CN103788117A - Technology for continuously synthesizing Dehydrate Catharanthine, vinorelbine and Vinflunine - Google Patents
Technology for continuously synthesizing Dehydrate Catharanthine, vinorelbine and Vinflunine Download PDFInfo
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- CN103788117A CN103788117A CN201210424177.5A CN201210424177A CN103788117A CN 103788117 A CN103788117 A CN 103788117A CN 201210424177 A CN201210424177 A CN 201210424177A CN 103788117 A CN103788117 A CN 103788117A
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- vinflunine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
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Abstract
The invention takes Catharanthine Tartrate and Vindoline as a synthesis starting point, the Dehydrate Catharanthine, vinorelbine and Vinflunine are continuously synthesized, and tartrate is prepared. The technology has the advantages of simple synthesis step, low synthesis cost, little toxic solvent, good dissolving clarification degree, little side reaction, stable finished product quality, and easy separating and purifying. Continuous synthesis and discontinuous synthesis of Dehydrate Catharanthine, vinorelbine tartrate and Vinflunine Ditartrate can be carried out according to real production requirement, and the technology is suitable for large scale industrial production reality.
Description
Technical field
The invention belongs to a kind of F 81097, vinorelbine tartrate and the continuous synthesis preparation method of tartrate Vinflunine, belong to field of biological pharmacy.
Background technology
F 81097, vinorelbine, Vinflunine is by the semisynthetic three kinds of antitumor drugs of Vinca extract, wherein, vinorelbine is one of most widely used antitumor clinical application in the world at present, F 81097, Vinflunine be also effect splendid grinding one of main flow antitumor drug, its drug effect mainly suppresses microtubule formation by being combined with tubulin monomer in the cell mitogen G2 phase, impel apoptosis of tumor cells, be used for the treatment of non-small cell carcinoma, mammary cancer, ovarian cancer, soft tissue and visceral metastases cancer and lymphatic cancer, the exploitation of these three kinds of medicines at present is all carried out separately, particularly Vinflunine, synthesis technology complexity at present, synthetic cost is high.Given this, the technical program is intended to design a kind of technical matters of continuously synthetic F 81097, vinorelbine and Vinflunine and separating-purifying thereof, reallocate resources, solve Vinca and utilize the present situation of disperseing, make it to form a complete production chain, and on this basis, set up the synthetic technology of the Vinflunine that simple, the synthetic cost of a kind of synthesis technology significantly reduces.
Summary of the invention
Simple, the synthetic cost of synthesis step of the present invention is low, noxious solvent is few, dissolving clarity is good, side reaction is few, final product quality is stable and be easy to separation and purification, can carry out that F 81097, vinorelbine tartrate and the serialization of tartrate Vinflunine are synthetic or discontinuous synthetic according to producing actual needs, be more suitable for large-scale commercial production reality.
The technical solution used in the present invention is as follows:
Route of the present invention is take tartrate Catharanthine, vindoline as synthetic starting point, and F 81097, vinorelbine, Vinflunine are synthesized in serialization, and make tartrate, and it thes contents are as follows:
Tartrate Catharanthine is by water-soluble with the mass volume ratio of 1:25---1:35, then add equimolar vindoline to reactor, add appropriate hydrochloric acid simultaneously, regulate pH value to 5.6 left and right, again by 0.5-0.7 times of mass ratio glycine, the ferric chloride Solution of 3-4 times of mass volume ratio joins in reactor, under normal temperature, be stirred to and react completely, then add the sodium borohydride solution termination reaction of 0.07-0.1 times of mass ratio, obtain F 81097 crude product, F 81097 crude product is repeated to crystallization and purification with methyl alcohol, obtain the F 81097 fine work that purity is greater than 99%.
