CN103601777A - Preparation method of capecitabine - Google Patents
Preparation method of capecitabine Download PDFInfo
- Publication number
- CN103601777A CN103601777A CN201310647451.XA CN201310647451A CN103601777A CN 103601777 A CN103601777 A CN 103601777A CN 201310647451 A CN201310647451 A CN 201310647451A CN 103601777 A CN103601777 A CN 103601777A
- Authority
- CN
- China
- Prior art keywords
- capecitabine
- preparation
- described step
- cytidine
- bis
- 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
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 title claims abstract description 46
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229960004117 capecitabine Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000002425 crystallisation Methods 0.000 claims abstract description 20
- 230000008025 crystallization Effects 0.000 claims abstract description 20
- 239000012043 crude product Substances 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 claims description 18
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 claims description 18
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012670 alkaline solution Substances 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 238000007670 refining Methods 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 238000010583 slow cooling Methods 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 12
- 239000000047 product Substances 0.000 abstract description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 2
- 239000007787 solid Substances 0.000 abstract description 2
- WMJHGZFQHPCWQZ-GWBBYGMBSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-[5-fluoro-2-oxo-4-(pentoxycarbonylamino)pyrimidin-1-yl]-2-methyloxolan-3-yl] acetate Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C)O1 WMJHGZFQHPCWQZ-GWBBYGMBSA-N 0.000 abstract 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 4
- 206010055113 Breast cancer metastatic Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229940053867 xeloda Drugs 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 1
- 230000001399 anti-metabolic effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of capecitabine. The method employs isopropyl ether and acetonitrile to carry out crystallization on an intermediate 2', 3'-bis-O-acetyl-5'-deoxy-5-fluoro-N-(pentyloxycarbonyl)cytidine, coverts an oil-like matter into a solid, improves the yield and purity of the intermediate, and can achieve precise feeding for the next step reaction, thus greatly lowering the reaction cost. Dichloromethane and toluene are employed to perform crystallization and refine capecitabine, thus overcoming the disadvantages of bad state, low yield and the like in the prior art using ethyl acetate/n-hexane to perform crystallization. Also, the method can effectively remove impurities from a crude product, and can make the purity of a capecitabine product reach 99.96%.
Description
Technical field
The present invention relates to the synthetic field of medicine, specifically, relate to a kind of preparation method of capecitabine.
Background technology
Capecitabine (Capecitabine), chemical name: the fluoro-N-[(pentyloxy of 5'-deoxidation-5-) carbonyl] cytidine, by company of Switzerland Roche Group (roche), developed, get permission listing with trade(brand)name xeloda (Xeloda) in the U.S. in April, 1998, within 2000, obtain the SFDA approval of import, listing formulation is tablet.Capecitabine is a kind of antimetabolic 5-FU deoxynucleoside amino formate medicine that can be transformed in vivo 5-FU, can suppress cell fission and RNA interfering and protein synthesis, be applicable to taxol and include advanced primary that anthracycline antibiotics chemotherapy regimen fails to respond to any medical treatment or the further treatment of metastatic breast cancer, be mainly used in advanced primary or metastatic breast cancer, the treatment of the rectum cancer, colorectal carcinoma and cancer of the stomach.
At present, many preparation methods about capecitabine have been reported.Wherein, in the preparation fluoro-N-of 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine step, most of anhydrous sodium sulphate of using is dewatered, and for example patent WO2009/082844, causes product yield significantly to reduce; In capecitabine crystallization step, major part is all to use ethyl acetate to carry out crystallization, for example patent CN101812104(retrieves less than patent by this patent publication No., please contriver check and revise), however capecitabine crude product is not soluble in ethyl acetate, and crystallization is out of order, yield is low, cost is high, and refining rear purity and crude product purity are very nearly the same, there is no practical significance.Therefore, finding a method of preparing cost-effectively the capecitabine of high purity, high yield is one of this area technical problem urgently to be resolved hurrily.
Summary of the invention
In order to solve the defect existing in prior art, the invention provides a kind of preparation method of capecitabine, make the raising of capecitabine product yield and purity reach 99.96%.
