CN102617368B - Preparation method of Alpha/Beta receptor dual inhibitors and salts thereof - Google Patents

Preparation method of Alpha/Beta receptor dual inhibitors and salts thereof Download PDF

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CN102617368B
CN102617368B CN201210045620.8A CN201210045620A CN102617368B CN 102617368 B CN102617368 B CN 102617368B CN 201210045620 A CN201210045620 A CN 201210045620A CN 102617368 B CN102617368 B CN 102617368B
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ethyl
acid
methoxyphenoxy
phenoxy group
amido
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CN102617368A (en
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李高
胡磊
陈邦银
裘军
斯陆勤
黄建耿
苏玉永
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Huazhong University of Science and Technology
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Abstract

The invention provides a preparation method of Alpha/Beta receptor dual inhibitors and salts thereof, wherein, the Alpha/Beta receptor dual inhibitors are expressed as (plus or minus)1-[4-(2-methoxyl ethyl) phenoxy]-3-[[2-(2-methoxyl phenoxy)ethyl]amino]-2-propanol; and 2-(2-methoxyl phenoxy)ethamine reacts with 3-[4-(2-methoxyl ethyl) phenoxy]-1, 2-epoxypropare in aprotic solvent to obtain (plus or minus)1-[4-(2-methoxyl ethyl) phenoxy]-3-[[2-(2-methoxyl phenoxy) ethyl] amino]-2-propanol. The (plus or minus) 1-[4-(2-methoxyl ethyl) phenoxy]-3-[[2-(2-methoxyl phenoxy) ethyl] amino]-2-propanol reacts with acid to obtain the salts thereof. The preparation method achieves simple and convenient preparation technology, lower manufacturing cost and high purity of products, is suitable for industrialized production, and is suitable for being used for preparing oral preparation or injection medicines.

