friendship.
Description
Technical field
The present invention relates to the key intermediate of production fluvoxamine maleate---the preparation method of 5-methoxyl group-1-(4-trifluoromethyl) pentanone.
Background technology
5-methoxyl group-1-(4-trifluoromethyl) pentanone is the key intermediate of production fluvoxamine maleate, fluvoxamine maleate is the widely used a kind of medicine for the treatment of obsession and dysthymia disorders efficiently of present American-European countries, and this medicine was put among the 200 kinds of best-selling drugses in the whole world in 2000.Following method is adopted in the preparation of 5-methoxyl group-1-(4-trifluoromethyl) pentanone at present usually: with 1-halogen-4-methyl butyl ether with to trifluoromethylbenzene cyanogen is basic raw material, earlier the former is made Grignard reagent in ether or THF, with the latter addition reaction takes place again, last acidified water solves 5-methoxyl group-1-(4-trifluoromethyl) pentanone.Its synthetic route is as follows:
The main drawback of this method is: (1) is stronger to trifluoromethylbenzene cyanogen toxicity as starting raw material, and its production and use meeting pollute environment; (2) volatility of 1-halogen-4-methyl butyl ether is stronger, and loss is serious with this understanding, and the actual recovery of product is lower, only is 60-65%; (3) reaction time long, efficient is low.
Summary of the invention
In view of the weak point that prior art exists, the object of the present invention is to provide a kind of preparation method of preparation 5-methoxyl group-1-(4-trifluoromethyl) pentanone.Its synthetic route is as follows:
The present invention includes following three steps:
The preparation of step 1, acyl chlorides
To put into flask to trifluoromethylbenzoic acid and 0.5% dimethyl formamide, stir on the limit, and the limit slowly drips the doubly normal thionyl chloride of 1.5-2, and 0.5-1h adds; Reflux 2-4h then, the gas of generation 40%NaOH solution absorption.Excessive thionyl chloride is reclaimed in distillation earlier, and the underpressure distillation remaining mixture is collected 85-90 ℃ of cut (16mmHg) again, gets pure product to trifluoromethyl benzoyl chloride.
The preparation of step 2,1-halogen-4-methyl butyl ether
(1) 1-chloro-4-methyl butyl ether
Add anhydrous methanol and anhydrous tetrahydro furan in the dry three-necked bottle of prolong, drying tube and constant pressure funnel is housed, the ice bath cooling is thionyl chloride down.Add post-heating to 100 ℃ backflow 2h, rise to 120 ℃ of backflow 3h then.Be cooled to room temperature, with normal hexane dilution, water, saturated sodium bicarbonate solution and water washing successively, anhydrous magnesium sulfate drying filters, and 140-147 ℃ of cut collected in the filtrate distillation, gets colourless liquid 1-chloro-4-methyl butyl ether.
(2) 1-bromo-4-methyl butyl ether
In being housed, the dry three-necked bottle of prolong, moisture eliminator and constant pressure funnel adds 1,4-dibromobutane and anhydrous methanol, and stirring mixes it, is heated to the methanol solution that begins to drip sodium methylate after 70 ℃., adding back backflow 2h, solid impurity is removed in question response liquid cooling but after-filtration, adds ether and water then in residuum, tells organic phase after fully stirring, and the water extracted with diethyl ether merges organic phase, uses the Calcium Chloride Powder Anhydrous drying.Steam ether and methyl alcohol earlier, 60-70 ℃ cut (15mmHg) is collected in underpressure distillation again, gets colourless liquid 1-bromo-4-methyl butyl ether.
The preparation of step 3, Grignard reagent
In being housed, the dry three-necked bottle of reflux condensing tube, drying tube and constant pressure funnel adds magnesium chips, 1-halogen-4-the methyl butyl ether of elder generation's adding about 1/5 and the mixed solution of dry solvent, with methyl iodide or iodine initiation reaction, slowly drip remaining mixed solution again, adding the back refluxes, all disappear up to magnesium chips, promptly make Grignard reagent 4-methoxyl group butyl magnesium halide.
