CN102276599A - Process for preparing vincamine by semisynthetic method - Google Patents
Process for preparing vincamine by semisynthetic method Download PDFInfo
- Publication number
- CN102276599A CN102276599A CN2011102376862A CN201110237686A CN102276599A CN 102276599 A CN102276599 A CN 102276599A CN 2011102376862 A CN2011102376862 A CN 2011102376862A CN 201110237686 A CN201110237686 A CN 201110237686A CN 102276599 A CN102276599 A CN 102276599A
- Authority
- CN
- China
- Prior art keywords
- vincamine
- reaction
- tabersonine
- methyl alcohol
- quality
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a synthetic process for chemical medicines, in particular to a process for preparing vincamine by a semisynthetic method. At present, the process for preparing the vincamine is divided into a total synthetic method and the semisynthetic method, wherein the semisynthetic method has the problems of unstable and inflammable hydrogenation catalyst, large using amount, high hydrogenation pressure, insecurity in the preparation of monoperoxide maleic acid and the like. The process comprises the following steps of: preparing tabersonine vincadifformine hydrochloride, preparing the monoperoxide maleic acid, performing oxidizing reaction, performing reduction reaction and transposition reaction, precipitating ammonia and purifying products, wherein the low-cost and stable Pd/C hydrogenation catalyst is selected to reduce the pressure of the hydrogenation reaction; tabersonine sulfate is replaced by the tabersonine hydrochloride; the monoperoxide maleic acid is prepared by using low-concentration hydrogen peroxide; the reaction temperature is below 0 DEG C, and security coefficients are improved; the temperature of the oxidizing reaction is reduced, and the generation of isomers is reduced; purification and solvent recrystallization are performed by column chromatography; and the quality of the products reaches the pharmaceutical-grade standard.
Description
Technical field
The present invention relates to the synthesis technique of chemicals, specifically a kind of preparation technology of semi-synthesis method vincamine.
Background technology
Vincamine English name vincamine, CAS NO 1617-90-9, its chemical name are 14,15-dihydro-14 β-hydroxy-(3 α, 16 α)-ebumamenine-14-carboxylic acid methyl ester, molecular formula is C
21H
26N
2O
3,Molecular weight is 354.43.White or flaxen crystalline powder, water insoluble, be slightly soluble in alcohols, be dissolved in chloroform or methylene dichloride, fusing point is 229 ℃-231 ℃, [α]
D 25+ 39
To+43
(C=0.0282, pyridine), IR: λ cm
-1: 1756,1074,747,727; UV has maximum absorption at 220nm and 268nm, at 243nm minimal absorption is arranged.
Vincamine can see through hemato encephalic barrier, makes the diseased region cerebral tissue keep and recover the oxygenolysis metabolism of glucose, make the generation of lactic acid and the release of carbonic acid gas recover normal, thereby the little blood vessel of expansion brain improves cerebral circulation; Blood flow to the normal brain activity district of normal cerebral tissue and patient's cerebral tissue does not have obvious influence, does not influence the systemic blood circulation yet; Also has slight sedative effect in addition.Be used for apoplexy and lose disease, ischemia hypertensive encephalopathy, cerebral arteriosclerosis, cerebral ischaemia, cerebral embolism, be suitable for the symptom elimination that the early ageing brain is degenerated, as dizzy, headache, hypomnesis, absent minded, aphasia, Meniere disease etc., also be the important source material of semi-synthetic cancer therapy drug vinpocetin simultaneously.
Vincamine has two kinds of preparation technologies at present, and a kind of is complete synthesizing process; Another kind is a semi-synthesis method, mainly is to extract the effective constituent tabersonine from the seed of African Voacanga, semi-syntheticly then goes out vincamine.The patent of semi-synthetic vincamine and document have been delivered a lot, and main operational path has two; Article one, be tabersonine starting raw material with biological extraction, behind hydrogenating reduction, with metachloroperbenzoic acid or to the oxidation of nitro benzoyl hydroperoxide, reduce with triphenylphosphine again, last acetic acid water transposition has just obtained vincamine, at patent US3892755, US3979395 and US4285949 detailed narration is arranged; Second is the tabersonine starting raw material with biological extraction, behind hydrogenating reduction, the hydrogenation thing is become vitriol, use single peroxy maleic acid oxidation again, through reduction, transposition, the settlement separate vincamine that makes, patent FR2577926 and FR2534920 have detailed explanation again.
At patent US3892755 and US3979395 and US4285949, in the technical scheme of disclosed article one technology, there is following problem:
1. the hydrogenation catalyst used therein amount is big, is to drop into about 20% of tabersonine weight, and is relatively more expensive simultaneously, as platinum oxide etc.;
2. that uses is highly purified to bad buying on the nitro benzoyl hydroperoxide market, and own preparation need be used content up to 90% hydrogen peroxide, and danger is very big; Make oxygenant with highly purified metachloroperbenzoic acid, the one, dangerous, the 2nd, it is very difficult thoroughly to remove metachloroperbenzoic acid;
3. remove reacted impurity triphenylphosphine and triphenylphosphine oxide, the one, sad filter, the 2nd, it is difficult to separate, and needs column chromatography;
4. the product vincamine purity difference that makes, crude product obtains 20% apo-vincamine through column chromatography for separation, 55% vincamine, 25% epi-vincamine.
5. isomer proportion is big, vincamine:epi-vincamine=2.5: 1, and reacting best is 3: 1.
At patent FR2577926 and FR2534920, there is following problem in the technical scheme of disclosed second technology:
1. used hydrogenation catalyst is Raney's nickel (Raney Nickel), active big extremely instability, and very easily burning in air, and add-on is also big, is to drop into about 20% of tabersonine weight;
2. the pressure height of hydrogenation reaction, 8-30bar(is equivalent to 8-30 normal atmosphere approximately), need high-tension apparatus, certain danger is arranged during operation;
3. in the process of the single peroxy maleic acid of preparation, the one, need hydrogen peroxide with 60%, bad having bought on the market all has certain danger in the process of storage, transportation and use; The 2nd, the temperature of reaction height needs 30 ℃ of reactions, and superoxide is all unstable, and temperature is high more unstable more, easily blast;
4. the vitriol of hydrogenation thing (vincadifformine), in the process of dropping oxidizing agent oxidation, temperature is-7 ℃ to-3 ℃, temperature drift, the ratio of isomer (vincamine: epivincamine=9: 1) bigger than normal;
5. all do not mention the content of the finished product and may reach the purge process of pharmaceutical grade standard.Experimental results show that: content in crude product (HPLC detection), all below 80%; Elaboration content is all below 90%.
