CN102718761A - Preparation method for nicergoline - Google Patents
Preparation method for nicergoline Download PDFInfo
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- CN102718761A CN102718761A CN2012101722491A CN201210172249A CN102718761A CN 102718761 A CN102718761 A CN 102718761A CN 2012101722491 A CN2012101722491 A CN 2012101722491A CN 201210172249 A CN201210172249 A CN 201210172249A CN 102718761 A CN102718761 A CN 102718761A
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- 0 CCN1C(Cc2c[n]c3c2c2ccc3)*2=CC(*)C1 Chemical compound CCN1C(Cc2c[n]c3c2c2ccc3)*2=CC(*)C1 0.000 description 4
- UFKTZIXVYHGAES-UHFFFAOYSA-N CN(CC(CO)C1)C(C2)C1c1cccc3c1c2c[nH]3 Chemical compound CN(CC(CO)C1)C(C2)C1c1cccc3c1c2c[nH]3 UFKTZIXVYHGAES-UHFFFAOYSA-N 0.000 description 1
- YSEXMKHXIOCEJA-FYOBAMORSA-N C[n](cc1CC2N(C)CC(COC(c3cncc(Br)c3)=O)C[C@@]22OC)c3c1c2ccc3 Chemical compound C[n](cc1CC2N(C)CC(COC(c3cncc(Br)c3)=O)C[C@@]22OC)c3c1c2ccc3 YSEXMKHXIOCEJA-FYOBAMORSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method for nicergoline. The preparation method for the nicergoline comprises the following steps: 1) reacting ergot alcohol in a methanol-sulfuric acid system under photocatalysis to prepare 10alpha-methoxyl-light ergot alcohol; 2) performing methylation on the 10alpha-methoxyl-light ergot alcohol and a methylated reagent in an aprotic polar solvent under the catalytic action of strong alkali to prepare 1-methyl-10alpha-methyl-light ergot alcohol; and 3) performing acylation reaction on the1-methyl-10alpha-methyl-light ergot alcohol and 5-bromine nicotinoyl halide in an aprotic hydrophobic solvent under the catalytic action of weak alkali to prepare the nicergoline. The solvents and catalysts adopted by the method have the advantages of low toxicity, low price, simple aftertreament and the like, so that the reaction residues of the products can be reduced, the quality of the product can be improved, and the requirement of environment-friendly production can be met.
Description
Technical field
The present invention relates to a kind of preparation method of nicergoline.
Background technology
Along with the continuous development and the continuous improvement of living condition of medicine technology, the elderly's of society ratio constantly increases, and has had 6.1% old man above 65 years old to suffer from senile dementia in the world.Because aging population, prediction show that the senile dementia morbidity will worldwide continue to rise, and will increase to 6,300 ten thousand of the year two thousand thirty by 2,500 ten thousand patients in 2000.Senile dementia patient's pallium is degenerated and caused it to lose normal movable function, comprises memory, judgment, abstract thinking power, inferential capability and spatial relation etc., and is last even can not accomplish simple task.Therefore understanding and the treatment to senile dementia has important medical and social effect.The treatment of senile dementia is contemporary geriatrics a great problem; It also is one of important topic of medical circle research both at home and abroad at present; Seeing that the pathogeny of senile dementia is varied; Therefore proposed the pharmacological agent of different approaches, as improved the medicine of choline system function, the medicine of correcting the calcium homeostasis imbalance, anti-oxidation medicine, interfering AP forms and sedimentary medicine, improve the medicine of cerebral circulation etc.Wherein in improving the medicine of cerebral circulation, nicergoline can improve chronic cerebral functional defect symptom rapidly, and senile dementia is had preferable curative effect.
(claim Varson again, nicergoline) be a kind of Ergot alkaloids to nicergoline, and the ability expansion of cerebral vascular improves brain blood and supplies; Have retardance of α acceptor and the metabolic effect of promotion brain, can reduce cerebral vascular resistance, significantly the cerebral blood flow increasing amount reaches the utilization to glucose, improves disturbance of intelligence.It can also promote the Dopamine HCL metabolism; Strengthen nerve conduction, improve on spirit and the mood unusually, and can promote the brain protein synthesis; Effectively improve memory; Recover the neurone normal function, improve the clinical symptom of the insufficient syndrome of chronic brain comprehensively, therefore the disturbance of intelligence of treating cerebrovascular disease and caused is had curative effect preferably.
