CN107936075A - A kind of synthetic method of capecitabine intermediate - Google Patents
A kind of synthetic method of capecitabine intermediate Download PDFInfo
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- CN107936075A CN107936075A CN201711463552.6A CN201711463552A CN107936075A CN 107936075 A CN107936075 A CN 107936075A CN 201711463552 A CN201711463552 A CN 201711463552A CN 107936075 A CN107936075 A CN 107936075A
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- synthetic method
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- cytidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The present invention provides a kind of synthetic method of capecitabine intermediate; by 2'; bis- O acetyl group 5' deoxidations of 3', 5 fluorine cytidine and carbonyl dimidazoles, n-amyl alcohol react generation 2', bis- O acetyl group 5' deoxidations of 3' 5 fluorine N4 (positive penta oxygen carbonyl) cytidine under cryogenic.The method of the present invention improves the yield of reaction, yield >=91%.The method of the present invention step is simple, easy to operate, and accessory substance is few, beneficial to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of synthetic method of capecitabine intermediate.
Background technology
Capecitabine (Capecitabine) is a kind of antimetabolic fluoropyrimidine deoxidation core that can be transformed into 5-FU in vivo
Glycosides carbamates medicine, is developed by Roche Holding Ag, and trade name is Xeloda, can suppress cell division and RNA interfering
Synthesized with protein (protein).Suitable for taxol and include anthracycline antibiotic chemotherapy regimen treatment invalid late period
The further treatment of primary or metastatic breast cancer.It is mainly used for advanced primary or metastatic breast cancer, the carcinoma of the rectum, colon
The treatment of cancer and stomach cancer.There is the serious side reaction of Xeloda or have allergies person's taboo to fluorouracil (metabolite of capecitabine)
Use capecitabine.
The bis- positive penta oxygen carbonyl cytidines of-O- fluoro- N4- of acetyl group -5'- deoxidations -5- of 2', 3'- are a kind of important of capecitabine
Intermediate, synthetic method primarily now is that bis--O- acetyl group -5'- deoxidations -5- fluorine cytidines of 3'- and chloro-carbonic acid are just by 2'
Pentyl ester reacts to obtain 2', 3'- bis--O- acetyl group -5'- deoxidations -5- fluoro- N4- (positive penta oxygen carbonyl) cytidine, and reaction equation is as follows：
Yang Jiannan etc., in synthesising process research (Chinese pharmacists, 6 phases of volume 14 in 2011) text of capecitabine, recording will
Bis--O- acetyl group -5'- deoxidation -5- fluorine cytidine 25g (76mmol) of 2', 3'- are dissolved in the mixed of dichloromethane 65ml and pyridine 12.8ml
In bonding solvent, under ice salt bath cooling, n-amyl chlorocarbonate 16ml (108mmol) is slowly dropped in reaction bulb, control is added dropwise
Speed, makes -5 DEG C of temperature control.Drop, which finishes, is warmed to room temperature stirring 30min, and TLC tracks extent of reaction, and (solvent is dichloromethane：First
Alcohol=8:1) (V/V), λ=254nm ultraviolet lights fluorescence developing).Reaction solution is concentrated under reduced pressure into dry, obtains yellow viscous liquid, adds
Enter ethyl acetate 250ml, saturated sodium bicarbonate 180ml, extract liquid separation, water is mutually extracted with ethyl acetate (120ml × 2), is merged
Organic phase, after saturated salt solution 150ml washings, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure into and dry obtains 2', bis--O- of 3'-
Acetyl group -5'- deoxidations -5- fluoro- N4- (positive penta oxygen carbonyl) cytidine 38.5g.
This reaction requires low (- 5 DEG C) of reaction temperature to be difficult to control, and since n-amyl chlorocarbonate is more active, reacts
Journey is also easy to produce impurity.In addition, use organic base pyridine in above-mentioned route, the more difficult removing of pyridine in last handling process, pyridine is residual
Height is stayed, toxicity is very big, and since pyridine dissolves each other in organic phase and water phase, causes waste water to be difficult to handle, cause environmental pollution.
