CN106565710A - New method for preparing lysergic acid through hydrolyzing - Google Patents
New method for preparing lysergic acid through hydrolyzing Download PDFInfo
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- CN106565710A CN106565710A CN201510647381.7A CN201510647381A CN106565710A CN 106565710 A CN106565710 A CN 106565710A CN 201510647381 A CN201510647381 A CN 201510647381A CN 106565710 A CN106565710 A CN 106565710A
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- acid
- reactant mixture
- ergotic
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- metal hydroxides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a new method for preparing lysergic acid through hydrolyzing. The method comprises the following steps: directly hydrolyzing ergometrine or ergometrinine with metal hydroxide to obtain lysergic acid. The method provided by the invention is safe, economical and suitable for industrial production, and the obtained lysergic acid is high in purity. Particularly, ergometrine or ergometrinine is hydrolyzed by metal hydroxide under the condition of heating, the purity requirements of the raw materials are low, the large-scale production is facilitated, and the raw material extraction and purification costs are reduced.
Description
Technical field
The invention belongs to field of medicine production, is related to the preparation method of ergotic acid, and in particular to a kind of method that hydrolysis prepares ergotic acid.
Background technology
Ergotic acid is a part for the basic structure of natural peptide.Can be used for many semi-synthetic peptide intermediates of synthesis.It has been found that these semi-synthetic peptides can be used as medicine, such as Nicergoline, methergine, nicergoline, desernil.Be applied not only to improve serious the elderly's Psychological Health Problem, achievement is striking on the retina problems that blood vessel causes, and acute cerebrovascular problem treatment also play the role of it is prominent.
Ergotic acid is typically by the detached ergotoxine of natural peptide such as ergot or ergotamine hydrolysis manufacture.Another kind of typical preparation method method for designing designs partially synthetic by the natural precursor of fermentation acquisition, such as paspalic acid isomerization（US6242603 or US20070135681 A1）Or the hydrolysis of ergotic acid hydroxyethyl amide.
And in China, the production technology of ergotic acid is almost blank out, finds safety, economy, a process route for feasible, effective high yield and be particularly important.The present invention under metal hydroxides heating condition i.e. by hydrolyzing the method that ergometrine or ergobasinine are obtained ergotic acid, this method is for two patents of foreign country, it is not high for the purity requirement of raw material, even the zymotic fluid of ergometrine can be used for hydrolysis, so greatly be conducive to large-scale production, while decreasing raw material is extracted and purifying is caused difficulty and required cost.At the same time, we have proposed a kind of method for quickly obtaining ergotic acid solid so that the purifying in later stage becomes effective and rapid.
The content of the invention
The invention discloses a kind of method for manufacturing ergotic acid by metal hydroxides direct hydrolysis ergometrine or ergobasinine, as follows：
Specifically, the invention discloses one kind is in a certain proportion of alcoholic solution, using metal hydroxides the method that ergometrine or ergobasinine manufacture ergotic acid is hydrolyzed.
The preferred NaOH of metal hydroxides of the present invention and potassium hydroxide.Other metal hydroxides（Such as lithium, rubidium, caesium, magnesium, zinc, iron, calcium, barium, strontium etc.）The present invention is also applied for, is also considered as the part of the present invention.
In order to can effectively be hydrolyzed, preferably at least there is the alcohol of 0wt%- 99wt%, the more preferably from about alcohol of 40wt%.The presence of alcohol is favorably improved the dissolubility of raw material and product, accelerates reaction speed, and preferred alcohol includes methyl alcohol, ethanol, propyl alcohol, isopropanol, n-butyl alcohol, 2- butanol, 3- butanol, isobutanol.Further preferably use about 1wt% -50wt% metal hydroxides（Such as potassium hydroxide）The aqueous solution, more preferably from about 15%.Determine percentage by weight divided by the gross weight of primary standard substance with the weight of given component.For example, at least 12% potassium hydroxide or sodium hydrate aqueous solution will need at least 12 g potassium hydroxide or NaOH/100
The g aqueous solution.Another kind of saying is that will have 12 g potassium hydroxide or NaOH and 88 g water.It is not only restricted to any theory, it is believed that the reactant mixture is that ergometrine or ergobasinine hydrolysis provide excellent medium.