The F 81097 obtaining is dissolved in reactor with the methylene dichloride of 1:5-1:7 ratio, liquid nitrogen refrigerating is to zero degree left and right, add trifluoroacetic acid, continue to be cooled to-80 ℃----90 ℃ time, add bromo-succinimide, stirring reaction, after completion of the reaction, be warming up to-20 ℃ of left and right, add amine acetate reaction 20min-30min, add again the acid of tetrafluoro boron silver, closed system, react after 2 hours with saturated sodium bicarbonate solution system furnishing alkalescence, termination reaction, the vinorelbine crude product trichloromethane obtaining is dissolved, cross silicagel column, with the mixed solution wash-out of trichloromethane and methyl alcohol, segmentation receives, can obtain the vinorelbine fine work that purity is greater than 99%, after appropriate methylene dichloride for vinorelbine (mass ratio is 1:6) is dissolved, temperature of reaction system is down to zero degree left and right, keep homo(io)thermism, add HF/SbF5[hydrofluoric acid/antimony pentafluoride] mixed solution, insulation reaction 2 hours, then uses appropriate saturated sodium bicarbonate solution by system furnishing alkalescence, repeatedly extract with chloroform again, merge organic phase, be evaporated to dryly, obtain Vinflunine crude product.After by the Vinflunine obtaining, for crude product, trichloromethane (mass ratio 1:3-1:3.5) dissolves, cross silicagel column, the amount of silica filler is 5-7 times of Vinflunine crude product quality, elutriant is the mixed solution (trichloromethane: methyl alcohol=9.5:0.5) of trichloromethane and methyl alcohol, segmentation receives, can obtain the Vinflunine fine work that purity is greater than 99%, obtaining in Vinflunine fine work, add tartrate by the mol ratio of 1:2, add again the dehydrated alcohol of 6-8 times of quality, stirring reaction under normal temperature, after be concentrated into dry.Thereafter in mass ratio the ratio of (tartrate Vinflunine: acetone)=(1:8 ~ 1:12) is dissolved tartrate Vinflunine, transfer them to again crystallization in zero degree refrigerator, separate supernatant liquid, solid is dried, and obtains the tartrate Vinflunine fine work that purity is greater than 99.5%.
The invention has the beneficial effects as follows:
Simple, the synthetic cost of synthesis step of the present invention is low, noxious solvent is few, dissolving clarity is good, side reaction is few, final product quality is stable and be easy to separation and purification, can carry out that F 81097, vinorelbine tartrate and the serialization of tartrate Vinflunine are synthetic or discontinuous synthetic according to producing actual needs, be more suitable for large-scale commercial production reality.
Embodiment
Can adopt the concentration of any material of change or a kind of reaction conditions wherein to accomplish according to practical situation above-mentioned, concrete enforcement as following instance:
Case study on implementation 1
To adding 51 grams of 50 grams of tartrate Catharanthines and vindolines in 5L reactor, add 1300ml purified water simultaneously, add again a small amount of hydrochloric acid soln, glycine etc., the 150ml ferric chloride Solution first having dissolved is poured in reactor, under normal temperature, closed system, reaction is spent the night, after treating that raw material reaction approaches, in reaction solution, add 0.7L sodium borohydride solution (containing 3.5 grams of sodium borohydride solids), and add appropriate alkaline liquor, regulation system is alkalescence, and stir, use again chloroform extraction, collect organic phase, merge organic phase, be concentrated into dry, weigh, obtain 98 grams of F 81097s, this walks yield 97.03%.By 98 grams of F 81097 500ml dissolve with methanol, be transferred in refrigerator, crystallization is spent the night, and repeats this operation 3 times, obtains F 81097 fine work, and HPLC detects, and its purity is 99.17%, dries, and quality is 68 grams, this walks yield 69.39%.68 grams of F 81097s are dissolved with 350ml methylene dichloride, join in 2000ml round-bottomed bottle, load liquid nitrogen, system temperature is down to 0 ℃, add rapidly 10ml trifluoroacetic acid, continue to be cooled to-80 ℃, add 17 grams of bromo-succinimides, after adding, enclosed system, reaction 2H, after reaction finishes, remove immediately-80 ℃ of liquid nitrogen, change-20 ℃ of liquid nitrogen, insulation, at this temperature, add 27.5 grams of ammonium acetates, after adding, add immediately 12.2 grams of silver tetrafluoroborates, and add 140ml tetrahydrofuran aqueous solution, add rear insulation reaction 30min, remove afterwards liquid nitrogen, under normal temperature, react 2H, after reaction finishes, with saturated sodium bicarbonate solution by system pH value furnishing alkalescence, termination reaction, with chloroform extraction, merging organic phase is spin-dried for, weigh, obtain 67.6 grams, the thick alkali of vinorelbine, this walks yield 99.4%.Thick vinorelbine alkali is dissolved with 200ml trichloromethane, carry out silica gel column chromatography, the silica gel amount of filling out is 500 grams, with chloroform: methyl alcohol=9.5:0.5(volume ratio) elutriant carry out wash-out, receive the elutriant that purity is greater than 99%, concentrated dry, weigh, obtain 18.3 grams of vinorelbine fine work, this walks yield 27.07%.
