CN109400600A - The novel preparation method of 10 α-methoxyl group -9,10- dihydro lysergol - Google Patents
The novel preparation method of 10 α-methoxyl group -9,10- dihydro lysergol Download PDFInfo
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- CN109400600A CN109400600A CN201811549307.1A CN201811549307A CN109400600A CN 109400600 A CN109400600 A CN 109400600A CN 201811549307 A CN201811549307 A CN 201811549307A CN 109400600 A CN109400600 A CN 109400600A
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- methoxyl group
- lysergol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
It is simple for process the invention discloses a kind of product yield height and good product quality, it is suitable for the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol of industrialized production.The preparation method of 10 α-methoxyl group -9,10- dihydro lysergol, comprising the following steps: S1, prepare intermediate, methoxylation is occurred into for ergotic acid and methanol and obtains 10 α of intermediate-methoxyl group -9,10- dihydrolysergic acid methyl esters after purification；S2,10 α of intermediate-methoxyl group -9,10- dihydrolysergic acid methyl esters is reacted with reducing agent, after purification, obtains 10 α-methoxyl group -9,10- dihydro lysergol.Preparation method reaction condition using 10 α-methoxyl group -9,10- dihydro lysergol is mild, easily operated, good product quality, high income, and total recovery is conducive to industrial application up to 75% or more.
Description
Technical field
The present invention relates to chemosynthesis technical fields；The especially preparation of one kind 10 α-methoxyl group -9,10- dihydro lysergol
Method.
Background technique
Nicergoline is clinically mainly used in the treatment of the elderly's cognition, emotion and behavior disorder, is particularly suitable for
The senile dementia of vascular.The pharmacological action of Nicergoline mainly acts on α receptor and is considered as one so as to cause blood vessel dilatation
Kind vasoactive agent.In vitro study, animal experiment and clinical test in recent years discloses its extensive pharmacological action and faces
Bed applies indication.
10 α-methoxyl group -9,10- dihydro lysergol, molecular formula C17H22N2O2, CAS No.:35121-60-9 are red
Brown ceramic powder.It is the important intermediate of synthesis Nicergoline, while being also Nicergoline main metabolites.It is domestic at present raw
Produce it is less, mainly by the chemical products of import.
Its structural formula is as shown in Equation 1.
Currently, less about report 10 α-methoxyl group -9,10- dihydro lysergol.Patent CN107936010A discloses one
In the method for kind Nicergoline, in acid condition, methoxylation occurs for the lysergol and methanol, obtains 10 α-after purification
Methoxyl group -9,10- dihydro lysergol.It is existing with lysergol in face of increasing market demand and product quality requirement
It prepares 10 α-methoxyl group -9,10- dihydro lysergol synthetic technology in acid condition for lysergol and methanol to be difficult to reach, mainly
Have the disadvantage that (1) severe reaction conditions, it is difficult to control；(2) reaction is difficult, and conversion ratio is low, higher cost；(3) by-product
It is more, it is difficult to purify；(4) poor product quality.
Therefore, while this field is badly in need of finding a kind of yield and product quality for improving product, production cost, behaviour are reduced
Make the simple purification process of step, to overcome above-mentioned defect existing in the prior art, meets the needs of industrialized production.
Summary of the invention
It is simple for process the purpose of the present invention is to provide a kind of product yield height and good product quality, it is suitable for work
The novel preparation method for the 10 α-methoxyl group -9,10- dihydro lysergol that industry metaplasia produces.
The technical solution adopted by the present invention to solve the technical problems is: one kind 10 α-methoxyl group -9,10- dihydro lysergol
Novel preparation method, comprising the following steps:
S1, intermediate is prepared, methoxylation is occurred into for ergotic acid and methanol and obtains 10 α of intermediate-first after purification
Oxygroup -9,10- dihydrolysergic acid methyl esters；
S2,10 α of intermediate-methoxyl group -9,10- dihydrolysergic acid methyl esters is reacted with reducing agent, after purification, is obtained
10 α-methoxyl group -9,10- dihydro lysergol.