Compare these two kinds of operational paths, article one route is not obviously preponderated: the one, and the hydrogenation catalyst costliness;
The 2nd, the superoxide purity requirement that oxidation is used is very high, and is very unstable again, poor stability, the bad realization of industrialization; The 3rd, product purity is poor, needs through the multistep column chromatography for separation.
At the second operational path, how to solve poor stability and the poor product quality and the higher problem of cost of industrialized production, be present research direction.
Summary of the invention
The preparation technology who the purpose of this invention is to provide a kind of semi-synthesis method vincamine, extremely unstable with the hydrogenation catalyst that solves prior art, be exposed to very easily burning in the air, very easily lose activity and consumption big; Hydrogenation reaction pressure is higher; The insecurity for preparing single peroxy maleic acid; Reduce the generation ratio of isomer; The refined product quality reaches the pharmaceutical grade standard.
Technical scheme provided by the present invention is as follows:
One, the preparation of tabersonine hydrogenation thing hydrochloride: in the enamel reaction still of stainless steel cauldron or conventional seals, add after the weighing industrial methanol, after starting stirring, the tabersonine hydrochloride that adds industrial methanol quality 5%-10% again, 7% the new Pd/C that adds tabersonine hydrochloride quality 20%, or add 7% new Pd/C of tabersonine hydrochloride quality 10%, and add the Pd/C of reaction back 50%-100% that reclaim, wet weight simultaneously; (after Pd/C number of recovery be 2 times, catalyst activity had reduced, and had not re-used, and concentrated to return and produced Pd/C catalyzer producer and carry out activating and regenerating and handle.) the good seal kettle cover, with nitrogen replacement three times, use hydrogen exchange three times again after, logical hydrogen slowly is warmed up to 25 ℃-30 ℃, with 100r/min speed stirring reaction to showing that to tensimeter pressure is 0.15Mpa-0.35 Mpa, react after 10 hours, from the thief hole sampling, with TLC point plate analysis, the volume ratio of developping agent is ethyl acetate: sherwood oil=2:3, consumption is 5ml, under ultraviolet lamp, observe with the wavelength of 254nm, up to no raw material tabersonine hydrochloride.After reaction finishes, filter Pd/C, and to add the raw catalyst amount with new Pd/C(be 10% of tabersonine quality at every turn, add the 50%-100% that goes up recovery Pd/C quality behind the secondary response again.) the 5-10 methyl alcohol filter wash cake doubly of quality, collect good seal Pd/C, weigh up weight, stand-by; Load weighted methyl alcohol filtrate is put into bucket, stand-by.
Two, the preparation of single peroxy maleic acid: in enamel reaction still, the adding mass percent concentration is 50% hydrogen peroxide, the mol ratio of hydrogen peroxide and tabersonine hydrogenation thing hydrochloride is 1.2-1.5:1, start and stir, speed 80r/min, open refrigeration system, cool to-5 ℃-0 ℃, add maleic anhydride (maleic anhydride divided batch and every batch adding weight, will remain at-5 ℃ of-0 ℃ of supports with the temperature of reaction control and hold) in batches, the total add-on of maleic anhydride is 5-8 a times of adding hydrogen peroxide quality, added in 3-5 hour, and added temperature and will remain at-5 ℃-0 ℃, add maleic anhydride after, under this temperature, continue reaction 5 hours, add the methyl alcohol dilution, the mass percent concentration that makes single peroxy maleic acid of preparation is 10%-15%, stirs 1 hour with 80r/min speed, preserve down for 0 ℃, stand-by.
Three, oxidizing reaction: in enamel reaction still, the tabersonine hydrogenation thing hydrochloride methanol solution that the first step that adding is weighed prepares, after toggle speed 80r/min stirs, open refrigeration system and cool to-15 ℃ to-10 ℃, slowly drip the good single peroxy maleic acid of the second step prepared in reaction, add-on is that the mol ratio of single peroxy maleic acid and tabersonine hydrogenation thing hydrochloride is 1.2-1.5:1, at the uniform velocity dripped with 5 hours, temperature remains at-15 ℃ to-10 ℃ in the dropping process, after dripping, continue reaction 2 hours, with TLC point plate analysis, the volume ratio of developping agent is a methylene dichloride: methyl alcohol: strong aqua=95:4.9:0.1, consumption is 5ml, under ultraviolet lamp, observe with the wavelength of 254nm, up to no raw material tabersonine hydrogenation thing hydrochloride.
Four, reduction reaction, translocation reaction and ammonia are heavy: be 20% S-WAT with mass percent, under-10 ℃-0 ℃, at the uniform velocity be added dropwise in the three-step reaction liquid in 2 hours, and under this temperature, stirred 30 minutes with 100r/min speed, sampling starch potassium iodide solution qualitative detection is not after solution shows purple, no superoxide has been described, slowly be warmed up to 30 ℃-35 ℃, constant temperature is after 5 hours, with TLC point plate analysis, the volume ratio of developping agent is methylene dichloride: methyl alcohol=95:5, consumption is 5ml, under ultraviolet lamp, observes with the wavelength of 254nm, during the spot size constant rate at product vincamine and assorted peak, translocation reaction finishes; Cool to 20 ℃, be added dropwise to 20% strong aqua, the mole number that adds ammoniacal liquor is 2.2-2.5 a times of tabersonine hydrogenation thing hydrochloride, transfer the pH=8.5-9 of reaction solution, be warmed up to 40 ℃ then, constant temperature 30 minutes cools to about 0 ℃, filter, filter cake is earlier with 0 ℃ methyl alcohol drip washing, and consumption and tabersonine hydrogenation thing hydrochloride identical in quality used cold water drip washing again, make till the pH=7.0-7.5 of filter cake, be tabersonine hydrogenation thing hydrochloride 3-5 70 ℃ of-80 ℃ of hot water drip washing doubly then, use the 2-3 methyl alcohol drip washing doubly of the quality of tabersonine hydrogenation thing hydrochloride at last, drain with quality, under 50 ℃, the decompression oven dry obtains the crude product vincamine, the HPLC qualitative analysis, get the area normalization content of vincamine and the area normalization content of table vincamine, calculate the ratio of vincamine and epivincamine.