In a round-bottomed bottle, add 18.3 grams of vinorelbines, add 95ml methylene dichloride to dissolve, be placed in zero degree ethanol bath, keep 10min, immediately to the mixed solution that adds 9ml HF/SbF5 in bottle, enclosed system, reaction 2H, with saturated sodium bicarbonate solution, by system pH value furnishing alkalescence, then use chloroform extraction, merge organic phase, be concentrated into dryly, obtain 17.7 grams of Vinflunine crude products, yield 96.72%.Vinflunine crude product dissolves with 50ml trichloromethane, crosses silicagel column, and the silica gel amount of filling out is 100 grams, and elutriant is chloroform: methyl alcohol=9.5:0.5, receives the elutriant that purity is greater than 99%, and merging is concentrated into dry, weighs, and obtains 4.7 grams of Vinflunine fine work, yield 26.55%.
Get 4.7 grams of Vinflunines, add 1.40 grams of tartrate, use 30ml anhydrous alcohol solution, salt-forming reaction 2H, filtration is drained, and obtains 5.9 grams of tartrate Vinflunines, yield 96.72%.
Get 5.9 grams of tartrate Vinflunine solids, use 70ml acetone solution, be placed in zero degree refrigerator, crystallization, after crystallization completes, take out, skim supernatant liquor, solid is drained, obtain 4.16 grams of tartrate Vinflunine finished products, yield 70.5%, finally the total recovery of synthetic tartrate Vinflunine is 4.12%.
Case study on implementation 2
25 grams of tartrate Catharanthines dissolve and join in 5L reactor by 880ml purified water, and add 26 grams of vindolines, stir, add appropriate hydrochloric acid solution, glycine and 100ml ferric chloride Solution simultaneously, closed system, under normal temperature, reaction is spent the night, and after treating that raw material reaction approaches, in reaction solution, adds 0.46L sodium borohydride solution, regulation system is alkalescence, and stir, then use chloroform extraction three times, merge organic phase, be evaporated to dry, weigh, obtain 51 grams of F 81097s, this walks yield 100%.By 51 grams of F 81097 280ml dissolve with methanol, be transferred in refrigerator, crystallization is spent the night, and repeats this operation 3 times, obtains F 81097 fine work, and HPLC detects, and its purity is 98.93%, dries, and quality is 37 grams, this walks yield 72.55%.37 grams of F 81097s are dissolved with 260ml methylene dichloride, join in 2000ml round-bottomed bottle, liquid nitrogen refrigerating, system temperature is down to 0 ℃, add trifluoroacetic acid 8ml, continue to be again cooled to-80 ℃, at this temperature, add 10.3 grams of bromo-succinimides, after adding, enclosed system, reaction 2H, after reaction finishes, remove immediately-80 ℃ of liquid nitrogen, change-20 ℃ of liquid nitrogen, insulation, at this temperature, add ammonium acetate grams 15.6 grams, 7.4 grams of silver tetrafluoroborates, and add the 75ml tetrahydrochysene furan aqueous solution, add rear insulation reaction 30min, remove afterwards liquid nitrogen, under normal temperature, react 2H, after reaction finishes, with saturated sodium bicarbonate solution by system pH value furnishing alkalescence, termination reaction, with chloroform extraction, merge organic phase, be concentrated into dry, weigh, obtain 35.9 grams, the thick alkali of vinorelbine, this walks yield 97.03%.Thick vinorelbine alkali is dissolved with 130ml trichloromethane, carry out silica gel column chromatography, the silica gel amount of filling out is 300 grams, the mixed solution of elutriant chloroform: methyl alcohol=9.5:0.5, with bottle reception, concentrated the doing of elutriant merging that purity is greater than 99%, obtain 9.27 grams of vinorelbine fine work, this walks yield 25.82%.In a round-bottomed bottle, add 9.27 grams of vinorelbines, add 56ml methylene dichloride to dissolve, be placed in zero degree ethanol bath, keep 10min, immediately to the mixed solution that adds 5ml HF/SbF5 in bottle, enclosed system, reaction 2H, with saturated sodium bicarbonate solution, by system pH value furnishing alkalescence, then use chloroform extraction, merge organic phase, be concentrated into dryly, obtain 9.12 grams of Vinflunine crude products, this walks yield 98.38%.Vinflunine crude product dissolves with 30ml trichloromethane, crosses silicagel column, and the silica gel amount of filling out is 100 grams, elutriant is chloroform: methyl alcohol=9.5:0.5, receives the elutriant that purity is greater than 99%, and merging is concentrated into dry, weigh, obtain 2.21 grams of Vinflunine fine work, this walks yield 24.23%.Get 2.21 grams of Vinflunines, add 0.62 gram of tartrate, use 50ml anhydrous alcohol solution, salt-forming reaction 2H, filtration is drained, and obtains 2.81 grams of tartrate Vinflunines, and this walks yield 99.29%.Get 2.81 grams of tartrate Vinflunine solids, use 28ml acetone solution, be placed in zero degree refrigerator, crystallization, after crystallization completes, take out, skim supernatant liquor, solid is drained, obtain 2.46 grams of tartrate Vinflunine finished products, this walks yield 87.54%, and synthetic tartrate Vinflunine total recovery is 4.92%.
