CN105566419A - Capecitabine preparation method - Google Patents
Capecitabine preparation method Download PDFInfo
- Publication number
- CN105566419A CN105566419A CN201511003275.1A CN201511003275A CN105566419A CN 105566419 A CN105566419 A CN 105566419A CN 201511003275 A CN201511003275 A CN 201511003275A CN 105566419 A CN105566419 A CN 105566419A
- Authority
- CN
- China
- Prior art keywords
- preparation
- reaction
- capecitabine
- controls
- hours
- 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.)
- Pending
Links
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a capecitabine preparation method; 5-FU as a raw material is subjected to a reaction with pentyloxy formyl chloride, then an intermediate is generated and then is coupled with a ribose derivative, an ethoxyl protective group of ethoxyl of the ribose derivative is removed in the coupling reaction, and thus the target compound capecitabine is obtained; the method comprises the following steps: step one, the 5-FU as the raw material is subjected to the reaction with pentyloxy formyl chloride, and then the intermediate is generated; and step two, the intermediate is coupled with the ribose derivative to generate the product capecitabine. The production cost can be saved, the medical expense of patients is reduced, the side effect is reduced, and the yield is higher.
Description
Technical field
The present invention relates to a kind of preparation method of antitumor drug, be specifically related to a kind of preparation method of capecitabine, belong to medical art.
Background technology
Global tumour patient increased year by year in the last few years, especially more obvious in the growth of new developing country, wherein China has become the highest country of newly-increased sickness rate, " 2013 Chinese tumour registration annual report " that whole nation tumour Register issues also shows, China over nearly 20 years cancer present the high trend of rejuvenation, M & M, tumor incidence is with the speed increment of annual 3%-5%, in anti-curing oncoma, need the antitumor drug that research and development are new badly, also urgently greatly develop antitumor imitation medicine of good performance.
Capecitabine is analogue before a kind of new oral flucytosine core, no cytotoxicity own, under the effect of enzyme in vivo, metabolism is 5 FU 5 fluorouracil (5-FU), it is researched and developed by Roche company, obtain U.S. FDA approval in September, 1998, clinically be used for the treatment of advanced primary to drug ineffective such as taxol (paclitaxel) and Dxs (adriamycin) or metastatic breast cancer, in April, 2003 goes on the market in Japan with identical indication.Calendar year 2001 FDA ratifies this product and is used for the treatment of metastatic colorectal cancer.Capecitabine also can with multi-medicament combined utilization, have good therapeutic effect, such as irinotecan associating capecitabine second line treatment advanced gastric carcinoma, curative effect is better, and untoward reaction can tolerate, and medication is convenient; Lapatinibditosylate can treat transitivity and non-metastatic breast cancer with combining of capecitabine.
Mainly contain the synthetic route that three classes are basic at present:
I, 1; 2; 3-O-triacetyl ribose and 5-flurocytosine condensation under anhydrous stannic chloride effect; obtain 2'; 3'-bis--O-acetyl-5'-deoxidation-5-fluorine cytidine and n-amyl chlorocarbonate react the last and sodium hydroxide of 2', 3'-bis--O-acetyl-5'-deoxidation-5-fluoro-N4-[(pentyloxy) carbonyl] cytosine(Cyt) ribose is obtained by reacting.
II, with D-ribose be raw material through acidylate, condensation, Deprotection, isopropyl methylenation, iodo, the reaction of shortening etc. 10 step is obtained.
III, with 5'-'-Deoxy-5-fluorouridine for raw material obtains 2' through acidylate; 3'-dibenzoyl-5'-'-Deoxy-5-fluorouridine; react to obtain 2', 3'-dibenzoyl-5'-deoxidation-5-fluorine cytidine again with phosphorus oxychloride and ammoniacal liquor, then react to obtain 2' with triphosgene and amylalcohol; 3'-bis--O-benzoyl-5'-deoxidation-5-fluoro-N4-[(pentyloxy) carbonyl] cytidine(C; then obtain with methanol solution of sodium methylate Deprotection, or become oxime, reduction; with n-amyl chlorocarbonate acidylate, hydrolysis is obtained.
