The synthetic method of beta-adrenaline excitant lecdopamine
Technical field
The invention belongs to the pharmaceutical chemistry field, particularly a kind of synthetic method of beta-adrenaline excitant lecdopamine.
Background technology
The chemical name of Ractopamine hydrochloride is 1-(4-hydroxy phenyl)-2-[1-methyl-3-(4-hydroxy phenyl)-third amino]-ethanol, English name is ractopamine; Its structure is:
Ractopamine hydrochloride is (the Eli Eilly﹠amp of Lilly Co., Eli.; Co.) Kai Fa a kind of a kind of medicine that belongs to the beta-adrenaline excitant class.Its (R, R)-and optically active isomer has stronger biological activity, pharmaceutically can be used as a kind of cardiac drug, and be used for the treatment of congestive heart failure disease, and can be used for diseases such as treatment of obesity and amyotrophy.The hydrochloride of its DL body (RR wherein, the SS-optically active isomer accounts for 51% ratio, and RS, the SR-optically active isomer accounts for 49%) can be used for livestock industry and make an addition in the feed and use, can improve efficiency of feed utilization and day weight gain rate and can increase considerably genetic ability for carcass weight, significantly improve lean meat growth rate.It is a unique like product that is applied to pig industry by FDA's approval because of having satisfied animal, environment and the food security standard of FDA harshness.Its mechanism of action is to stimulate beta-receptor at cell surface layer, and these acceptors are present in skeletal muscle and the fatty tissue, and its main effect is to increase lean meat content by directly nutritive substance being changed into protein.Great deal of research results shows that it does not all have side effects to animal, and to the local flavor of animal, quality all has no adverse effects.
Relevant Ractopamine hydrochloride synthetic, bibliographical information following several method and route:
One, Dijk J.V; Moed H.D.Rec.Trav.Chim.1973,92,1281 and U.S. Eli Eilly﹠amp; Co. patent (UK Patent Application GB2133986A; US patent 4690951).
Above-mentioned literature method is respectively:
(1) Dijk J.V; Moed H.D.Rec.Trav.Chim.1973, the route method of 92,1281 reports, its core are methyl phenyl ketone bromo-derivative and aminate butt joint reduction then, route is as follows:
(2) in GB2133986A (1984), provide two kinds of methods:
One carries out amidation butt joint reaction to first protection back deutero-raspberry ketone aminate and the p-hydroxyphenylethanol protected, carries out the reduction of two steps again, obtains end product behind the salify, and route is as follows:
Its two, be to restore by the butt joint of raspberry ketone and p-hydroxyphenylethanol amine to obtain end product, route is as follows:
Two, patent (CN1073983C) and improve one's methods (CN1082042C) of proposition such as (1) Chen Daimo, route is as follows:
(2) patent (CN1315318A) that proposes such as Chen Xinzi, route is as follows:
(3) patent (CN1660775A) route that proposes such as Bu Xianzhang is as follows:
Method that these patents propose and route all are earlier the aromatic hydrocarbons side chain of parahydroxyacet-ophenone to be carried out single bromo, and raspberry ketone with the diverse ways acquisition aminate of deriving, carry out the hydrocarbylation butt joint reaction on the N atom again, reduction and salify obtain final product at last.
Comprehensive above-mentioned document as can be known, U.S. Eli Lilly﹠amp; Co. the patent route of Ti Chuing, the raw material sources difficulty, by product is more in the reaction process, and reaction conditions, separation, purifying be difficulty quite.Chen Daimo, Chen Xinzi, several Chinese patent routes of propositions such as Bu Xianzhang have all carried out improvement in various degree to United States Patent (USP), and significant improvement has been arranged all on reaction conditions and yield, but still exist some significantly not enough, as in reaction process or use Raney nickel/hydrogen catalytic hydrogenation and palladium/carbon catalytic hydrogenation, or use metal borohydride to obtain the free alkali of final product, make that yield is very low when in the end forming hydrochloride at aqueous phase; All will use the more expensive liquid bromine of price to carry out bromo-reaction when preparation ω-bromo-parahydroxyacet-ophenone intermediate, yield is low, and purifying is difficulty.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of beta-adrenaline excitant lecdopamine, adopt chemical feedstocks inexpensive, that be easy to get, with simple, gentle condition, the synthetic Ractopamine hydrochloride of high yield.