Application number 201210560079.4, a kind of entitled 2 ＇, 3-5 ＇ of ＇-two-O- acetyl group-fluoro- N4- of deoxidation-5-
The application for a patent for invention of (penta oxygen carbonyl) cytidine preparation method, using natrium carbonicum calcinatum or Anhydrous potassium carbonate as alkali, using quaternary ammonium salt as
Phase transfer catalyst, using 4 ﹣ substituent pyridines as catalyst, 2 ＇, 3-5 ＇ of ＇-two-O- acetyl group-deoxidation-5- fluorine cytidine and chloro-carbonic acid
N-pentyl ester carries out amidation process and obtains 2 ＇, 3-5 ＇ of the ＇-two-O- acetyl group-fluoro- N4- of deoxidation-5- (penta oxygen carbonyl) cytidine.It is described
Reaction temperature is 20 DEG C of boiling points to dicyandiamide solution.The invention replaces toxicity bigger using natrium carbonicum calcinatum or Anhydrous potassium carbonate
Organic base pyridine, while by being adjusted to reaction condition, achieve preferable yield (product yield >=85%) and production
Product purity (product purity >=98.0%).But also due to n-amyl chlorocarbonate is more active, reaction process is also easy to produce miscellaneous
Matter.This is because containing acid chloride groups in n-amyl chlorocarbonate, the chlorine atom in acyl chlorides has sucting electronic effect, enhances the parent of carbon
Electrically, acyl chlorides is made to be easier the attack for being subject to nucleopilic reagent, and Cl-And a good leaving group, therefore raw material chlorine
The chemical property of formic acid n-pentyl ester is very active, is also easy to produce impurity.And the n-amyl chlorocarbonate market price is higher, about 130
Member/kg, adds into production cost.
The content of the invention
The present invention overcome the deficiencies of the prior art and provide a kind of bis--O- acetyl group of capecitabine intermediate 2', 3'--
The synthetic method of the fluoro- N4- of 5'- deoxidations -5- (positive penta oxygen carbonyl) cytidine.
The concrete scheme that the present invention uses is：A kind of synthetic method of capecitabine intermediate, by 2', bis--O- acetyl of 3'-
Base -5'- deoxidations -5- fluorine cytidine and carbonyl dimidazoles, n-amyl alcohol react under cryogenic generates 2', and bis--O- acetyl group of 3'- -
The fluoro- N4- of 5'- deoxidations -5- (positive penta oxygen carbonyl) cytidine.
The specific reaction equation of the present invention is as follows：
A kind of synthetic method of capecitabine intermediate of the present invention, specifically includes following steps：
A. solvent, bis--O- acetyl group -5'- deoxidation -5- fluorine cytidine of 2', 3'-, carbonyl dimidazoles, just are added into reaction bulb
Amylalcohol, when 20 DEG C~25 DEG C of temperature control reaction 3.8~5 is small, TLC monitoring the reaction was complete (solvent, dichloromethane：Methanol=20：
1)；
B. the washing of 10% hydrochloric acid solution is added into reaction solution, separates organic layer；Again with purifying water washing, separate organic
Layer, controls 50 DEG C~60 DEG C of bath temperature, and the organic layer that is concentrated under reduced pressure adds ethyl acetate into residue, n-hexane stirs to doing
Mix 30 minutes, be cooled to less than 10 DEG C, start to filter, obtain white solid, 60 DEG C~70 DEG C of temperature control, dries to obtain 2', bis--O- of 3'-
Acetyl group -5'- deoxidations -5- fluoro- N4- (positive penta oxygen carbonyl) cytidine.
Preferably, solvent is dichloromethane in the step a.
Preferably, reaction temperature is 20 DEG C in the step a.
Preferably, when the reaction time in the step a is 4 small.
Preferably, bis--O- acetyl group -5'- deoxidation -5- fluorine cytidine of 2' in the step a, 3'-, carbonyl dimidazoles, positive penta
The molar ratio of alcohol is 1:1.15~1.2:1.1~1.3.
Preferably, the volume ratio of ethyl acetate and n-hexane used is ethyl acetate in the step b：N-hexane=1:
2。
The present invention has the advantages that：
(1) the method for the present invention is raw material without using n-amyl chlorocarbonate, with carbonyl dimidazoles, n-amyl alcohol and 2', 3'- bis--
O- acetyl group -5'- deoxidation -5- fluorine cytidine reacts, and improves the yield of reaction, and avoid the generation of impurity.