Further, the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol, in step sl by ergot
The specific steps of methoxylation occur with methanol for acid are as follows:
S11, it is protected from light lower ergotic acid is added in methanol and sulfuric acid mixture liquid and is transferred to photochemical reactor, control is quenched
It 10 ± 5 DEG C of temperature, opens ultraviolet light irradiation and reacts 10-18 hours, illumination reaction terminates；Wherein, the ergotic acid and methanol and
The weight ratio of sulfuric acid mixture liquid is 1:10-50；Wherein, the weight ratio of methanol and sulfuric acid mixture liquid is in methanol and sulfuric acid mixture liquid
1.0-10.0:1.0；
S12, control are quenched 10 ± 5 DEG C of temperature, reaction solution are added in the purified water of addition organic solvent and are quenched；
S13,10 ± 5 DEG C of temperature of control are added dropwise aqueous slkali and adjust pH to 9.6 ± 0.2, and stratification, water phase is with organic molten
Agent is extracted twice；Merge organic phase, anhydrous sodium sulfate dries, filters, and organic solvent is distilled off in filtrate decompression, is added organic molten
Agent decompression band steams, and band, which steams, to be finished, and is cooled to 0 DEG C, stirs 2-3 hours, filtering, with organic solvent washing filter cake, filter cake product exists
It is dried in vacuo 7-8 hours at 65 ± 5 DEG C, obtains intermediate；
10 α of intermediate-methoxyl group -9,10- dihydrolysergic acid methyl esters is reacted with reducing agent in step s 2, is made
The specific steps of 10 α-methoxyl group -9,10- dihydro lysergol are as follows:
S21, intermediate, organic solvent, metal chloride are added in reaction flask, control 20 ± 5 DEG C of temperature, reduction is added
Agent adds, and 20 ± 5 DEG C of temperature of control is stirred to react 1 hour, is warming up to 33 ± 2 DEG C and reacts 1.5 hours, reaction terminates；
S22,10 ± 5 DEG C of temperature of control are added purified water and dilute acid for adjusting pH to 4.0 ± 0.1, stir 30 minutes, be added
Diatomite and active carbon stir 30 minutes, filtering, filter cake purifying water washing；
S23, filtrate control 20 ± 5 DEG C of temperature, and aqueous slkali is added dropwise and adjusts pH to 7.5 ± 0.5；
45 ± 5 DEG C of S24, control vacuum distillations, distillation finishes, and cools to 15 ± 5 DEG C, be added dropwise appropriate aqueous slkali adjust pH to
10.5 ± 0.5,5 ± 3 DEG C are cooled to, is stirred 1-1.5 hours, filtering, filter cake purifying water washing,
S25,65 ± 5 DEG C of filter cake be dried under reduced pressure to constant weight, obtain 10 α-methoxyl group -9,10- dihydro lysergol.
Further, in step s 11, the ultraviolet lamp wavelength is 290-370nm.
Further, in step S13 and step S23, the aqueous slkali refers to potassium carbonate, sodium carbonate, cesium carbonate, hydrogen
The aqueous solution of one or more of sodium oxide molybdena, potassium hydroxide.
Further, in step S12 and step S21, the organic solvent refers to chloroform, methylene chloride, 2-
Methyltetrahydrofuran, isopropyl acetate, methanol, toluene, dimethylbenzene, ethyl acetate, tetrahydrofuran, ethyl alcohol, one in isopropanol
Kind is several.
Further, in the step s 21, the metal chloride refers to alchlor, zinc dichloride, calcium chloride, chlorine
Change one or more of cobalt.
Further, in the step s 21, the reducing agent refers to borine, Lithium Aluminium Hydride, red aluminum, sodium borohydride, BH
(CH3COO)3Middle one or more.
Further, in the step s 21, the diluted acid refers to hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, one in potassium acid sulfate
Kind or several aqueous solutions.
