CN1453267A - New Dofetilide preparing method - Google Patents
New Dofetilide preparing method Download PDFInfo
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- CN1453267A CN1453267A CN 02117190 CN02117190A CN1453267A CN 1453267 A CN1453267 A CN 1453267A CN 02117190 CN02117190 CN 02117190 CN 02117190 A CN02117190 A CN 02117190A CN 1453267 A CN1453267 A CN 1453267A
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Abstract
The new preparation process of Dofetilide includes joint between p-nitrophenyl ethylamine hydrochloride and 4-(2-chloro oxethyl)nitrophenyl, methylation reaction to form N-[2-(4-nitrophenoxy) ethyl]-4-nitrophenyl ethylamine, conventional reduction and methylsulfonuylation reaction.
Description
Invention field
The present invention relates to the new preparation method of formula (I) compound of general P162a by name (Dofetilide), the chemistry of P162a is called N[4-[2-[methyl [2-[4-[(sulfonyl methane) amino] phenoxy group] ethyl] amino] phenyl] amsacrine.
Background of invention
Serious irregular pulse is as quick type ventricular tachycardia, quiver in the chamber and cardiac sudden death is the major reason of cardiovascular disorder death.P162a is the oral anti-arrhythmic at atrial fibrillation of U.S. Pfizer company exploitation, has the effect that higher reverse is a sinus rhythm, and be III class antiarrhythmic drug in U.S.'s Initial Public Offering in May, 2000.
Be disclosed in European patent EP-A-0245997 as antiarrhythmic P162a, its patent families has US4959366 (US5079248 divides an application), CN1014529 etc., the multiple synthetic method of P162a has been described in the patent of the disclosure, but all exist raw material to be not easy to obtain, the industrial production cost problem of higher.
The method of disclosed synthetic P162a is among the EP-A-0245997: method A:
X is a halogen in the formula, down together.Method B:
Method C:
Method D:
Method E:
Method F:
Contain two Toluidrin groups in the structure of P162a; in above disclosed synthetic method; method A-D is and introduces a Toluidrin group earlier in certain intermediate; dock then, reduce; introducing another Toluidrin group at last; therefore must carry out two deuterzooid methylsulfonyl reactions respectively, this has increased synthesis cycle undoubtedly, is unfavorable for economic large-scale production.
Earlier synthetic dinitrobenzene thing is once introduced two Toluidrin groups through the methylsulfonyl reaction after the reduction again among method E and the F, and the production efficiency height is suitable for the suitability for industrialized production of P162a.But intermediate N methyl-2-(4-nitrophenyl) ethamine used among the method E does not have the commercial goods, and synthesis step is also more, can increase the difficulty of production.Method F is butt joint earlier then, and the own methyl iodide in back methylates, and raw material is simple and easy to relatively, but there is no specific descriptions among the EP-A-0245997, and it is more to use methyl iodide that secondary amine is directly carried out methylation reaction impurity, is difficult for purifying, and this has seriously restricted the application of this method.
Therefore, be necessary to seek abundant, cheap, an easy and simple to handle synthesis technique of raw material sources and come the scale operation P162a.
Goal of the invention
The purpose of this invention is to provide the preparation technology that a kind of raw material sources are abundant, synthesis technique is simple, be suitable for suitability for industrialized production.This technology comprises docks the p-nitrophenyl ethylamine hydrochloride with 4-(2-chloroethoxy) oil of mirbane; through methylation reaction; form N-[2-(4-nitrophenoxy) ethyl]-4-oil of mirbane ethamine, again by conventional reduction reaction and methylsulfonyl prepared in reaction P162a.
Summary of the invention
As mentioned above, the existing synthetic method of P162a is unsuitable for the scale of economization and produces P162a in batches.The present invention is directed to the problem that above method exists, adopt cheap commercially available industrial chemicals and synthesis technique easy and simple to handle to prepare P162a, be easy to economy of large scaleization ground and produce P162a.
