CN1022625C - Improving technology of making concha-eliminating ephedrine - Google Patents

Improving technology of making concha-eliminating ephedrine Download PDF

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CN1022625C
CN1022625C CN 89106150 CN89106150A CN1022625C CN 1022625 C CN1022625 C CN 1022625C CN 89106150 CN89106150 CN 89106150 CN 89106150 A CN89106150 A CN 89106150A CN 1022625 C CN1022625 C CN 1022625C
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norephedrine
reduction
refining
phenyl
hydro
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CN1039801A (en
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金寄春
赵立民
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EAST-CHINA CHEMICAL ENGINEERING COLLEGE
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Abstract

The present invention discloses an improved technology for preparing norephedrine. In the method, when Zn<+>H2SO4 is used for hydrogenating and reducing an intermediate of 1-phenyl-2-nitryl-1-propyl alcohol for preparing norephedrine, the pH value of systems needs to be controlled to be from 4 to 7, and reaction temperature can be raised to 50 to 100 DEG C for causing the conversion rate of hydrogenation and reduction to be more than 90%; when alkalization refining is carried out, ammonia water is used as an alkalizing agent, and the pH value of systems is adjusted to be from 9 to 11 for causing Zn<++> to remain in water phases in the Zn (NH3) 4<++> mode; thus, purification technology is greatly simplified and the refining rate of products can reach 90 to 95%.