The beneficial effects of the present invention are:
Compared to the prior art, major advantage is technical scheme:
(1) in this technology method using ergotic acid directly with methanol in acid condition, carry out methoxylation, reaction
Condition is simple, strong operability, is easy to technology production；
(2) 10 α-methoxyl group -9,10- dihydrolysergic acid methyl esters is obtained after the completion of ergotic acid acid methoxylation, it is molten
Solution property is preferable, convenient for post-processing purifying；
(3) methoxylation finishes post-processing simply, obtains the high-quality of intermediate, high income；
(4) 10 α-methoxyl group -9,10- dihydrolysergic acid methyl esters directly reacts to obtain 10 α-methoxyl group -9,10- with reducing agent
Dihydro lysergol, condition is simple, easy to operate, and post-processing is simple, good product quality, high income.
(5) according to the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol provided herein, target product 10
α-methoxyl group -9,10- dihydro lysergol purity > 97%, total recovery are 75% or more.Therefore compared with prior art, this Shen
The preparation method for 10 α-methoxyl group -9, the 10- dihydro lysergol that please be provided not only increases product quality, and largely
On alleviate technological operation and the requirement to equipment, reduce labor intensity and production cost, and environmentally friendly, it is especially suitable
Close industrialized production.
Specific embodiment
Present invention will be further explained below with reference to specific examples.
The present invention provides the novel preparation methods of one kind 10 α-methoxyl group -9,10- dihydro lysergol, comprising the following steps:
S1, intermediate is prepared, methoxylation is occurred into for ergotic acid and methanol and obtains 10 α of intermediate-first after purification
Oxygroup -9,10- dihydrolysergic acid methyl esters；
S2,10 α of intermediate-methoxyl group -9,10- dihydrolysergic acid methyl esters is reacted with reducing agent, after purification, is obtained
10 α-methoxyl group -9,10- dihydro lysergol.
Further, the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol, in step sl by ergot
The specific steps of methoxylation occur with methanol for acid are as follows:
S11, it is protected from light lower ergotic acid is added in methanol and sulfuric acid mixture liquid and is transferred to photochemical reactor, control is quenched
It 10 ± 5 DEG C of temperature, opens ultraviolet light irradiation and reacts 6-18 hours, illumination reaction terminates；Wherein, the ergotic acid and methanol and
The weight ratio of sulfuric acid mixture liquid is 1:10-50；Wherein, the weight ratio of methanol and sulfuric acid mixture liquid is in methanol and sulfuric acid mixture liquid
1.0-10.0:1.0；
S12, control are quenched 10 ± 5 DEG C of temperature, reaction solution are added in the purified water of addition organic solvent and are quenched；
S13,10 ± 5 DEG C of temperature of control are added dropwise aqueous slkali and adjust pH to 9.6 ± 0.2, and stratification, water phase is with organic molten
Agent is extracted twice；Merge organic phase, anhydrous sodium sulfate dries, filters, and organic solvent is distilled off in filtrate decompression, is added organic molten
Agent decompression band steams, and band, which steams, to be finished, and is cooled to 0 DEG C, stirs 2-3 hours, filtering, with organic solvent washing filter cake, filter cake product exists
It is dried in vacuo 7-8 hours at 65 ± 5 DEG C, obtains intermediate；
10 α of intermediate-methoxyl group -9,10- dihydrolysergic acid methyl esters is reacted with reducing agent in step s 2, is made
The specific steps of 10 α-methoxyl group -9,10- dihydro lysergol are as follows:
S21, intermediate, organic solvent, metal chloride are added in reaction flask, control 0-25 DEG C of temperature, reduction is added
Agent adds, and 20 ± 5 DEG C of temperature of control is stirred to react 1 hour, is warming up to 33 ± 2 DEG C and reacts 1.5 hours, reaction terminates；
S22,10 ± 5 DEG C of temperature of control are added purified water and dilute acid for adjusting pH to 4.0 ± 0.1, stir 30 minutes, be added
Diatomite and active carbon stir 30 minutes, filtering, filter cake purifying water washing；
S23, filtrate control 20 ± 5 DEG C of temperature, and aqueous slkali is added dropwise and adjusts pH to 7.5 ± 0.5；
45 ± 5 DEG C of S24, control vacuum distillations, distillation finishes, and cools to 15 ± 5 DEG C, be added dropwise appropriate aqueous slkali adjust pH to
10.5 ± 0.55,5 ± 3 DEG C are cooled to, is stirred 1-1.5 hours, filtering, filter cake purifying water washing,
S25,65 ± 5 DEG C of filter cake be dried under reduced pressure to constant weight, obtain 10 α-methoxyl group -9,10- dihydro lysergol.