Nicergoline is that raw material carries out synthetic with the analogue of sphacelic acid normally, and traditional synthetic route commonly used has following two kinds:
Synthetic route one: with sphacelic acid methyl esters (II) is starting raw material, under methyl alcohol, the vitriol oil, photochemical catalysis, makes 10 α-methoxyl group-light sphacelic acid methyl esters (III); Be solvent with THF (THF) then, obtain 10 α-methoxyl group-light lysergol (IV) through lithium aluminium hydride reduction; Be solvent then with the pyridine, obtain 10 α-methoxyl group-5-ergot bromo-nicotinic acid ester (V) with the reaction of 5-bromine nicotinoyl chlorine; Last and methyl iodide reacts under potassium amide catalysis and makes nicergoline (I).
The whole productive rate of this method is lower than 10%, and wherein, the sphacelic acid methyl esters (II) that is adopted is difficult to obtain in reality, and its preparation process is complicated, severe reaction conditions, and productive rate is lower, is unfavorable for production application; In addition the pyridine toxicity that adopted of 10 α-methoxyl group-light lysergol (IV) and 5-bromine nicotinoyl chlorine reaction big, cost an arm and a leg and the aftertreatment trouble; Because the boiling point of pyridine is high; Reaction is carried out the concentration time and effort consuming after finishing, and is often residual in product easily, also need use a large amount of acid solution washings usually repeatedly; If adopt a large amount of pyridines to carry out suitability for industrialized production, can cause environment to have a strong impact on.
Synthetic route two: with lysergol (VI) is raw material, in the concentrated sulfuric acid solution of methyl alcohol, through making 10 α-methoxyl group-light lysergol (IV) behind the ultraviolet catalytic; Being solvent then with the DMSO 99.8MIN., under the effect of highly basic Pottasium Hydroxide, is that methylating reagent makes 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol (VII) with the methyl iodide; Be solvent with THF (THF) at last, N, N'-NSC 57182 (DCC) is a catalyzer, makes nicergoline (I) with the condensation of 5-bromo-nicotinic acid.
The starting raw material lysergol (VI) that this method adopted has conventional commercial source, and reaction is also simpler.But also there are some following problems in the application of this method on producing: the DCC price that (1) three-step reaction is adopted is higher, and itself has certain volatility, and its hypertoxic steam is harmful; The N that the reaction back generates, N '-dicyclohexylurea is insoluble to any organic solvent, the aftertreatment trouble; Residual in product easily, need special filtration and purification apparatus, and the product after handling is difficult to solidify and separates out; Because its no uv-absorbing, general detection method is difficult to it is carried out quality control.
Summary of the invention
Based on this; Be necessary problem big to the organic reagent toxicity that is adopted in traditional nicergoline synthesis technique, the aftertreatment trouble; A kind of new nicergoline preparation method is provided; Nicergoline preparation method of the present invention adopts that toxicity is low, the simple reagent of aftertreatment, more meets the requirement that environmental protection is produced.
A kind of preparation method of nicergoline may further comprise the steps:
1) lysergol (compound VI) reacts under photocatalysis in methyl alcohol-sulfuric acid system, makes 10 α-methoxyl group-light lysergol (compound IV);
2) 10 α-methoxyl group-light lysergol (compound IV) and methylating reagent carry out methylation reaction under the alkaline katalysis in aprotic polar solvent, make 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol (compound VI I);
3) 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol (compound VI I) and 5-bromine nicotinoyl halogen are in non-proton hydrophobic solvent; Under weakly alkaline katalysis, carry out acylation reaction; Make nicergoline ((8 β)-10-methoxyl group-1; 6-dimethyl-ergot woods-8-methanol-based-5-bromo-3-pyridine carboxylic acid ester, compound I).
In step 1), methyl alcohol in said methyl alcohol-sulfuric acid system and vitriolic mass ratio are 20 ︰, 1 ~ 20 ︰ 3, and the ultraviolet source of 250nm ~ 380nm is adopted in described photocatalysis, and temperature of reaction is 10 ℃ ~ 25 ℃.
