CN101037446A

CN101037446A - Synthesizing method of vinorelbine tartrate

Info

Publication number: CN101037446A
Application number: CN 200710097400
Authority: CN
Inventors: 刘全胜
Original assignee: Individual
Current assignee: Individual
Priority date: 2007-05-15
Filing date: 2007-05-15
Publication date: 2007-09-19

Abstract

The invention discloses a synthesis method of vinorelbine bitartrate which is characterized in that the method includes following steps: (1) having the catharanthine tartrate and vindoline as initial material, reacting with ferric trichloride and hydrochloric acid; (2) reacting the above product with the sldium borohydride to get dehydrated vinblastine; (3) ring-opening the dehydrated vinblastine by trifluoroacetic anhydride and rearranging to obtain the vinorelbine bitartrate. The method has a low production cost and a high yield and has a good application future.

Description

The synthetic method of vinorelbine tartrate

Technical field

The present invention relates to the Catharanthine that the Vinca intensive processing of a kind of anticancer vegetable drug source obtains and the synthetic method of the synthetic vinorelbine tartrate of vindoline.

Background technology

Vinorelbine tartrate is a kind of broad-spectrum anti-tumor medicine of cell cycle specific, by the development of French Pieer Fabre company and in 1989 in French Initial Public Offering, and begin the approval of import in China in 1993.The synthetic method of the vinorelbine tartrate of bibliographical information has following four kinds, now is summarized as follows:

1) the dehydration vincaleucoblastine is through metachloroperbenzoic acid (MCPBA) oxidation, the N-oxide compound, handle open loop with trifluoroacetic anhydride then, then in the presence of water, reset and get vinorelbine, get vinorelbine tartrate with the tartrate salify then.

2) the dehydration vincaleucoblastine is through N-chlorinated benzotriazole chloro, gained 6 '-the chloro thing contracts to encircle with the silver processing of tetrafluoride boron in the presence of water and obtains vinorelbine, gets vinorelbine tartrate with the tartrate salify then.

3) the dehydration vincaleucoblastine gets the N-oxide compound through metachloroperbenzoic acid (MCPBA) oxidation, handles open loop with trifluoroacetic anhydride then, then handles the ring that contracts with tetrafluoride boron silver and obtains vinorelbine, gets vinorelbine tartrate with the tartrate salify then.

4) with the Vinblastine sulphate be starting raw material, form the dehydration vincaleucoblastine with the DMF dehydration, then through N-chlorinated benzotriazole chloro, gained 9 '-position chloro thing handles to contract to encircle with tetrafluoride boron silver in the presence of water and obtains vinorelbine, at last and the tartrate salify get vinorelbine tartrate.

Estimate: four kinds of synthetic methods are similar substantially, but since the substituting group of introducing successively different with to the different and difference to some extent of substituent modification mode.First kind of synthetic method step is less, the reaction conditions gentleness, side reaction is less, but it (now is 500 yuan/g that synthetic starting raw material dehydration vincaleucoblastine costs an arm and a leg, and about 80 yuan of our raw materials used Catharanthine, vindoline cost/g), cause cost higher (the about 6500 yuan/g of synthetic vinorelbine tartrate, adopt gained vinorelbine tartrate of the present invention only be 2500 yuan/g); Second kind of synthetic method and the third synthetic method, both identical points are more, and these two kinds of synthetic method side reactions are more, therefore need carry out under very low temperature, and are therefore wayward in suitability for industrialized production, increased production cost simultaneously; The 4th kind of synthetic method and other synthetic methods compare, and difference shows that having adopted with the Vinblastine sulphate is starting raw material, and forming the dehydration vincaleucoblastine with the DMF dehydration is the first step, other steps and second kind of synthetic method broadly similar.

Synthetic method is also used the comparatively expensive chemical reagent tetrafluoride boron silver of price in other second kind of synthetic method, the third synthetic method, the 4th.

The present invention through screening study, finds better processing condition based on this promptly, and the synthesis material that has solved vinorelbine tartrate costs an arm and a leg, and obtains the problem of difficulty.

Summary of the invention

Purpose of the present invention just is to provide a kind of new production method of vinorelbine tartrate, and this method raw material is cheap, can significantly reduce the synthetic tartrate Changchun cost of shore again.