Further, in step s 11, the ultraviolet lamp wavelength is 290-370nm.
Further, in step S13 and step S23, the aqueous slkali refers to potassium carbonate, sodium carbonate, cesium carbonate, hydrogen
The aqueous solution of one or more of sodium oxide molybdena, potassium hydroxide.
Further, in step S12 and step S21, the organic solvent refers to chloroform, methylene chloride, 2-
Methyltetrahydrofuran, isopropyl acetate, methanol, toluene, dimethylbenzene, ethyl acetate, tetrahydrofuran, ethyl alcohol, one in isopropanol
Kind is several.
Further, in the step s 21, the metal chloride refers to alchlor, zinc dichloride, calcium chloride, chlorine
Change one or more of cobalt.
Further, in the step s 21, the reducing agent refers to borine, Lithium Aluminium Hydride, red aluminum, sodium borohydride, BH
(CH3COO)3Middle one or more.
Further, in the step s 21, the diluted acid refers to hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, one in potassium acid sulfate
Kind or several aqueous solutions.
Embodiment 1
10 α-methoxyl group-is prepared using the novel preparation method of 10 α-methoxyl group -9,10- dihydro lysergol of the present invention
Specific step is as follows for 9,10- dihydro lysergol:
1, it the step of preparing intermediate: is protected from light and lower 5.0g ergotic acid is added to 100.0g methanol and 40.0g sulfuric acid mixes
Photochemical reactor is transferred in liquid, control is quenched 10 ± 5 DEG C of temperature, and it opens ultraviolet light irradiation and reacts 10 hours, illumination reaction
Terminate, control is quenched 10 ± 5 DEG C of temperature, and reaction solution is added in organic solvent and purified water and is quenched.Control temperature 10 ± 5
DEG C, aqueous slkali is added dropwise and adjusts pH to 9.4-9.8, stratification, water phase is extracted twice with organic solvent.Merge organic phase, it is anhydrous
Sodium sulphate dries, filters, and organic solvent is distilled off in filtrate decompression, and organic solvent decompression band is added and steams, and band, which steams, to be finished, and is cooled to
It 0 DEG C, stirs 2-3 hours, filtering, with organic solvent washing filter cake, filter cake product is dried in vacuo 7-8 hours at 65 ± 5 DEG C, obtains
To 4.72g intermediate；
2, the preparation step of 10 α-methoxyl group -9,10- dihydro lysergol is prepared by intermediate: being added in reaction flask
3.5g intermediate, 70ml organic solvent, 3.0g metal chloride control 10 ± 5 DEG C of temperature, and 1.5g reducing agent is added, adds, and control
20 ± 5 DEG C of temperature processed are stirred to react 1 hour, are warming up to 33 ± 2 DEG C and react 1.5 hours, reaction terminates.10 ± 5 DEG C of temperature of control,
Purified water and dilute acid for adjusting pH is added to 4.0 ± 0.1, stirs 30 minutes, diatomite is added and active carbon stirs 30 minutes, mistake
Filter, filter cake purifying water washing.Filtrate controls 20 ± 5 DEG C of temperature, and aqueous slkali is added dropwise and adjusts pH to 7.5 ± 0.5.Control 45 ± 5
DEG C vacuum distillation, distillation finishes, and cools to 15 ± 5 DEG C, and appropriate aqueous slkali is added dropwise and adjusts pH to 10.5 ± 0.5, cools to 5 ± 3
DEG C, it stirs 1-1.5 hours, filtering, filter cake purifying water washing, 65 ± 5 DEG C of filter cake are dried under reduced pressure to constant weight, obtain 3.2g10 α-
Methoxyl group -9,10- dihydro lysergol, purity 97.7%, total recovery 80.5%.