Description

The preparation method of a kind of α/β acceptor double inhibitor and salt thereof
Technical field
The present invention relates to a kind of α/β acceptor double inhibitor (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] preparation method of-2-propyl alcohol and salt thereof, belong to field of medicine and chemical technology.
Background technology
Have the beta-receptor blockader of alpha-receptor blocking effect concurrently, in hypertensive treatment, show great advantage, this class medicine also can be blocked alpha-receptor and make vasorelaxation in blocking-up beta-receptor, effectively improve the hypotensive effect of medicine, and alleviated the untoward reaction of medicine to blood vessel, segmental bronchus and heart.This type of marketed drug has carvedilol (US4697022), amosulalol (US4724148), bucindolol (US4463176) etc., and these medicines have been widely used in the cardiovascular disordeies such as treatment hypertension.The mechanism of action of these medicines is mainly beta-receptor blocking effect, has the relatively weak alpha-receptor blocking effect of intensity concurrently.
(±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido]-2-propyl alcohol; English name is (±) 1-[4-(2-methoxyethyl) phenoxy]-3-[[2-(2-methoxyphenoxy) ethyl] amino]-2-propanol), there is the structure of formula I.
Figure BDA0000138638700000011
Pharmacodynamic study shows, (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido]-2-propyl alcohol has the effect of selective exclusion alpha-receptor and beta-receptor, is a kind of α/β acceptor double inhibitor.Its mechanism of action is to have beta-receptor blocking effect and alpha-receptor blocking effect concurrently, is further to have optionally β concurrently 1the effect of-receptor blocking and optionally α 1the effect of-receptor blocking, and β 1the effect of-receptor blocking and α 1-receptor blocking action intensity is suitable, and hypotensive effect is stronger, and less to blood vessel, segmental bronchus and heart condition reaction.
1-[4-(2-methoxy ethyl) phenoxy group has been described in Czechoslovakia's patent (CS247575)]-3-[[2-(2-methoxyphenoxy) ethyl] amido] preparation method of-2-propyl alcohol.The method is by the benzyl protection form of 2-(2-methoxyphenoxy) ethamine; be O-methoxy phenoxybenzamine and 3-[4-(2-methoxy ethyl) phenoxy group]-1; 2-propylene oxide reaction, then catalytic hydrogenation obtains 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido]-2-propyl alcohol.In the method, for benzyl being gone to protection, need to use expensive catalyzer, preparation cost is high, is unfavorable for realizing suitability for industrialized production.
Therefore, the object of the present invention is to provide one to prepare (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] modification method of-2-propyl alcohol.Preparation method of the present invention compares tool with existing method and has the following advantages: preparation technology is easy, production cost is low, product is pure, yield is high, is applicable to suitability for industrialized production.
The present invention also provides a kind of (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] preparation method of salt of-2-propyl alcohol.About the preparation method of its salt, in the patent (CS247575) of having delivered, do not report.(±) 1-[4-in the present invention (2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] salt of-2-propyl alcohol is preferably its hydrochloride, products obtained therefrom purity is high, good stability, very easily water-soluble, become the property of medicine good, be suitable for preparing oral preparations or injection medicine.
Summary of the invention
Task of the present invention is to provide one and prepares (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] modification method of-2-propyl alcohol, the method comprises formula II compound 3-[4-(2-methoxy ethyl) phenoxy group]-1,2 epoxy prapane
Figure BDA0000138638700000021
With formula III compound 2-(2-methoxyphenoxy) ethamine
Figure BDA0000138638700000022
The step of reaction.
Preferably formula III Compound Phase is for formula II compound molar excess.The molar ratio of formula III compound and formula II compound is preferably approximately 1.5: 1 to approximately 100: 1, more preferably the molar ratio of formula III compound and formula II compound is approximately 1.5: 1 to approximately 10: 1, and most preferably the molar ratio of formula III compound and formula II compound is approximately 1.5: 1 to approximately 2.8: 1.
In one embodiment of the invention, described reactions steps is carried out in a kind of aprotic solvent.Described aprotic solvent is selected from methyl-sulphoxide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, toluene, dimethylbenzene, heptane, diox, ethylene glycol dimethyl ether etc.In another optional embodiment, described reactions steps is carried out in the solvent mixture that comprises multiple aprotic solvent.The aprotic solvent of preferred described solvent mixture is selected from methyl-sulphoxide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, toluene, dimethylbenzene, heptane, diox, ethylene glycol dimethyl ether etc.
Described reactions steps is preferably carried out at the temperature of approximately 25 DEG C-Yue 150 DEG C, and most preferably described reactions steps is carried out at the temperature of approximately 60 DEG C-Yue 100 DEG C.