Five, purifying products:
A, usefulness potassium methylate, methanol solution transform isomer: the crude product in the step 4, add the methyl alcohol of 10-20 times of crude product quality, the potassium methylate of crude product quality 1%-3%, in 50 ℃-60 ℃ of temperature, constant temperature 3h-5h, cool to 10 ℃-15 ℃, filter, obtain the product II, the HPLC qualitative analysis gets the area normalization content of vincamine, the area normalization content of table vincamine;
B, column chromatography separates purification impurity: the said products II, carrying out 200-300 purpose silica gel column chromatography separates, use respectively the volume ratio methylene dichloride (v): methyl alcohol (v)=98:2, methylene dichloride (v): methyl alcohol (v)=95:5 makees eluent, carry out wash-out, control with TLC, the volume ratio of developping agent be methylene dichloride (v): methyl alcohol (v): strong aqua (v)=95:4.9:0.1, consumption 5ml, with wavelength is the ultraviolet lamp observation down of 254nm, with apo-vincamine, vincamine and epi-vincamine separate one by one with ordinary method, the vincamine that wherein obtains is the product III, HPLC analyzes, and gets the area normalization content of vincamine, the area normalization content of epi-vincamine, the area normalization content of apo-vincamine;
C, further purify: in the product III with methyl alcohol and methylene dichloride mixed solvent, the adding quality is that the 2-5 methylene dichloride and the methyl alcohol volume ratio doubly of product III quality is methylene dichloride: methyl alcohol=1.5:1 mixed solvent, at 35 ℃ of-45 ℃ of constant temperature 3-6h, cooling is filtered, obtain pharmaceutical grade vincamine IV, HPLC analyzes, the assorted peak value of content, single maximum, the total assorted peak value of area normalization.
Further, 7% Pd/C is meant the degree of the quality of pure Pd in the Pd/C total mass in the step 1.
Further, add the Pd/C that reclaim the reaction back described in the step 1, be meant for the first time and the Pd/C that reclaims for the second time.
Further, the pressure of hydrogenation reaction in the step 1, preferred 0.25 Mpa.
Further, use nitrogen replacement three times in the step 1, use hydrogen exchange again three times, nitrogen gas purity 99.9%, hydrogen purity 〉=99.5%.
Further, the mole number that adds S-WAT in the step 4 be the mole number that single peroxy maleic acid is in excess in tabersonine hydrogenation thing hydrochloride in the step 3 oxidizing reaction be 0.2-0.5 1-2 doubly.
Further, the glass chromatography column in the step 5, diameter 500mm, high 3m, the column chromatography silica gel of adding are 200 orders-300 orders, the silica gel consumption is 20-40 a times of product II quality.
Product III of the present invention can be used as the starting raw material sale that semi-synthesis method prepares the anticarcinogen vinpocetin; The product IV can be used as bulk drug, is used to prepare the pharmaceutical grade vincamine.
Advantage of the present invention is:
One, hydrogenation catalyst is selected inexpensive, metastable Pd/C for use, and reclaims, applied mechanically catalyzer, has reduced the add-on of catalyzer, has reduced cost.
Two, reduced the pressure of hydrogenation reaction, industrialization selects for use common reaction enamel still of normal pressure or stainless steel cauldron just can realize.
Three, with the tabersonine hydrochloride that sale is arranged on easy preparation and the market, substitute tabersonine vitriol, cancelled dropping vitriol oil acidifying salify step.
Four, prepared in the process of single oxidation toxilic acid, selecting the mass percent concentration that sale is arranged on the market for use is 50% hydrogen peroxide.Temperature of reaction changes under 0 ℃; Do not influencing under the product quality premise, be convenient to the big production of safe.
Five, the temperature of selecting the optimum oxidation reaction has reduced the generation of isomer (epi-vincamine) at-15 ℃ to-10 ℃.
Six, purify and solvent recrystallization by column chromatography, make quality product reach the pharmaceutical grade standard.
Description of drawings
Fig. 1 is the process flow sheet of prior art;
Fig. 2 is a process flow sheet of the present invention.
Embodiment
Embodiment 1:
One, the preparation of tabersonine hydrogenation thing hydrochloride:
In the enamel reaction still of the sealing of a 100L, the industrial methanol that adds 50Kg, after starting stirring, add 5Kg(13.42mol again) the tabersonine hydrochloride, fast adding weight is 1Kg(tabersonine hydrochloride quality 20%) the mass percentage content of pure Pd be that 7% Pd/C(manufacturer is Shaanxi Ruike New Materials Co., Ltd.), good seal kettle cover then, with 99.9% nitrogen replacement three times, use the hydrogen exchange three times of hydrogen (purity 〉=99.5%) again after, logical hydrogen is 0.25Mpa to pressure, slowly be warmed up to 25 ℃, with 100r/min speed stirring reaction, react after 10 hours, take a sample from thief hole, with TLC point plate analysis, the volume ratio of developping agent is ethyl acetate: sherwood oil=2:3, and consumption 5ml is under ultraviolet lamp, wavelength with 254nm is observed, up to no raw material tabersonine hydrochloride.After reaction finishes, filter Pd/C, and wash Pd/C, collect good seal Pd/C with 5Kg methyl alcohol, weight in wet base 2Kg, stand-by; The methyl alcohol filtrate that obtains 60Kg is put into bucket, and is stand-by.