The present invention adopts following technical scheme: this method comprises the steps:

(1) is starting raw material with tartrate Catharanthine and vindoline, reacts through the effect of iron trichloride and hydrochloric acid; Reaction formula is

(2) reaction product and sodium borohydride are reacted obtain F 81097; Structural formula is

(3) F 81097 is handled open loop, is reset and to obtain vinorelbine at last through trifluoroacetic anhydride; Structural formula is

(4) vinorelbine and tartrate salify are obtained vinorelbine tartrate, structural formula is

The synthetic method of vinorelbine tartrate of the present invention is compared with prior art, its beneficial effect is embodied in: starting raw material is tartrate Catharanthine and vindoline, raw material is cheap, thereby can reduce production costs significantly, with present dehydration vincaleucoblastine price is 500 yuan/g, and the about 80 yuan/g of Catharanthine, vindoline price calculates, with the dehydration vincaleucoblastine is the about 6500 yuan/g of cost of the explained hereafter vinorelbine tartrate of raw material, adopting gained vinorelbine tartrate of the present invention is 2500 yuan/g only, and cost significantly reduces.

Embodiment

The invention will be further described below in conjunction with specific embodiment.

(1) in a round-bottomed flask, add tartrate Catharanthine 34.8g (being equivalent to 23.9g Catharanthine (M:336.43)) and vindoline 32.5g, after adding a small amount of diluted hydrochloric acid dissolution then, add the abundant mixing of 4.7L iron trichloride, reaction is 13 hours under 4 ℃ of air-proof conditions, termination reaction, in reaction solution, add proper ammonia and regulate pH to 7, abandoning supernatant behind the reaction solution high speed centrifugation, lower floor's thing soaks repeatedly with chloroform, collect and obtain compound after chloroform volatilizes mutually, be the product of the first step reaction.

(2) add the 0.4mol dissolving with hydrochloric acid in collecting the product that obtains after chloroform volatilizes mutually, then add the 5.7L sodium borohydride in solute, 25 ℃ of air-proof conditions of room temperature reaction were down collected product with chloroform extraction after 45 minutes, volatilize behind the chloroform crystallisate.

In order to improve yield, can also in this crystallisate, add small amount of methanol and carry out recrystallization, be specially in this crystallisate and add small amount of methanol and make its dissolving, 0 ℃ of air-proof condition is placed 24 down and crystallization as a child occurred, collects crystallisate and obtains F 81097 19.40g (yield 34.29%).

(3) in a round-bottomed flask, add methylene dichloride 100ml and F 81097 19.4g, nitrogen filled protection; cryosel is bathed and is stirred; make reacting liquid temperature reduce to 0 ℃, maintain the temperature at 0～5 ℃ and add trifluoroacetic anhydride 15ml, finish and continue to maintain the temperature at 0～5 ℃ of reaction 3h.Decompression and solvent recovery under the room temperature, in resistates, add tetrahydrofuran (THF) 400ml, fully stir and make dissolving, the complete back of dissolving is to wherein adding entry 2ml, room temperature reaction 2h, the reaction finish after with among the reaction solution impouring saturated brine 500ml, divide three extractions with the 1500ml chloroform, united extraction liquid, extracting solution washs to pH7 with saturated nacl aqueous solution, in organic layer, add anhydrous sodium sulfate drying, filter, filtrate decompression reclaims solvent, and residuum is by column chromatography purification [eluent: chloroform-ethanol (volume ratio is 9: 1)], get vinorelbine 5.14g, yield 27.5%.Differentiate that with TLC (the developping agent chloroform: ethanol=9: 1 (volume ratio)), judging criterion is if existing impurity spot must not be crossed 2% of own control to purity.In this step, by column chromatography purification, its purpose is to improve the purity of existing shore, intermediate Changchun, helps next step reaction.

(4) get under vinorelbine 5.14g and the tartrate 2.0g room temperature and be dissolved in the 300ml ethanol, stir 0.5h, filter, be evaporated to dried, in resistates, add acetone 250ml, stirring makes dissolving, is evaporated to the about 100ml of volume after the dissolving fully, is added dropwise to anhydrous diethyl ether 500ml under stirring, the adularescent precipitation is separated out, leave standstill 0.5h, filter, with anhydrous diethyl ether 10ml washing crystal, crystal is through vacuum-drying (temperature: room temperature, vacuum tightness: 0.095Mpa) 4 hours, get vinorelbine tartrate 5.86g, yield 82.3%.