Description

Improving technology of making concha-eliminating ephedrine
The invention belongs to the field of organic synthesis, relate to a kind of preparation technology's of ephedra alkaloid improvement.
Norephedrine is a kind of of ephedra alkaloid, and formal name used at school is 1-phenyl-2-amino-1-propyl alcohol, and its chemical structural formula is:
Figure 891061509_IMG1
Its pharmacological action is similar to racephedrine, it is a kind of plan suprarenal gland medicine, the segmental bronchus smooth muscle is had relaxation effect, the rhythm of the heart is accelerated, peripheral blood vessel shrinks, increased blood pressure, central nervous system also there is excitation, and the energy depress appetite, anoretic can be made, compare with racephedrine, its effect is weak and lasting.
Norephedrine also is the important intermediate of synthesizing heterocyclic compounds, as Ke He Cheng oxazolidine, chromene, tetrahydro benzo isoquinoline 99.9, oxazoline, thieno-[2,3-C-] pyridine, the derivative of two imidazoles and pyrimidine etc.
Industrial main employing phenyl aldehyde, nitroethane are that raw material makes intermediate 1-phenyl-2-nitro-1-propyl alcohol by base catalysis at present, then with gained intermediate Zn+H 2SO 4Norephedrine (1-phenyl-2-amino-1-propyl alcohol) product is produced in reduction, again through the refining pure product of norephedrine that obtain that alkalize, this is because this technology has raw material and is easy to get, produce easy, all advantages such as the three wastes are few, so be suitable for suitability for industrialized production, but this method is the same with additive method, exists two big shortcomings:
1. when hydro-reduction, require temperature of reaction to be controlled at below 45 ℃, thereby speed of reaction is very slow, the reaction times reached more than 12 hours, and transformation efficiency is also lower, only was 50~55%.
2. in the alkalization treating process,, thereby, produce Zn(OH inevitably) making the norephedrine product alkalize into the water-insoluble free alkaloidal while by water soluble sulfate because employing NaOH or KOH make basifier 2Gel precipitation, thereby increased the difficulty of separation and purification, the refining yield of product is reduced greatly, the yield when it is refining is no more than 60% usually.
In a word, because there are as above two big shortcomings in this method on technology, making the total recovery of hydro-reduction and the refining secondary product of alkalization is about 30% only, has caused most of raw-material meaningless waste.
The objective of the invention is to overcome the above-mentioned shortcoming of prior art, a kind of improvement technology for preparing norephedrine is provided, the total recovery of product is reached more than 80%.
Design of the present invention is such:
1. by improving the condition of hydro-reduction, make intermediate 1-phenyl-2-nitro-1-propyl alcohol with Zn+H 2SO 4During reduction reaction, its transformation efficiency reaches more than 90%.
2. by improving alkaline refining process, avoid Zn(OH) 2Gel precipitation generates, thereby the refining yield of product is reached more than 90%.
The present invention also is achieved in that
1. the contriver is by change pH, temperature, Zn ++All conditions such as ionic concn are carried out the stability study discovery to intermediate 1-phenyl-2-nitro-1-propyl alcohol and product norephedrine: system is heat-staple in certain pH range.
For a long time people think habitually always " aromatic nitro alcohol ", " aromatic series amino alcohol " be heat-labile, as L.F.Fiecer[J.A.C.S.NO68P2248(1946)] point out " aromatic nitro alcohol "
Figure 891061509_IMG2
Unless temperature is very low, otherwise easily dehydration decomposition under the effect of acid of the ore deposit of trace or alkali; F.W.HooVer[J.O.C.NO12P506(1947 and for example)] also spelling out aromatic nitro alcohol, to be reduced into aromatic series with metal+acid amino when pure, it is enough low that temperature is wanted, otherwise intermediate easily decomposes dehydration, product easily decomposes deamination [J.C.S.P4576(1961)], in a word, these traditional ideas make intermediate 1-phenyl-2-nitro-1-propyl alcohol Zn+H 2SO 4When 1-phenyl-2-amino-1-propyl alcohol is produced in reduction, require temperature of reaction must be strict controlled in below 45 ℃, the hydrogenation reaction rate of system is very slow, even through 12 hours reaction, its transformation efficiency (hydrogenation) only is 50~55%.The contriver finds by a large amount of experiments:
(1) with regard to specific intermediate 1-phenyl-2-nitro-1-propyl alcohol and product 1-phenyl-2-amino-1-propyl alcohol, pH is bigger to their influence, intermediate is unsettled really under alkaline condition, but in the pH1-7 scope, be stable, product is unsettled under strong acidic condition, but in pH4~14 scopes is stable, and therefore when hydro-reduction reacted, the pH of system should be controlled between 4~7.
(2) in the scope of pH4~7, temperature of reaction does not all have obvious influence to the stability of intermediate and product.But stable best during with pH=4.For example, intermediate: work as pH=4, temperature in 50~100 ℃ of scopes, the stirring heating through 6 hours, its index of stability all 〉=95%; Product: work as pH=4, temperature in 50~100 ℃ of scopes, the stirring heating through 6 hours, its index of stability all 〉=90%.As seen intermediate in the system and product all are not the materials of thermo-sensitivity.It is more satisfactory conditions (optimal conditions) that the pH of system is controlled at 4.
(3) improve temperature and not only can accelerate the hydro-reduction speed of system effectively, and improved transformation efficiency (hydrogenation) greatly.
When pH=4~7, when temperature was 60 ℃, the hydro-reduction process of system can be finished in 6 hours, in the product that reaction ends, had not had tangible nitro charateristic avsorption band with the infrared spectra detection, and visible intermediate all is hydrogenated to product.
When pH=4~7, when temperature was 90 ℃, the hydro-reduction process of system can be finished in 4 hours, had not had tangible nitro charateristic avsorption band with the infrared spectra detection in the reaction product at the end.
In a word, facts have proved:
1. improve temperature and can accelerate speed of reaction greatly, shorten the reaction times, the hydro-reduction reaction can be finished in 4~6 hours, shortened 1~2 times than reaction times of prior art.
2. improve temperature, can improve transformation efficiency significantly, react at the end, its effective transformation efficiency can reach 90%~92%, is much higher than the transformation efficiency of prior art.
In sum, for system of the present invention, promptly by intermediate 1-phenyl-2-nitro-1-propyl alcohol Zn+H 2SO 4Hydro-reduction prepares the system of 1-phenyl~2-amino-1-propyl alcohol, as long as control pH=4~7 of system well, the hydro-reduction reaction can be carried out under 50~100 ℃, for fear of peracid, reaction system must slowly drip sulfuric acid under violent stirring, usually in a single day sulfuric acid dropwise, hydro-reduction reaction that is end, therefore improvement technology of the present invention be convenient to very much industrialized.Owing to adopt improvement technology of the present invention, not only can shorten the reaction times greatly, the hydro-reduction reaction can be finished in 4~6 hours, and can improve transformation efficiency greatly, the transformation efficiency right side of product reaches more than 90%, thereby the present invention has significant technical progress compared with prior art.