The synthetic method route of the beta-adrenaline excitant lecdopamine that the present invention proposes is as follows:
Synthetic method of the present invention specifically comprises the steps:
(1) parahydroxyacet-ophenone is dissolved in the organic solvent 1, at a certain temperature, feeds chlorine and finish, filter and obtain white needle-like crystals, be ω-two chloro-parahydroxyacet-ophenone, i.e. intermediate muriate up to reaction.
(2) ω-two chloro-parahydroxyacet-ophenone is dissolved in the organic solvent 2, adds saturated aqueous sodium carbonate, further heated and stirred refluxes.After reaction was finished, the treated crude product that obtains was alpha, omega-dihydroxy-parahydroxyacet-ophenone.Without separation and purification, promptly can be used for the next step.
(3) above-mentioned not refining thing is dissolved in the organic solvent 3, add 1-methyl-3-(4-hydroxy phenyl)-propylamine, reacting by heating gets solid 1-(4-hydroxy phenyl)-2-[1-methyl-3-(4-hydroxy phenyl)-third imino-]-ethyl ketone, need not can be directly used in the next step through refining.
(4) above-mentioned refining solid 1-(4-hydroxy phenyl)-2-[1-methyl-3-(4-hydroxy phenyl)-third imino-]-ethyl ketone is dissolved in the organic solvent 4, add hydroboration tetraalkyl ammonium, reaction at a certain temperature, make end product 1-(4-hydroxy phenyl)-2-[1-methyl-3-(4-hydroxy phenyl)-third amino]-ethanol, be Ractopamine hydrochloride behind the hcl acidifying.
Said organic solvent 1 can be Glacial acetic acid in the first step, tetracol phenixin, chloroform; Methylene dichloride, tetrahydrofuran (THF), the mixed solvent of methyl alcohol or ethanol and chloroform or methylene dichloride, wherein preferred chloroform or methylene dichloride.Chlorination reaction temperature when leading to chlorine is preferably between 50 ℃~70 ℃ between-5 ℃~100 ℃.Be placed into room temperature after question response is finished, promptly have mass crystallization to separate out.This process itself is a crystallisation process, so product does not need to use further recrystallization again, purity can be used for the next step completely, and yield is 99.5%.
Said organic solvent 2 is the protic polar solvent in second step, as alcohols.Such as methyl alcohol, ethanol, propyl carbinol; Or tetrahydrofuran (THF), DMF, DMSO etc.Wherein tetrahydrofuran (THF) or DMF are better, and first-selected methyl alcohol, ethanol are solvent.Temperature of reaction can be between 40 ℃~120 ℃, stirring reaction 3-4 hour.Wherein, the weight-volume ratio of ω-two chloro-parahydroxyacet-ophenone and saturated sodium carbonate is 1.0: 30.0~1.0: 40.0 (grams per milliliter).After reaction is finished, steam and remove organic solvent, the system ethyl acetate extraction, after the organic layer drying, steaming desolventizes, and promptly can be used for the next step.Yield 97%.
Said organic solvent 3 can be toluene in the three-step reaction, benzene, dimethylbenzene, chlorinated benzene, tetracol phenixin, chloroform, methylene dichloride, 1,2-ethylene dichloride, wherein first-selected toluene or chlorinated benzene.Reaction simultaneously must be carried out in inert atmosphere, can use hydrogen or nitrogen to protect.Temperature of reaction is between 25 ℃~100 ℃.Wherein the mol ratio of alpha, omega-dihydroxy-parahydroxyacet-ophenone and 1-methyl-3-(4-hydroxy phenyl)-propylamine is 1.05: 1.0~2.0: 1.0.Best proportion is 1.1: 1.0~1.5: 1.0, react finished in 4~6 hours after, making system be as cold as room temperature promptly has a large amount of solids to separate out, suction filtration, the oven dry, need not make with extra care, be directly used in next step reaction.Yield 95%.
