CN102190569B - Method for preparing Prasugrel intermediate alpha-cyclopropylcarbonyl-2-fluorobenzyl bromide - Google Patents
Method for preparing Prasugrel intermediate alpha-cyclopropylcarbonyl-2-fluorobenzyl bromide Download PDFInfo
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- CN102190569B CN102190569B CN201010134912.XA CN201010134912A CN102190569B CN 102190569 B CN102190569 B CN 102190569B CN 201010134912 A CN201010134912 A CN 201010134912A CN 102190569 B CN102190569 B CN 102190569B
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Abstract
The invention discloses a new method for preparing a Prasugrel intermediate alpha-cyclopropylcarbonyl-2-fluorobenzyl bromide which is a compound shown as a formula (III). In the method, a compound shown as a formula (I), namely cyclopropyl-2-fluorobenzyl ketone is taken as a raw material, and is bromized by a compound show as a formula (II), namely phenyltrimethylammonium tribromide to form the target product of alpha-cyclopropylcarbonyl-2-fluorobenzyl bromide, namely the compound in the formula (III). The method has the advantages of mild reaction conditions, high selectivity, high yield, low cost and environmental friendliness, and is suitable for large-scale industrial production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to the preparation method of Prasugrel intermediate alpha-cyclopropylcarbonyl-2-fluorobenzyl bromide.
Background technology
Prasugrel is and the similar tetrahydrothieno pyridines compounds of clopidogrel, has the advantages such as platelet aggregation restraining effect, good oral absorptivity, stronger metabolic activity and toxicity is weak.Clinical three phases demonstrate the activity, tolerance and the security that are better than clopidogrel, are therefore a kind of rising antithrombotic reagents.
At present about the preparation method of prasugrel mainly contains EP192535, EP542411, US4740510, US5288726, US5874581, WO04098713, CN101250193, CN92111584, CN10117743 etc.In these all disclosed methods, α-cyclopropyl carbonyl-2-fluoro benzyl bromide (formula compound III) be one prepare prasugrel must obligato important intermediate.
In current published patent, the preparation of α-cyclopropyl carbonyl-2-fluoro benzyl bromide is all to adopt bromine or N-bromo-succinimide (NBS) to make brominated reagent, bromine can produce a large amount of Hydrogen bromides, NBS also can use bromine in the process of recycling, also exist selectivity lower simultaneously, product yield is low, cost is high, bromine is difficult for the shortcomings such as circulation is reclaimed, product purity is not high, separation and purification is difficult, and it is many unfavorable that this just causes above-mentioned two kinds of brominated reagents to exist at aspects such as operational safety, environmental protection, economy.
Summary of the invention
For above technological deficiency, the invention provides the preparation method of a kind of prasugrel key intermediate formula (III) compound α-cyclopropyl carbonyl-2-fluoro benzyl bromide, described method comprises:
In organic solvent, formula (I) compound 1-cyclopropyl base-2-(2-fluorophenyl) ethyl ketone reacts at-40 ℃～60 ℃ with formula (II) compound, obtains formula (III) compound α-cyclopropyl carbonyl-2-fluoro benzyl bromide
In preparation method of the present invention, described organic solvent includes but not limited in anhydrous diethyl ether, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, chloroform, acetone, butanone, hexone, toluene, dimethylbenzene, chlorinated benzene, ethyl acetate, butylacetate, dioxane, acetonitrile, methyl alcohol, ethanol, Virahol, propyl carbinol, DMF, DEF, DMSO or DME or they mixture arbitrarily; Described organic solvent is tetrahydrofuran (THF) or anhydrous diethyl ether more preferably.
In preparation method of the present invention, as one of preferred embodiment, the consumption of described organic solvent is calculated as 1～50ml by every 1g formula (I) compound, and further preferably the consumption of organic solvent is that every 1g formula (I) compound is calculated as 15～20ml.
The temperature of reaction of described bromo-reaction, those skilled in the art can adopt this area routine according to the difference of solvent, are generally-40 ℃～60 ℃, are preferably 5 ℃～10 ℃.
In preparation method of the present invention, the mol ratio of described formula (I) compound and formula (II) compound is 0.8: 1-1.5: 1, and further preferred 1.00-1.10; Further be preferably 1.05: 1.
