CN107382750B - A kind of preparation method of isoproterenol sulfate - Google Patents
A kind of preparation method of isoproterenol sulfate Download PDFInfo
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- CN107382750B CN107382750B CN201710487481.7A CN201710487481A CN107382750B CN 107382750 B CN107382750 B CN 107382750B CN 201710487481 A CN201710487481 A CN 201710487481A CN 107382750 B CN107382750 B CN 107382750B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
Abstract
The invention discloses a kind of preparation methods of isoproterenol sulfate, including the following steps: (1) at room temperature, isoprel ketoboidies obtains isoprel with hydrogenated reduction under sodium borohydride effect in the solvent of methanol；(2) solvent methanol has been concentrated in negative pressure, and water is added and then is extracted with ethyl acetate, and with 60% sulfuric acid tune system pH to acidity, is warming up to 30 minutes dissolved clarifications of reflux later；(3) freeze overnight obtains white powder crystallization；(4) it filters, is dried after washing, then obtain isoproterenol sulfate with ethyl alcohol recrystallization；The present invention has evaded the dangerous hidden danger of high-pressure hydrogenation, keeps reaction safer using sodium borohydride reduction；Using synthesis under normal pressure, avoid using metal high voltage reaction kettle；Raw material is easy to get, and simple process is reasonable.
Description
Technical field
The present invention relates to a kind of environment-friendly preparation method thereofs of isoproterenol sulfate, belong to field of medicaments.
Background technique
Isoproterenol sulfate, No. CAS: 299-95-6, English name: Isoproterenol Sulfate
Dihydrate, molecular formula: C22H34N2O6 H2SO4 2H2O, chemical name: 4- [(2- isopropylamino -1- hydroxyl) ethyl] -
1,2- benzenediol sulfate dihydrate.Isoprel drug is mainly used for treating bronchial asthma, is suitable for control and roars
Acute attack is breathed heavily, normal aerosol inhalation, effect is fast and strong, but duration.Sudden cardiac arrest, for treating a variety of causes such as
Cardiac arrest caused by drowned, electric shock, operation accident and drug poisoning etc..It when necessary can be mixed with norepinephrine.Chamber
Block.Hemorrhagic shock can be used for cardiogenic shock and infectious shock.Its chemical structural formula is as follows:
Production isoproterenol sulfate mainly takes following reaction route at present:
The aqueous solution of isoprel ketoboidies sulfate is under palladium carbon effect again through a system after catalytic hydrogenating reduction
Column post-processing obtains isoproterenol sulfate.Need to use palladium-carbon catalyst, palladium-carbon catalyst easily spontaneous combustion in this route
Also easily inactivation poisoning, simultaneous reactions need to keep Hydrogen Vapor Pressure in 0.3-0.6MPa, there is security risk in use.
And isoproterenol sulfate aqueous solution cannot be contacted with metal, otherwise be easy to lose activity.In conclusion no matter from peace
Full property or stable product quality comprehensively consider the catalytic hydrogenation in high-pressure metal reaction kettle and synthesize isoprel sulfuric acid
The technique of salt is not very scientific, not reasonable.
Summary of the invention
The purpose of the present invention is to existing defect, a kind of simple process, safety and environmental protection and convenient for practical behaviour are provided
The isoproterenol sulfate green synthesis process of work.
It is as follows that the present invention synthesizes isoproterenol sulfate reaction equation:
Realize that the object of the invention is adopted the technical scheme that:
A kind of preparation method of isoproterenol sulfate, mainly includes the following steps:
(1) at room temperature, hydrogenated reduction under isoprel ketoboidies acts in the solvent of methanol with sodium borohydride
Obtain isoprel；
(2) solvent methanol has been concentrated in negative pressure, and water is added and then is extracted with ethyl acetate, with 60% sulfuric acid tune system pH
To acidity, it is warming up to 30 minutes dissolved clarifications of reflux later；
(3) freeze overnight obtains white powder crystallization；
(4) it filters, is dried after washing, then obtain isoproterenol sulfate with ethyl alcohol recrystallization.
Preferably as the present invention, in the step (1), the molar ratio of sodium borohydride and isoprel ketoboidies is 4-
10:1。
Preferably as the present invention, in the step (2), isoprel ketoboidies is dissolved in methanol, solvent methanol with it is different
The mass ratio of third adrenaline ketoboidies is 8-15:1；
Preferably as the present invention, in the step (2), extract liquor selects ethyl acetate, on ethyl acetate and isopropyl kidney
The mass ratio of parathyrine ketoboidies is 4-8:1；
Preferably as the present invention, in the step (4), the temperature of drying is 25-40 DEG C；The time of drying is that 2-5 is small
When.
Preferably as the present invention, in the step (2), tune pH value is 1-3.
The positive effect of the present invention is: (1) having evaded the dangerous hidden danger of high-pressure hydrogenation, made to react using sodium borohydride reduction
It is safer.(2) synthesis under normal pressure is used, is avoided using metal high voltage reaction kettle, to evade isoproterenol sulfate
Aqueous solution is contacted with metal, deactivated possibility.(3) raw material is easy to get, and simple process is reasonable.With existing traditional production technology
It compares, the present invention has obviously economic benefit and environmental benefit.
Specific embodiment
Using specific embodiment, the present invention is further illustrated below.
Embodiment 1
With mechanical stirring, thermometer, air guide outlet four-hole boiling flask in be added isoprel ketoboidies (94.1g,
0.45mol), methanol 750g is mixed, and sodium borohydride (69.6g, 1.8mol) is added portionwise at 25 DEG C, add sodium borohydride it
2 hours are kept the temperature afterwards, deionized water 1000g is added in reaction, with ethyl acetate (2 × 400g), combined ethyl acetate layer.With 60% sulphur
Acid adjusts system pH to 2, is warming up to 30 minutes dissolved clarifications of reflux later.Freeze overnight later obtains white powder crystallization.Filtering,
It is dried after washing, then obtains isoprenaline hydrochloride (102.7g, 0.369mol), yield 82.0% with ethyl alcohol recrystallization.