Two, the preparation of single peroxy maleic acid:
In the enamel reaction still of a 50L, the hydrogen peroxide 1.37Kg(20.15mol of adding 50%), start and stir, open refrigeration system and cool to-5 ℃-0 ℃, divide 6 batches of maleic anhydrides that add 6.85Kg, every batch of add-on is respectively 0.5Kg, 0.5Kg, 0.5Kg, 1.5Kg, 1.85Kg, 2 Kg, temperature will remain at 0 ℃, added in 3 hours, add maleic anhydride after, under this temperature, continue reaction 5 hours, add single peroxy maleic acid that methyl alcohol 18Kg dilution dissolving makes, stir after 1 hour, sampling is the sodium thiosulfate standard solution mensuration of 0.1M with volumetric molar concentration, and the mass percent concentration of single peroxy maleic acid of preparation is 10.2%, be discharged in the plastic tank of sealing, net weight 26.0Kg preserves down for 0 ℃, and is stand-by.
Three, oxidizing reaction:
In the enamel reaction still of a 100L, add 60Kg and (include the about 5.03Kg of tabersonine hydrogenation thing hydrochloride, 13.42mol) the tabersonine hydrogenation thing hydrochloride methanol solution for preparing of the first step, after starting stirring, open refrigeration system and cool to-15 ℃, slowly drip 10.2% good single peroxy maleic acid methanol solution 26Kg (20.13mol) of the second step prepared in reaction, dripped with 3 hours, temperature remains at-15 ℃ in the dropping process, after dripping, continue reaction 2 hours, with TLC point plate analysis, the developping agent volume ratio is a methylene dichloride: methyl alcohol: strong aqua=95:4.9:0.1, consumption 5ml, under ultraviolet lamp, observe with the wavelength of 254nm, up to no raw material tabersonine hydrogenation thing hydrochloride.
Four, reduction reaction, translocation reaction and ammonia are heavy:
With mass percent 20% S-WAT 4.3Kg (containing S-WAT 6.8mol), under-10 ℃, be added dropwise in the three-step reaction liquid, and under this temperature, stirred 30 minutes with 100r/min speed, sampling slowly is not warmed up to 30 ℃ with starch potassium iodide solution qualitative detection, solution after not showing purple, behind the constant temperature 5 hours, with TLC point plate analysis, the developping agent volume ratio is methylene dichloride: methyl alcohol=95:5, consumption 5ml, under ultraviolet lamp, wavelength with 254nm is observed, the spot size constant rate change at product vincamine and assorted peak, translocation reaction finishes; Cool to 20 ℃, be added dropwise to 20% strong aqua 10Kg, transfer the pH=8.5-9 of reaction solution, be warmed up to 40 ℃, constant temperature 30 minutes cools to about 0 ℃, filters, filter cake earlier with 0 ℃ methyl alcohol 5Kg drip washing, is used cold water 10Kg drip washing again, makes till the pH=7.0-7.5 of filter cake; Then with 70 ℃ of-80 ℃ of hot water 25Kg drip washing, use the methyl alcohol drip washing of 15Kg at last, drain, under 50 ℃, the decompression oven dry, obtain crude product vincamine 3.9Kg, crude product yield 81.97%, the HPLC qualitative analysis, the area normalization content of vincamine is 92%, the area normalization content of table vincamine is 4.5%, vincamine:epivincamine=20.4:1.
Five, purifying products:
A, usefulness potassium methylate, methanol solution transform isomer: crude product 2Kg, methyl alcohol 40Kg, 50 ℃ of potassium methylate 60g temperature, constant temperature 3h, cool to 10 ℃, filter, obtain product II 1.7Kg, the HPLC qualitative analysis, the area normalization content of vincamine is 95%, the area normalization content of table vincamine is 1.8%;
B, column chromatography separates purification impurity: product II 1.7Kg, 200 purpose column chromatography silica gel 34Kg, the self-control glass chromatography column, diameter 500mm, high 3m, carry out column chromatography for separation, use methylene dichloride respectively, methylene dichloride (v): methyl alcohol (v)=98:2 and methylene dichloride (v): methyl alcohol (v)=95:5 makees eluent, carry out wash-out, with TLC control, developping agent be methylene dichloride (v): methyl alcohol (v): strong aqua (v)=95:4.9:0.1, wavelength is that the ultraviolet lamp of 254nm is observed down, with apo-vincamine, vincamine and epi-vincamine separate one by one, and the vincamine that wherein obtains is the product III, and weight is 1.5Kg, HPLC analyzes, the area normalization content of vincamine is 99.00%, and the area normalization content of epi-vincamine is 0.25%, and the area normalization content of apo-vincamine is 0.30%;
C, further purify: product III 1.5Kg with methyl alcohol and methylene dichloride mixed solvent, ((v): methyl alcohol (v)=1.5:1) for methylene dichloride to add the methylene dichloride of 7.5Kg and the mixed solvent of methyl alcohol, at 35 ℃ of constant temperature 6h, cooling is filtered, obtain pharmaceutical grade vincamine IV 1.3Kg, HPLC analyzes, and area normalization content is 99.5%, the single maximum peak 0.15% of mixing, always assorted peak＜0.5%.
The product III can be used as the starting raw material that semi-synthesis method prepares the anticarcinogen vinpocetin; The product IV can be used as bulk drug, is used to prepare the pharmaceutical grade vincamine.
Embodiment 2:
One, the preparation of tabersonine hydrogenation thing hydrochloride:
In the stainless steel cauldron of a 100L, the industrial methanol that adds 50Kg, after starting stirring, add 5Kg(13.42mol again) the tabersonine hydrochloride, fast adding weight is 0.5Kg(tabersonine hydrochloride quality 10%) freshly prepd 7% Pd/C, the recovery Pd/C that adds weight in wet base 1.5Kg collection good seal in the example 1 again, the good seal kettle cover, with high pure nitrogen displacement three times, use the hydrogen exchange three times of hydrogen (purity 〉=99.5%) again after, logical hydrogen is 0.35 Mpa to the pressure of reactor upward pressure table, slowly be warmed up to 30 ℃, stirring reaction reacts after 15 hours, take a sample from thief hole, with TLC point plate analysis, developping agent is ethyl acetate: sherwood oil=2:3, under ultraviolet lamp, wavelength with 254nm is observed, up to no raw material tabersonine hydrochloride.After reaction finishes, filter Pd/C, and wash Pd/C, collect good seal Pd/C with 5Kg methyl alcohol, stand-by; The methyl alcohol filtrate that obtains 60Kg is put into bucket, and is stand-by.