In step 2) in, described methylating reagent is methyl iodide or methyl-sulfate, described aprotic polar solvent is DMSO 99.8MIN. (DMSO), N (DMF), N,N-DIMETHYLACETAMIDE (DMA), acetonitrile or acetone; Described highly basic is Pottasium Hydroxide, sodium hydroxide, sodium amide, potassium amide, sodium methylate, sodium ethylate, sodium hydride or potassium hydride KH.
In step 2) in, the mol ratio of 10 α-methoxyl group-light lysergol and methylating reagent is 1 ︰, 1 ~ 1 ︰ 1.1; 10 α-methoxyl group-light lysergol and alkaline mol ratio are 1 ︰, 2 ~ 1 ︰ 4, are preferably 1 ︰ 3; The temperature of reaction of said methylation reaction is 15 ℃ ~ 20 ℃, is preferably 15 ℃ ~ 17 ℃.
In step 3), described 5-bromine nicotinoyl halogen is 5-bromine nicotinoyl chlorine or 5-bromine nicotinoyl bromine, is preferably 5-bromine nicotinoyl chlorine; Described non-proton hydrophobic solvent is methylene dichloride, trichloromethane, tetrachloromethane, ETHYLE ACETATE or ethyl formate, wherein is preferably methylene dichloride or trichloromethane; Described weak base is triethylamine, diethylamine, diisopropyl ethylenediamine, salt of wormwood, yellow soda ash, saleratus or sodium hydrogencarbonate, wherein is preferably triethylamine or salt of wormwood.
In step 3), the mol ratio of 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol and 5-bromine nicotinoyl halogen is 1 ︰, 1 ~ 1 ︰ 4, is preferably 1 ︰, 2 ~ 1 ︰ 3; 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol and weakly alkaline mol ratio are 1 ︰, 1.5 ~ 1 ︰ 2, are preferably 1 ︰ 2.
Further, the described acylation reaction of step 3) is earlier 5-bromine nicotinoyl halogen and weak base to be dissolved in the non-proton hydrophobic solvent, adds 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol down at 10 ℃ ~ 25 ℃, under 20 ℃ ~ 35 ℃, reacts then.
Further, the prepared nicergoline of step 3) adopts strong base solution to stir, and removes by filter insolubles, and filtrating is washed with weakly acid soln, carries out recrystallization after concentrating, and obtains the nicergoline of purifying.Wherein, described strong base solution is the aqueous solution or the strong aqua of 10% ~ 20% sodium hydroxide, Pottasium Hydroxide, Marinco H, calcium hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate or saleratus; Described weakly acid soln is 2% ~ 5% Hydrogen chloride, dilute sulphuric acid or dilute phosphoric acid; The solvent of recrystallization is selected from the combination of a kind of in acetone, ETHYLE ACETATE, the Virahol or two kinds, perhaps the mixed solvent formed of a kind of and ether in acetone, ETHYLE ACETATE, the Virahol or isopropyl ether.
Further, prepared 10 α of step 1)-methoxyl group-light lysergol and step 2) before described methylating reagent carries out methylation reaction, adopt acetonitrile to carry out recrystallization earlier.
Further, step 2) before prepared 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol and the described 5-bromine of step 3) nicotinoyl halogen carry out acylation reaction, adopt acetone to carry out recrystallization earlier.
Nicergoline preparing method's of the present invention synthetic route is following:
In traditional nicergoline preparation technology, often need adopt pyridine or this type of DDC toxicity big, cost an arm and a leg, the reagent of aftertreatment trouble, it often is difficult to carry out suitability for industrialized production, and can cause greatly harm to environment.The present invention is directed to the problems referred to above, traditional preparation method improved, and have following beneficial effect:
Advantages such as the solvent that (1) the present invention adopted, catalyzer have all that toxicity is low, low price, aftertreatment are simple can reduce the reaction residue in the product, improve the quality of products, and meet the requirement that environmental protection is produced;
(2) each step reaction all can be carried out at normal temperatures, and required equipment is simple, energy consumption is low, and reaction yield is high, can reach more than 90%;
(3) unreacted 5-bromine nicotinoyl halogen can reclaim through alkali lye alkalization back and reuses in the step 3), can save originally, and the 5-bromine nicotinoyl chlorine that reclaims still has higher activity, need not activation again.