(2) the method for the present invention step is simple, easy to operate, and accessory substance is few, beneficial to industrialized production.
Embodiment
Following instance is the further explanation to the present invention, but the present invention is not limited thereto.
Embodiment 1. adds dichloromethane 500ml, 2' into 1000ml reaction bulbs, and bis--O- acetyl group -5'- deoxidations of 3'- -
5- fluorine cytidines 75g, carbonyl dimidazoles 44.3g, n-amyl alcohol 22g, when 20 DEG C of reactions 4 of temperature control are small, TLC monitoring reaction end (expansion
Agent, dichloromethane：Methanol=20：1) washing of 200ml10% hydrochloric acid solutions, is added into reaction solution, separates organic layer, is used
200ml purifies water washing, separates organic layer, controls 50 DEG C of bath temperature, and the organic layer that is concentrated under reduced pressure is added to doing into residue
150ml ethyl acetate, 300ml n-hexanes stir 30 minutes, cool down less than 10 DEG C, start to filter, obtain white solid, temperature control 65
DEG C, dry to obtain 2', 3'- bis--O- acetyl group -5'- deoxidations -5- fluoro- N4- (positive penta oxygen carbonyl) cytidine 92.5g, yield 91.6%,
Purity 99.6%.
Embodiment 2. adds dichloromethane 660ml, 2' into 1000ml reaction bulbs, and bis--O- acetyl group -5'- deoxidations of 3'- -
5- fluorine cytidines 97.8g, carbonyl dimidazoles 56.9g, n-amyl alcohol 29.1g, when 20 DEG C of reactions 4 of temperature control are small, TLC monitoring reaction ends
(solvent, dichloromethane：Methanol=20：1) washing of 250ml10% hydrochloric acid solutions, is added into reaction solution, separates organic layer,
Purify water washing with 250ml, separate organic layer, control 55 DEG C of bath temperature, the organic layer that is concentrated under reduced pressure to dry, into residue plus
Enter 170ml ethyl acetate, 340ml n-hexanes stir 30 minutes, cool down less than 10 DEG C, start to filter, obtain white solid, temperature control 70
DEG C, dry to obtain 2', the bis--O- acetyl group -5'- deoxidations -5- positive penta oxygen carbonyl cytidine 120.9g of fluoro- N4- of 3'-, yield 91.5% is pure
Degree 99.6%.
Embodiment 3. adds dichloromethane 600ml, 2' into 1000ml reaction bulbs, and bis--O- acetyl group -5'- deoxidations of 3'- -
5- fluorine cytidines 84.8g, carbonyl dimidazoles 48.6g, n-amyl alcohol 25.2g, when 20 DEG C of reactions 4 of temperature control are small, TLC monitoring reaction ends
(solvent, dichloromethane：Methanol=20：1) washing of 220ml10% hydrochloric acid solutions, is added into reaction solution, separates organic layer,
Purify water washing with 220ml, separate organic layer, control 60 DEG C of bath temperature, the organic layer that is concentrated under reduced pressure to dry, into residue plus
Enter 160ml ethyl acetate, 320ml n-hexanes stir 30 minutes, cool down less than 10 DEG C, start to filter, obtain white solid, temperature control 65
DEG C, dry to obtain 2', the bis--O- acetyl group -5'- deoxidations -5- positive penta oxygen carbonyl cytidine 104.8g of fluoro- N4- of 3'-, yield 91.6% is pure
Degree 99.7%.
Claims (7)
1. a kind of synthetic method of capecitabine intermediate, it is characterized in that, by 2', bis--O- acetyl group -5'- deoxidation -5- fluorine of 3'-
Cytidine and carbonyl dimidazoles, n-amyl alcohol react generation 2', the bis- fluoro- N4- of-O- acetyl group -5'- deoxidations -5- of 3'- under cryogenic
(positive penta oxygen carbonyl) cytidine.