Embodiment 2
Methoxyl group -9 10 α-are prepared using the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol of the present invention,
Specific step is as follows for 10- dihydro lysergol:
1, it the step of preparing intermediate: is protected from light and lower 5.0g ergotic acid is added to 100.0g methanol and 40.0g sulfuric acid mixes
Photochemical reactor is transferred in liquid, control is quenched 10 ± 5 DEG C of temperature, and it opens ultraviolet light irradiation and reacts 18 hours, illumination reaction
Terminate, control is quenched 10 ± 5 DEG C of temperature, and reaction solution is added in organic solvent and purified water and is quenched.Control temperature 10 ± 5
DEG C, aqueous slkali is added dropwise and adjusts pH to 9.6 ± 0.2, stratification, water phase is extracted twice with organic solvent.Merge organic phase, it is anhydrous
Sodium sulphate dries, filters, and organic solvent is distilled off in filtrate decompression, and organic solvent decompression band is added and steams, and band, which steams, to be finished, and is cooled to
It 0 DEG C, stirs 2-3 hours, filtering, with organic solvent washing filter cake, filter cake product is dried in vacuo 7-8 hours at 65 ± 5 DEG C, obtains
To 4.75g intermediate 1；
2, the preparation step of 10 α-methoxyl group -9,10- dihydro lysergol is prepared by intermediate: being added in reaction flask
20g intermediate, 420ml organic solvent, 18.0g metal chloride control 20 ± 5 DEG C of temperature, and 9.0g reducing agent is added, adds,
20 ± 5 DEG C of temperature of control is stirred to react 1 hour, is warming up to 33 ± 2 DEG C and is reacted 1.5 hours, reaction terminates.Control temperature 10 ± 5
DEG C, purified water and dilute acid for adjusting pH is added to 4.0 ± 0.1, stirs 30 minutes, diatomite is added and active carbon stirs 30 minutes,
Filtering, filter cake purifying water washing.Filtrate controls 20 ± 5 DEG C of temperature, and aqueous slkali is added dropwise and adjusts pH to 7.5 ± 0.5.Control 45 ±
5 DEG C of vacuum distillations, distillation finish, and cool to 15 ± 5 DEG C, and appropriate aqueous slkali is added dropwise and adjusts pH to 10.5 ± 0.5, cools to 5 ± 3
DEG C, it stirs 1-1.5 hours, filtering, filter cake purifying water washing, 65 ± 5 DEG C of filter cake are dried under reduced pressure to constant weight, obtain 18.2g10
α-methoxyl group -9,10- dihydro lysergol, purity 97.6%, total recovery 81.0%.