Description of drawings
Fig. 1 is the mass spectrum of nicergoline;
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of nicergoline;
Fig. 3 is the carbon-13 nmr spectra figure of nicergoline.
Embodiment
Embodiment one: the preparation of 5-bromine nicotinoyl chlorine
8.65kg 5-bromo-nicotinic acid is dissolved in the 175kg methylene dichloride, adds the N of 0.5% ~ 1% mass equivalent, dinethylformamide (DMF) stirred and adds the 7.5kg thionyl chloride down, with mixture stirring and refluxing 5 hours.After treating the raw material complete reaction, methylene dichloride is removed in underpressure distillation, and the gained solid adds dry toluene 1.5kg, and to remove remaining thionyl chloride, toluene is removed in underpressure distillation then, obtains white powder solid 5-bromine nicotinoyl chlorine, and productive rate is 92.6%.
The preparation of two: 10 α-methoxyl group-light lysergols (compound IV) of embodiment
In the light-catalyzed reaction still, add the 50kg methyl alcohol and the 5kg vitriol oil; Preparation methyl alcohol-vitriol oil mixing solutions stirs adding 2.0kg lysergol (compound VI) down, and the unlatching wavelength region is 280nm ~ 350nm; Power is the ultraviolet high voltage mercury lamp of 1500W; Under nitrogen protection, temperature control stirred successive reaction 48 hours below 25 ℃.After treating the raw material complete reaction, reaction solution is poured in the 1000kg frozen water, stirred adding strong aqua down, transfer to pH=9 ~ 10, with the sulfuric acid in the neutralization reaction system.Extract (20kg * 3 time) with methylene dichloride, extraction liquid removes 35 ℃ of following underpressure distillation then and desolvates with the water washing of 100kg saturated common salt, obtains red powder solid crude product 2.0kg.This bullion carries out recrystallization with the 150kg acetonitrile, obtains faint yellow needle-like crystal 10 α-methoxyl group-light lysergol 1.7kg, and yield is 85%.
Embodiment three: the preparation of 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol (compound VI I)
In the 40kg DMSO 99.8MIN., add the Powdered Pottasium Hydroxide of 4.8kg; Stir after 15 minutes; Add 12.3kg 10 α-methoxyl group-light lysergol (compound IV), at room temperature continue to stir 30 minutes, temperature control is under 15 ℃ ~ 20 ℃; Slowly drip the dimethyl sulphoxide solution of 7.92kg methyl iodide, stirring reaction 1 hour.After treating the raw material complete reaction, reaction solution is poured in the 400kg frozen water, stirred 10 minutes.Extract (100kg * 3 time) with methylene dichloride, extraction liquid removes 35 ℃ of following underpressure distillation then and desolvates with the water washing of 200kg saturated common salt, the red powder solid crude product.This bullion carries out recrystallization with 530kg acetone, obtains incarnadine crystal 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol 8.2kg, and yield is 60%.
Embodiment four: the preparation of nicergoline (compound I)
Getting 7.0kg 5-bromine nicotinoyl chlorine joins in the 100kg methylene dichloride; Stir adding 1.9kg triethylamine down, temperature control slowly drips the dichloromethane solution of 3.0kg 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol (compound VI I) at 15 ℃ ~ 20 ℃; Rise to room temperature, stirring reaction 2 hours.After treating the raw material complete reaction, add the 20kg strong aqua and stirred 10 minutes,, separate out 5-bromine nicotinoyl salt, remove by filter insolubles 5-bromine nicotinoyl salt, reclaim after the acidifying and use with the unreacted 5-bromine of cancellation nicotinoyl chlorine.Filtrating is washed with 100kg water, and organic layer to remove residual triethylamine, is used 25kg saturated aqueous common salt washed twice with the Hydrogen chloride washing of 25kg5% then, at 35 ℃ of following concentrating under reduced pressure, obtains solid crude product subsequently.This bullion is added in the 4.8kg ETHYLE ACETATE, stir down at 40 ℃ ~ 50 ℃ and carry out recrystallization, separate out pulverulent solids; Leave standstill to room temperature and filter, obtain white powder solid nicergoline 2.8kg, fusing point is 134.0 ℃～135.0 ℃; Specific optical rotation is+21.07 °, and yield is 90%.