The present invention is raw material with the phenylethylamine, through the nitrated p-nitrophenyl ethylamine hydrochloride that makes, in suitable solvent, (press Journal of OrganicChemistry with 4-(2-chloroethoxy) oil of mirbane, 49,3114-21, the preparation of 1984 reported method) butt joint, form N-[2-(4-nitrophenoxy) ethyl earlier]-4-oil of mirbane ethamine, carry out methylation reaction by formic acid-formaldehyde again, obtain key intermediate N-methyl-N-[2-(4-nitrophenoxy) ethyl of P162a]-4-oil of mirbane ethamine.This intermediate can prepare P162a through reduction, the methylsulfonyl reaction of routine.Reaction formula is as follows:
The invention is characterized in and earlier the p-nitrophenyl ethylamine hydrochloride is docked with 4-(2-chloroethoxy) oil of mirbane, methylate again, form N-methyl-N-[2-(4-nitrophenoxy) ethyl]-4-oil of mirbane ethamine.Wherein, the p-nitrophenyl ethylamine hydrochloride can be by ordinary method well known in the art by the nitrated preparation of phenylethylamine, and 4-(2-chloroethoxy) oil of mirbane is that raw material is by Journal of Organic Chemistry, 49 by p-Nitrophenyl chloride, 3114-21,1984 method is synthetic.The oil of mirbane ethylamine hydrochloride reacts with docking of 4-(2-chloroethoxy) oil of mirbane can carry out homogeneous reaction in polar solvent, also can be undertaken by the method for phase-transfer catalyst by suspending in water.Described polar solvent comprises lower aliphatic alcohols, nitrile, dipolar aprotic class, particular methanol, ethanol, acetonitrile, dimethyl formamide and dimethyl sulfoxide (DMSO).Described phase-transfer catalyst comprises ammonium salt class, crown ether-like, and preferred ammonium salt class more preferably contains the ammonium salt of 15 to 25 carbon atoms.Temperature of reaction can be room temperature-150 ℃, and preferred 50-120 ℃, more preferably 80-100 ℃.Reaction times is 3-72 hour, preferred 3-24 hour, and more preferably 3-12 hour.
The methylation reaction that carries out with formic acid and formaldehyde can carry out in the presence of organic solvent, also can be not with an organic solvent.Described organic solvent comprises lower aliphatic alcohols, nitrile, dipolar aprotic class, preferably only reacts in the presence of formic acid.Temperature of reaction is a room temperature-120 ℃, preferred 40-100 ℃, and more preferably 60-90 ℃.
Following embodiment just is used to illustrate the present invention, and unrestricted the present invention.
EmbodimentEmbodiment 1 N-[2-(4-nitrophenoxy) ethyl]-4-oil of mirbane ethamine
In 250 milliliters of there-necked flasks, add 20 gram 4-(2-chloroethoxy) oil of mirbane, 20 gram p-nitrophenyl second hydrochlorides, 15 gram Anhydrous potassium carbonates, 3 gram potassiumiodides, 2 gram Tetrabutyl amonium bromides, 70 ml waters, after mechanical stirring refluxed 3 hours, reaction solution was transferred in 1 liter of there-necked flask, adds 300 milliliters of ethyl acetate, stir static layering after 10 minutes, the water ethyl acetate extraction merges organic layer, washes with saturated common salt.Organic phase is concentrated into dried, 19.5 gram oily matter, adds 80 milliliters of ethyl acetate, heat moltenly entirely, be cooled to 20 ℃, add 80 milliliters of 5N aqueous hydrochloric acids, suction filtration mass crystallization appears, in stirring.Acetonitrile recrystallization, vacuum-drying weigh 26.5 grams, yield 73%.
1H-NMR(300MHz，CDCl
3)：δ(ppm)3.00(6H，m)，4.13(2H，t)，6.90(2H，t)，7.36(2H，d)，8.16(4H，m)。Embodiment 2 N-methyl-N-[2-(4-nitrophenoxy) ethyls]-4-oil of mirbane ethamine
In 500 milliliters of there-necked flasks, add 12 gram N-[2-(4-nitrophenoxy) ethyls]-4-oil of mirbane ethamine, 200 milliliters of dehydrated alcohols, stir, be warming up to 35 ℃, add 24 gram anhydrous formic acids, continue to heat to 55 ℃, add 10 grams, 37% formaldehyde solution, back flow reaction, after reacting completely, reaction solution is added in 200 ml waters, concentrates to remove part ethanol, transfer to Ph greater than 7 with the 2N aqueous sodium hydroxide solution, precipitation in a large number occurs, suction filtration, vacuum-drying weighs 8.8 grams, yield 78.1%.