The preparation of step 4, ketone
Under ice bath cooling, acyl chlorides, catalyst Fe Cl that step 1 is made
3Mix with anhydrous solvent, stir the slow down Grignard reagent that step 2 makes that adds, the mol ratio of two kinds of reactants is 1: 1-1.2: 1, and reaction 3h.Use the hydrochloric acid soln hydrolysis then, tell organic layer, the water ether extraction merges organic phase, uses sodium hydroxide solution and saturated common salt water washing respectively, anhydrous CaCl
2Or Na
2SO
4Drying, column chromatography (silica gel, petrol ether/ethyl acetate 4: 1) gets white crystal 5-methoxyl group-1-(4-trifluoromethyl) pentanone, fusing point, 43-45 ℃.Infrared and nuclear magnetic spectrum is proved conclusively its structure, and is consistent with target product.
IR(KBr)：v/cm
-1＝2937，1687，1580，1325，1132；
1HNMR (400MHz, CDCl
3): (m, 2H), 1.83 (m, 2H), 3.03 (2H), 3.32 (s, 3H), 3.42 (2H), 7.72 (2H), 8.05 (d, J=8.4Hz 2H) (see Fig. 1, Fig. 2) for d, J=8.4Hz for t, J=12.4Hz for t, J=14.4Hz in δ=1.67.
The beneficial effect of advantage of the present invention and generation is:
(1), raw material easily purchases, cost is lower, for the commercial scale production and the commercialization of product creates good conditions;
(2), reaction time is short, efficient is higher, compared with prior art, productive rate will exceed more than ten percentage point;
(3), the advantages of nontoxic raw materials that adopts of the present invention, production process is pollution-free, and is environmentally friendly, meets the industry policy of country.
Description of drawings
Fig. 1 is the infrared spectrogram (IR) of 5-methoxyl group-1-(4-trifluoromethyl) pentanone,
Fig. 2 be the hydrogen nuclear magnetic resonance wave spectrogram (
1HNMR).
Embodiment
Below by embodiment the present invention is further described again:
In the 50mL round-bottomed flask, add to trifluoromethylbenzoic acid (3.81g, 20mmol), thionyl chloride (4.5g, 38mmol) with 1 dimethyl formamide, stir next time and slip, with sulfurous gas and the hydrogen chloride gas that the reaction of 40%NaOH solution absorption produces, reaction is emitted to extremely up to no gas.Excessive thionyl chloride is reclaimed in distillation, and the underpressure distillation remaining mixture is collected 85-90 ℃ of (16mmHg) cut again, gets colourless liquid to trifluoromethyl benzoyl chloride (3.90g), productive rate 93%.
Step 2
In the dry three-necked bottle of the 250mL that prolong, drying tube and constant pressure funnel are housed, add anhydrous methanol (30mL, 0.75mol) and anhydrous tetrahydro furan (60mL, 0.75mol), ice bath cooling time thionyl chloride adds in the 1h..Add post-heating to 100 ℃ backflow 2h, rise to 120 ℃ of backflow 3h then.Be cooled to room temperature, with normal hexane (150mL) dilution, successively water (100 * 3mL), saturated sodium bicarbonate solution (100 * 3mL) and water (100 * 3mL) wash, anhydrous magnesium sulfate drying filters, and 140-147 ℃ of cut collected in the filtrate distillation, get colourless liquid 57.1g, yield 62.1%.
Step 3
Reflux condensing tube, CaCl are being housed
2Add magnesium chips (0.25g in the dry three-necked bottle of moisture eliminator and constant pressure funnel, 10mmol), add earlier 1-chloro-4-methyl butyl ether (1.22g, 10mmol) and the mixed solution (2ml) of anhydrous diethyl ether (10mL), a 1-2 drips the methyl iodide initiation reaction, under agitation slowly drip remaining mixed solution again, 40-60min adds, and refluxes then, and is bright up to the reaction mixture clarification that becomes, the magnesium chips completely dissolve promptly makes Grignard reagent 4-methoxyl group butyl magnesium chloride solution, and concentration is 1mol/L.