In above-mentioned reactant mixture, easily at relatively high temperatures hydrolysis makes ergometrine and the like change into ergotic acid and isolysergic acid.For example at a reflux temperature afterwards under these reaction conditions, the conversion ratio of ergometrine and the like is preferably greater than 90,91,92,93,94,95,96,97,98 or 99%, more preferably greater than 99% within about 2 hours.It is therefore preferable that the reactant mixture after hydrolysis contains below about 2% ergometrine and the like.
In general, making ergometrine or the mixing of ergobasinine, water, alcohol and metal hydroxides implement the present invention.In order that these blending constituents under stirring enough long-time obtaining the conversion ratio compared with homolysergic acid（E.g., from about 0.5,1,2,3,4,5,6 or more hours）.Reaction temperature is from about 30,40,50,55,60,65,70,75,80,85,90,95, to 100 DEG C, preferred 80-100 DEG C, more preferably 80 DEG C.
The acid for being used to adjust pH values in the embodiment of the present invention is acetic acid, hydrochloric acid, and the alkali for adjusting pH values is ammoniacal liquor.
Other features of the present invention will embody in the description of following typical embodiments, and these embodiments are used to illustrate rather than the restriction present invention.
Specific embodiment
The content of the invention is made further explanation and description with reference to specific embodiment, but, they are simultaneously not meant to limit the scope of the invention or limit.
The separating effect of ergotic acid with purity is obtained by HPLC detections, and chromatographic condition is as follows：
HPLC INSTRUMENT MODELs are Shimadzu LC-2010CHT
Chromatographic column：Wetch Uitimate
XB-C8250mm*4.6mm*5um
Mobile phase：A phases are 0.01mol/L K3PO4The aqueous solution：Nitrile=95:5（v/v）, B phases are 0.01mol/L K3PO4The aqueous solution：Nitrile=65:35（v/v）.
Gradient elution：
| Time（min） | A phases % | B phases % |
| 0 | 100 | 0 |
| 10 | 100 | 0 |
| 15 | 0 | 100 |
| 20 | 0 | 100 |
| 25 | 100 | 0 |
| 30 | 100 | 0 |
Detection wavelength：254nm
Flow velocity：1.0 mL/min
Column temperature：10 ℃
Embodiment 1
By 100 g ergometrines（Purity 95.00%）In being dissolved in 5% potassium hydroxide solution（1000 mL）, the mL of methyl alcohol 1000 is added, it was observed that forming two-phase mixture.Then two-phase mixture is made to mix about 2 hours in about 80 DEG C under nitrogen atmosphere.Reactant mixture is cooled to about 5 DEG C, reactant mixture pH value about 6.7 is adjusted with glacial acetic acid/15% hydrochloric acid, after organic solvent is evaporated off, reactant mixture is cooled to into 0 DEG C, crystallization two hours, filter at low temperature, filter cake adds the methanol solutions of 200 mL 80%, 0.5 h, filter cake (60 mL are beaten in 80 DEG C
* 3) ethanol rinse.Vacuum drying（24 hours under 60 DEG C and 30 mbar）Afterwards, the g of ergotic acid 45.2 (purity 96.31%) is obtained.
Make the ethanol solution obtained after mother liquor and cleaning product after ergotic acid beating be evaporated to the mL of volume about 200, then use in embodiment 3.