Embodiment five: the preparation of nicergoline (compound I)
Getting 8.8kg 5-bromine nicotinoyl chlorine joins in the 120kg methylene dichloride; Stir adding 1.38kg finely powdered salt of wormwood down, temperature control slowly drips the dichloromethane solution of 4.0kg 1-methyl 10 α-methoxyl group-light lysergol (compound VI I) at 10 ℃ ~ 15 ℃; Rise to room temperature, stirring reaction 2 hours.After treating the raw material complete reaction, add the 25kg strong aqua and stirred 10 minutes,, separate out 5-bromine nicotinoyl salt, remove by filter insolubles 5-bromine nicotinoyl salt, reclaim after the acidifying and use with the unreacted 5-bromine of cancellation nicotinoyl chlorine.Filtrating is washed with 120kg water, and organic layer to remove residual salt of wormwood, is used 28kg saturated aqueous common salt washed twice with the Hydrogen chloride washing of 28kg 5% then, at 35 ℃ of following concentrating under reduced pressure, obtains solid crude product subsequently.This bullion is added in the 4.8kg acetone, stir down at 40 ℃ ~ 50 ℃ and carry out recrystallization, separate out pulverulent solids, be cooled to 10 ℃ ~ 15 ℃, leave standstill and filter after 30 minutes, obtain white powder solid nicergoline 3.6kg, yield is 90%.
Embodiment six: the preparation of nicergoline (compound I)
Getting 10.67kg 5-bromine nicotinoyl bromine joins in the 100kg trichloromethane; Stir adding 1.77kg diisopropylethylamine down, temperature control slowly drips the chloroform soln of 3.5kg 1-methyl 10 α-methoxyl group-light lysergol (compound VI I) at 10 ℃ ~ 15 ℃; Rise to room temperature, stirring reaction 2 hours.After treating the raw material complete reaction, the sodium hydroxide solution that adds 25kg 12.5% stirred 10 minutes, with the unreacted 5-bromine of cancellation nicotinoyl bromine, separated out 5-bromo-nicotinic acid salt, removed by filter insolubles 5-bromo-nicotinic acid salt, reclaimed after the acidifying and used.Filtrating is washed with 100kg water, and organic layer to remove residual diisopropylethylamine, is used 20kg saturated aqueous common salt washed twice with the Hydrogen chloride washing of 20kg 5% then, at 35 ℃ of following concentrating under reduced pressure, obtains solid crude product subsequently.This bullion is added in the 4.0kg ETHYLE ACETATE, stir down at 40 ℃ ~ 50 ℃ and carry out recrystallization, separate out pulverulent solids, be cooled to 10 ℃ ~ 15 ℃, leave standstill and filter after 30 minutes, obtain white powder solid nicergoline 3.0kg, yield is 90%.