Comparatively speaking, route I route is shorter, but use tin tetrachloride in a large number, tin tetrachloride easily absorbs water generation chemical transformation, so require higher to working condition, and tin is the virose metal of a kind of tool, such photograph becomes environmental pollution, cost high, tin metal ion easily remains in product, causes the toxic metal ions of medicine to exceed standard, and produces hidden danger to the security of medicine.Route II route is longer, and yield is lower, very unfavorable for suitability for industrialized production, reduces the actual utilization of production validity and supplementary material.Route III uses triphosgene in reacting, triphosgene in storage process because the reason such as wet, hot can slowly be decomposed, decomposing the phosgene produced is severe poisonous chemicals, in large-scale commercial production, toxicity is larger, produce potentially dangerous to operator and environment, route is partially long, produces larger consumption to supplementary material.
Summary of the invention
The object of the invention is to, a kind of preparation method of capecitabine is provided, to overcome the above-mentioned shortcoming and defect existing for prior art.The present invention reaches by reduction reactions steps the usage quantity reducing supplementary material, improves yield, thus saves production cost, and reduces the medical expense of patient.Avoid using some susceptibility, virose material simultaneously, reduce the harm to patient and environment, reduce side effect and protection of the environment.
Simple principle of the present invention:
The present invention take 5-FU as initial feed, after reacting with penta oxygen formyl chloride, generate intermediate, after again with ribose derivates coupling, in linked reaction, the ethoxyethoxy blocking group of ribose derivates is sloughed, and namely obtains the compound capecitabine of target.
The technical problem that will solve required for the present invention, can be achieved through the following technical solutions:
A preparation method for capecitabine, is characterized in that, it comprises step:
Step one take 5-FU as initial feed, generates intermediate after reacting with penta oxygen formyl chloride;
Step 2, intermediate and ribose derivates coupling generate product capecitabine;
Its reaction formula is as follows:
5-flurocytosine in step one: pyridine: penta oxygen formyl chloride=1:1.25 ~ 1.4:1.1 ~ 1.3, preferred 5-flurocytosine: pyridine: penta oxygen formyl chloride=1:1.33:1.21.
Dropping penta oxygen formyl chloride temperature in step one controls at-10 DEG C ~ 0 DEG C, preferably-10 DEG C ~-5 DEG C;
In step one, temperature of reaction controls at 0 DEG C ~ 40 DEG C, preferred room temperature.
The hydrochloric acid content that in step one, cancellation reaction uses controls: HCl:5-flucytosine=0.25 ~ 0.025:1, preferred HCl:5-flucytosine=0.05:1.
The first step product in step 2: ribose derivates=1:1.0 ~ 1.3, preferred the first step product: ribose derivates=1:1.05.
Select boron trifluoride diethyl etherate as condensing agent in step 2.
The first step products weight (kg) in step 2: boron trifluoride diethyl etherate volume (L)=1:1.25 ~ 1.45, preferred the first step products weight (w): boron trifluoride diethyl etherate volume (v)=1:1.34.
In step 2, temperature of reaction controls at 10 DEG C ~ 30 DEG C, preferred room temperature.
In step 2, the reaction times controls at 2 hours ~ 4 hours, preferably 2 hours.
In step 2, purification system is ethyl acetate and normal hexane, and volume ratio is about 1:1.
Beneficial effect of the present invention:
Positive progressive effect of the present invention is: the present invention reduces medical expense, the minimizing side effect of patient, and improves the utilization of raw and auxiliary material, reduces the impact on environment.
The present invention avoids using the virose metallic tin Ion reagent of tool, can not cause any tin ion risk of exceeding criterion to product.
The product purity that the present invention obtains is high, and impurity is low, and single assorted≤0.05%, total purity >=99.9%, uses the rear side effect to human body little.
The present invention adopts the new technology route synthesize capecitabine of two-step reaction, simple to operate, high to the effective rate of utilization of supplementary material, effectively can reduce cost of drugs, and intermediate is stablized, and is suitable for Produce on a large scale.
Accompanying drawing explanation
Fig. 1 is hydrogen of the present invention spectrum nuclear-magnetism.