Embodiment 2
With mechanical stirring, thermometer, air guide outlet four-hole boiling flask in be added isoprel ketoboidies (94.1g,
0.45mol), methanol 940g is mixed, and sodium borohydride (104.4g, 2.7mol) is added portionwise at 25 DEG C, adds sodium borohydride
3 hours are kept the temperature later, deionized water 1000g is added in reaction, with ethyl acetate (2 × 470g), combined ethyl acetate layer.With 60%
Sulfuric acid tune system pH is warming up to 30 minutes dissolved clarifications of reflux to 3 later.Freeze overnight later obtains white powder crystallization.It crosses
Filter, is dried, then obtain isoprenaline hydrochloride (104.3g, 0.375mol), yield 83.4% with ethyl alcohol recrystallization after washing.
Embodiment 3
With mechanical stirring, thermometer, air guide outlet four-hole boiling flask in be added isoprel ketoboidies (94.1g,
0.45mol), methanol 1030g is mixed, and sodium borohydride (121.8g, 3.15mol) is added portionwise at 25 DEG C, adds hydroboration
4 hours are kept the temperature after sodium, deionized water 1000g is added in reaction, with ethyl acetate (2 × 560g), combined ethyl acetate layer.With
60% sulfuric acid tune system pH is warming up to 30 minutes dissolved clarifications of reflux to 1.5 later.Freeze overnight later obtains white powder knot
It is brilliant.Filtering, is dried, then obtain isoprenaline hydrochloride (104.8g, 0.377mol), yield with ethyl alcohol recrystallization after washing
83.8%。
Embodiment 4
With mechanical stirring, thermometer, air guide outlet four-hole boiling flask in be added isoprel ketoboidies (94.1g,
0.45mol), methanol 1200g is mixed, and sodium borohydride (139.2g, 3.6mol) is added portionwise at 25 DEG C, adds sodium borohydride
4 hours are kept the temperature later, deionized water 1000g is added in reaction, with ethyl acetate (2 × 650g), combined ethyl acetate layer.With 60%
Sulfuric acid tune system pH is warming up to 30 minutes dissolved clarifications of reflux to 1 later.Freeze overnight later obtains white powder crystallization.It crosses
Filter, is dried, then obtain isoprenaline hydrochloride (105.7g, 0.380mol), yield 84.5% with ethyl alcohol recrystallization after washing.
Embodiment 5
With mechanical stirring, thermometer, air guide outlet four-hole boiling flask in be added isoprel ketoboidies (94.1g,
0.45mol), methanol 1400g is mixed, and sodium borohydride (174.0g, 4.5mol) is added portionwise at 25 DEG C, adds sodium borohydride
4 hours are kept the temperature later, deionized water 1000g is added in reaction, with ethyl acetate (2 × 750g), combined ethyl acetate layer.With 60%
Sulfuric acid tune system pH is warming up to 30 minutes dissolved clarifications of reflux to 1.8 later.Freeze overnight later obtains white powder crystallization.It crosses
Filter, is dried, then obtain isoprenaline hydrochloride (107.2g, 0.386mol), yield 85.7% with ethyl alcohol recrystallization after washing.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise of not departing from technical principle of the invention, several improvements and modifications can also be made, these improve and become
Type also should be regarded as protection scope of the present invention.
Claims (6)
1. a kind of preparation method of formula (III) compound, the reaction equation of the preparation method are as follows:
It is characterized in that, mainly including the following steps:
(1) at room temperature, formula (I) described compound obtains in the solvent of methanol with hydrogenated reduction under sodium borohydride effect different
Third adrenaline；
(2) solvent methanol has been concentrated in negative pressure, and water is added and then is extracted with ethyl acetate, with 60% sulfuric acid tune system pH to acid
Property, it is warming up to 30 minutes dissolved clarifications of reflux later；
(3) freeze overnight obtains white powder crystallization；
(4) it filters, is dried after washing, then obtain formula (III) described compound with ethyl alcohol recrystallization.
2. a kind of preparation method of formula (III) as described in claim 1 compound, which is characterized in that the step (1)
In, the molar ratio of sodium borohydride and formula (I) described compound is 4-10:1.
3. a kind of preparation method of formula (III) as described in claim 1 compound, which is characterized in that the step (2)
In, formula (I) described compound is dissolved in methanol, and the mass ratio of solvent methanol and formula (I) described compound is 8-15:1.
4. a kind of preparation method of formula (III) as described in claim 1 compound, which is characterized in that the step (2)
In, extract liquor selects ethyl acetate, and the mass ratio of ethyl acetate and formula (I) described compound is 4-8:1.
5. a kind of preparation method of formula (III) as described in claim 1 compound, which is characterized in that the step (4)
In, the temperature of drying is 25-40 DEG C；The time of drying is 2-5 hours.
6. a kind of preparation method of formula (III) as described in claim 1 compound, which is characterized in that the step (2)
In, the tune pH value is 1-3.
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| CN112724027B (en) * | 2021-01-19 | 2022-03-01 | 河北坤安药业有限公司 | Preparation method of isoproterenol hydrochloride |
| CN115611750A (en) * | 2022-10-31 | 2023-01-17 | 成都新恒创药业有限公司 | Synthesis method of isoproterenol hydrochloride |
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| US7368221B2 (en) * | 2002-06-17 | 2008-05-06 | Verification Technologies, Inc. | Changing light absorption by disruption of conjugation |
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