Two, the preparation of single peroxy maleic acid:
In the enamel reaction still of a 50L, the hydrogen peroxide 1.1Kg(16.1mol of adding 50%), start and stir, open refrigeration system and cool to-5 ℃-0 ℃, divide 9 batches of maleic anhydrides that add 8.8Kg, every batch of add-on is respectively 0.25Kg, 0.25Kg, 0.5Kg, 0.5Kg, 1.0Kg, 1.0Kg, 1.5Kg, 1.5Kg, 2.3Kg, temperature will remain at-5 ℃, adds in 5 hours, add maleic anhydride after, under this temperature, continue reaction 5 hours, add single peroxy maleic acid that methyl alcohol 4.3Kg dilution dissolving makes, the mass percent concentration that makes single peroxy maleic acid of preparation is 10%-15%, stirs after 1 hour, sampling is the sodium thiosulfate standard solution mensuration of 0.1M with volumetric molar concentration, the mass percent concentration of single peroxy maleic acid of preparation is 15.0%, is discharged in the plastic tank of sealing net weight 14.2Kg, preserve down for 0 ℃, stand-by.
Three, oxidizing reaction:
In the enamel reaction still of a 100L, add 50Kg(and include the about 4.19Kg of tabersonine hydrogenation thing hydrochloride, 11.18mol) the tabersonine hydrogenation thing hydrochloride methanol solution for preparing of the first step, after starting stirring, open refrigeration system and cool to-10 ℃, slowly drip 15.0% good single peroxy maleic acid methanol solution 11.81Kg (13.42mol) of the second step prepared in reaction, dripped with 5 hours, temperature remains at-10 ℃ in the dropping process, after dripping, continue reaction 2 hours, with TLC point plate analysis, the developping agent volume ratio is a methylene dichloride: methyl alcohol: strong aqua=95:4.9:0.1, consumption 5ml, under ultraviolet lamp, observe with the wavelength of 254nm, up to no raw material tabersonine hydrogenation thing hydrochloride.
Four, reduction reaction, translocation reaction and ammonia are heavy:
With mass percent 20% S-WAT 2.8Kg (containing S-WAT 4.48mol), under 0 ℃, be added dropwise in the three-step reaction liquid, and under this temperature, stirred 30 minutes with 100r/min speed, sampling slowly is not warmed up to 35 ℃ with starch potassium iodide solution qualitative detection, solution after not showing purple, behind the constant temperature 5 hours, with TLC point plate analysis, the developping agent volume ratio is methylene dichloride: methyl alcohol=95:5, consumption 5ml, under ultraviolet lamp, wavelength with 254nm is observed, the spot size constant rate change at product vincamine and assorted peak, translocation reaction finishes; Cool to 20 ℃, be added dropwise to 20% strong aqua 10Kg, transfer the pH=8.5-9 of reaction solution, be warmed up to 40 ℃, constant temperature 30 minutes cools to about 0 ℃, filters, filter cake earlier with 0 ℃ methyl alcohol 5Kg drip washing, is used cold water 10Kg drip washing again, makes till the pH=7.0-7.5 of filter cake; Then with 70 ℃ of-80 ℃ of hot water 15Kg drip washing, use the methyl alcohol drip washing of 10Kg at last, drain, under 50 ℃, the decompression oven dry, obtain crude product vincamine 3.2Kg, crude product yield (mole number of the tabersonine hydrogenation thing hydrochloride that drops into respect to reality) 80.0%, the HPLC qualitative analysis, the area normalization content of vincamine is 90.0%, the area normalization content of table vincamine is 6.0%, vincamine:epivincamine=15:1.
Five, purifying products:
A, usefulness potassium methylate, methanol solution transform isomer: crude product 2Kg, methyl alcohol 20Kg, 60 ℃ of potassium methylate 20g temperature, constant temperature 5h cools to 15 ℃, filters, obtain product II 1.5Kg, the HPLC qualitative analysis, the area normalization content of vincamine is 94.00%, the area normalization content of table vincamine is 2.00%;
B, column chromatography separates purification impurity: product II 1.5Kg, 300 purpose column chromatography silica gel 60Kg, the self-control glass chromatography column, diameter 500mm, high 3m, carry out column chromatography for separation, use methylene dichloride respectively, methylene dichloride (v): methyl alcohol (v)=98:2 and methylene dichloride (v): methyl alcohol (v)=95:5 makees eluent, carry out wash-out, with TLC control, developping agent be methylene dichloride (v): methyl alcohol (v): strong aqua (v)=95:4.9:0.1, wavelength is that the ultraviolet lamp of 254nm is observed down, with apo-vincamine, vincamine and epi-vincamine separate one by one, and the vincamine that wherein obtains is the product III, and weight is 1.2Kg, HPLC analyzes, the area normalization content of vincamine is 99.2%, and the area normalization content of epi-vincamine is 0.15%, and the area normalization content of apo-vincamine is 0.2%;
C, further purify: product III 1.2Kg with methyl alcohol and methylene dichloride mixed solvent, ((v): methyl alcohol (v)=1.5:1) for methylene dichloride to add the methylene dichloride of 3Kg and the mixed solvent of methyl alcohol, at 45 ℃ of constant temperature 3h, cooling is filtered, obtain pharmaceutical grade vincamine IV 1.1Kg, HPLC analyzes, and area normalization content is 99.7%, the single maximum peak 0.09% of mixing, always assorted peak＜0.3%.