Fig. 2 is high performance liquid chromatography of the present invention.
Embodiment
Below in conjunction with specific embodiment, progressive explanation is done to the present invention.Should be understood that following examples only for illustration of the present invention but not for limiting scope of the present invention.
The preparation method of capecitabine of the present invention: comprise the following steps:
Step one take 5-FU as initial feed, generates intermediate after reacting with penta oxygen formyl chloride; 5-flurocytosine: pyridine: penta oxygen formyl chloride=1:1.25 ~ 1.4:1.1 ~ 1.3, preferred 5-flurocytosine: pyridine: penta oxygen formyl chloride=1:1.33:1.21.Dripping penta oxygen formyl chloride temperature controls at-10 DEG C ~ 0 DEG C, preferably-10 DEG C ~-5 DEG C.Temperature of reaction controls at 0 DEG C ~ 40 DEG C, preferred room temperature.The concentration of hydrochloric acid that cancellation reaction uses controls at 0.1 ~ 1.0N, preferred 0.2N.The hydrochloric acid content that cancellation reaction uses controls: HCl:5-flucytosine=0.25 ~ 0.025:1, preferred HCl:5-flucytosine=0.05:1.
Step 2, intermediate and ribose derivates coupling generate product capecitabine; The first step product: sugar derivatives=1:1.0 ~ 1.3, preferred the first step product: sugar derivatives=1:1.05.Select boron trifluoride diethyl etherate as condensing agent.The first step products weight (kg): boron trifluoride diethyl etherate volume (L)=1:1.25 ~ 1.45, preferred the first step products weight (w): boron trifluoride diethyl etherate volume (v)=1:1.34.Temperature of reaction controls at 10 DEG C ~ 30 DEG C, preferred room temperature.Reaction times controls at 2 hours ~ 4 hours, preferably 2 hours.Purification system is ethyl acetate and normal hexane, and volume ratio is about 1:1.
Get three mouthfuls of reaction flasks that step reactor product 262g puts into 1L, after loading onto thermometer, magnetic stir bar, add tetrahydrofuran (THF) 5.0L, add 393g sugar derivatives.Above-mentioned solution stirring, after 10 minutes, is cooled to 0 DEG C.In there-necked flask, drip boron trifluoride ether solution 350ml, within 20 minutes, dropwise.Temperature of reaction is risen to room temperature, stirs 5 hours.Reaction is heated to 40 DEG C, reacts 2 hours.Be cooled to room temperature, add 2N hydrochloric acid 40ml, react 1 hour.Filter, by insolubles filtering, add water 200ml, extraction into ethyl acetate reaction solution (1.0L × 3).Merge organic phase, use purified water 500ml.Anhydrous sodium sulfate drying organic phase, filters, concentrates filtrate to about 1.0L, add 1.0L normal hexane crystallization, and leave standstill 2 hours, get solid after filtration, vacuum 40 DEG C of dryings 20 hours, obtain product 325g, yield 84.3%.
Reaction formula of the present invention is as follows:
Innovative point of the present invention:
(1) own technology, route is simple, and method is simple, is applicable to suitability for industrialized production;
(2) reaction temperature and, be easy to control, the few product purity of side reaction is high, is conducive to the utilization ratio improving product yield and main raw material 5-FU and ribose, improves utilization of resources rate.
(3) avoid using tool virose metallic tin Ion reagent photoreactive gas, reduce the impact on environment.
Embodiment 1
Methylene dichloride 80ml is joined 1L to be equipped with in three mouthfuls of reaction flasks of thermometer and constant pressure funnel, start magnetic agitation, in reaction flask, add 5-flurocytosine 3.04g, then add pyridine 7.1g.Under nitrogen protection, in constant pressure funnel, add n-amyl chlorocarbonate 11.7g, then add methylene dichloride 10ml.Reaction solution is cooled to-10 DEG C, starts the dichloromethane solution dripping n-amyl chlorocarbonate, control dropping temperature at-10 DEG C ~-5 DEG C, remove refrigerating fulid after adding, room temperature stirs reaction 2 hours.After reaction terminates, suction 30ml0.2N hydrochloric acid, stirs 15 minutes, collects lower floor's methylene dichloride phase, and methylene dichloride uses 0.2N salt acid elution three times (20ml × 3) mutually again.Finally wash methylene dichloride phase (50ml × 1) with water.Methylene dichloride uses anhydrous sodium sulfate drying mutually, filters, is done by filtrate 35 DEG C of concentrating under reduced pressure, obtain product 12.1g, yield 94.3%.