Step 4
Under ice bath cooling (5-0 ℃), to dropping funnel and CaCl are housed
2Add the acyl chlorides (2.1g that step 1 makes rapidly in the dry three-necked bottle of the 100mL of drying tube, 10mmo10), Anhydrous Ferric Chloride (0.08g, 0.5mmol) and anhydrous diethyl ether (10mL), slowly be added dropwise to the Grignard reagent (10mL that step 3 makes after stirring 5min, 10mmol), reaction 2h removes ice bath, rises to room temperature reaction 1h.Reaction mixture hydrochloric acid (2mol/L, 10mL) hydrolysis, tell organic phase, (3 * 5mL) extractions merge organic phase to water, use sodium hydroxide solution (1mol/L respectively with ether, 10mL) and saturated aqueous common salt (10mL) washing, anhydrous CaCl2 drying, after the evaporation concentration, column chromatography (chromatographic column 30 * 3mm; Sorbent material silica gel 200-300 order, elutriant petrol ether/ethyl acetate v/v4: 1) get white crystal (1.90g), productive rate 73%.
Embodiment 2
In the round-bottomed flask of 50mL, adding is to trifluoromethylbenzoic acid (3.81g, 20mmol), (4.5g 38.0mmol) with 1 dimethyl formamide, stirs down and refluxes sulfur oxychloride, absorb the gas that produces with sodium hydroxide solution, disappear up to sulfurous gas and hydrogen chloride gas. steam excessive thionyl chloride, the redistillation remaining mixture is collected 85-90 ℃/16mmHg, get colourless liquid to trifluoromethyl benzoyl chloride (3.80g), yield 91%.
Step 2
In being housed, the dry three-necked bottle of prolong, drying tube and constant pressure funnel adds 1, (21.5g 0.1mol) and anhydrous methanol (10ml), stirs it is mixed the 4-dibromobutane, be heated to the methanol solution (sodium methylate 5.4g, anhydrous methanol 30mL) that begins to drip sodium methylate after 70 ℃.Add back backflow 2h, solid impurity is removed in question response liquid cooling but after-filtration, adds ether (20mL) and water (15mL) then in residuum, tell organic phase after fully stirring, (3 * 10ml) extractions merge organic phase to water, use the Calcium Chloride Powder Anhydrous drying with ether.Steam 30-70 ℃ of cut ether and methyl alcohol earlier, the cut (15mmHg) of 60-70 is collected in underpressure distillation again, gets colourless liquid 1-bromo-4-methyl butyl ether (13.01g), yield 78%.
Step 3
In the dry three-necked bottle of the 100mL that reflux condensing tube, CaCl2 drying tube and constant pressure funnel are housed, add magnesium chips (0.25g, 10mmol), add 1-bromo-4-methyl butyl ether (1.67g earlier, 10mmol) and the mixed solution (2mL) of anhydrous tetrahydro furan (10mL), add an iodine initiation reaction, under agitation slowly drip remaining mixed solution again, about 40-60min adds, reflux then, make reaction mixture become the clarification bright, magnesium chips is close to completely dissolve and promptly makes Grignard reagent 4-methoxyl group butyl bromination magnesium solution, and concentration is 1mol/L.