Embodiment 3
10 α-methoxyl group-is prepared using the novel preparation method of 10 α-methoxyl group -9,10- dihydro lysergol of the present invention
Specific step is as follows for 9,10- dihydro lysergol:
1, it the step of preparing intermediate: is protected from light and lower 2.0kg ergotic acid is added to 40.0kg methanol and 16.0kg sulfuric acid mixes
It closes and is transferred to photochemical reactor in liquid, control is quenched 10 ± 5 DEG C of temperature, opens ultraviolet light irradiation and reacts 15 hours, illumination is anti-
It should terminate, control is quenched 10 ± 5 DEG C of temperature, and reaction solution is added in organic solvent and purified water and is quenched.Control temperature 10 ± 5
DEG C, aqueous slkali is added dropwise and adjusts pH to 9.6 ± 0.2, stratification, water phase is extracted twice with organic solvent.Merge organic phase, it is anhydrous
Sodium sulphate dries, filters, and organic solvent is distilled off in filtrate decompression, and organic solvent decompression band is added and steams, and band, which steams, to be finished, and is cooled to
It 0 DEG C, stirs 2-3 hours, filtering, with organic solvent washing filter cake, filter cake product is dried in vacuo 7-8 hours at 65 ± 5 DEG C, obtains
To 1.84kg intermediate 1；
2, the preparation step of 10 α-methoxyl group -9,10- dihydro lysergol is prepared by intermediate: being added in reaction flask
1.84kg intermediate, 38.64L organic solvent, 1.656kg metal chloride control 20 ± 5 DEG C of temperature, and 0.828kg is added also
Former agent, adds, and 20 ± 5 DEG C of temperature of control is stirred to react 1 hour, is warming up to 33 ± 2 DEG C and reacts 1.5 hours, reaction terminates.Control
10 ± 5 DEG C of temperature, purified water and dilute acid for adjusting pH is added to 4.0 ± 0.1, stirs 30 minutes, diatomite is added and active carbon stirs
It mixes 30 minutes, filters, filter cake purifying water washing.20 ± 5 DEG C of temperature of filtrate control, dropwise addition aqueous slkali adjusting pH to 7.5 ±
0.5.45 ± 5 DEG C of vacuum distillations of control, distillation finishes, and cools to 15 ± 5 DEG C, be added dropwise appropriate aqueous slkali adjust pH to 10.5 ±
0.5,5 ± 3 DEG C are cooled to, is stirred 1-1.5 hours, filtering, filter cake purifying water washing, 65 ± 5 DEG C of filter cake are dried under reduced pressure to perseverance
Weight, obtains 1.61kg10 α-methoxyl group -9,10- dihydro lysergol, purity 98.4%, total recovery 75.4%.
The foregoing is merely illustrative of the preferred embodiments of the present invention, it should be appreciated that these embodiments are merely to illustrate the present invention
And not meaning that the present invention there is an any restrictions, any modification done within the spirit and principles of the present invention is equally replaced
It changes or improves, should all be included in the protection scope of the present invention.
Claims (8)
1. the preparation method of one kind 10 α-methoxyl group -9,10- dihydro lysergol, which comprises the following steps:
S1, intermediate is prepared, methoxylation is occurred into for ergotic acid and methanol and obtains 10 α of intermediate-methoxyl group-after purification
9,10- dihydrolysergic acid methyl esters；
S2,10 α of intermediate-methoxyl group -9,10- dihydrolysergic acid methyl esters is reacted with reducing agent, after purification, obtains 10 α -
Methoxyl group -9,10- dihydro lysergol.