Get three mouthfuls of reaction flasks that step reactor product 12.1g puts into 250ml, after loading onto thermometer, magnetic stir bar, add tetrahydrofuran (THF) 100ml, add 14.3g sugar derivatives.Above-mentioned solution stirring, after 10 minutes, is cooled to 0 DEG C.In there-necked flask, drip boron trifluoride ether solution 13ml, within 20 minutes, dropwise.Temperature of reaction is risen to room temperature, stirs 4 hours.Reaction is heated to 40 DEG C, reacts 2 hours.Be cooled to room temperature, add 2N hydrochloric acid 1ml, react 1 hour.Filter, by insolubles filtering, add water 20ml, extraction into ethyl acetate reaction solution (50ml × 3).Merge organic phase, use purified water 50ml.Anhydrous sodium sulfate drying organic phase, filters, concentrates filtrate to about 20ml, add 20ml normal hexane crystallization, and leave standstill 2 hours, get solid after filtration, vacuum 40 DEG C of dryings 20 hours, obtain product 12.1g, yield 83.3%.
Embodiment 2
Methylene dichloride 3.8L is joined 10L to be equipped with in three mouthfuls of reaction flasks of thermometer and constant pressure funnel, start mechanical stirring, in reaction flask, add 5-flurocytosine 152g, then add pyridine 122g.Under nitrogen protection, in constant pressure funnel, add n-amyl chlorocarbonate 212g, then add methylene dichloride 200ml.Reaction solution is cooled to-10 DEG C, starts the dichloromethane solution dripping n-amyl chlorocarbonate, control dropping temperature at-10 DEG C ~-5 DEG C, remove refrigerating fulid after adding, room temperature stirs reaction 2 hours.After reaction terminates, suction 1.5L0.2N hydrochloric acid, stirs 15 minutes, collects lower floor's methylene dichloride phase, and methylene dichloride uses 0.2N salt acid elution three times (500ml × 3) mutually again.Finally wash methylene dichloride phase (500ml × 1) with water.Methylene dichloride uses anhydrous sodium sulfate drying mutually, filters, is done by filtrate 35 DEG C of concentrating under reduced pressure, obtain product 262g, yield 92.3%.
Get three mouthfuls of reaction flasks that step reactor product 262g puts into 1L, after loading onto thermometer, magnetic stir bar, add tetrahydrofuran (THF) 5.0L, add 393g sugar derivatives.Above-mentioned solution stirring, after 10 minutes, is cooled to 0 DEG C.In there-necked flask, drip boron trifluoride ether solution 350ml, within 20 minutes, dropwise.Temperature of reaction is risen to room temperature, stirs 5 hours.Reaction is heated to 40 DEG C, reacts 2 hours.Be cooled to room temperature, add 2N hydrochloric acid 40ml, react 1 hour.Filter, by insolubles filtering, add water 200ml, extraction into ethyl acetate reaction solution (1.0L × 3).Merge organic phase, use purified water 500ml.Anhydrous sodium sulfate drying organic phase, filters, concentrates filtrate to about 1.0L, add 1.0L normal hexane crystallization, and leave standstill 2 hours, get solid after filtration, vacuum 40 DEG C of dryings 20 hours, obtain product 325g, yield 84.3%.