2. the contriver finds the alkaline refining process research back of prior art, produce at present the refining yield why lower (≤60%) of going up norephedrine, be that basifier is selected improper event, when with sodium, when potassium class alkali is made basifier, though can make the norephedrine (hydro-reduction reaction product at the end) in the system alkalize into water-insoluble free alkaloid, make the Zn in the system simultaneously by water soluble sulfate ++Form Zn(OH) 2Gel precipitation has brought very big difficulty to the refining purifying of norephedrine, thereby the refining yield of norephedrine is reduced greatly.
Refining improvement technology of the present invention adopts ammoniacal liquor to make basifier, and the pH=9 of Controlling System~11, and the norephedrine in the system changes into insoluble free alkaloid by water miscible vitriol at this moment, and Zn ++Ion then with NH 3Complexing forms the complexing ion Zn(NH of water miscible four-coordination 3) ++ 4, staying aqueous phase, can by water-and-oil separator norephedrine (oil reservoir) be separated easily like this, drying, underpressure distillation again obtains the pure product of norephedrine, and its refining yield can reach 90~95%.
In a word, improvement technology provided by the present invention comprises hydro-reduction technology and alkaline refining process, can make the total recovery of norephedrine can reach 80%~85%.
Further illustrate content of the present invention below in conjunction with embodiment:
The preparation of intermediate 1-phenyl-2-nitro-1-propyl alcohol (adopting phenyl aldehyde, nitroethane is raw material, reacts under base catalysis):
Get the there-necked flask that new distillatory phenyl aldehyde 53 gram+nitroethanes (C.P.) 41 gram places the band whipping appts, at room temperature agitation and dropping 5%KOH(C.P.) 138 milliliters of the aqueous solution, react that system becomes thickness milky white liquid after 4 hours.Add 25 milliliters of ether, after stirring a little, pour in the separating funnel, standing demix divides oil-yielding stratum.Water layer divides reextraction with 50 milliliters of ether again, tells ether liquid.Ether liquid and oil reservoir are merged, use saturated NaHSO then 3Unreacted phenyl aldehyde is removed in three washings of 150 milliliters of branches of the aqueous solution.Oil reservoir is again through 50 milliliters of washings and anhydrous MgSO 3After the drying, boil off unreacted nitroethane (50mmHg, 43 ℃) under the decompression, it is standby to obtain light yellow viscous liquid-1-phenyl-2-nitro-1-propyl alcohol intermediate, the refractive index n of gained intermediate 20 DFor:
Measured value: 1.5213(literature value: 1.5202).
Embodiment 1
Get 54.3 gram 1-phenyl-2-nitro-1-propyl alcohol (abbreviation intermediate) and etoh solvent (C.P.) and place there-necked flask for 100 milliliters, add Zn powder (C.P.) 90 grams, under 60 ℃ of high degree of agitation, slowly drip the H of 375 grams 30% 2SO 4The pH value of system is controlled between 4~7, dropwised, continue reaction after 15 minutes, reactant is cooled to 0 ℃, the ZnSO that unreacted excessive Zn powder of elimination and cold analysis go out through 5 hours 45 minutes 4(part), filtrate are removed the impurity of ether dissolubility with 50 milliliters of extracted with diethyl ether, use NH then 3It is blue that scaleization to litmus paper is, pH=9~11, and product is separated out with oil reservoir.Divide oil-yielding stratum, water layer divides reextraction with 100 milliliters of ether again.Ether extraction liquid and oil reservoir merge, and use anhydrous Na 2SO 4Dry.Dried oil reservoir boils off ether earlier, after carry out underpressure distillation (5mmHg, 118-124 ℃), obtain thick liquid, place after fixing, its fusing point is 48~52 ℃, and then carry out secondary recrystallization with ethanol, get elaboration, its m.P. value is 101~102 ℃ (literature value is 101~101.5 ℃), and the total recovery of product is 84%.
Embodiment 2
Except temperature of reaction is 90 ℃, 30%H 2SO 4The dropping time be outside 3 hours 45 minutes, all the other conditions are all with embodiment 1, the total recovery of final product is 80%.
By embodiment 1,2 contrast as seen: the temperature of reaction among the embodiment 2 is higher, reaction rate accelerates, and the reaction times can further shorten, but its total recovery is low during really than 60 ℃, this is owing to 30%H when reacting for 90 ℃ 2SO 4Drop rate is fast during than 60 ℃, operation control is difficult for, so easily cause pH value≤4 in partial area, it is unfavorable for the stable of product, cause the reduction of the effective transformation efficiency of product, therefore the product total recovery the when total recovery of final product is lower than 60 ℃ has on the contrary been taken all factors into consideration after the stability of energy consumption and operation, the contriver is recommended in that to carry out hydro-reduction reaction under 60 ℃ be suitable, the temperature the when contriver relatively thinks hydro-reduction by a large amount of experiments in other words with 60 ℃ for good.
In a word, adopt improvement technology of the present invention, its advantage is fairly obvious:
1. can greatly improve the speed of hydrogenation, effectively shorten the reaction time, reduce 1~2 times than prior art.
2. can improve significantly conversion ratio, make the conversion efficiency of product up to 90%~92%.
3. can improve widely the refining rate of product, refining rate can reach 90~95%, and the refining afterproduct total recovery of hydro-reduction and alkalization is reached more than 80%, 30% high more than 1.6 times than prior art.

Claims (3)

1, a kind of improvement technology for preparing norephedrine comprises with phenyl aldehyde, nitroethane being that raw material makes intermediate 1-phenyl-2-nitro-1-propyl alcohol through base catalysis, uses Zn+H then 2SO 4Hydro-reduction is produced the technology of norephedrine and the alkaline refining process of norephedrine, and said norephedrine is that a kind of formal name used at school is 1-phenyl-2-amino-1-propanol compounds, the invention is characterized in:
(1) uses Zn+H 2SO 4During hydro-reduction, the pH of system should be controlled between 4~7, and temperature of reaction is 50~100 ℃;
When (2) alkalization is refining, adopt ammoniacal liquor to make basifier;
(3) when alkalization was refining, the pH of system should be controlled between 9~11.
2, improvement technology according to claim 1, the temperature when it is characterized in that hydro-reduction is 60 ℃.
3, improvement technology according to claim 1 is characterized in that the pH value that alkalizes when making with extra care is 4.
CN 89106150 1989-07-22 1989-07-22 Improving technology of making concha-eliminating ephedrine Expired - Fee Related CN1022625C (en)

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