1H-NMR(300MHz，CDCl
3)：δ(ppm)2.44(3H，s)，2.79(2H，m)，2.91(4H，m)，4.14(2H，t)，6.93(2H，m)，7.37(2H，d)，8.18(4H，m)。Embodiment 3 N-[2-(4-amino-benzene oxygen) ethyl]-4-amino-benzene ethamine
In 1 liter of hydrogenation bottle, add 10 gram N-methyl-N-[2-(4-nitrophenoxy) ethyls]-4-oil of mirbane ethamine, 600 milliliters of ethanol, 6 gram Raney's nickels after hydrogenation reaction is complete, filter.Mother liquor concentrates and steams solvent, obtains 7.28 gram canescence oily cured articles, and ethyl acetate is refining, gets pale solid and weighs 6.76 grams, fusing point 71.4-71.9 ℃, yield 81.8%.Embodiment 4 P162as
In 100 milliliters of there-necked flasks, add 2.6 gram N-[2-(4-amino-benzene oxygen) ethyls]-4-amino-benzene ethamine, 60 milliliters of dry pyridines, stirring and dissolving is cooled to 0～3 ℃, slowly drips 1.42 milliliters of methanesulfonics, stirs under the room temperature and spends the night.After reacting completely, stopped reaction, concentrate reddish-brown oily matter.100 milliliters of 2N sodium bicarbonate aqueous solutions of adding and 100 milliliters of ethyl acetate stirred 10 minutes in this oily matter, layering, and the water ethyl acetate extraction, anhydrous magnesium sulfate drying, filtering and concentrating obtains orange red oily matter.This oily matter slowly is added drop-wise in 100 milliliters of isopropyl ethers, obtains pale precipitation, stir after 30 minutes, filter, obtain pale solid.Recrystallizing methanol gets white solid 2.7 grams, yield 67.1%, fusing point 130.8-131.9 ℃.
Claims (5)
1. method for preparing P162a; this method comprises docks the p-nitrophenyl ethylamine hydrochloride with 4-(2-chloroethoxy) oil of mirbane; through methylation reaction; form N-[2-(4-nitrophenoxy) ethyl]-4-oil of mirbane ethamine, again by conventional reduction, methylsulfonyl prepared in reaction P162a.
2. the described method of claim 1, wherein the p-nitrophenyl ethylamine hydrochloride dock in water with 4-(2-chloroethoxy) oil of mirbane and phase-transfer catalyst in the presence of carry out.
3. the described method of claim 2, wherein said phase-transfer catalyst is an ammonium salt.
4. the described method of claim 1, wherein methylation reaction is to be methylating reagent with formaldehyde, carries out in formic acid and polar organic solvent.
5. the described method of claim 1, wherein methylation reaction is to be methylating reagent with formaldehyde, carries out in formic acid.
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| CN 02117190 CN1453267A (en) | 2002-04-25 | 2002-04-25 | New Dofetilide preparing method |
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| CN 02117190 CN1453267A (en) | 2002-04-25 | 2002-04-25 | New Dofetilide preparing method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ307826B6 (en) * | 2017-12-01 | 2019-05-29 | Farmak, A.S. | Method of preparing N- [4- (2 - {[2- (4-methanesulfonamidophenoxy) ethyl] (methyl) amino} ethyl) phenyl] methanesulfonamide (Dofetilide) |
-
2002
- 2002-04-25 CN CN 02117190 patent/CN1453267A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ307826B6 (en) * | 2017-12-01 | 2019-05-29 | Farmak, A.S. | Method of preparing N- [4- (2 - {[2- (4-methanesulfonamidophenoxy) ethyl] (methyl) amino} ethyl) phenyl] methanesulfonamide (Dofetilide) |
| US10450267B2 (en) | 2017-12-01 | 2019-10-22 | Farmak, A.S. | Method for preparing N-[4-(2-{[2-(4-methane sulfonamidophenoxy) ethyl] (methyl)amino}ethyl)phenyl]methanesulfonamide (dofetilide) |
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