Embodiment 3
Methylene dichloride 380L is joined in 1000L reactor, starts stirring, in reactor, add 5-flurocytosine 15.2kg, then add pyridine 14.4kg.Nitrogen replacement three times, suction n-amyl chlorocarbonate 21.2kg in dropping bath, then suction methylene dichloride 20L.Open cryogenic freezing, reaction solution is cooled to-10 DEG C, opens dropping valve, start the dichloromethane solution dripping n-amyl chlorocarbonate, control dropping temperature at-10 DEG C ~-5 DEG C, add rear closedown freeze cycle, be warming up to room temperature, stirring reaction 2 hours.After reaction terminates, suction 150L0.2N hydrochloric acid, stirs 15 minutes, leaves standstill separatory, collects lower floor's methylene dichloride phase, and methylene dichloride uses 0.2N salt acid elution three times (50L × 3) mutually again.Finally wash methylene dichloride phase (50L × 1) with water.Methylene dichloride uses anhydrous sodium sulfate drying mutually, filters, is done by filtrate 35 DEG C of concentrating under reduced pressure, obtain product 26.4kg, yield 93.0%.
Get the reactor that step reactor product 26.4kg puts into 1000L, start stirring, add tetrahydrofuran (THF) 500L, add 39.6kg sugar derivatives.Above-mentioned solution stirring, after 10 minutes, is cooled to 0 DEG C.In reactor, drip boron trifluoride ether solution 35.2L, within 1 hour, dropwise.Temperature of reaction is risen to room temperature, stirs 5 hours.Reaction is heated to 40 DEG C, reacts 2 hours.Be cooled to room temperature, add 2N hydrochloric acid 4L, react 1 hour.Filter, by insolubles filtering, add water 20L, extraction into ethyl acetate reaction solution (100L × 3).Merge organic phase, use purified water 50L.Anhydrous sodium sulfate drying organic phase, filters, concentrates filtrate to about 100L, add 100L normal hexane crystallization, and leave standstill 2 hours, get solid after filtration, vacuum 40 DEG C of dryings 20 hours, obtain product 33.2kg, yield 85.5%.
CPTB120522-cdcl3-140523 hydrogen spectrum nuclear-magnetism of the present invention.As shown in Figure 1.
HPLC collection of illustrative plates of the present invention, as shown in Figure 2 and Table 1.
Table 1 HPLC collection of illustrative plates of the present invention
Ignition residue of the present invention detects (the micro-spectral technology in Shanghai), sample ID: capecitabine (CPTB201511001), sample number into spectrum CS2015120181, and detection method is with reference to " Chinese Pharmacopoeia " version in 2010 two annex VIII N.Detected result is as shown in table 2.
Detection (the micro-spectral technology in the Shanghai) result that table 2 is ignition residue of the present invention
Be illustrated the specific embodiment of the present invention above, but the present invention is not as limit, only otherwise depart from aim of the present invention, the present invention can also have various change.
Claims (10)
1. a preparation method for capecitabine, is characterized in that, it comprises step:
Step one take 5-FU as initial feed, generates intermediate after reacting with penta oxygen formyl chloride;
Step 2, intermediate and ribose derivates coupling generate product capecitabine;
Its reaction formula is as follows:
2. preparation method according to claim 1, is characterized in that: the 5-flurocytosine in step one: pyridine: penta oxygen formyl chloride=1:1.25 ~ 1.4:1.1 ~ 1.3.
3. preparation method according to claim 1, is characterized in that: the dropping penta oxygen formyl chloride temperature in step one controls at-10 DEG C ~ 0 DEG C;
In step one, temperature of reaction controls at 0 DEG C ~ 40 DEG C.
4. preparation method according to claim 1, is characterized in that: the hydrochloric acid content that in step one, cancellation reaction uses controls: HCl:5-flucytosine=0.25 ~ 0.025:1.
5. preparation method according to claim 1, is characterized in that: the first step product in step 2: ribose derivates=1:1.0 ~ 1.3.
6. preparation method according to claim 1, is characterized in that: select boron trifluoride diethyl etherate as condensing agent in step 2.
7. preparation method according to claim 1, is characterized in that: the first step products weight (kg) in step 2: boron trifluoride diethyl etherate volume (L)=1:1.25 ~ 1.45.
8. preparation method according to claim 1, is characterized in that: in step 2, temperature of reaction controls at 10 DEG C ~ 30 DEG C.