Described method also comprise regulate pH from reaction mixture, to separate (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] step of-2-propyl alcohol.
The present invention also provides a kind of (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] preparation method of salt of-2-propyl alcohol, comprise the phenoxy group to (±) 1-[4-making (2-methoxy ethyl)]-3-[[2-(2-methoxyphenoxy) ethyl] amido] in-2-propyl alcohol, add dehydrated alcohol and acid, obtain crystallization, refining (±) 1-[4-(2-methoxy ethyl) phenoxy group that to obtain]-3-[[2-(2-methoxyphenoxy) ethyl] amido] acid salt of-2-propyl alcohol.
Described acid is selected from hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, pentanedioic acid, Hydrogen bromide, acetic acid, Citric Acid, lactic acid, amygdalic acid, toxilic acid, phenylformic acid, methylsulfonic acid, oxalic acid etc.Be preferably hydrochloric acid.
Described refining (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] acid salt of-2-propyl alcohol adopts the method for recrystallization, and recrystallization solvent is one or more in ethanol, ethyl acetate, propyl acetate, butylacetate, normal hexane etc.
Chemical equation is as follows:
Figure BDA0000138638700000031
Figure BDA0000138638700000041
Described refining (±) 1-[4-(2-methoxy ethyl) phenoxy group that to obtain]-3-[[2-(2-methoxyphenoxy) ethyl] amido] acid salt of-2-propyl alcohol is (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido]-2-propylate hydrochlorate.Adopt high performance liquid chromatography (HPLC method) to check purity, the relative retention time at its peak is 9.4min, and normalized area is greater than 99.50%; Only there are two major impurity peaks, relative retention time is respectively 5.0min and 6.6min, single impurity peaks normalized area is all less than 0.1%, and impurity peaks normalized area sum is less than 0.5%, specifically sees Fig. 1 (a), Fig. 1 (b) (retention time t in figure r=2.0min place chromatographic peak is solvent peak).(±) 1-[4-(2-methoxy ethyl) phenoxy group obtaining by the inventive method]-3-[[2-(2-methoxyphenoxy) ethyl] amido]-2-propylate hydrochlorate has high purity, be applicable to prepare oral preparations or injection medicine, and the security having had.
Brief description of the drawings
Fig. 1-a, Fig. 1-b are (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido]-2-propylate hydrochlorate related substance checks the high-efficient liquid phase chromatogram of contrast solution and need testing solution.
Fig. 2 is (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] uv absorption spectra of-2-propylate hydrochlorate.
Fig. 3 is (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] infrared absorpting light spectra of-2-propylate hydrochlorate.
Fig. 4 is (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] the hydrogen nuclear magnetic resonance spectrogram of-2-propylate hydrochlorate.
Fig. 5 is (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] the nuclear magnetic resonance of carbon spectrogram of-2-propylate hydrochlorate.
Fig. 6 is (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] mass spectrum of-2-propylate hydrochlorate.
Embodiment
Embodiment 1 takes 2-(2-methoxyphenoxy) ethamine 167g and puts in reaction flask, add methyl-sulphoxide 500ml and be heated to approximately 70 DEG C, slowly add 3-[4-(2-methoxy ethyl) phenoxy group]-1, 2-propylene oxide 104g, add the post-heating about 20h that refluxes, pressure reducing and steaming solvent, by in reaction mixture impouring 1000ml frozen water, branch vibration layer, residuum is dissolved in chloroform 600ml, then use 2% hydrochloric acid by two-phase mixture pH regulator to 5, remove water layer, evaporated under reduced pressure chloroform, add ethyl acetate 500ml, stirring and crystallizing 3 hours, suction filtration, 100ml ethyl acetate washing leaching cake.By filter cake in ethyl acetate 500ml and 5% aqueous sodium carbonate reslurry until pH arrive 7.5.Separate organic phase and use dried over sodium sulfate, filter, stirring and crystallizing 12 hours, filtering separation, 45 DEG C of vacuum-dryings obtain white solid (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido]-2-propyl alcohol.
Embodiment 2 takes 2-(2-methoxyphenoxy) ethamine 167g and puts in reaction flask, add methyl-sulphoxide 500ml and be heated to approximately 70 DEG C, slowly add 3-[4-(2-methoxy ethyl) phenoxy group]-1,2 epoxy prapane 104g, add the post-heating about 20h that refluxes, pressure reducing and steaming solvent, by in reaction mixture impouring 1000ml frozen water, branch vibration layer, residuum is dissolved in chloroform 600ml, then use 2% hydrochloric acid by two-phase mixture pH regulator to 5, remove water layer.Regulate pH to 7.5 with 5% aqueous sodium carbonate again, remove water layer, evaporated under reduced pressure chloroform, adds dehydrated alcohol 150ml and hydrochloric acid 50ml, and stirring at room temperature 1 hour, removes solvent under reduced pressure, adds ethyl acetate 500ml, activated carbon decolorizing, suction filtration.Ethyl acetate 250ml recrystallization, 45 DEG C of vacuum-dryings, obtain white crystalline powder (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido]-2-propylate hydrochlorate.
Purity: 99.92% (HPLC);
Ultimate analysis:
mp：93.5～95.5℃；IR(cm -1)：3444，3375，1570，1508，1453，1257，1122，1069，864，764； 1H-NMR(δppm)：2.79，3.34，3.42，3.49，3.52，3.54，3.78，3.95，4.01，4.38，4.44，4.67，5.43，6.76，6.84，6.87，6.94，6.97，7.06； 13C-NMR(δppm)：35.18，47.22，51.08，55.57，58.56，65.42，65.50，69.60，73.70，111.86，114.33，115.90，121.07，123.03，129.72，131.54，146.65，149.74，156.58；ESI-MS：375.28。

