Abstract
The invention relates to a chemical method for synthesizing ephedrine. In the
technology, (+/-)alpha-methylaminophenylpropanone hydrochloride is taken as a raw
material and reduced to the mixtures of (+/-)ephedrine and (+/-)pseudoephedrine by
a proper reducing agent; the (+/-)ephedrine is separated, and the l-ephedrine or l-
ephedrine hydrochloride is separated by using chiral organic acid as a resolving
agent. The method enjoys simple technology, less equipment investment, less
environment pollution, less hazardous and poisonous chemical reagents which are
used and the like.
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CN101570492B
China
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Other languages Chinese Inventor 刘玉梅骆骏才刘奎钫李新德刘玉英 Current Assignee QINGHAI QINGHAIHU
PHARMACEUTICAL CO Ltd
Worldwide applications
2009 CN
Application CN2009101133584A events
2009-06-08
Application filed by QINGHAI QINGHAIHU PHARMACEUTICAL CO Ltd, Xinjiang University
2009-06-08
Priority to CN2009101133584A
2009-11-04
Publication of CN101570492A
2012-07-04
Application granted
2012-07-04
Publication of CN101570492B
Status
Active
2029-06-08
Anticipated expiration
Info Cited by (3) Legal events Similar documents Priority and Related Applications
External links EspacenetGlobal DossierDiscuss
Description
A kind of method of chemosynthesis racephedrine
Technical field
The present invention relates to a kind of method that adopts chemical synthesis
process to produce racephedrine.More specifically; The present invention relates to
a kind of hydrochloride with (±) α-methylamino Propiophenone is raw material; After
adopting suitable reductive agent that it is reduced into the mixture of (±)
ephedrine and (±) pseudoephedrine; Isolate (±) ephedrine wherein, further adopting
chiral organic acid again is resolving agent, splits the method that obtains
sanedrine or left-handed ephedrine hydrochloride.
Background technology
Racephedrine is the general name of the main alkaloid such as ephedrine,
pseudoephedrine and N-Methylephedrine from Herba Ephedrae, extracted; It is the
abbreviation of ephedrine hydrochloride, pseudoephedrine hydrochloride and 3
medicines of Methylephedrine HCL; General ephedrine commonly used means sanedrine;
It and dextral pseudoephedrine be isomer each other, is main for two kinds with
sanedrine and dextrorotation pseudoephedrine in the natural Chinese medicine
Chinese ephedra plant.Sanedrine has stimulating central nervous system, rising
blood pressure, enlarges segmental bronchus, shrinks nasal mucosa and antitussive
action; The mydriasis effect is also arranged; Be usually used in preventing
bronchial asthma attack clinically and alleviate the mild asthma outbreak;
Ypotension that subarachnoid anesthesia or epidural anesthesia cause and chronic
hypotension disease, and be used to treat the nasal obstruction that nasal mucosa
is congested, swelling causes that a variety of causes causes etc.The
dextrorotation pseudoephedrine has loose bronchial smooth muscle, vasoconstriction
effect, can be used for nasal congestion symptom that bronchial asthma, allergic
rhinitis, sinusitis paranasal sinusitis causes etc.Owing to have and shrink the
nasal mucosa vessels effect preferably; Normal and other drug compatibility is
processed compound preparation and is used to improve cold symptoms in clinical;
Like new contac, paracetamol, day and night hundred clothes are given repeated
exhortations etc. and all to be contained the composition of ephedrine in tens of
kinds of flu commonly used, the medicine for the treatment of cough and asthma, use
very extensive.
China is that the world receives the most serious country of desertification harm,
and desertification has caused huge harm for many geographic ecotopes, Economic
development and people's life and existence.With " green gold ", " desert bodyguard
" and the plant Chinese ephedra that is celebrated has been suffered destructive
excavating owing to its magical pharmaceutical use; The wild Chinese ephedra plant
resources that the ground big area distributes in the northern China Inner Mongol,
Gansu, Ningxia, Qinghai, Xinjiang etc. faces exhaustion frequently; Although
governments at all levels and scientific research personnel are in order to protect
the medicine industry of environment, protection grassland, protection deserta and
protection and development China; Dropped into a large amount of research efforts
from many-sided exploitation such as artificial culture, tissue culture, gene
engineering technique and development Chinese ephedra resource; But since the Herba
Ephedrae of artificial growth from planting cost still from the content of
ephedrine all far away from wild Herba Ephedrae, the method that therefore adopts
the method for plant extract to produce ephedrine is faced with increasing
difficulty.Because it is as broad as long that natural racephedrine (from the
natural drug Herba Ephedrae, extracting) and synthetic racephedrine are seen from
drug effect, people are utilizing the new way of method development research
production ephedrines such as various method such as tissue culture,
chemosynthesis, semi-synthetic, transgenic microorganism fermentation.Chemical
synthesis is produced ephedrine has number of ways to select, and from attending
world twenties, just has a lot of scientific research personnel to be engaged in
the research of this respect, has also obtained very big breakthrough.On the whole,
study the more three kinds of technologies that mainly contain, can be simply from
the selection of synthesis material with its be divided into that phenylpropyl
alcohol is rare, Propiophenone and propionic aldehyde method etc.At present; Can
produce the whole world of synthetic racephedrine and have only three countries
such as Germany, India and China; China also has only two tame enterprises can
produce this product; But all exist complex manufacturing, production cycle long,
use the value volume and range of product of chemical reagent, particularly organic
solvent more, problem such as environmental pollution is serious.