Obviously, the above embodiment of the present invention only is for example of the present invention clearly is described, and is not to be qualification to embodiments of the present invention.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here can't give exhaustive to all embodiments.Everyly belong to the row that conspicuous variation that technical scheme of the present invention extends out or change still are in protection scope of the present invention.
Claims (7)
1. the preparation technology of a semi-synthesis method vincamine is characterized in that may further comprise the steps:
One, the preparation of tabersonine hydrogenation thing hydrochloride: in the enamel reaction still of stainless steel cauldron or conventional seals, add after the weighing industrial methanol, after starting stirring, the tabersonine hydrochloride that adds industrial methanol quality 5%-10% again, 7% the new Pd/C that adds tabersonine hydrochloride quality 20%, or add 7% new Pd/C of tabersonine hydrochloride quality 10%, and add the Pd/C of reaction back 50%-100% that reclaim, wet weight simultaneously; The good seal kettle cover, with nitrogen replacement three times, use hydrogen exchange three times again after, logical hydrogen shows that to tensimeter pressure is 0.15Mpa-0.35 Mpa, slowly is warmed up to 25 ℃-30 ℃, with 100r/min speed stirring reaction, react after 10 hours, from the thief hole sampling, with TLC point plate analysis, the volume ratio of developping agent is ethyl acetate: sherwood oil=2:3, consumption is 5ml, under ultraviolet lamp, observe with the wavelength of 254nm, up to no raw material tabersonine hydrochloride; After reaction finishes, filter, reclaim Pd/C, and with the 5-10 methyl alcohol filter wash cake doubly of quality, collection good seal Pd/C weighs up weight, and is stand-by; Load weighted methyl alcohol filtrate is put into bucket, stand-by;
Two, the preparation of single peroxy maleic acid: in enamel reaction still, the adding mass percent concentration is 50% hydrogen peroxide, the mol ratio of hydrogen peroxide and tabersonine hydrogenation thing hydrochloride is 1.2-1.5:1, start and stir, speed 80r/min, open refrigeration system, cool to-5 ℃-0 ℃, add maleic anhydride in batches, total amount that adds maleic anhydride is 5-8 a times of adding hydrogen peroxide quality, added in 3-5 hour, and added temperature and will remain at-5 ℃-0 ℃, maleic anhydride divided batch and every batch adding weight, make temperature of reaction be controlled at-5 ℃-0 ℃, after adding maleic anhydride, under this temperature, continue reaction 5 hours, add the methyl alcohol dilution, the mass percent concentration that makes single peroxy maleic acid of preparation is 10%-15%, stirred 1 hour with 80r/min speed, preserve down for 0 ℃, stand-by;
Three, oxidizing reaction: in enamel reaction still, the tabersonine hydrogenation thing hydrochloride methanol solution that the first step that adding is weighed prepares, after toggle speed 80r/min stirs, open refrigeration system and cool to-15 ℃ to-10 ℃, slowly drip the good single peroxy maleic acid of the second step prepared in reaction, add-on is that the mol ratio of single peroxy maleic acid and tabersonine hydrogenation thing hydrochloride is 1.2-1.5:1, at the uniform velocity dripped with 5 hours, temperature remains at-15 ℃ to-10 ℃ in the dropping process, after dripping, continue reaction 2 hours, with TLC point plate analysis, the volume ratio of developping agent is a methylene dichloride: methyl alcohol: strong aqua=95:4.9:0.1, consumption is 5ml, under ultraviolet lamp, observe with the wavelength of 254nm, up to no raw material tabersonine hydrogenation thing hydrochloride;
Four, reduction reaction, translocation reaction and ammonia are heavy: be 20% S-WAT with mass percent, under-10 ℃-0 ℃, at the uniform velocity be added dropwise in the three-step reaction liquid in 2 hours, and under this temperature, stirred 30 minutes with 100r/min speed, sampling starch potassium iodide solution qualitative detection is not after solution shows purple, no superoxide has been described, slowly be warmed up to 30 ℃-35 ℃, constant temperature is after 5 hours, with TLC point plate analysis, the volume ratio of developping agent is methylene dichloride: methyl alcohol=95:5, consumption is 5ml, under ultraviolet lamp, observes with the wavelength of 254nm, during the spot size constant rate at product vincamine and assorted peak, translocation reaction finishes; Cool to 20 ℃, be added dropwise to 20% strong aqua, the mole number that adds ammoniacal liquor is 2.2-2.5 a times of tabersonine hydrogenation thing hydrochloride, transfer the pH=8.5-9 of reaction solution, be warmed up to 40 ℃ then, constant temperature 30 minutes cools to about 0 ℃, filter, filter cake is earlier with 0 ℃ methyl alcohol drip washing, and consumption and tabersonine hydrogenation thing hydrochloride identical in quality used cold water drip washing again, make till the pH=7.0-7.5 of filter cake, be tabersonine hydrogenation thing hydrochloride 3-5 70 ℃ of-80 ℃ of hot water drip washing doubly then, use the 2-3 methyl alcohol drip washing doubly of the quality of tabersonine hydrogenation thing hydrochloride at last, drain with quality, under 50 ℃, the decompression oven dry obtains the crude product vincamine, the HPLC qualitative analysis, get the area normalization content of vincamine and the area normalization content of table vincamine, calculate the ratio of vincamine and epivincamine;
Five, purifying products:
A, usefulness potassium methylate, methanol solution transform isomer: the crude product in the step 4, add the methyl alcohol of 10-20 times of crude product quality, the potassium methylate of crude product quality 1%-3%, in 50 ℃-60 ℃ of temperature, constant temperature 3h-5h, cool to 10 ℃-15 ℃, filter, obtain the product II, the HPLC qualitative analysis gets the area normalization content of vincamine, the area normalization content of table vincamine;
B, column chromatography separates purification impurity: the said products II, carrying out silica gel column chromatography separates, use volume ratio methylene dichloride: methyl alcohol=98:2 respectively, methylene dichloride: methyl alcohol=95:5 makees eluent, carry out wash-out, control with TLC, the volume ratio of developping agent is a methylene dichloride: methyl alcohol: strong aqua=95:4.9:0.1, consumption 5ml, with wavelength is the ultraviolet lamp observation down of 254nm, with apo-vincamine, vincamine and epi-vincamine separate one by one with ordinary method, the vincamine that wherein obtains is the product III, HPLC analyzes, and gets the area normalization content of vincamine, the area normalization content of epi-vincamine, the area normalization content of apo-vincamine;
C, further purify: in the product III with methyl alcohol and methylene dichloride mixed solvent, the adding quality is that the 2-5 methylene dichloride and the methyl alcohol volume ratio doubly of product III quality is methylene dichloride: methyl alcohol=1.5:1 mixed solvent, at 35 ℃ of-45 ℃ of constant temperature 3-6h, cooling is filtered, obtain pharmaceutical grade vincamine IV, HPLC analyzes, the assorted peak value of content, single maximum, the total assorted peak value of area normalization.