Claims

1, a kind of synthetic method of vinorelbine tartrate is characterized in that, this method comprises the steps: that (1) is starting raw material with tartrate Catharanthine and vindoline, reacts through the effect of iron trichloride and hydrochloric acid; (2) reaction product and sodium borohydride are reacted obtain F 81097; (3) F 81097 is handled open loop, is reset and to obtain vinorelbine at last through trifluoroacetic anhydride; (4) vinorelbine and tartrate salify are obtained vinorelbine tartrate.

2, the synthetic method of vinorelbine tartrate as claimed in claim 1, it is characterized in that, described step (1) working method is: in reactor, after adding described tartrate Catharanthine and vindoline, add a small amount of diluted hydrochloric acid dissolution earlier, add the abundant mixing of described iron trichloride again, reaction is 13 hours under 4 ℃ of air-proof conditions, termination reaction, in reaction solution, add proper ammonia and regulate pH to 7, abandoning supernatant behind the reaction solution high speed centrifugation, lower floor's thing soaks repeatedly with chloroform, collects to obtain compound after chloroform volatilizes mutually.

3, the synthetic method of vinorelbine tartrate as claimed in claim 1 or 2, it is characterized in that: in the described step (2), add hydrochloric acid in the compound that in step (1), obtains earlier and make its dissolving, and then the described sodium borohydride of adding reacts in solute, room temperature ℃ air-proof condition reacts after 45 minutes down, collect product with chloroform extraction, volatilize behind the chloroform crystallisate.

4, the synthetic method of vinorelbine tartrate as claimed in claim 3, it is characterized in that: also will in obtaining crystallisate, add methyl alcohol and make its dissolving, place 24 down in 0 ℃ of air-proof condition and crystallization as a child occurred, collect this crystallisate and obtain described F 81097.

5; the synthetic method of vinorelbine tartrate as claimed in claim 1 or 2; it is characterized in that: in the described step (3); make described F 81097 dissolving with methylene dichloride; nitrogen filled protection then; and make reacting liquid temperature reduce to 0 ℃, and maintain the temperature at 0～5 ℃ and add described trifluoroacetic anhydride, finish and continue to maintain the temperature at 0～5 ℃ of reaction 3h; decompression and solvent recovery under the room temperature; add tetrahydrofuran (THF) in resistates, fully stir and make dissolving, the complete back of dissolving is to wherein adding entry; room temperature reaction 2h; after finishing, reaction, divides three extractions, united extraction liquid with chloroform with in the reaction solution impouring saturated brine; extracting solution washs to pH 7 with saturated nacl aqueous solution; add anhydrous sodium sulfate drying in organic layer, filter, filtrate decompression reclaims solvent; residuum gets vinorelbine by column chromatography purification.

6, the synthetic method of vinorelbine tartrate as claimed in claim 5 is characterized in that: the eluent of using in the described chromatography process is chloroform-ethanol elution agent, and chloroform and alcoholic acid volume ratio are 9: 1.

7, the synthetic method of vinorelbine tartrate as claimed in claim 1 or 2, it is characterized in that: in the described step (4), get earlier under described vinorelbine and the tartrate room temperature and be dissolved in the ethanol, stir, filter, be evaporated to driedly, in resistates, add acetone, stir and make dissolving, be evaporated to dried after the dissolving fully, be added dropwise to anhydrous diethyl ether under stirring, the adularescent precipitation is separated out, and leaves standstill 0.5h, filter, with the anhydrous diethyl ether washing crystal, crystal gets vinorelbine tartrate through vacuum-drying 4 hours.

8, the synthetic method of vinorelbine tartrate as claimed in claim 7 is characterized in that: described vacuum-drying temperature condition is a room temperature, and pressure is 0.095Mpa.

9, the synthetic method of vinorelbine tartrate as claimed in claim 1 or 2 is characterized in that: described tartrate Catharanthine is for extracting the tartrate Catharanthine that obtains from Vinca.