2. the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol according to claim 1, it is characterised in that: in step
Ergotic acid and methanol to that the specific steps of methoxylation occur in rapid S1 are as follows:
S11, it is protected from light lower ergotic acid is added in methanol and sulfuric acid mixture liquid and is transferred to photochemical reactor, temperature is quenched in control
It 10 ± 5 DEG C, opens ultraviolet light irradiation and reacts 10~18 hours, illumination reaction terminates；Wherein, the ergotic acid and methanol and sulfuric acid
The weight ratio of mixed liquor is 1:10-50；Wherein, the weight ratio of methanol and sulfuric acid mixture liquid is 1.0- in methanol and sulfuric acid mixture liquid
10.0:1.0；
S12, control are quenched 10 ± 5 DEG C of temperature, reaction solution are added in the purified water of addition organic solvent and are quenched；
S13,10 ± 5 DEG C of temperature of control are added dropwise aqueous slkali and adjust pH to 9.6 ± 0.2, and stratification, water phase is extracted with organic solvent
It takes twice；Merge organic phase, anhydrous sodium sulfate dries, filters, and organic solvent is distilled off in filtrate decompression, and organic solvent is added and subtracts
Pressure zone steams, and band, which steams, to be finished, and is cooled to 0 DEG C, stirs 2-3 hours, filtering, with organic solvent washing filter cake, filter cake product is 65 ± 5
It is dried in vacuo 7-8 hours at DEG C, obtains intermediate；
10 α of intermediate-methoxyl group -9,10- dihydrolysergic acid methyl esters is reacted with reducing agent in step s 2,10 α-are made
The specific steps of methoxyl group -9,10- dihydro lysergol are as follows:
S21, intermediate, organic solvent, metal chloride are added in reaction flask, control 20 ± 5 DEG C of temperature, reducing agent is added,
It adds, 20 ± 5 DEG C of temperature of control is stirred to react 1 hour, is warming up to 33 ± 2 DEG C and is reacted 1.5 hours, reaction terminates；
S22,10 ± 5 DEG C of temperature of control are added purified water and dilute acid for adjusting pH to 4.0 ± 0.1, stir 30 minutes, diatom is added
Soil and active carbon stir 30 minutes, filtering, filter cake purifying water washing；
S23, filtrate control 20 ± 5 DEG C of temperature, and aqueous slkali is added dropwise and adjusts pH to 7.5 ± 5；
45 ± 5 DEG C of S24, control vacuum distillations, distillation finish, and cool to 15 ± 5 DEG C, appropriate aqueous slkali is added dropwise and adjusts pH to 10.5
± 0.5,5 ± 3 DEG C are cooled to, is stirred 1-1.5 hours, filtering, filter cake purifying water washing,
S25,65 ± 5 DEG C of filter cake be dried under reduced pressure to constant weight, obtain 10 α-methoxyl group -9,10- dihydro lysergol.
3. the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol according to claim 2, it is characterised in that: in step
In rapid S11, the ultraviolet lamp wavelength is 290-370nm.
4. the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol according to claim 2, it is characterised in that: in step
In rapid S13 and step S23, the aqueous slkali refers to potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, one in potassium hydroxide
Kind or several aqueous solutions.
5. the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol according to claim 2, it is characterised in that: in step
In rapid S12 and step S21, the organic solvent refers to chloroform, methylene chloride, 2- methyltetrahydrofuran, isopropyl acetate
One or more of ester, methanol, toluene, dimethylbenzene, ethyl acetate, tetrahydrofuran, ethyl alcohol, isopropanol.
6. the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol according to claim 2, it is characterised in that: in step
In rapid S21, the metal chloride refers to one or more of alchlor, zinc dichloride, calcium chloride, cobalt chloride.
7. the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol according to claim 2, it is characterised in that: in step
In rapid S21, the reducing agent refers to borine, Lithium Aluminium Hydride, red aluminum, sodium borohydride, BH (CH3COO)3Middle one or more.
8. the preparation method of 10 α-methoxyl group -9,10- dihydro lysergol according to claim 2, it is characterised in that: in step
In rapid S21, the diluted acid refers to the aqueous solution of one or more of hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, potassium acid sulfate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111004233A (en) * | 2019-12-27 | 2020-04-14 | 上海应用技术大学 | Novel preparation method of nicergoline |
| CN114181215A (en) * | 2021-12-27 | 2022-03-15 | 四川仁安药业有限责任公司 | Preparation method of related impurities of ketorolac or ketorolac salt |
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| CN111004233A (en) * | 2019-12-27 | 2020-04-14 | 上海应用技术大学 | Novel preparation method of nicergoline |
| CN114181215A (en) * | 2021-12-27 | 2022-03-15 | 四川仁安药业有限责任公司 | Preparation method of related impurities of ketorolac or ketorolac salt |
| CN114181215B (en) * | 2021-12-27 | 2024-03-01 | 四川仁安药业有限责任公司 | Preparation method of ketorolac or related impurities of ketorolac salt |
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Application publication date: 20190301 |