2. the preparation technology of a kind of semi-synthesis method vincamine as claimed in claim 1 is characterized in that described in the step 1 7% Pd/C, is meant the degree of the quality of pure Pd in the Pd/C total mass.
3. the preparation technology of a kind of semi-synthesis method vincamine as claimed in claim 1 is characterized in that the logical hydrogen described in the step 1 shows that to tensimeter pressure is 0.15Mpa-0.35 Mpa, is preferably 0.25 Mpa.
4. the preparation technology of a kind of semi-synthesis method vincamine as claimed in claim 1 is characterized in that in the step 1, and described usefulness nitrogen replacement three times is used hydrogen exchange three times, nitrogen gas purity 99.9%, hydrogen purity 〉=99.5% again.
5. the preparation technology of a kind of semi-synthesis method vincamine as claimed in claim 1, the mole number that it is characterized in that in the step 4 adding S-WAT be single peroxy maleic acid is in excess in tabersonine hydrogenation thing hydrochloride in the step 3 oxidizing reaction mole number be 0.2-0.5 1-2 doubly.
6. the preparation technology of a kind of semi-synthesis method vincamine as claimed in claim 1 is characterized in that the glass chromatography column described in the step 5, and diameter 500mm, high 3m, the column chromatography silica gel of adding are 200 orders-300 orders, and the silica gel consumption is 20-40 a times of product II quality.
7. the preparation technology of a kind of semi-synthesis method vincamine as claimed in claim 1 is characterized in that adding the Pd/C that reclaim the reaction back described in the step 1, is meant for the first time and the Pd/C that reclaims for the second time.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110237686A CN102276599B (en) | 2011-08-18 | 2011-08-18 | Process for preparing vincamine by semisynthetic method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110237686A CN102276599B (en) | 2011-08-18 | 2011-08-18 | Process for preparing vincamine by semisynthetic method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102276599A true CN102276599A (en) | 2011-12-14 |
| CN102276599B CN102276599B (en) | 2012-10-17 |
Family
ID=45102384
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110237686A Expired - Fee Related CN102276599B (en) | 2011-08-18 | 2011-08-18 | Process for preparing vincamine by semisynthetic method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102276599B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104327073A (en) * | 2014-10-16 | 2015-02-04 | 广州普星药业有限公司 | Semisynthetic production method of vinpocetine |
| CN104788447A (en) * | 2015-04-21 | 2015-07-22 | 张家港威胜生物医药有限公司 | Production process using semi-synthetic method to prepare vincamine |
| CN106749229A (en) * | 2016-12-20 | 2017-05-31 | 东北制药集团股份有限公司 | A kind of process for purification of pervone |
| CN106749230A (en) * | 2016-12-20 | 2017-05-31 | 东北制药集团股份有限公司 | A kind of preparation method of pervone |
| CN114702494A (en) * | 2022-06-06 | 2022-07-05 | 张家港威胜生物医药有限公司 | Automatic continuous-flow semisynthesis method for vincamine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2534920A1 (en) * | 1982-10-25 | 1984-04-27 | Corvi Mora Paolo | Vincamine and 14,15-dehydro-vincamine prepn |
| ES8606340A1 (en) * | 1985-03-07 | 1986-04-16 | Elmu Sa | Vincamine prepn. from tabersonine |
| FR2577926A1 (en) * | 1985-02-28 | 1986-08-29 | Arysearch Arylan Ag | Process for the manufacture of vincamine from tabersonine |
| CN102040606A (en) * | 2011-01-26 | 2011-05-04 | 陕西嘉禾植物化工有限责任公司 | Synthetic method of vinpocetine |
| CN102108082A (en) * | 2009-12-23 | 2011-06-29 | 广州斯威森科技有限公司 | Industrialized semisynthesis of medicine-vincamine for treating cerebral ischemia |
-
2011
- 2011-08-18 CN CN201110237686A patent/CN102276599B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2534920A1 (en) * | 1982-10-25 | 1984-04-27 | Corvi Mora Paolo | Vincamine and 14,15-dehydro-vincamine prepn |
| FR2577926A1 (en) * | 1985-02-28 | 1986-08-29 | Arysearch Arylan Ag | Process for the manufacture of vincamine from tabersonine |
| ES8606340A1 (en) * | 1985-03-07 | 1986-04-16 | Elmu Sa | Vincamine prepn. from tabersonine |
| CN102108082A (en) * | 2009-12-23 | 2011-06-29 | 广州斯威森科技有限公司 | Industrialized semisynthesis of medicine-vincamine for treating cerebral ischemia |
| CN102040606A (en) * | 2011-01-26 | 2011-05-04 | 陕西嘉禾植物化工有限责任公司 | Synthetic method of vinpocetine |
Non-Patent Citations (5)
| Title |
|---|
| 《The Journal of Organic Chemistry》 19980310 Martin E. Kuehne et al. Application of Ferrocenylalkyl Chiral Auxiliaries to Syntheses of Indolenine Alkaloids: Enantioselective Syntheses of Vincadifformine, �- and 20-epi-�-Vincadifformines, Tabersonine,Ibophyllidine, and Mossambine 2172-2183 1-7 第63卷, * |
| CHRISTOPHE DUPONT ET AL.: "D-Ring Substituted Rhazinilam Analogues: Semisynthesis and Evaluation of Antitubulin Activity", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 7, 31 December 1999 (1999-12-31), pages 2961 - 2969, XP085050441, DOI: doi:10.1016/S0968-0896(99)00241-2 * |
| JANOS ELES ET AL.: "Synthesis of Vinca Alkaloids and Related Compounds. 100. Stereoselective Oxidation Reactions of Compounds with the Aspidospermane and Quebrachamine Ring System. First Synthesis of Some Alkaloids Containing the Epoxy Ring", 《THE JOURNAL OF ORGANIC CHEMISTRY》, vol. 67, 21 September 2002 (2002-09-21), pages 7255 - 7260 * |