Claims (2)

1. prepare (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido] modification method of-2-propyl alcohol and salt thereof, it is characterized in that, comprise the following steps:
A) in a kind of aprotic solvent or the solvent mixture that comprises multiple aprotic solvent, make formula II compound 3-[4-(2-methoxy ethyl) phenoxy group]-1,2 epoxy prapane
Figure FDA0000400281730000011
Formula III compound 2-(2-methoxyphenoxy) ethamine with relative type motor II compound molar excess
Figure FDA0000400281730000012
In 60 DEG C～100 DEG C reactions, regulate pH from reaction mixture, to separate (±) 1-[4-(2-methoxy ethyl) phenoxy group]-3-[[2-(2-methoxyphenoxy) ethyl] amido]-2-propyl alcohol;
B) (±) 1-[4-(2-methoxy ethyl) phenoxy group obtaining to separation]-3-[[2-(2-methoxyphenoxy) ethyl] amido] in-2-propyl alcohol, add dehydrated alcohol and acid, obtain crystallization, adopt refining high purity (±) 1-[4-(2-methoxy ethyl) phenoxy group that to obtain of recrystallization method]-3-[[2-(2-methoxyphenoxy) ethyl] amido] acid salt of-2-propyl alcohol;
Described steps A) in a kind of aprotic solvent or the solvent mixture that comprises multiple aprotic solvent be selected from methyl-sulphoxide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, toluene, dimethylbenzene, heptane, diox, ethylene glycol dimethyl ether; B) in, recrystallization solvent is one or more in ethanol, ethyl acetate, propyl acetate, butylacetate, normal hexane etc.; Described acid is selected from hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, pentanedioic acid, Hydrogen bromide, acetic acid, Citric Acid, lactic acid, amygdalic acid, toxilic acid, phenylformic acid, methylsulfonic acid, oxalic acid.
2. high purity (±) 1-[4-(2-methoxy ethyl) phenoxy group that according to claim 1 prepared by method]-3-[[2-(2-methoxyphenoxy) ethyl] amido]-2-propylate hydrochlorate, it is characterized in that, adopt high performance liquid chromatography (HPLC method) to check purity, the relative retention time at its peak is 9.4min, and normalized area reaches more than 99.5%; Only have 2 major impurity peaks, relative retention time is 5.0min and 6.6min respectively, and impurity peaks normalized area sum is less than 0.5%, and single impurity peaks normalized area is all less than 0.1%.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CS247575B1 (en) * 1985-06-11 1987-01-15 Ludvik Blaha Derivatives of 1-phenoxy-3-phenoxyethylamino-2-propanol and method of their preparation
US4697022A (en) * 1983-05-26 1987-09-29 Boehringer Mannheim Gmbh Process for the preparation of optically-active carbazole derivatives, new R- and S-carbazole derivatives and pharmaceutical compositions containing these compounds
CN101508652A (en) * 2008-05-08 2009-08-19 华中科技大学 Hyperpiesis resistant compound and method of preparing the same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4697022A (en) * 1983-05-26 1987-09-29 Boehringer Mannheim Gmbh Process for the preparation of optically-active carbazole derivatives, new R- and S-carbazole derivatives and pharmaceutical compositions containing these compounds
CS247575B1 (en) * 1985-06-11 1987-01-15 Ludvik Blaha Derivatives of 1-phenoxy-3-phenoxyethylamino-2-propanol and method of their preparation
CN101508652A (en) * 2008-05-08 2009-08-19 华中科技大学 Hyperpiesis resistant compound and method of preparing the same

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