CN1552716A - Synthesis of vinorelbine - Google Patents
Synthesis of vinorelbine Download PDFInfo
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- CN1552716A CN1552716A CNA031364403A CN03136440A CN1552716A CN 1552716 A CN1552716 A CN 1552716A CN A031364403 A CNA031364403 A CN A031364403A CN 03136440 A CN03136440 A CN 03136440A CN 1552716 A CN1552716 A CN 1552716A
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- vinorelbine
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- bromide
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Abstract
A process for synthesizing vinorelbine and its medicinal salt features that the ammonium chloromethylene dimethyl chloride prepared from DMF and SOCl2 or oxalyl chloride is used as the dewatering agent of velban. Its advantage is high output increased from 20% to 30% or more.
Description
The present invention relates to chemical pharmacy field, particularly, the present invention relates to a kind of new synthetic anticarcinogen vinorelbine and the method for pharmacologically acceptable salt thereof.
Vinorelbine (trade(brand)name: nvelbine (Navelbing)) be a kind of novel semi-synthetic vinca anticarcinogen.Because its particular structure changes, make it littler and stronger anti-tumor activity arranged than other vinca alkaloids neurotoxicities such as vincaleucoblastine, vincristine(VCR), vindesines.Bibliographical informations such as US4307100A the synthetic method of multiple vinorelbine, still, because the complex structure of vinorelbine, the productive rate of these synthetic methods is all lower, the synthesis yield of intermediate F 81097 especially wherein is low.The inventor finds through long term studies, by using new technical schemes such as dewatering agent, can improve the productive rate of product significantly, finishes the present invention thus.
The novel method that the purpose of this invention is to provide a kind of synthetic vinorelbine and pharmacologically acceptable salt thereof.
The synthetic of vinorelbine and pharmacologically acceptable salt thereof generally is to be raw material with the Vinblastine sulphate, prepares vinorelbine and pharmacologically acceptable salt thereof through steps such as dehydration, bromination, the ring salifies that contracts.In the prior art, one step of mat woven of fine bamboo strips dehydration reaction adopts POCl usually
3Or SOCl
2The dehydration of/DMF reagent.But it is many to be to use these reagent to exist side reaction, the component complexity, and many shortcomings such as easy emulsification during extraction make that dehydration reaction and total synthetic yield are on the low side.The inventor is by changing yield and the quality that dewatering agent improves the first step dehydration reaction.The reagent that the present invention uses is Weir David Smail reagent (Vilsmeier Reagent[ClCH=N (CH
3)
2Cl], promptly chloromethane is pitched alkyl dimethyl ammonium chloride), this reagent can be by DMF and SOCl
2Or oxalyl chloride makes.By method of the present invention and method of the prior art are compared, as can be seen, use Vilsmeier Reagent[ClCH=N (CH
3)
2Cl] carry out dehydration reaction, the purity and the yield of the F 81097 that obtains all are significantly improved, simultaneously because the raising of F 81097 purity also has tangible influence to the post component efficiency of back, thereby the total recovery of vinorelbine is improved, and total recovery can be original 20% brings up to more than 30%.
The method that the present invention prepares vinorelbine and pharmacologically acceptable salt thereof comprises the steps:
(1). vinealeucoblastine(VLB) (I) carries out dehydration reaction and obtains F 81097 (II) under the effect of Weir David Smail reagent:
Wherein
Be reflected in the polar solvent and carry out, described polar solvent can be lower alcohol, dimethyl formamide, and acetonitrile or their mixture etc., preferred acetonitrile, reaction conditions are comparatively gentle, do not need deep cooling, can carry out at normal temperatures;
(2). F 81097 (II) is carried out halogenation (as bromination) reaction obtain compound (III):
Wherein
Bromide reagent can use phthalic imidine bromide (NBS), and its usage quantity can be reduced to theoretical amount reduces impurity relatively;
(3). contract ring reaction of compound (III) is obtained vinorelbine, if desired, vinorelbine can be changed into its pharmacologically acceptable salt such as tartrate:
Wherein
Another characteristics of the present invention are dewatering agent Weir David Smail reagent ([ClCH=N (CH
3)
2Cl]) join in the vinealeucoblastine(VLB) dehydration reaction after being produced, handle like this, not only improve the productive rate of dehydration reaction, and reduced side reaction and product thereof, simplify the treatment step of subsequent reactions thus, improved the overall yield of vinorelbine and pharmacologically acceptable salt thereof.