| MARTIN E. KUEHNE ET AL.: "Application of Ferrocenylalkyl Chiral Auxiliaries to Syntheses of Indolenine Alkaloids: Enantioselective Syntheses of Vincadifformine, ã- and 20-epi-ã-Vincadifformines, Tabersonine,Ibophyllidine, and Mossambine", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| MARTIN E. KUEHNE ET AL.: "Application of Ferrocenylalkyl Chiral Auxiliaries to Syntheses of Indolenine Alkaloids: Enantioselective Syntheses of Vincadifformine, ã- and 20-epi-ã-Vincadifformines, Tabersonine,Ibophyllidine, and Mossambine", 《THE JOURNAL OF ORGANIC CHEMISTRY》, vol. 63, 10 March 1998 (1998-03-10), pages 2172 - 2183 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104327073A (en) * | 2014-10-16 | 2015-02-04 | 广州普星药业有限公司 | Semisynthetic production method of vinpocetine |
| CN104788447A (en) * | 2015-04-21 | 2015-07-22 | 张家港威胜生物医药有限公司 | Production process using semi-synthetic method to prepare vincamine |
| CN106749229A (en) * | 2016-12-20 | 2017-05-31 | 东北制药集团股份有限公司 | A kind of process for purification of pervone |
| CN106749230A (en) * | 2016-12-20 | 2017-05-31 | 东北制药集团股份有限公司 | A kind of preparation method of pervone |
| CN106749229B (en) * | 2016-12-20 | 2018-08-17 | 东北制药集团股份有限公司 | A kind of process for purification of pervone |
| CN106749230B (en) * | 2016-12-20 | 2019-01-08 | 东北制药集团股份有限公司 | A kind of preparation method of pervone |
| CN114702494A (en) * | 2022-06-06 | 2022-07-05 | 张家港威胜生物医药有限公司 | Automatic continuous-flow semisynthesis method for vincamine |
| CN114702494B (en) * | 2022-06-06 | 2022-09-27 | 张家港威胜生物医药有限公司 | Automatic continuous flow semisynthesis method of vincamine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102276599B (en) | 2012-10-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102276599B (en) | Process for preparing vincamine by semisynthetic method | |
| CN101580477B (en) | Dehydroabietylamine derivatives and application thereof in bactericidal and antineoplastic medicaments | |
| CN112110969B (en) | Triazole glucoside derivative of 3-nitro-1-ethyl formate-7-azaindole, and preparation method and application thereof | |
| CN101337956A (en) | Scutellarein carbamate derivates, preparation method and application thereof | |
| Sudta et al. | Potent activity against multidrug-resistant Mycobacterium tuberculosis of α-mangostin analogs | |
| CN108440330A (en) | A kind of preparation method of Doxycycline Hyclate | |
| CN109761924A (en) | A kind of post-processing approach of improved Valsartan reaction mixture | |
| CN105026388A (en) | Substituted pyridine derivatives useful as c-fms kinase inhibitors | |
| CN108586250A (en) | A kind of sodium stearyl fumarate auxiliary material and preparation method thereof | |
| CN109053839A (en) | The novel processing step of 3 '-O-CH2N3-2 '-O-Me- cytidine of nucleosides modifier | |
| CN110117255A (en) | A kind of pleasure is cut down for Buddhist nun's impurity and preparation method thereof | |
| CN108329300B (en) | Nitrobenzo [ d ] aza-quinazoline compound and preparation method and application thereof | |
| CN113321673A (en) | Preparation method and application of neobynine boric acid compound | |
| CN115721661A (en) | Application of purine nucleoside medicament in preventing or treating coronavirus infectious diseases | |
| CN108440376B (en) | Preparation method of ropinirole hydrochloride | |
| CN113880872A (en) | Preparation of camptothecin boric acid compound and application of camptothecin boric acid compound in anti-tumor aspect | |
| CN104098524B (en) | 1-meta-methoxy benzoyl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and Synthesis and applications | |
| CN108484623B (en) | Camptothecin derivative and preparation method and application thereof | |
| CN111269242A (en) | Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof | |
| CN108276394A (en) | Daidzein derivative, preparation method and application | |
| CN115160399B (en) | Soap-skin acid compound, preparation method and medical application thereof | |
| CN103848756B (en) | Preparation method of teriflunomide and intermediate thereof | |
| CN109879873B (en) | Tetrahydrodibenzonaphthyridine compound and synthesis method and application thereof | |
| CN112851535B (en) | Synthesis and application of novel 4,4' - (((polyhalogenated phenyl) azadiyl) bis (methylene)) dibenzoic acid | |
| CN108409754A (en) | The Preparation method and use of Yi Dushaban oxidative degradation impurity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Process for preparing vincamine by semisynthetic method Effective date of registration: 20140901 Granted publication date: 20121017 Pledgee: Zhangjiakou woo Company limited by guarantee Pledgor: Zhangjiakou Gerui High-Tech Co.,Ltd. Registration number: 2014990000721 |
|
| PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20150730 Granted publication date: 20121017 Pledgee: Zhangjiakou woo Company limited by guarantee Pledgor: Zhangjiakou Gerui High-Tech Co.,Ltd. Registration number: 2014990000721 |
|
| PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20121017 Termination date: 20150818 |
|
| EXPY | Termination of patent right or utility model |