In the inventive method, those skilled in the art can select different feeding modes according to the organic solvent difference with reaction, in the time selecting haloalkane, alcohol, ester to make solvent, the mode that described formula (I) compound and formula (II) compound react is: first formula is dissolved in (I) compound in organic solvent, then disposable or point 10-20 equal portions join formula (II) compound to contain in formula (I) compound solvent in batches and react, preferably 30 minutes～6 hours reaction times;
In the time selecting other organic solvent, the mode that described formula (I) compound and formula (II) compound react is: first in formula (I) compound, be dissolved in the organic solvent that accounts for total organic solvent amount 30%-40%, and formula (II) compound is dissolved in residual solvent, then be added dropwise in the organic solvent that contains formula (I) compound and react containing formula (II) compound organic solvent, take under the condition of the mode that drips preferably 30 minutes～2 hours reaction times after dropwising.
The invention provides that a kind of selectivity is good, yield is high, the method for environmental friendliness, with low cost and applicable industrially producing alpha-cyclopropyl carbonyl-2-fluoro benzyl bromide (III).
Embodiment
Now further illustrate the present invention by following examples, but protection scope of the present invention is not limited in this.
Embodiment 1
20g (0.112mol) cyclopropyl-2-luorobenzyl ketone is dissolved in 100mlTHF, stir lower 5 ℃ of left and right and be slowly added dropwise to tribromide phenyl TMA (TriMethylAmine) (PTT) 40g (0.1064mol) that 200ml tetrahydrofuran (THF) (THF) dissolves, there is gradually solid to separate out, within approximately 10 hours, dropwise, after dropwising, continue to maintain 5 ℃-10 ℃ reactions 2 hours, after reaction stops, in reaction solution, add 100ml water, at 30 ℃, most of THF is reclaimed in underpressure distillation, debris 100ml, the extraction of 50ml ethyl acetate, merge organic layer, and with the water washing of 3 × 50ml saturated common salt, anhydrous sodium sulfate drying, the desolventizing of reducing pressure at 40 ℃, obtain α-cyclopropyl carbonyl-2-fluoro benzyl bromide crude product 28.3g, yield 97.9%, HPLC:> 94%.
1H?NMR(CDCl
3)δppm：0.93-1.04(2H，m)，1.11-1.19(2H，m)，2.11-2.17(2H，m)，5.96(1H，s)，7.05-7.49(2H，m).
Mass spectrum (Cl, m/z): 259 (M
++ 1).
Embodiment 2
Substitute tetrahydrofuran (THF) with anhydrous diethyl ether, other reactions steps, with embodiment 1, reacts complete, in reaction solution, add 100ml water, after layering, water layer 50ml extracted with diethyl ether, merges organic layer, and with the water washing of 3 × 50ml saturated common salt, anhydrous sodium sulfate drying, the desolventizing of reducing pressure at 40 ℃, obtains α-cyclopropyl carbonyl-2-fluoro benzyl bromide crude product 27.8g, yield 96.2%, HPLC:> 94.5%.
Embodiment 3
20g (0.112mol) cyclopropyl-2-luorobenzyl ketone is dissolved in 300ml methylene dichloride, stir lower 10 ℃ of left and right small quantities of tribromide phenyl TMA (TriMethylAmine) (PTT) 40g (0.1064mol) several times, the reddish-brown dissolution of solid adding before this, then adularescent solid is separated out gradually, within approximately 8 hours, add, continue to maintain about 10 ℃ reactions 2 hours, after reaction stops, in reaction solution, add 100ml water, after layering, water layer 50ml dichloromethane extraction, merge organic layer, and with the water washing of 3 × 50ml saturated common salt, anhydrous sodium sulfate drying, the desolventizing of reducing pressure at 40 ℃, obtain α-cyclopropyl carbonyl-2-fluoro benzyl bromide crude product 28g, yield 96.9%, HPLC:> 93.5%.
Embodiment 4
20.8g (0.117mol) cyclopropyl-2-luorobenzyl ketone is dissolved in 100ml toluene, stir lower 5 ℃ of left and right and be slowly added dropwise to tribromide phenyl TMA (TriMethylAmine) (PTT) 40g (0.1064mol) that 200ml toluene dissolves, there is gradually solid to separate out, within approximately 10 hours, dropwise, after dropwising, continue to maintain 5 ℃-10 ℃ reactions 2 hours, after reaction stops, in reaction solution, add 100ml water, after layering, 50ml toluene extraction for water layer, merge organic layer, and with the water washing of 3 × 50ml saturated common salt, anhydrous sodium sulfate drying, the desolventizing of reducing pressure at 40 ℃, obtain α-cyclopropyl carbonyl-2-fluoro benzyl bromide crude product 27.3g, yield 94.5%, HPLC:> 92.6%.