Case study on implementation 3
Get 30 grams of tartrate Catharanthines, 31 grams of vindolines, dissolve by 820ml purified water, join in clean 5L reactor, stir, stir while add appropriate hydrochloric acid and glycine, and add ferric chloride Solution 95ml, closed system, under normal temperature, reaction is spent the night, and raw material approaches after complete reaction, adds 480ml sodium borohydride solution (containing 2.9 grams of sodium borohydride solids), regulation system is alkalescence, and stir, with chloroform extraction twice, the trichloromethane obtaining merging is spin-dried for, obtain 60 grams of F 81097s, this walks yield 98.4%.60 grams of F 81097s are used 450ml dissolve with methanol, are then placed in zero degree refrigerator, crystallization, and suction filtration, solid repeats crystallization 3 times, gets solid and carries out HPLC detection, and purity 99.09%, dries solid, obtains 41.9 grams of F 81097 fine work, and this walks yield 69.83%.41.9 grams of F 81097s 250ml methylene dichloride of receiving is dissolved, join in 2000ml still, with liquid nitrogen refrigerating, cool the temperature to 0 ℃, be added dropwise to trifluoro second 7ml, continue cooling, in the time that temperature drops to-80 ℃, 11.2 grams of bromo-succinimides are joined in system, maintain this homo(io)thermism, react 2 hours, after end, remove-80 ℃ of liquid nitrogen, change-20 ℃ of liquid nitrogen insulations, after 10 minutes, in system, add 17.3 grams of ammonium acetates and the acid of 8.0 grams of tetrafluoro boron silver immediately, add rear enclosed system, continue reaction 2 hours, after reaction finishes, with saturated solution of sodium bicarbonate by system pH value furnishing alkalescence, with twice of chloroform extraction, chloroform merging is spin-dried for, obtain 41 grams of the auspicious sick crude products in Changchun, this walks yield 97.85%.41 grams of vinorelbine crude products dissolve with 150ml trichloromethane, cross silica gel column chromatography decolouring separation and purification, the mixed solution of trichloromethane and methyl alcohol for elutriant, trichloromethane: methyl alcohol=9.5:0.5, the purity receiving being greater than to 99% vinorelbine is spin-dried for together, obtain 11.2 grams of vinorelbine fine work, this walks yield 27.32%.In a round-bottomed bottle, add 11.2 grams of vinorelbines, add 65ml methylene dichloride to dissolve, be placed in zero degree ethanol bath, keep 10min, immediately to the mixed solution that adds 5.5ml HF/SbF5 in bottle, enclosed system, reaction 2H, with saturated sodium bicarbonate solution, by system pH value furnishing alkalescence, then use chloroform extraction, merge organic phase, be concentrated into dryly, obtain 11 grams of Vinflunine crude products, this walks yield 98.21%.
Vinflunine crude product dissolves with 35ml trichloromethane, crosses silicagel column, and the silica gel amount of filling out is 150 grams, and de-liquid is chloroform: methyl alcohol=9.5:0.5, receives the elutriant that purity is greater than 99%, and merging is concentrated into dry, weighs, and obtains 3.39 grams of Vinflunine fine work, and this walks yield 30.82%.Get 3.39 grams of Vinflunines, add 0.97 gram of tartrate, use 50ml anhydrous alcohol solution, salt-forming reaction 2H, filtration is drained, and obtains 4.30 grams of tartrate Vinflunines, and this walks yield 98.62%.Get 4.30 grams of tartrate Vinflunine solids, use 45ml acetone solution, be placed in zero degree refrigerator, crystallization, after crystallization completes, take out, skim supernatant liquor, solid is drained, obtain 3.7 grams of tartrate Vinflunine finished products, this walks yield 86.05%, and synthetic tartrate Vinflunine total recovery is 6.07%.