Embodiment seven: structure is identified
Adopt high-resolution mass spectrometer to measure the molecular weight of embodiment four to six prepared nicergolines, it is as shown in table 1 to measure the result:
Table 1
| The molecule measuring definite value | The molecular weight theoretical value | Molecular formula |
| 483.1160 | 483.1152 | ?C 24H 26O 3N 3Br 1 |
| 485.1135 | 485.1132 | ?C 24H 26O 3N 3 81Br 1 |
Adopt BRUKER AVANCE 400 nuclear magnetic resonance spectrometers, with deuterochloroform (CDCl
3) be solvent, TMS is interior mark, measures the nuclear magnetic resonance map of embodiment four to six prepared nicergolines, measures the result shown in table 2 ~ 3:
Table 2
1H-NMR collection of illustrative plates determination data
| δ H(ppm) | Peak shape | Proton number | J(Hz) | δ H(ppm) | Peak shape | Proton number | J(Hz) |
| 9.10,9.11 | |
1 | 1.8 | 3.05,3.07 | |
1 | 9 |
| 8.97,8.98 | |
1 | 1.8 | 3.03~3.05 | |
1 | 4.2,10.4 |
| 8.47~8.48 | |
1 | 1.8,1.8 | 2.98,2.99 | |
1 | 13.8 |
| 7.29,7.31 | |
1 | 7.8 | 2.83 | s | 3 | |
| 7.10~7.12 | |
1 | 7.8,7.2 | 2.75~2.80 | |
1 | 12.6,13.2 |
| 7.01,7.02 | |
1 | 7.2 | 2.39~2.41 | b?r.s | 1 | |
| 6.97 | |
1 | 2.32 | S | 3 | ||
| 4.34~4.37 | |
1 | 4.8,10.8 | 2.19~2.22 | |
1 | 4.2,11.4 |
| 4.22~4.25 | |
1 | 7.2,10.8 | 1.97~2.01 | |
1 | 10.8,11.4 |
| 3.75 | s | 3 | 1.23~1.27 | |
1 | 13.2,13.2 |
Table 3
13C-NMR collection of illustrative plates determination data
| δ C(ppm) | Type | δ C(ppm) | Type | δ C(ppm) | Type |
| 163.52 | C | 123.62 | CH | 68.21 | CH 2 |
| 154.67 | CH | 120.99 | CH | 59.83 | CH 2 |
| 148.51 | CH | 120.46 | C | 48.46 | CH 3 |
| 139.16 | CH | 114.53 | CH | 43.05 | CH 3 |
| 134.86 | C | 109.71 | C | 32.98 | CH 3 |
| 129.95 | C | 109.12 | CH | 30.68 | CH |
| 127.48 | C | 73.6 | C | 29.69 | CH 2 |
| 126.05 | C | 69.22 | CH | 21.5 | CH 2 |
Carry out the structure evaluation through mass spectrum and nuclear magnetic resonance map, embodiment four to six prepared end products are the title product nicergoline.
The above embodiment has only expressed several kinds of embodiments of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to claim of the present invention.Should be pointed out that for the person of ordinary skill of the art under the prerequisite that does not break away from the present invention's design, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with accompanying claims.
Claims (10)
1. the preparation method of a nicergoline may further comprise the steps:
1) lysergol reacts under photocatalysis in methyl alcohol-sulfuric acid system, makes 10 α-methoxyl group-light lysergol;
2) 10 α-methoxyl group-light lysergol and methylating reagent carry out methylation reaction under the alkaline katalysis in aprotic polar solvent, make 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol;
3) 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol and 5-bromine nicotinoyl halogen carry out acylation reaction under weakly alkaline katalysis in non-proton hydrophobic solvent, make nicergoline.
2. preparation method according to claim 1 is characterized in that, in the step 3), described 5-bromine nicotinoyl halogen is 5-bromine nicotinoyl chlorine or 5-bromine nicotinoyl bromine; Described non-proton hydrophobic solvent is methylene dichloride, trichloromethane, tetrachloromethane, ETHYLE ACETATE or ethyl formate; Described weak base is triethylamine, diethylamine, diisopropyl ethylenediamine, salt of wormwood, yellow soda ash, saleratus or sodium hydrogencarbonate.
3. preparation method according to claim 1 and 2 is characterized in that, in the step 3), the mol ratio of 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol and 5-bromine nicotinoyl halogen is 1 ︰, 1 ~ 1 ︰ 4; 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol and weakly alkaline mol ratio are 1 ︰, 1.5 ~ 1 ︰ 2.
4. preparation method according to claim 1 and 2; It is characterized in that; In the step 3); Described acylation reaction is earlier 5-bromine nicotinoyl halogen and weak base to be dissolved in the non-proton hydrophobic solvent, adds 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol down at 10 ℃ ~ 25 ℃, under 20 ℃ ~ 35 ℃, reacts then.
5. preparation method according to claim 1 further comprises, the prepared nicergoline of step 3) is stirred with strong base solution; Remove by filter insolubles; Filtrating is washed with weakly acid soln, will filtrate and carry out recrystallization after concentrating, and obtains the nicergoline of purifying.