Embodiment 2
By 100 g ergobasinines（Purity 96.33%）In being dissolved in 5% potassium hydroxide solution（1000
mL）, the mL of methyl alcohol 1000 is added, it was observed that forming two-phase mixture.Then two-phase mixture is made to mix about 2 hours in about 80 DEG C under nitrogen atmosphere.Reactant mixture is cooled to about 5 DEG C, with glacial acetic acid/
15% hydrochloric acid adjusts reactant mixture pH value about 6.8, after organic solvent is evaporated off, reactant mixture is cooled to into 0 DEG C, and crystallization two hours, filter at low temperature, filter cake adds the methanol solutions of 200 mL 50%, and in 80 DEG C 0.5 h, filter cake (60 mL are beaten
* 3) ethanol rinse.Vacuum drying（24 hours under 60 DEG C and 30 mbar）Afterwards, the g of ergotic acid 46.8 (purity 95.7%) is obtained.
Make the ethanol solution obtained after mother liquor and cleaning product after ergotic acid beating be evaporated to the mL of volume about 200, then use in embodiment 3.
Embodiment 3
By 100 g ergometrines（Purity 95.00%）In being dissolved in 10% potassium hydroxide solution（800 mL）, the mL of methyl alcohol 800 is added, add the concentrated mother liquor of embodiment 1 and embodiment 2.It was observed that forming two-phase mixture.Then two-phase mixture is made to mix about 2 hours in about 80 DEG C under nitrogen atmosphere.Reactant mixture is cooled to about 5 DEG C, reactant mixture pH value about 6.8 is adjusted with glacial acetic acid/15% hydrochloric acid, after organic solvent is evaporated off, reactant mixture is cooled to into 0 DEG C, crystallization two hours, filter at low temperature, filter cake adds the methanol solutions of 200 mL 50%, 0.5 h, filter cake (60 mL * 3) ethanol rinse are beaten in 80 DEG C.Vacuum drying（At 60 DEG C and 30
Mbar is lower 24 hours）Afterwards, ergotic acid 61.4 is obtained
G (purity 95.6%).
Make the ethanol solution obtained after mother liquor and cleaning product after ergotic acid beating be evaporated to the mL of volume about 200, prepare used in next group.
Embodiment 4
By 100 g ergometrines（Purity 95.00%）In being dissolved in 15% sodium hydroxide solution（1000 mL）, the mL of ethanol 1000 is added, it was observed that forming two-phase mixture.Then two-phase mixture is made to mix about 2 hours in about 80 DEG C under nitrogen atmosphere.Reactant mixture is cooled to about 5 DEG C, reactant mixture pH value about 6.7 is adjusted with glacial acetic acid/15% hydrochloric acid, after organic solvent is evaporated off, reactant mixture is cooled to into 0 DEG C, crystallization two hours, filter at low temperature, filter cake adds the methanol solutions of 200 mL 80%, 0.5 h, filter cake (60 mL * 3) ethanol rinse are beaten in 80 DEG C.Vacuum drying（At 60 DEG C and 30
Mbar is lower 24 hours）Afterwards, ergotic acid 43.9 is obtained
G (purity 95.2%).
Make the ethanol solution obtained after mother liquor and cleaning product after ergotic acid beating be evaporated to the mL of volume about 200, prepare used in next group.
Embodiment 5
By 100 g ergometrines（Purity 95.00%）In being dissolved in 20% potassium hydroxide solution（1600 mL）, the mL of ethanol 400 is added, it was observed that forming two-phase mixture.Then two-phase mixture is made to mix about 2 hours in about 80 DEG C under nitrogen atmosphere.Reactant mixture is cooled to about 5 DEG C, reactant mixture pH value about 6.7 is adjusted with glacial acetic acid/15% hydrochloric acid, after organic solvent is evaporated off, reactant mixture is cooled to into 0 DEG C, crystallization two hours, filter at low temperature, filter cake adds the methanol solutions of 200 mL 80%, 0.5 h, filter cake (60 mL * 3) ethanol rinse are beaten in 80 DEG C.Vacuum drying（At 60 DEG C and 30
Mbar is lower 24 hours）Afterwards, ergotic acid 47.1 is obtained
G (purity 94.8%).