Claims (5)
1. F 81097, vinorelbine and a Vinflunine serialization synthesis technique, is characterized in that: take tartrate Catharanthine, vindoline as synthetic starting point, F 81097, vinorelbine, Vinflunine are synthesized in serialization, and make tartrate.
2. preparation method according to claim 1, it is characterized in that: tartrate Catharanthine is by water-soluble with the mass volume ratio of 1:25---1:35, add equimolar vindoline to reactor, add appropriate hydrochloric acid simultaneously, regulate pH value to 5.6 left and right, again by 0.5-0.7 times of mass ratio glycine, the ferric chloride Solution of 3-4 times of mass volume ratio joins in reactor, under normal temperature, be stirred to and react completely, then add the sodium borohydride solution termination reaction of 0.07-0.1 times of mass ratio, obtain F 81097 crude product, F 81097 crude product is repeated to crystallization and purification with methyl alcohol, obtain the F 81097 fine work that purity is greater than 99%.
3. preparation method according to claim 1, it is characterized in that: the methylene dichloride of F 81097 1:5-1:7 ratio is dissolved in reactor, liquid nitrogen refrigerating is to zero degree left and right, add trifluoroacetic acid, continue to be cooled to-80 ℃---90 ℃ time, add bromo-succinimide, stirring reaction, after completion of the reaction, be warming up to-20 ℃ of left and right, add amine acetate reaction 20min-30min, add again the acid of tetrafluoro boron silver, closed system, react after 2 hours with saturated sodium bicarbonate solution system furnishing alkalescence, termination reaction, the vinorelbine crude product trichloromethane obtaining is dissolved, cross silicagel column, with the mixed solution wash-out of trichloromethane and methyl alcohol, segmentation receives, can obtain the vinorelbine fine work that purity is greater than 99%.
4. preparation method according to claim 1, it is characterized in that: after appropriate methylene dichloride for vinorelbine (mass ratio is 1:6) dissolves, temperature of reaction system is down to about zero degree, keeps homo(io)thermism, add HF/SbF5[hydrofluoric acid/antimony pentafluoride] mixed solution, insulation reaction 2 hours, then use appropriate saturated sodium bicarbonate solution by system furnishing alkalescence, more repeatedly extract with chloroform, merge organic phase, be evaporated to dryly, obtain Vinflunine crude product.After by the Vinflunine obtaining, for crude product, trichloromethane (mass ratio 1:3-1:3.5) dissolves, cross silicagel column, the amount of silica filler is 5-7 times of Vinflunine crude product quality, elutriant is the mixed solution (trichloromethane: methyl alcohol=9.5:0.5) of trichloromethane and methyl alcohol, segmentation receives, and can obtain the Vinflunine fine work that purity is greater than 99%.
5. preparation method according to claim 1, is characterized in that: in Vinflunine fine work, add tartrate by the mol ratio of 1:2, then add the dehydrated alcohol of 6-8 times of quality, stirring reaction under normal temperature, after be concentrated into dry.Thereafter in mass ratio the ratio of (tartrate Vinflunine: acetone)=(1:8 ~ 1:12) is dissolved tartrate Vinflunine, transfer them to again crystallization in zero degree refrigerator, separate supernatant liquid, solid is dried, and obtains the tartrate Vinflunine fine work that purity is greater than 99.5%.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109988184A (en) * | 2017-12-29 | 2019-07-09 | 江苏豪森药业集团有限公司 | The purification process of vinorelbine |
| CN112480148A (en) * | 2020-12-22 | 2021-03-12 | 海南长春花药业有限公司 | Synthesis method of vinblastine sulfate |
| CN112552319A (en) * | 2020-12-22 | 2021-03-26 | 海南长春花药业有限公司 | Preparation method of vinorelbine tartrate |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109988184A (en) * | 2017-12-29 | 2019-07-09 | 江苏豪森药业集团有限公司 | The purification process of vinorelbine |
| CN109988184B (en) * | 2017-12-29 | 2021-12-17 | 江苏豪森药业集团有限公司 | Purification method of vinorelbine |
| CN112480148A (en) * | 2020-12-22 | 2021-03-12 | 海南长春花药业有限公司 | Synthesis method of vinblastine sulfate |
| CN112552319A (en) * | 2020-12-22 | 2021-03-26 | 海南长春花药业有限公司 | Preparation method of vinorelbine tartrate |
| CN112480148B (en) * | 2020-12-22 | 2022-05-31 | 海南长春花药业有限公司 | Synthesis method of vinblastine sulfate |
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Application publication date: 20140514 |