6. preparation method according to claim 5; It is characterized in that described strong base solution is the aqueous solution or the strong aqua of 10% ~ 20% sodium hydroxide, Pottasium Hydroxide, Marinco H, calcium hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate or saleratus; Described weakly acid soln is 2% ~ 5% Hydrogen chloride, dilute sulphuric acid or dilute phosphoric acid; The solvent of said recrystallization is selected from the combination of a kind of in acetone, ETHYLE ACETATE, the Virahol or two kinds, perhaps the mixed solvent formed of a kind of and ether in acetone, ETHYLE ACETATE, the Virahol or isopropyl ether.
7. preparation method according to claim 1; It is characterized in that in the step 1), methyl alcohol in said methyl alcohol-sulfuric acid system and vitriolic mass ratio are 20 ︰, 1 ~ 20 ︰ 3; The ultraviolet source of 250nm ~ 380nm is adopted in described photocatalysis, and temperature of reaction is 10 ℃ ~ 25 ℃.
8. preparation method according to claim 1; It is characterized in that; Step 2) in, described methylating reagent is methyl iodide or methyl-sulfate, and described aprotic polar solvent is DMSO 99.8MIN., N, N,N-DIMETHYLACETAMIDE, acetonitrile or acetone; Described highly basic is Pottasium Hydroxide, sodium hydroxide, sodium amide, potassium amide, sodium methylate, sodium ethylate, sodium hydride or potassium hydride KH.
9. according to claim 1 or 8 described preparing methods, it is characterized in that step 2) in, the mol ratio of 10 α-methoxyl group-light lysergol and methylating reagent is 1 ︰, 1 ~ 1 ︰ 1.1; 10 α-methoxyl group-light lysergol and alkaline mol ratio are 1 ︰, 2 ~ 1 ︰ 4; The temperature of reaction of said methylation reaction is 15 ℃ ~ 20 ℃.
10. preparation method according to claim 1 further comprises, prepared 10 α of step 1)-methoxyl group-light lysergol is carried out recrystallization with acetonitrile; To rapid 2) prepared 1-methyl isophthalic acid 0 α-methoxyl group-light lysergol carries out recrystallization with acetone.
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| CN107936010A (en) * | 2017-10-16 | 2018-04-20 | 广州普星药业有限公司 | A kind of synthetic method of Nicergoline |
| CN109400600A (en) * | 2018-12-18 | 2019-03-01 | 四川仁安药业有限责任公司 | The novel preparation method of 10 α-methoxyl group -9,10- dihydro lysergol |
| CN111116580A (en) * | 2019-12-27 | 2020-05-08 | 上海应用技术大学 | Improved preparation method of nicergoline |
| CN111116579A (en) * | 2019-12-18 | 2020-05-08 | 江苏汉斯通药业有限公司 | Synthesis method of nicergoline |
| CN113121523A (en) * | 2021-04-15 | 2021-07-16 | 福建海西新药创制有限公司 | Method for preparing nicergoline intermediate by using microchannel reactor |
| CN113480532A (en) * | 2021-07-06 | 2021-10-08 | 福安药业集团重庆博圣制药有限公司 | Synthesis method of nicergoline |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107936010A (en) * | 2017-10-16 | 2018-04-20 | 广州普星药业有限公司 | A kind of synthetic method of Nicergoline |
| CN109400600A (en) * | 2018-12-18 | 2019-03-01 | 四川仁安药业有限责任公司 | The novel preparation method of 10 α-methoxyl group -9,10- dihydro lysergol |
| CN111116579A (en) * | 2019-12-18 | 2020-05-08 | 江苏汉斯通药业有限公司 | Synthesis method of nicergoline |
| CN111116580A (en) * | 2019-12-27 | 2020-05-08 | 上海应用技术大学 | Improved preparation method of nicergoline |
| CN111116580B (en) * | 2019-12-27 | 2022-08-23 | 上海应用技术大学 | Improved preparation method of nicergoline |
| CN113121523A (en) * | 2021-04-15 | 2021-07-16 | 福建海西新药创制有限公司 | Method for preparing nicergoline intermediate by using microchannel reactor |
| CN113480532A (en) * | 2021-07-06 | 2021-10-08 | 福安药业集团重庆博圣制药有限公司 | Synthesis method of nicergoline |
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