CN102190569A - 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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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 α-cyclopropyl carbonyl-2-fluoro benzyl bromide.
Background technology
Prasugrel is and similar tetramethylene sulfide of clopidogrel and pyridine compounds and their, has advantages such as platelet aggregation restraining effect, good oral absorption, stronger metabolic activity and toxicity is weak.Clinical three phases demonstrate activity, tolerance and the security that is better than clopidogrel, are a kind of rising antithrombotic reagents therefore.
The preparation method of at present relevant 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) is that a kind of preparation prasugrel must obligato important intermediate.
In the disclosed at present patent, the preparation of α-cyclopropyl carbonyl-2-fluoro benzyl bromide all is to adopt bromine or N-bromo-succinimide (NBS) to make brominated reagent, bromine can produce a large amount of Hydrogen bromides, NBS then also can use bromine in the process of recycling, simultaneously also exist selectivity lower, shortcomings such as product yield is low, cost is high, bromine is difficult for the circulation recovery, product purity is not high, separation and purification difficulty, 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
At 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 and formula (II) compound react under-40 ℃～60 ℃, promptly get formula (III) compound α-cyclopropyl carbonyl-2-fluoro benzyl bromide
Among the 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.
Among the preparation method of the present invention, as one of embodiment preferred, the consumption of described organic solvent is calculated as 1～50ml by every 1g formula (I) compound, and the consumption of further preferred 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 ℃.
Among the 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, when select haloalkane, alcohol, when ester is made solvent, the mode that described formula (I) compound and formula (II) compound react is: first formula is dissolved in (I) compound in the organic solvent, disposable then or branch 10-20 equal portions join formula (II) compound to contain in formula (I) the compound solvent in batches and react preferred 30 minutes～6 hours of reaction times;
When selecting other organic solvent, the mode that described formula (I) compound and formula (II) compound react is: be dissolved in the organic solvent that accounts for total organic solvent amount 30%-40% in formula (I) compound earlier, and formula (II) compound is dissolved in the residual solvent, to contain formula (II) compound organic solvent then is added dropwise in the organic solvent that contains formula (I) compound and reacts, take under the condition of the mode of dripping preferred 30 minutes～2 hours of the 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 suitable industrially producing alpha-cyclopropyl carbonyl-2-fluoro benzyl bromide (III).
Embodiment
Now further specify the present invention, but protection scope of the present invention is not limited in this by following examples.
Embodiment 1
20g (0.112mol) cyclopropyl-2-luorobenzyl ketone is dissolved among the 100mlTHF, stir following about 5 ℃ and slowly be added dropwise to 200ml tetrahydrofuran (THF) (THF) dissolved tribromide phenyl TMA (TriMethylAmine) (PTT) 40g (0.1064mol), there is solid to separate out gradually, dropwised in about 10 hours, continue to keep 5 ℃-10 ℃ reactions 2 hours after dropwising, after reaction stops, in reaction solution, add 100ml water, most of THF is reclaimed in 30 ℃ of following underpressure distillation, debris 100ml, the 50ml ethyl acetate extraction, merge organic layer, and with the water washing of 3 * 50ml saturated common salt, anhydrous sodium sulfate drying, decompression is desolvated under 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 is with embodiment 1, and reaction finishes, in reaction solution, add 100ml water, after the 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, 40 ℃ of following decompressions are desolvated, and obtain 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 the 300ml methylene dichloride, stir following about 10 ℃ small quantities of several times tribromide phenyl TMA (TriMethylAmine) (PTT) 40g (0.1064mol), the reddish-brown solid dissolving that added before this, then the adularescent solid is separated out gradually, added in about 8 hours, and continued to keep about 10 ℃ and reacted 2 hours, after reaction stops, in reaction solution, add 100ml water, after the layering, water layer 50ml dichloromethane extraction merges organic layer, and with the water washing of 3 * 50ml saturated common salt, anhydrous sodium sulfate drying, 40 ℃ of following decompressions are desolvated, and 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 the 100ml toluene, stir following about 5 ℃ and slowly be added dropwise to 200ml toluene dissolved tribromide phenyl TMA (TriMethylAmine) (PTT) 40g (0.1064mol), there is solid to separate out gradually, dropwised in about 10 hours, continue to keep 5 ℃-10 ℃ reactions 2 hours after dropwising, after reaction stops, in reaction solution, adding 100ml water, after the layering, water layer extracts with 50ml toluene, merge organic layer, and with the water washing of 3 * 50ml saturated common salt, anhydrous sodium sulfate drying, decompression is desolvated under 40 ℃, obtain α-cyclopropyl carbonyl-2-fluoro benzyl bromide crude product 27.3g, yield 94.5%, HPLC:＞92.6%.
Claims (8)
1. the preparation method of intermediate formula (III) compound α-cyclopropyl carbonyl-2-fluoro benzyl bromide of a prasugrel is characterized in that described method comprises:
In organic solvent, formula (I) compound 1-cyclopropyl base-2-(2-fluorophenyl) ethyl ketone and formula (II) compound react under-40 ℃～60 ℃, promptly get formula (III) compound α-cyclopropyl carbonyl-2-fluoro benzyl bromide
2. preparation method according to claim 1, it is characterized in that described organic solvent is 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.
3. preparation method according to claim 2 is characterized in that, described organic solvent is tetrahydrofuran (THF) or anhydrous diethyl ether.
4. preparation method according to claim 3 is characterized in that, the consumption of described organic solvent is calculated as 1～50ml by every 1g formula (I) compound, preferred 15-20ml.
5. preparation method according to claim 4 is characterized in that, the mol ratio of described formula (I) compound and formula (II) compound is 0.8: 1-1.5: 1.
6. preparation method according to claim 5 is characterized in that, the mol ratio of described formula (I) compound and formula (II) compound is 1.00-1.10; Preferred 1.05: 1.
7. preparation method according to claim 6, it is characterized in that, the mode that described formula (I) compound and formula (II) compound react is: earlier formula (I) compound is dissolved in the organic solvent, disposable then or branch 10-20 equal portions join formula (II) compound to contain in formula (I) the compound solvent in batches and react 30 minutes～6 hours reaction times; Or in formula (I) compound, be dissolved in the organic solvent that accounts for total organic solvent amount 30%-40% earlier, and formula (II) compound is dissolved in the residual solvent, to contain formula (II) compound organic solvent then is added dropwise in the organic solvent that contains formula (I) compound and reacts preferred 30 minutes～2 hours of the reaction times after dropwising.
8. preparation method according to claim 7 is characterized in that, the temperature of reaction that described formula (I) compound and formula (II) compound react is-40 ℃～60 ℃, is preferably 5 ℃～10 ℃.
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| WO2012153348A2 (en) * | 2011-05-09 | 2012-11-15 | Glenmark Generics Limited | Process for preparation of prasugrel and its intermediates |
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| WO2012153348A2 (en) * | 2011-05-09 | 2012-11-15 | Glenmark Generics Limited | Process for preparation of prasugrel and its intermediates |
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