Make the ethanol solution obtained after mother liquor and cleaning product after ergotic acid beating be evaporated to the mL of volume about 200, prepare used in next group.
Embodiment 6
By 100 g ergometrines（Purity 95.00%）In being dissolved in 25% potassium hydroxide solution（400 mL）, the mL of isopropanol 1600 is added, it was observed that forming two-phase mixture.Then two-phase mixture is made to mix about 2 hours in about 80 DEG C under nitrogen atmosphere.Reactant mixture is cooled to about 5 DEG C, reactant mixture pH value about 6.7 is adjusted with glacial acetic acid/15% hydrochloric acid, after organic solvent is evaporated off, reactant mixture is cooled to into 0 DEG C, crystallization two hours, filter at low temperature, filter cake adds the methanol solutions of 200 mL 80%, 0.5 h, filter cake (60 mL * 3) ethanol rinse are beaten in 80 DEG C.Vacuum drying（At 60 DEG C and 30
Mbar is lower 24 hours）Afterwards, ergotic acid 49.3 is obtained
%（Purity 95.9%）.
Make the ethanol solution obtained after mother liquor and cleaning product after ergotic acid beating be evaporated to the mL of volume about 200, prepare used in next group.
Claims (8)
1. a kind of preparation method of ergotic acid, it by ergometrine or ergobasinine metal hydroxides direct hydrolysis is ergotic acid that the method is, as follows：
2. the method for claim 1, it is characterised in that the metal hydroxides is dissolved in a certain proportion of alcoholic solution.
3. method as claimed in claim 1 or 2, it is characterised in that the concentration of the metal hydroxides is 5%-25%.
4. method as claimed in claim 1 or 2, it is characterised in that the metal hydroxides is NaOH or potassium hydroxide.
5. method as claimed in claim 1 or 2, it is characterised in that hydrolysis temperature is 80-100 DEG C.
6. method as claimed in claim 5, it is characterised in that hydrolysis temperature is 80 DEG C.
7. method as claimed in claim 2, it is characterised in that described alcohol is selected from methyl alcohol, ethanol, propyl alcohol, isopropanol, n-butyl alcohol, 2- butanol, 3- butanol, one or several in isobutanol.
8. method as claimed in claim 1 or 2, it is characterised in that the method is that ergometrine is dissolved in 5% potassium hydroxide solution, adds methyl alcohol, it was observed that forming two-phase mixture；Then two-phase mixture is made to mix about 2 hours in about 80 DEG C under nitrogen atmosphere；Reactant mixture is cooled to about 5 DEG C, reactant mixture pH value 6.7 is adjusted with glacial acetic acid/15% hydrochloric acid, after organic solvent is evaporated off, reactant mixture is cooled to into 0 DEG C, crystallization two hours, filter at low temperature, filter cake adds 80% methanol solution, and in 80 DEG C 0.5h, filter cake ethanol rinse are beaten；After vacuum drying, ergotic acid is obtained.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510647381.7A CN106565710A (en) | 2015-10-09 | 2015-10-09 | New method for preparing lysergic acid through hydrolyzing |
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|---|---|---|---|
| CN201510647381.7A CN106565710A (en) | 2015-10-09 | 2015-10-09 | New method for preparing lysergic acid through hydrolyzing |
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| CN106565710A true CN106565710A (en) | 2017-04-19 |
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| CN201510647381.7A Pending CN106565710A (en) | 2015-10-09 | 2015-10-09 | New method for preparing lysergic acid through hydrolyzing |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106883227A (en) * | 2017-04-25 | 2017-06-23 | 成都倍特药业有限公司 | The method that ergometrine is prepared by ergot fermentation waste |
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2015
- 2015-10-09 CN CN201510647381.7A patent/CN106565710A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106883227A (en) * | 2017-04-25 | 2017-06-23 | 成都倍特药业有限公司 | The method that ergometrine is prepared by ergot fermentation waste |
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Application publication date: 20170419 |
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