9. preparation method according to claim 1, is characterized in that: in step 2, the reaction times controls at 2 hours ~ 4 hours.
10. preparation method according to claim 1, is characterized in that: in step 2, purification system is ethyl acetate and normal hexane, and volume ratio is about 1:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511003275.1A CN105566419A (en) | 2015-12-28 | 2015-12-28 | Capecitabine preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511003275.1A CN105566419A (en) | 2015-12-28 | 2015-12-28 | Capecitabine preparation method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105566419A true CN105566419A (en) | 2016-05-11 |
Family
ID=55877106
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201511003275.1A Pending CN105566419A (en) | 2015-12-28 | 2015-12-28 | Capecitabine preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105566419A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336827A (en) * | 2018-12-21 | 2019-02-15 | 山东铂源药业有限公司 | The preparation method of capecitabine impurity (the fluoro- 2- oxo -1,2- dihydro-pyrimidin -4- base of 5-) amyl carbamate |
Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005080351A1 (en) * | 2004-02-23 | 2005-09-01 | Shanghai Desano Pharmaceutical Holding Co., Ltd. | The preparation and application of a n4-oxycarbonylcytosine derivatives |
| WO2008131062A2 (en) * | 2007-04-20 | 2008-10-30 | Dr. Reddy's Laboratories Ltd. | Process for preparing capecitabine |
| CN101812104A (en) * | 2010-04-20 | 2010-08-25 | 江苏吴中苏药医药开发有限责任公司 | New method for continuously operating to synthesize capecitabine |
| CN101830953A (en) * | 2010-05-26 | 2010-09-15 | 南京亚东启天药业有限公司 | Method for preparing capecitabine and intermediate thereof |
| EP2241556A1 (en) * | 2007-12-06 | 2010-10-20 | Coll Farma S.L. | Method for the preparation of capecitabine and intermediates used in said method |
| CN101928314A (en) * | 2010-08-27 | 2010-12-29 | 广东肇庆星湖生物科技股份有限公司 | Preparation method for capecitabine |
| CN102140124A (en) * | 2011-02-26 | 2011-08-03 | 湖南欧亚生物有限公司 | Novel synthesis process of capecitabine |
| CN102382160A (en) * | 2011-03-23 | 2012-03-21 | 上海昕盛医药科技有限公司 | Preparation method of capecitabine |
| CN102924548A (en) * | 2012-11-30 | 2013-02-13 | 安润医药科技（苏州）有限公司 | Synthesis method of capecitabine |
| CN103897004A (en) * | 2012-12-27 | 2014-07-02 | 鲁南制药集团股份有限公司 | Synthesis method for capecitabine |
| CN104628804A (en) * | 2015-01-30 | 2015-05-20 | 吉林修正药业新药开发有限公司 | Synthesis method of capecitabine impurity acetyl condensate |
| CN104744537A (en) * | 2015-04-09 | 2015-07-01 | 山东大学 | Synthetic method of capecitabine |
| CN104926901A (en) * | 2015-06-15 | 2015-09-23 | 广安凯特医药化工有限公司 | Synthetic method for capecitabine key intermediate |
-
2015
- 2015-12-28 CN CN201511003275.1A patent/CN105566419A/en active Pending
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005080351A1 (en) * | 2004-02-23 | 2005-09-01 | Shanghai Desano Pharmaceutical Holding Co., Ltd. | The preparation and application of a n4-oxycarbonylcytosine derivatives |
| WO2008131062A2 (en) * | 2007-04-20 | 2008-10-30 | Dr. Reddy's Laboratories Ltd. | Process for preparing capecitabine |
| EP2241556A1 (en) * | 2007-12-06 | 2010-10-20 | Coll Farma S.L. | Method for the preparation of capecitabine and intermediates used in said method |
| CN101812104A (en) * | 2010-04-20 | 2010-08-25 | 江苏吴中苏药医药开发有限责任公司 | New method for continuously operating to synthesize capecitabine |
| CN101830953A (en) * | 2010-05-26 | 2010-09-15 | 南京亚东启天药业有限公司 | Method for preparing capecitabine and intermediate thereof |