Said organic solvent 4 can be chloroform in the four-step reaction, tetracol phenixin, methylene dichloride, chlorinated benzene, 1,2-ethylene dichloride, or propyl carbinol, the trimethyl carbinol.Wherein optimal selection chloroform or methylene dichloride.Employed hydroboration tetraalkyl ammonium is the quaternary ammonium hydroborate in the reaction, can directly be dissolved in the nonpolar organic solvent.It is at first to generate borine (BH to the reduction mechanism of the two keys of ketone group or C=N in chloride organic solvent
3), again substrate is reduced.The substrate that utilizes this character to make to be reduced in non-aqueous solvent by metal borohydride for example: sodium borohydride or POTASSIUM BOROHYDRIDE are reduced, but also can improve reduction rate.Hydroboration tetraalkyl ammonium can be the hydroboration tetramethyl-ammonium, hydroboration tetraethyl ammonium, hydroboration TBuA, hydroboration benzyl triethyl ammonium amine, hydroboration benzyl tributylamine.Wherein optimal selection is hydroboration tetramethyl-ammonium or hydroboration TBuA.The temperature of reduction reaction can be between 0 ℃~100 ℃.Molar ratio between reduction substrate and the hydroboration tetraalkyl ammonium can be 1.0: 1.5~and 1.0: 5.0.Reaction times is 4~6 hours.Reaction is finished after acid treatment, after the organic layer drying, steam desolventize white solid thing, i.e. final product Ractopamine hydrochloride.Yield 92%.
The Ractopamine hydrochloride that adopts the inventive method to make, the yield height, good product purity, raw materials used cheap and easy to get.Greatly reduce production cost, wherein the side-chain chlorination of the first step parahydroxyacet-ophenone adopts directly to feed the dog-cheap chlorine of price, the product yield height, and purity is good.Product directly precipitation draws easy handling.Particularly the 4th step reduction reaction is with an organic solvent done reaction system, has avoided water react, after reduction finishes, directly steams and removes organic solvent, can obtain solid product; Simultaneously, owing to used hydroboration tetraalkyl ammonium class reductive agent, the catalytic hydrogenation of having avoided using noble metal to make catalyzer and carrying out, avoided using dangerous hydrogen.Entire reaction is reduced in homogeneous phase, and operation is easily gone, and is fit to scale operation.
Description of drawings
Fig. 1 is a gained intermediate muriate of the present invention, i.e. the IR spectrogram of ω-two chloro-parahydroxyacet-ophenone.
Fig. 2 is a gained intermediate muriate of the present invention, i.e. the MS spectrogram of ω-two chloro-parahydroxyacet-ophenone.
Fig. 3 is the IR of the prepared Ractopamine hydrochloride of the present invention, spectrogram.
Fig. 4 is the prepared Ractopamine hydrochloride of the present invention
1H NMR spectrogram.
Fig. 5 is the MS spectrogram of the prepared Ractopamine hydrochloride of the present invention.
Embodiment
Example 1
(1) add 250ml chloroform and 25.0 gram (0.184mol) parahydroxyacet-ophenones in the 500ml there-necked flask, be heated to 50 ℃, feed chlorine, reaction is to no longer absorbing till the chlorine.After reaction is finished.System is cooled to 0 ℃, places, have a large amount of white crystals to separate out.Suction filtration gets white solid, oven dry.Mother liquor concentrates cooling and places, and still has solid thing to separate out, suction filtration, and oven dry merges solid thing.Weigh 37.53 grams.mp?131-134℃。Yield 99.5%.
(2) get above-mentioned muriate 20.5 grams (0.1mol), methyl alcohol 50ml, saturated Na
2CO
3Solution 600ml adds in the there-necked flask of 1000ml, reflux, and stirring reaction 4 hours, reaction end is determined in the monitoring of thin layer silica gel chromatosheet.After finishing reaction, be chilled to room temperature, decompression steams methyl alcohol, aqueous solution ethyl acetate extraction.Collect and merge organic layer, anhydrous MgSO
4Dry.Remove by filter siccative, steam solvent, obtain the heavy-gravity hydrolyzate, need not make with extra care and be directly used in the next step, yield 97%.