2. the synthetic method of capecitabine intermediate as claimed in claim 1, it is characterized in that, comprise the following steps that：
A. solvent, bis--O- acetyl group -5'- deoxidation -5- fluorine cytidine of 2', 3'-, carbonyl dimidazoles, positive penta are added into reaction bulb
Alcohol, when 20 DEG C~25 DEG C reactions 3.8~5 of temperature control are small, the reaction was complete for TLC monitoring；
B. the washing of 10% hydrochloric acid solution is added into reaction solution, separates organic layer；Again with purifying water washing, organic layer is separated, is controlled
50 DEG C~60 DEG C of bath temperature processed, the organic layer that is concentrated under reduced pressure add ethyl acetate into residue to doing, and n-hexane stirs 30 points
Clock, is cooled to less than 10 DEG C, starts to filter, and obtains white solid, 60 DEG C~70 DEG C of temperature control, dries to obtain 2', and bis--O- acetyl group of 3'--
The fluoro- N4- of 5'- deoxidations -5- (positive penta oxygen carbonyl) cytidine.
3. the synthetic method of capecitabine intermediate as claimed in claim 2, it is characterized in that, solvent is dichloro in the step a
Methane.
4. the synthetic method of capecitabine intermediate as claimed in claim 2, it is characterized in that, reaction temperature is in the step a
20℃。
5. the synthetic method of capecitabine intermediate as claimed in claim 2, it is characterized in that, the reaction time in the step a
For 4 it is small when.
6. the synthetic method of capecitabine intermediate as claimed in claim 1 or 2, it is characterized in that, bis--O- acetyl of the 2', 3'-
Base -5'- deoxidation -5- fluorine cytidine, carbonyl dimidazoles, the molar ratio of n-amyl alcohol are 1:1.15~1.2:1.1~1.3.
7. the synthetic method of capecitabine intermediate as claimed in claim 2, it is characterized in that, acetic acid second used in the step b
The volume ratio of ester and n-hexane is ethyl acetate：N-hexane=1:2.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102199180A (en) * | 2011-04-12 | 2011-09-28 | 连云港杰瑞药业有限公司 | Preparation method of capectabine |
| CN102206239A (en) * | 2010-03-29 | 2011-10-05 | 上海医药工业研究院 | Preparation method of capecitabine |
| CN102219817A (en) * | 2011-04-12 | 2011-10-19 | 连云港杰瑞药业有限公司 | Method for carrying out carbalkoxylation acylation on fluorouracil compound with active coupling agent |
| CN102858791A (en) * | 2009-07-23 | 2013-01-02 | 台湾神隆股份有限公司 | Process for producing flurocytidine derivatives |
| CN103288897A (en) * | 2013-06-18 | 2013-09-11 | 山东大学 | 4'-O-(1-aralkyl-1,2,3-triazole-4-methyl-formamyl) azithromycin derivatives |
| CN106478751A (en) * | 2015-09-02 | 2017-03-08 | 正大天晴药业集团股份有限公司 | The preparation method of 2 ', 3 '-two-O- acetyl -5 '-fluoro- N4- of deoxidation -5- [(amoxy) carbonyl] cytidines |
-
2017
- 2017-12-28 CN CN201711463552.6A patent/CN107936075A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102858791A (en) * | 2009-07-23 | 2013-01-02 | 台湾神隆股份有限公司 | Process for producing flurocytidine derivatives |
| CN102206239A (en) * | 2010-03-29 | 2011-10-05 | 上海医药工业研究院 | Preparation method of capecitabine |
| CN102199180A (en) * | 2011-04-12 | 2011-09-28 | 连云港杰瑞药业有限公司 | Preparation method of capectabine |
| CN102219817A (en) * | 2011-04-12 | 2011-10-19 | 连云港杰瑞药业有限公司 | Method for carrying out carbalkoxylation acylation on fluorouracil compound with active coupling agent |
| CN103288897A (en) * | 2013-06-18 | 2013-09-11 | 山东大学 | 4'-O-(1-aralkyl-1,2,3-triazole-4-methyl-formamyl) azithromycin derivatives |
| CN106478751A (en) * | 2015-09-02 | 2017-03-08 | 正大天晴药业集团股份有限公司 | The preparation method of 2 ', 3 '-two-O- acetyl -5 '-fluoro- N4- of deoxidation -5- [(amoxy) carbonyl] cytidines |
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Application publication date: 20180420 |