The dewatering agent chloromethane fork alkyl dimethyl ammonium chloride ([ClCH=N (CH that the present invention uses
3)
2Cl]) can obtain by using dimethyl formamide (DMF) and chlorination reagent prepared in reaction in organic solvent such as chlorination sulfoxide or oxalyl chloride:
Reaction requires anhydrous condition, and organic solvent can be ether, tetrahydrofuran (THF), acetonitrile or their mixture etc., preferred ether.
Great advantage of the present invention is the change of the first step dehydration reaction reagent, has improved the productive rate of reaction widely.Because complex structure, synthetic difficulty is big, improves the vinorelbine synthetic yield and has very high economic worth.
The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.Except as otherwise noted, the percentage ratio among the present invention is molecular fraction.
Embodiment 1: by vinealeucoblastine(VLB) (I) preparation F 81097 (II)
(1). the inventive method:
A. prepare Weir David Smail reagent (Vilsmeier Reagent) chloromethane fork alkyl dimethyl ammonium chloride
In the 5000ml reaction flask, add 3.3 liters of anhydrous diethyl ethers and 112 gram dimethyl formamides (DMF is in advance through dehydration), stir and be added dropwise to 195 gram oxalyl chlorides down, react and be evaporated to dried 140 after one hour and restrain the reagent products;
B. with Weir David Smail reagent the Vinblastine sulphate dehydration is prepared F 81097
Wherein
Under nitrogen protection; the Vilsmeier Reagent reagent and the 60ml DMF that prepare among the 48 gram step a are added in the reaction flask; stir down in 0 ℃ of acetonitrile (460ml) solution that adds sulfur acid vinealeucoblastine(VLB) (I) 22 grams (24.2mmol); reaction solution was in 10 ℃ of reactions 2 hours; be raised to room temperature reaction again 6 hours; reaction is cooled to 0 ℃ after finishing; add the 800ml frozen water; and regulate pH to 9 with ammoniacal liquor; ether extraction, washing, organic phase concentrates to such an extent that (II) 20 restrains; HPLC purity is 80%, and yield is 83%.
(2). the comparative example
Under nitrogen protection; raw material sulphuric acid vinealeucoblastine(VLB) (I) 18 grams (19.8mmol) are dissolved among the 240ml DMF; be chilled to-40 ℃ of DMF (60ml) solution that are added dropwise to 36ml (0.497mol) SOCL2, be warming up to 0 to 5 ℃ of stirring reaction after dripping off 12 hours, be chilled to again below 5 ℃; stir and add the 720ml frozen water down; transfer pH to 9 with strong aqua, ether extraction, washing; water concentrates to such an extent that solid product (II) 13 restrains, and HPLC purity is 67%.Yield 55%.
Wherein, the impurity of relative retention time (vinorelbine alkali relatively) 0.86 is reduced to below 3% of method (1) (this impurity post branch is difficult to remove) by 10% of method (2), has improved the yield that post divides widely.
Embodiment 2: prepare compound (III) by F 81097 (II) bromination
Wherein
Under nitrogen protection; 20 gram F 81097s (II) (HPLC purity is 80%) are joined in the reaction flask; add the stirring of 400ml methylene dichloride and make its dissolving; after reducing to 0 ℃; methylene dichloride (100ml) solution that adds trifluoroacetic acid (13ml); be cooled to-55 ℃; (NBS, methylene dichloride 3.6g) (250ml) solution stir under this temperature after dripping off and answered 10 minutes slowly to be added dropwise to the phthalic imidine bromide; after TLC shows that raw material disappears; add saturated sodium bicarbonate aqueous solution 1200ml, layering, organic phase washes with water to neutrality; concentrate to do to such an extent that 18 digest compound (III), directly drop into next step reaction.
Embodiment 3: by compound (III) preparation vinorelbine alkali (VI) compound
Wherein
Under nitrogen protection; above-mentioned bromide 18g (III) is joined in the reaction flask, add the dissolving of 1000ml tetrahydrofuran (THF), add the aqueous solution (150ml) of 5 gram tetrafluoro boron silver again; be warming up to 50 ℃ of reactions 40-60 minute; TLC reduces to room temperature after showing that raw material disappears, and filters; filtrate is transferred pH to 8.5-9 with saturated sodium bicarbonate; chloroform extraction is concentrated into dried vinorelbine alkali (IV) 16.8 grams, and HPLC purity is more than 76%.
With vinorelbine alkali (IV) 16.8 gram upper props, 80 gram alkali alumina posts are used the eluent wash-out then, collect product purity 90% (HPLC) above (can only obtain 80-85% originally), concentrate do 14 grams.