| CN101928314A (en) * | 2010-08-27 | 2010-12-29 | 广东肇庆星湖生物科技股份有限公司 | Preparation method for capecitabine |
| CN102140124A (en) * | 2011-02-26 | 2011-08-03 | 湖南欧亚生物有限公司 | Novel synthesis process of capecitabine |
| CN102382160A (en) * | 2011-03-23 | 2012-03-21 | 上海昕盛医药科技有限公司 | Preparation method of capecitabine |
| CN102924548A (en) * | 2012-11-30 | 2013-02-13 | 安润医药科技（苏州）有限公司 | Synthesis method of capecitabine |
| CN103897004A (en) * | 2012-12-27 | 2014-07-02 | 鲁南制药集团股份有限公司 | Synthesis method for capecitabine |
| CN104628804A (en) * | 2015-01-30 | 2015-05-20 | 吉林修正药业新药开发有限公司 | Synthesis method of capecitabine impurity acetyl condensate |
| CN104744537A (en) * | 2015-04-09 | 2015-07-01 | 山东大学 | Synthetic method of capecitabine |
| CN104926901A (en) * | 2015-06-15 | 2015-09-23 | 广安凯特医药化工有限公司 | Synthetic method for capecitabine key intermediate |
Non-Patent Citations (2)
| Title |
|---|
| 刘杨 等: "卡培他宾的合成工艺研究", 《中国药物化学杂志》 * |
| 姚刚 等: "卡培他滨的合成工艺研究", 《山西医科大学学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336827A (en) * | 2018-12-21 | 2019-02-15 | 山东铂源药业有限公司 | The preparation method of capecitabine impurity (the fluoro- 2- oxo -1,2- dihydro-pyrimidin -4- base of 5-) amyl carbamate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2423215A1 (en) | Prodrugs based on gemcitabine structure as well as synthetic method and application thereof | |
| CN106539810A (en) | A kind of compositionss for being enriched NUC-1031 individual isomers and its production and use | |
| CN102417491A (en) | Method for preparing cabazitaxel by taking 10-deacetylate-baccatin III as raw material | |
| CN102311410A (en) | Preparation method for cabazitaxel | |
| CN101967140A (en) | Deuterated crizotinib as well as derivant, preparation method and application thereof | |
| CN102731573A (en) | Hydroxyl phosphate amino acid ester derivatives of Brefeldin A, preparation method thereof, and application thereof | |
| CN105566419A (en) | Capecitabine preparation method | |
| WO2006120472A2 (en) | Novel beta-steroid compounds | |
| CN110156841B (en) | Pt (IV) ionic complex and preparation method thereof | |
| CN102391356B (en) | Steroid n-glycoside analogue taking dihydro-pyranoid ring as D ring and preparation and application thereof | |
| CN113024557B (en) | Penamine A alkaloid structure simplified substance and application thereof | |
| CN104311518A (en) | Preparation method for 6-methoxyscutellarin | |
| CN101016319B (en) | Benzoisoselenothiazolidone aminosugar derivative, preparing method and application therheof | |
| CN108586564B (en) | A kind of C5 substitution diosgenin derivative and its preparation and application | |
| CN103739645A (en) | Preparation method of decitabine | |
| CN102617677A (en) | Method for preparing 2-deoxidized-2, 2-hydrochloric acid difluoro deoxycytidine | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN107365322B (en) | A kind of novel rutaecarpin analog derivative, preparation method and the usage | |
| CN105712994B (en) | Imidazolone-morphinan as well as preparation method and application thereof | |
| CN106336443B (en) | The synthetic method of a kind of nucleoside compound | |
| CN101993464A (en) | Preparation method of capecitabine | |
| CN107281180B (en) | Application of 8-alkyl berberine salt in preparing medicine for preventing and treating lung cancer | |
| CN111377988A (en) | Capecitabine intermediate | |
| CN106317147B (en) | nucleoside compound and preparation method thereof | |
| CN103319485B (en) | 6-(beta-alkylnaphthy)mercaptopurine compound, and synthesis method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160511 |
|
| WD01 | Invention patent application deemed withdrawn after publication |