Claims (4)
1. a preparation method for intermediate α-cyclopropyl carbonyl-2-fluoro benzyl bromide of prasugrel, is characterized in that, described method comprises:
20g cyclopropyl-2-luorobenzyl ketone is dissolved in 100ml tetrahydrofuran (THF), stir lower 5 ℃ and be slowly added dropwise to the tribromide phenyl TMA (TriMethylAmine) 40g that 200ml tetrahydrofuran (THF) dissolves, there is gradually solid to separate out, within 10 hours, dropwise, after dropwising, continue to maintain 5 ℃-10 ℃ reactions 2 hours, after reaction stops, in reaction solution, add 100ml water, at 30 ℃, most of THF is reclaimed in underpressure distillation, debris 100ml, the extraction of 50ml ethyl acetate, merge organic layer, and with the water washing of 3 × 50ml saturated common salt, anhydrous sodium sulfate drying, the desolventizing of reducing pressure at 40 ℃, obtain α-cyclopropyl carbonyl-2-fluoro benzyl bromide crude product 28.3g, yield 97.9%, HPLC:>94%,
1H?NMR(CDCl
3)δppm:0.93-1.04(2H,m),1.11-1.19(2H,m),2.11-2.17(2H,m),5.96(1H,s),7.05-7.49(2H,m)；
Mass spectrum (Cl, m/z): 259(M
++ 1).
2. a preparation method for intermediate α-cyclopropyl carbonyl-2-fluoro benzyl bromide of prasugrel, is characterized in that, described method comprises:
20g cyclopropyl-2-luorobenzyl ketone is dissolved in 100ml anhydrous diethyl ether, stir lower 5 ℃ and be slowly added dropwise to the tribromide phenyl TMA (TriMethylAmine) 40g that 200ml anhydrous diethyl ether dissolves, there is gradually solid to separate out, within 10 hours, dropwise, after dropwising, continue to maintain 5 ℃-10 ℃ reactions 2 hours, after reaction stops, in reaction solution, add 100ml water, after layering, water layer 50ml extracted with diethyl ether, merge organic layer, and with the water washing of 3 × 50ml saturated common salt, anhydrous sodium sulfate drying, the desolventizing of reducing pressure at 40 ℃, obtain α-cyclopropyl carbonyl-2-fluoro benzyl bromide crude product 27.8g, yield 96.2%, HPLC:>94.5%.
3. a preparation method for intermediate α-cyclopropyl carbonyl-2-fluoro benzyl bromide of prasugrel, is characterized in that, described method comprises:
20g cyclopropyl-2-luorobenzyl ketone is dissolved in 300ml methylene dichloride, stir lower 10 ℃ of small quantities of tribromide phenyl TMA (TriMethylAmine) 40g several times, the reddish-brown dissolution of solid adding before this, then adularescent solid is separated out gradually, within 8 hours, add, continue to maintain 10 ℃ of reactions 2 hours, after reaction stops, in reaction solution, add 100ml water, after layering, water layer 50ml dichloromethane extraction, merge organic layer, and with the water washing of 3 × 50ml saturated common salt, anhydrous sodium sulfate drying, the desolventizing of reducing pressure at 40 ℃, obtain α-cyclopropyl carbonyl-2-fluoro benzyl bromide crude product 28g, yield 96.9%, HPLC:>93.5%.
4. a preparation method for intermediate α-cyclopropyl carbonyl-2-fluoro benzyl bromide of prasugrel, is characterized in that, described method comprises:
20.8g cyclopropyl-2-luorobenzyl ketone is dissolved in 100ml toluene, stir lower 5 ℃ and be slowly added dropwise to the tribromide phenyl TMA (TriMethylAmine) 40g that 200ml toluene dissolves, there is gradually solid to separate out, within 10 hours, dropwise, after dropwising, continue to maintain 5 ℃-10 ℃ reactions 2 hours, after reaction stops, in reaction solution, add 100ml water, after layering, 50ml toluene extraction for water layer, merge organic layer, and with the water washing of 3 × 50ml saturated common salt, anhydrous sodium sulfate drying, the desolventizing of reducing pressure at 40 ℃, obtain α-cyclopropyl carbonyl-2-fluoro benzyl bromide crude product 27.3g, yield 94.5%, HPLC:>92.6%.
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| WO2012153348A2 (en) * | 2011-05-09 | 2012-11-15 | Glenmark Generics Limited | Process for preparation of prasugrel and its intermediates |
| CN102643180B (en) * | 2012-03-23 | 2015-04-15 | 广东药学院 | Preparation method of 2-halogenated-2-(2-fluorophenyl)-1-cyclopropylethanone |
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