Summary of the invention
The present invention adopts long, use chemical reagent of the complex
manufacturing, the production cycle that exist in the technology of chemical
synthesis process production racephedrine in order to solve prior art; Particularly
the value volume and range of product of organic solvent is more, the environmental
pollution important disadvantages, and it is raw material that a kind of
hydrochloride with (±) α-methylamino Propiophenone is provided; Reach the purpose
of selective reduction through control reaction temperature; Reaction yield is
high, and raw material is handled without free, has reduced the loss of pre-
treatment process significantly; The entire reaction course operational path is
simple, and the required equipment investment is little, can combine racephedrine
factory existing installation to realize the production of novel process, and
tangible competitive edge is arranged; No matter employed organic solvent still is
all less on the kind, and do not use the serious organic solvent of environmental
pollution basically in quantity in the building-up reactions, and the discharging
of waste liquid quantity in the production process is few, and great majority all
can be recycled.The organic acid resolving agent that is adopted among the present
invention can concentrate through simple distillation after fractionation, reuse
with the way recovery back of deionized water recrystallization, and cost recovery
is low, and the recovery is high.
Technical solution of the present invention is; The hydrochloride of a kind of
utilization (±) α-methylamino Propiophenone is a raw material, through or without
adding under the condition that alkali dissociates to become (±) α-methylamino
Propiophenone, with in its dissolving organic solvent (like methyl alcohol, ethanol
or other soluble organic solvent); The carbonyl reduction agent or the catalyzer
(like hydroborate, Lithium Aluminium Hydride, aluminum isopropylate etc.) that add
aequum; Control corresponding temperature of reaction and reaction times, after
question response finishes, filter; Remove the insolubles in the reaction system,
obtain the solution of (±) ephedrine and a small amount of (±) pseudoephedrine
mixture; Concentrate; To remove solvent wherein; Under constantly stirring, add
alkaline solution (like NaOH, KOH solution etc.) then, (±) ephedrine is emanated
out from the system middle reaches with (±) pseudoephedrine mixture, and cooled and
filtered gets (±) ephedrine and a spot of (±) pseudoephedrine; Use deionized water
wash, obtain (±) ephedrine; (±) ephedrine is dissolved in the organic solvents such
as anhydrous methanol, ethanol; Adding chiral organic acids such as a certain
amount of chiral mandelic acid, camphorsulfonic acid, tartrate, YLENE acyl group
tartrate (like D-racemic melic acid, L-racemic melic acid, D-camphorsulfonic acid,
L-tartrate, L-YLENE acyl group tartrate and D-YLENE acyl group tartrate etc.) is
resolving agent, the heating it is dissolved in the solvent fully, treat solution
limpid transparent after; Stop heating; If any insolubles, need filtered while hot
with the impurity in the system of removing, leave standstill; Make its natural
cooling crystallization, obtain the salt that chiral organic acid and sanedrine
generate; Filter, the little solvent wash crystallization is used in the
crystallization of resulting separation, and is not enough like gained
crystallization purity, can handle with an amount of solvent recrystallization in
addition; It is free that resulting crystallization is added alkali, leaves
standstill to separate after making its layering, or carry out extracting and
separating with toluene, YLENE, ether equal solvent; Isolate organic phase, boil
off solvent, or directly in solvent, add the appropriate hydrochloric acid
acidifying; Promptly get the crystallization of left-handed ephedrine
hydrochloride, filter, filtrating can evaporate behind the partial solvent more
further crystallisation by cooling in right amount; Obtain left-handed ephedrine
hydrochloride crystallization, the treatment process of crystallisate is the same,
and filtrating is reclaimed solvent.