Step 4
Under ice bath cooling (5-0 ℃), in the dry three-necked bottle of the 100mL that dropping funnel and CaCl2 drying tube are housed, add acyl chlorides (2.1g rapidly, 10mmol), Anhydrous Ferric Chloride (0.16g1mmol) and anhydrous tetrahydro furan (10mL), slowly drip Grignard reagent (10mL after stirring 5min, 10mmol), reaction 2h removes ice bath, rises to room temperature reaction 1h.Reaction mixture hydrochloric acid (2mol/L, 10mL) hydrolysis, tell organic phase, (3 * 5mL) extractions merge organic phase to water, use sodium hydroxide solution (1mol/L respectively with ether, 10mL) and saturated aqueous common salt (10mL) washing, anhydrous Na 2SO4 drying, after the evaporation concentration, column chromatography (chromatographic column 30 * 3mm; Sorbent material silica gel 200-300 order; Elutriant petrol ether/ethyl acetate v/v4: 1) get white crystal (2.09g), productive rate 80%.
Claims (4)
1. the preparation method of a 5-methoxyl group-1-(4-trifluoromethyl) pentanone, its step comprises:
The preparation of step 1, acyl chlorides
To put into flask to trifluoromethylbenzoic acid and 0.5% dimethyl formamide, stir on the limit, and the limit slowly drips the doubly normal thionyl chloride of 1.5-2, and 0.5-1h adds; Reflux 2-4h then, the gas of generation absorbs with 40% sodium hydroxide solution; Excessive thionyl chloride is reclaimed in distillation earlier, and the underpressure distillation remaining mixture is collected 85-90 ℃ of cut (16mmHg) again, gets pure product to trifluoromethyl benzoyl chloride;
The preparation of step 2,1-halogen-4-methyl butyl ether
(1) 1-chloro-4-methyl butyl ether
Add anhydrous methanol and anhydrous tetrahydro furan in the dry three-necked bottle of prolong, moisture eliminator and constant pressure funnel is housed, the ice bath cooling is thionyl chloride down; Add post-heating to 100 ℃ backflow 2h, rise to 120 ℃ of backflow 3h then; Be cooled to room temperature, with normal hexane dilution, water, saturated sodium bicarbonate solution and water washing successively, anhydrous magnesium sulfate drying filters, and 140-147 ℃ of cut collected in the filtrate distillation, gets colourless liquid 1-chloro-4-methyl butyl ether;
(2) 1-bromo-4-methyl butyl ether
Prolong is being housed, add 1 in the dry three-necked bottle of moisture eliminator and constant pressure funnel, 4-dibromobutane and anhydrous methanol, stirring mixes it, be heated to the methanol solution that begins to drip sodium methylate after 70 ℃, add back backflow 2h, solid impurity is removed in question response liquid cooling but after-filtration, in residuum, add ether and water then, tell organic phase, the water extracted with diethyl ether after fully stirring, merge organic phase, use the Calcium Chloride Powder Anhydrous drying, filter, steam ether and methyl alcohol earlier, 60-70 ℃ cut (15mmHg) is collected in underpressure distillation again, gets colourless liquid 1-bromo-4-methyl butyl ether;
The preparation of step 3, Grignard reagent
In being housed, the dry three-necked bottle of reflux condensing tube, moisture eliminator and constant pressure funnel adds magnesium chips, 1-halogen-4-the methyl butyl ether of elder generation's adding about 1/5 and the mixed solution of dry solvent, with methyl iodide or iodine initiation reaction, slowly drip remaining mixed solution again, adding the back backflow heats up in a steamer, all disappear up to magnesium chips, promptly make Grignard reagent 4-methoxyl group butyl magnesium halide;
The preparation of step 4, ketone
Under ice bath cooling, acyl chlorides, catalyst Fe Cl that step 1 is made
3Mix with anhydrous solvent, stir the slow down Grignard reagent that step 2 makes that adds, the mol ratio of two kinds of reactants is 1: 1-1.2: 1, and reaction 3h; Use the hydrochloric acid soln hydrolysis then, tell organic layer, the water ether extraction merges organic phase, uses sodium hydroxide solution and saturated common salt water washing respectively, anhydrous CaCl
2Or Na
2SO
4Drying, column chromatography (silica gel, petrol ether/ethyl acetate 4: 1) gets white crystal 5-methoxyl group-1-(4-trifluoromethyl) pentanone, fusing point: 43-45 ℃.