(3) get said hydrolyzed thing crude product 16.7 grams (0.1mol); toluene 150ml adds in the there-necked flask of 500ml, nitrogen protection, heat temperature raising to 100 ℃; drip the 50ml toluene solution of 1-methyl-3-(4-the hydroxy phenyl)-propylamine of 15 grams (0.091mol) with constant pressure funnel, drip in half an hour.Insulation reaction 6 hours.After finishing reaction, make system be cooled to room temperature, have the solid thing of a large amount of yellow to separate out.Suction filtration is washed with toluene, is directly used in the next step without recrystallization, yield 91%.
(4) in a 500ml there-necked flask, add 50.8 gram (0.25mol) hydroboration 4-butyl amines, chloroform, 1,2-ethylene dichloride 200ml, be heated to 50 ℃, drip 1-(4-hydroxy phenyl)-2-[1-methyl-3-(4-hydroxy phenyl)-third imino-of 29.7 grams (0.1mol) to the inside]-the 60ml chloroformic solution of ethyl ketone crude product, stirring reaction 6 hours, after TLC monitoring reaction is finished, be chilled to room temperature, drip concentrated hydrochloric acid (content of hydrochloric acid is 0.1mol), concentrating under reduced pressure solvent then to the inside, place cooling, the solid thing of adularescent is separated out.The suction filtration oven dry gets the solid thing of Powdered white, weighs 27.3 grams, and mp 185-187 ℃, yield 92%.
Example 2
(1) in the 100ml there-necked flask, adds the parahydroxyacet-ophenone that 50ml methylene dichloride and 5.0 restrains (0.037mol), be heated to 70 ℃, feed chlorine.Reaction is monitored with TLC.After reaction is finished, system temperature is cooled to 0 ℃, places, have a large amount of white crystals to separate out.Suction filtration gets white solid, washing, oven dry.Mother liquor concentrates postcooling and places, and still has more solid thing to separate out, suction filtration, and oven dry merges solid thing, weighs 7.5 grams.Mp 131-134 ℃, yield 99.5%.
(2) get above-mentioned muriate 4.1 grams (0.02mol), ethanol 10ml, saturated Na
2CO
3Solution 160ml adds in the there-necked flask of 250ml reflux, stirring reaction 4 hours.TLC monitors reaction.After finishing reaction, be chilled to room temperature, decompression steams solvent, aqueous solution ethyl acetate extraction.Collect and merge organic layer, anhydrous MgSO
4Dry.Remove by filter siccative, steaming desolventizes, and obtains dope, is directly used in the next step, yield 97%.
(3) get said hydrolyzed thing 3.34 grams (0.02mol), 1 of 20ml, the 2-ethylene dichloride adds in the there-necked flask of 100ml.Nitrogen protection is heated to backflow, in system, drip 2.76 grams (0.0167mol) 1-methyl-3-(4-hydroxy phenyl)-propylamine 1,2-dichloroethane solution (15ml).Drip insulation reaction 6 hours in half an hour.After finishing reaction, make system be cooled to room temperature, have the solid thing of a large amount of yellow to separate out.Suction filtration is washed with toluene, is directly used in the next step without recrystallization, yield 95%
(4) in a 500ml there-necked flask, add 101.5 gram (0.5mol) hydroboration 4-butyl amines, methylene dichloride 200ml, 1 of 100ml, 2-ethylene dichloride.Be heated to 35 ℃, drip 1-(4-hydroxy phenyl)-2-[1-methyl-3-(4-hydroxy phenyl)-third imino-of 29.7 grams (0.1mol) to the inside]-the ethyl ketone crude product 1,2-dichloroethane solution (70ml), insulated and stirred reaction 6 hours.TLC monitors reaction, after finishing, is chilled to room temperature, drips concentrated hydrochloric acid (content of hydrochloric acid is 0.1mol) to the inside.The concentrating under reduced pressure solvent is placed cooling then, and the solid thing of adularescent is separated out.Suction filtration, oven dry gets the solid thing of Powdered white, weighs 27.6 grams, and mp 185-187 ℃, yield 92%.