For achieving the above object, the present invention adopts following technical
scheme to be achieved:
A kind of method of chemosynthesis racephedrine comprises following flow process:
(1) hydrochloride with (±) α-methylamino Propiophenone is a raw material; Through
or after add the step that alkali dissociates to become (±) α-methylamino
Propiophenone; It is dissolved in (like methyl alcohol, ethanol or other soluble
organic solvent) in the organic solvent, adds the carbonyl reduction agent or the
catalyzer (like hydroborate, Lithium Aluminium Hydride, aluminum isopropylate etc.)
of aequum, control corresponding temperature of reaction and reaction times; After
question response finishes; Filter, remove the insolubles in the reaction system,
obtain the solution of (±) ephedrine and a small amount of (±) pseudoephedrine
mixture;
(2) solution that obtains (±) ephedrine and (±) pseudoephedrine mixture in the
above-mentioned steps is concentrated to remove solvent wherein; It is free under
constantly stirring, to add alkali then; Dissociate (±) ephedrine and a small
amount of (±) pseudoephedrine mixture in the system, cooling is filtered; Use the
small amount of deionized water washing precipitation, get the solid of (±)
ephedrine;
(3) resulting (±) ephedrine in the above-mentioned steps is dissolved in the
organic solvents such as anhydrous methanol, ethanol, adding chiral organic acids
such as a certain amount of chiral mandelic acid, camphorsulfonic acid, tartrate,
YLENE acyl group tartrate is resolving agent, and heating makes it be dissolved in
the solvent fully; Treat solution limpid transparent after, stop the heating, if
any insolubles; Need filtered while hot with the impurity in the system of
removing; Leave standstill, make its natural cooling crystallization, obtain the
salt that chiral organic acid and sanedrine generate;
(4) with resulting crystallization filtering separation in the above-mentioned
steps, use the little solvent wash crystallization, not enough like gained
crystallization purity, can handle with an amount of solvent recrystallization in
addition;
(5) it is free resulting crystallization in the above-mentioned steps to be added
alkali, leaves standstill to make its layering or carry out extracting and
separating with toluene, YLENE, ether equal solvent, isolates organic phase; Water
is waited until next step processing, and organic phase boils off solvent, or
directly in solvent, adds the appropriate hydrochloric acid acidifying; Promptly
get the crystallization of left-handed ephedrine hydrochloride, filter, filtrating
can evaporate behind the partial solvent more further crystallisation by cooling in
right amount; Obtain left-handed ephedrine hydrochloride crystallization, the
treatment process of crystallisate is the same, and filtrating is reclaimed;
The raw material that the present invention selected for use is the hydrochloride
of (±) α-methylamino Propiophenone; This raw material can directly be dissolved in
the reaction solvent; Also can with its be dissolved in make it dissociate to
become (±) α-methylamino Propiophenone in the certain density alkaline solution
after; After separating water layer wherein, it is dissolved in the corresponding
reaction solvent, its preferred reaction solvent is anhydrous methanol or absolute
ethyl alcohol etc. again.
The carbonyl reduction agent that the present invention selected for use is
hydroborate preferably, more specifically is Peng Qinghuana or POTASSIUM
BOROHYDRIDE 97MIN etc.; Temperature of reaction is-10～50 ℃, is more preferably 0～
25 ℃; Reaction times is 0～6h, and the preferred described reaction times is 1～2h.
The resulting reduzate of the present invention is the mixture of (±) ephedrine and
(±) pseudoephedrine.Under optimized reaction conditions, the content of (±)
ephedrine is apparently higher than the content of (±) pseudoephedrine, and (±)
ephedrine accounts for more than 85% of amount of the mixture.
The chiral organic acid resolving agent that the present invention selected for use
combines to generate the salt of ephedrine and chiral organic acid for an
enantiomorph in ability and the ephedrine; Or two enantiomorphs of ability and
ephedrine all can generate the salt of ephedrine and chiral organic acid; Separate
out but one of them enantiomorph solubleness in the solvent of being selected for
use is less, another enantiomorph is then stayed in the solvent and is realized
chiral separation in advance; Described organic acid is D-racemic melic acid, L-
racemic melic acid, D-camphorsulfonic acid, L-tartrate, D-YLENE acyl group tartrate
or L-YLENE acyl group tartrate etc.; Preferably selecting the D-racemic melic acid
for use is resolving agent; Make like this sanedrine and the formed salt of D-
racemic melic acid at first crystallization separate out, and resulting crystal
optics purity is high.