2. the preparation method of a kind of 5-methoxyl group-1-as claimed in claim 1 (4-trifluoromethyl) pentanone is characterized in that employed catalyzer is in the above-mentioned steps four: anhydrous FeCl
3, its consumption is the 5-10mol% of acyl chlorides.
3. the preparation method of a kind of 5-methoxyl group-1-as claimed in claim 1 (4-trifluoromethyl) pentanone is characterized in that the acyl chlorides in the above-mentioned steps four and the mol ratio of Grignard reagent are 1: 1-1.2: 1.
4. the preparation method of a kind of 5-methoxyl group-1-as claimed in claim 1 (4-trifluoromethyl) pentanone is characterized in that the temperature of reaction in the above-mentioned steps four is-5-0 ℃.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602658B (en) * | 2009-07-14 | 2013-09-18 | 青岛和兴精细化学有限公司 | Synthesis method of 5-Methoxy-1-[4-(trifluoromethyl) phenyl]-1-pentanone |
| CN104402693A (en) * | 2014-11-26 | 2015-03-11 | 千辉药业（安徽）有限责任公司 | Preparation method of 5-methoxyl-1-[4-(trifluoromethyl) phenyl]-1-pentanone |
| CN108191630A (en) * | 2018-02-07 | 2018-06-22 | 千辉药业（安徽）有限责任公司 | 1- is to the synthetic method of fluoroform phenyl -5- methoxyl groups-pentanone |
| CN108689818A (en) * | 2018-06-18 | 2018-10-23 | 东莞市联洲知识产权运营管理有限公司 | A kind of intermediate 5- methoxyl groups -1- of fluvoxamine maleate(4- trifluoromethyls)The production method of pentanone |
| CN108828092A (en) * | 2018-06-22 | 2018-11-16 | 广东省药品检验所（广东省药品质量研究所、广东省口岸药品检验所） | A kind of method of each degradation impurity in measurement fluvoxamine maleate |
| CN116023296A (en) * | 2022-12-29 | 2023-04-28 | 上海国创医药股份有限公司 | Preparation method of fluvoxamine maleate |
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2006
- 2006-08-30 CN CNA2006101045289A patent/CN101134721A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602658B (en) * | 2009-07-14 | 2013-09-18 | 青岛和兴精细化学有限公司 | Synthesis method of 5-Methoxy-1-[4-(trifluoromethyl) phenyl]-1-pentanone |
| CN104402693A (en) * | 2014-11-26 | 2015-03-11 | 千辉药业（安徽）有限责任公司 | Preparation method of 5-methoxyl-1-[4-(trifluoromethyl) phenyl]-1-pentanone |
| CN108191630A (en) * | 2018-02-07 | 2018-06-22 | 千辉药业（安徽）有限责任公司 | 1- is to the synthetic method of fluoroform phenyl -5- methoxyl groups-pentanone |
| CN108689818A (en) * | 2018-06-18 | 2018-10-23 | 东莞市联洲知识产权运营管理有限公司 | A kind of intermediate 5- methoxyl groups -1- of fluvoxamine maleate(4- trifluoromethyls)The production method of pentanone |
| CN108828092A (en) * | 2018-06-22 | 2018-11-16 | 广东省药品检验所（广东省药品质量研究所、广东省口岸药品检验所） | A kind of method of each degradation impurity in measurement fluvoxamine maleate |
| CN108828092B (en) * | 2018-06-22 | 2021-04-23 | 广东省药品检验所（广东省药品质量研究所、广东省口岸药品检验所） | Method for determining various degradation impurities in fluvoxamine maleate |
| CN116023296A (en) * | 2022-12-29 | 2023-04-28 | 上海国创医药股份有限公司 | Preparation method of fluvoxamine maleate |
| CN116023296B (en) * | 2022-12-29 | 2023-07-07 | 上海国创医药股份有限公司 | Preparation method of fluvoxamine maleate |
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