Divide on the product 400 grams thin silicagel column the 14 gram alumina columns that obtain, the eluent wash-out is collected purity and is being concentrated after doing to such an extent that 8.5 restrain 97% or more.(this step post branch purity of former technology is having only 6.5 grams more than 97%, and post divides cycle and the more former technology of raw material consumption all to shorten dramatically and reduces)
With the 80 gram alkali alumina posts on the 8.5 gram products more than 97% that obtain, eluent wash-out is then collected purity and is component 99.5% or more and concentrates and do to such an extent that 6.6 restrain.Embodiment 2 embodiment 3 merging total recoverys are 42% after above processing.
Embodiment 4: the crystallization of preparation preparing vinorelbine tartrate (V)
Wherein
The purity that embodiment 3 is obtained is added dropwise to the tartaric acetone soln 120ml of 2.41 grams after 99.5% above product 6.6 gram IV are with the 33ml acetone solutions, filter, filtrate decompression is concentrated into crystallization and separates out, and refrigerator is freezing to make crystallization complete, filters, dry to such an extent that 7.92 digest compound (V), yield 87%.
The synthetic total recovery 30.4% of embodiment 1-4.
Claims (9)
1. a method for preparing vinorelbine or its pharmacologically acceptable salt comprises the steps:
(1). vinealeucoblastine(VLB) (I) is carried out dehydration reaction obtain F 81097 (II) under the effect of Weir David Smail reagent:
Wherein
Be reflected in the polar solvent and carry out;
(2). F 81097 (II) is carried out halogenating reaction obtain compound (III):
Wherein
Bromide reagent can use phthalic imidine bromide (NBS), and its usage quantity can be reduced to theoretical amount reduces impurity relatively;
(3). contract ring reaction of compound (III) is obtained vinorelbine, if desired, vinorelbine can be changed into its pharmacologically acceptable salt:
Wherein
2. according to the method for claim 1, it is characterized in that in the step (1) the Weir David Smail reagent for preparing being joined in the reaction system.
3. according to the method for claim 2, it is characterized in that polar solvent is selected from lower alcohol described in the step (1), dimethyl formamide, acetonitrile or their mixture.
4. according to the method for claim 3, it is characterized in that polar solvent is an acetonitrile described in the step (1).
5. according to the method for claim 4, it is characterized in that step (1) at room temperature carries out.
6. according to the method for one of claim 1-5, it is characterized in that the halogenating reaction in the step (2) is a bromination reaction.
7. according to the method for claim 6, wherein bromide reagent uses the phthalic imidine bromide.
8. according to the method for claim 7, wherein the usage quantity of phthalic imidine bromide can be a theoretical amount.
9. according to the method for claim 6, wherein the vinorelbine alkali and the tartrate effect that obtain of step (3) prepares the preparing vinorelbine tartrate compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031364403A CN1552716A (en) | 2003-06-03 | 2003-06-03 | Synthesis of vinorelbine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031364403A CN1552716A (en) | 2003-06-03 | 2003-06-03 | Synthesis of vinorelbine |
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|---|---|
| CN1552716A true CN1552716A (en) | 2004-12-08 |
Family
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|---|---|---|---|
| CNA031364403A Pending CN1552716A (en) | 2003-06-03 | 2003-06-03 | Synthesis of vinorelbine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101284842B (en) * | 2008-05-19 | 2010-06-09 | 华中科技大学 | Method for preparing vinorelbine tartrate with vinblastine sulfate |
| CN101638413B (en) * | 2009-08-28 | 2011-12-14 | 广州汉方现代中药研究开发有限公司 | Separation and purification method for vinca alkaloids |
| CN103936769A (en) * | 2014-04-30 | 2014-07-23 | 淮海工学院 | Method for preparing high-optical pure dehydrate catharanthine |
| CN108779129A (en) * | 2016-03-09 | 2018-11-09 | 赛比亚斯药业股份公司 | Vinorelbine list tartrate and its medicinal usage |
-
2003
- 2003-06-03 CN CNA031364403A patent/CN1552716A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101284842B (en) * | 2008-05-19 | 2010-06-09 | 华中科技大学 | Method for preparing vinorelbine tartrate with vinblastine sulfate |
| CN101638413B (en) * | 2009-08-28 | 2011-12-14 | 广州汉方现代中药研究开发有限公司 | Separation and purification method for vinca alkaloids |
| CN103936769A (en) * | 2014-04-30 | 2014-07-23 | 淮海工学院 | Method for preparing high-optical pure dehydrate catharanthine |
| CN103936769B (en) * | 2014-04-30 | 2016-10-05 | 淮海工学院 | A kind of method preparing high optical voidness F 81097 |
| CN108779129A (en) * | 2016-03-09 | 2018-11-09 | 赛比亚斯药业股份公司 | Vinorelbine list tartrate and its medicinal usage |
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