The ephedrine that the present invention selected for use can be realized under
certain molar ratio not to becoming to split with the chiral organic acid resolving
agent; And the optical purity of resolved product is very high; The mol ratio of
the resolving agent of general control (±) ephedrine and chiral organic acid is 1:
0.1～1: 2.0, and what more optimize is 1: 0.25～1: 0.6.
The resulting product of the present invention have with natural Herba Ephedrae in
extract sanedrine or identical chemical property and the effect of left-handed
ephedrine hydrochloride prepare; It is simple to have production technique
simultaneously; Easy to use; The technological operation difficulty is little, step
is few, the poisonous and harmful organic solvent that uses seldom or basically do
not use the advantage of poisonous and harmful organic solvent, be more suitable
for large-scale industrial production.
Embodiment
Adopt the mode of specific embodiment to explain the present invention particularly
below, but the present invention is not limited to embodiment.
Embodiment 1:
α-methylamino Propiophenone hydrochloride 10g is dissolved in the 40-50mL methyl
alcohol (content is more than 99%), stirs adding 5.5g Na BH down 4, the borane
reducing agent sodium hydride can slowly add in the time in 15-30min, is not higher
than 30 ℃ with the control temperature of reaction system and is advisable; Add
continued and stir reaction 30min down, after reaction finished, methyl alcohol was
reclaimed in underpressure distillation; Enriched material adds 10%NaOH solution
makes its dissolving, transfers the pH value of solution value greater than 11, and
the free postprecipitation of ephedrine is separated out; Filter, vacuum-drying,
the mixture that gets (±) ephedrine and (±) pseudoephedrine amounts to 7.5g;
Calculating reaction yield with α-methylamino Propiophenone is 93.8%, through
liquid-phase chromatographic analysis wherein the ratio of (±) ephedrine and (±)
pseudoephedrine be 93.5: 6.5.
Embodiment 2:
α-methylamino Propiophenone hydrochloride 20g is dissolved in the 100mL absolute
ethyl alcohol, stirs adding KBH down 42g, the borane reducing agent potassium
hydride KH can slowly add in the time in 15-30min, is not higher than 30 ℃ with
the control temperature of reaction system and is advisable; Add continued and stir
reaction 3h down, after reaction finished, ethanol was reclaimed in underpressure
distillation; Enriched material adds 10%NaOH solution makes its dissolving,
transfers the pH value of solution value greater than 11, and the free
postprecipitation of ephedrine is separated out; Filter, steam empty drying, the
mixture that gets (±) ephedrine and (±) pseudoephedrine amounts to 15.3;
Calculating reaction yield with α-methylamino Propiophenone is 95.6%, through
liquid-phase chromatographic analysis wherein the ratio of (±) ephedrine and (±)
pseudoephedrine be 97.1: 2.9.
Embodiment 3:
α-methylamino Propiophenone hydrochloride 100g is dissolved in the 300mL methyl
alcohol (content is more than 99%), stirs adding 9.9g KBH down 4, the borane
reducing agent sodium hydride can slowly add in the time in 15-30min, is not higher
than 30 ℃ with the control temperature of reaction system and is advisable; Add
continued and stir reaction 30min down, after reaction finished, methyl alcohol was
reclaimed in underpressure distillation; Enriched material adds 10%NaOH solution
makes its dissolving, transfers the pH value of solution value greater than 11, and
the free postprecipitation of ephedrine is separated out; Filter, steam empty
drying, the mixture that gets (±) ephedrine and (±) pseudoephedrine amounts to
76.8g; Calculating reaction yield with α-methylamino Propiophenone is 96.0%,
through liquid-phase chromatographic analysis wherein the ratio of (±) ephedrine
and (±) pseudoephedrine be 94.7: 5.3.
Embodiment 4:
20g (±) ephedrine (content is 97.1%) is dissolved in the hot absolute ethyl alcohol
of 50mL, adds resolving agent D-racemic melic acid (for 0.5 times of amount of
ephedrine mol ratio) simultaneously, and slowly heated soln is to limpid
transparent; After stopping heating, the ethanolic soln placement is made its
naturally cooling (for improving its crystallization velocity, also can place cold
water or refrigerator to make its crystallization); Usually in 2h, can obtain the
crystallization of the salt of racemic melic acid and sanedrine formation; Filter,
and, get the crystallization 15.62g that D-racemic melic acid and sanedrine form
with small amount of cold washing with alcohol crystallization 2-3 time; Through
measuring this crystalline melt point is 167-169 ℃, consistent with literature
value.
Embodiment 5:
With 15% NaOH solution dissolving, ephedrine is free separates out, and extracts at
twice with the 25mL extracted with diethyl ether with the crystallization 15.62g of
the D-racemic melic acid of above-mentioned experiment gained and sanedrine;
Combining extraction liquid; Concentrating under reduced pressure is sloughed
ether, adds 20% hcl acidifying in the enriched material, and left-handed ephedrine
hydrochloride crystallization is separated out; Filtration, drying get left-handed
ephedrine hydrochloride 8.62g.
Claims (5)
Hide Dependent
1. the method for a chemosynthesis racephedrine is characterized in that may
further comprise the steps:
(1) hydrochloride with (±) α-methylamino Propiophenone is a raw material; It is
dissolved in methyl alcohol or the ethanol, adds the carbonyl reduction agent or
the catalyzer hydroborate of aequum, it is 0～6h with the reaction times that
control reaction temperature is-10 ℃～50 ℃; After question response finishes;
Filter, remove the insolubles in the reaction system, contained the solution of (±)
ephedrine and a small amount of (±) pseudoephedrine mixture;
(2) concentrated containing the solution of (±) ephedrine in the above-mentioned
steps with a small amount of (±) pseudoephedrine mixture; Remove solvent wherein,
under constantly stirring, add alkali then, (±) ephedrine is emanated out from the
system middle reaches with a small amount of (±) pseudoephedrine mixture; Cooling;
Filter, use the small amount of deionized water washing precipitation, get the
solid of (±) ephedrine;
(3) resulting (±) ephedrine in the above-mentioned steps is dissolved in the
organic solvents such as anhydrous methanol, ethanol; Add (±) ephedrine: the chiral
organic acid mol ratio is that chiral organic acid D-racemic melic acid, L-racemic
melic acid, D-camphorsulfonic acid, L-tartrate, D-YLENE acyl group tartrate or the
L-YLENE acyl group tartrate of 1: 0.1～1: 2.0 respective amount is resolving agent,
and heating is dissolved in the solvent it fully, treat solution limpid transparent
after; Stop heating; If any insolubles, need filtered while hot with the impurity
in the system of removing, leave standstill; Make its natural cooling
crystallization; Obtain the salt that chiral organic acid and sanedrine generate,
the filtering separation crystallization is handled with little solvent wash
crystallization or recrystallization;
(4) it is free resulting crystallization in the above-mentioned steps to be added
alkali, leaves standstill and makes its layering, isolates oil phase, obtains the
crystallization of sanedrine;
(5) or with resulting crystallization in the above-mentioned steps (3) add alkali
free after; Carry out extracting and separating with toluene, YLENE, ether equal
solvent, isolate organic phase, boil off solvent; Or directly in solvent, add the
appropriate hydrochloric acid acidifying; Promptly get the crystallization of left-
handed ephedrine hydrochloride, filter, obtain the crystallization of left-handed
ephedrine hydrochloride.
2. method according to claim 1, the raw material of the hydrochloride of (±) α-
methylamino Propiophenone that it is characterized in that being selected for use
also can adopt and add alkali earlier and make its step of dissociating to become
(±) α-methylamino Propiophenone, it are dissolved in methyl alcohol or the absolute
ethyl alcohol again.
3. method according to claim 1 is characterized in that described carbonyl
reduction agent or catalyzer are hydroborate, more specifically is Peng Qinghuana
or POTASSIUM BOROHYDRIDE 97MIN etc.
4. method according to claim 1 is characterized in that preferably D-racemic melic
acid of described chiral organic acid.
5. method according to claim 1, the mol ratio that it is characterized in that the
resolving agent of (±) ephedrine and chiral organic acid is 1: 0.25～1: 0.6.
Cited By (3)
Publication number Priority date Publication date Assignee Title
Family To Family Citations
CN101870660A * 2010-05-10 2010-10-27 青海省青海湖药业有限公司 Preparation method of L-
(-)-ephedrine chloride and d-(+)-pseudoephedrine hydrochloride
CN102399158B * 2010-09-16 2014-04-02 哈尔滨工业大学 Chemical technology for
preparing ephedrine
CN108969448A * 2018-10-17 2018-12-11 刘怀 Draft white jade returns face cream
* Cited by examiner, † Cited by third party, ‡ Family to family citation
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Priority And Related Applications
Priority Applications (1)
Application Priority date Filing date Title
CN2009101133584A 2009-06-08 2009-06-08 Chemical method for synthesizing
ephedrine
Applications Claiming Priority (1)
Application Filing date Title
CN2009101133584A 2009-06-08 Chemical method for synthesizing ephedrine
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