The preparation method who the present invention relates to a kind of capecitabine, is achieved through the following technical solutions:
A preparation method for capecitabine, comprises following processing step:
The preparation of the fluoro-N-of (1) 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine
With 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine is raw material, at methylene dichloride, ethylene dichloride, acetonitrile, N, under any one organic solvent in dinethylformamide and basifier exist, carry out acylation reaction with n-amyl chlorocarbonate and generate the fluoro-N-of 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine; Extracting in water, merges organic phase; Concentrating under reduced pressure organic phase is to flowing out without distillate, add isopropyl ether, acetonitrile to oily matter, after normal temperature all dissolves, crystallization behind slow cooling to 0～5 ℃, obtain the fluoro-N-of white powder 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine;
(2) preparation of capecitabine crude product
The white powder 2 ' that step (1) is obtained, under the fluoro-N-of 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine room temperature, join in any one organic solvent in methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) to dissolving, reaction under alkaline solution exists, after completion of the reaction, use concentrated hydrochloric acid to regulate pH value to 2-6, then dichloromethane extraction is twice, obtain organic phase, extracting in water, merge organic phase, concentrating under reduced pressure organic phase, to thickness, adds toluene crystallization, suction filtration, toluene wash, obtain capecitabine crude product;
(3) capecitabine crude product refining
Under room temperature, capecitabine crude product to the solution that uses methylene dichloride dissolving step (2) to obtain is clarified, and adds toluene crystallization, suction filtration, and toluene wash, obtains capecitabine.
In described step (1), acylation reaction temperature is-5 ℃～-10 ℃.
Any one organic solvent in described step (1) in methylene dichloride, ethylene dichloride, acetonitrile, DMF is methylene dichloride.
In described step (1), basifier is pyridine, triethylamine or salt of wormwood.
In described step (1), basifier is pyridine.
Any one organic solvent in described step (2) in methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) is methyl alcohol.
In described step (2), alkaline solution is sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide.
In described step (2), alkaline solution is sodium hydroxide.
In described step (2), using concentrated hydrochloric acid to regulate pH value is 4.5-4.6.
In described step (2) and step (3), the crystallization time is 2 hours.
The preparation method's of capecitabine of the present invention reaction formula is as follows:
Compared with prior art, the present invention has the following advantages:
1, the present invention is by 2 ' of the first step acquisition; the fluoro-N-of 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine (being intermediate) oily matter is through isopropyl ether crystallization; be converted into solid; not only improve yield and the purity of intermediate; also can be next step reaction and accurately feed intake, greatly save reaction cost.
2, the present invention uses methylene dichloride and toluene carry out crystallization and capecitabine is refined, overcome in prior art, use ethyl acetate/normal hexane crystallization out of order, the shortcoming such as yield is low, and effectively remove the impurity in crude product, make refining after purity reach 99.96%.
When 3, the present invention prepares the fluoro-N-of 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine, do not use anhydrous sodium sulphate to dewater, significantly improve product yield cost-saving.
Embodiment
By following examples, further describe the present invention, but should notice that scope of the present invention is not subject to any restriction of these embodiment.
The preparation of the fluoro-N-of embodiment 12 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine
2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine 20g, room temperature is dissolved in 50ml methylene dichloride, adds 4ml pyridine, is stirred to dissolving.At-5 ℃～-10 ℃, drip n-amyl chlorocarbonate 10ml.After dropwising, react 2 hours.With 60ml water washing 15 minutes, washed twice, discarded water layer, obtains organic layer.Organic layer is evaporated to without distillate and flows out; add isopropyl ether 80ml; acetonitrile 4ml is to oily matter; normal temperature all dissolves, after slow cooling to 0 ℃～5 ℃, and slow crystallization; obtain white powder 2 '; the fluoro-N-of 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine 17g, mass yield 85%, purity 99.86%.
The preparation of embodiment 2 capecitabine crude products
By the fluoro-N-of 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine 10g, room temperature is added in 27ml methyl alcohol extremely dissolves, and cools to-7 ℃ and drips 5N sodium hydroxide solution 15ml, and after dropwising ,-3 ℃ are reacted 0.5 hour.After completion of the reaction, add concentrated hydrochloric acid adjust pH to 4.5-4.6, after dropwising, the 50ml that adds methylene chloride extraction 15 minutes, extracting twice, merge organic layer, add water 30ml washing 15 minutes, organic layer adds anhydrous sodium sulfate drying, filter, be evaporated to stickyly, slowly drip 150ml toluene crystallization 2 hours, obtain capecitabine crude product 8.7g.Suction filtration, toluene wash.Mass yield 87%, purity 99.86%.
Embodiment 3 capecitabine crude product refinings
3g capecitabine crude product, is dissolved in 10ml methylene dichloride, and room temperature is dissolved to clarification, drips 50ml toluene, after dripping and finishing, and crystallization 2 hours.Suction filtration, toluene wash, obtains capecitabine product 2.79g.Mass yield is 93%, and purity is 99.96%.
Although illustrate and described exemplary embodiments more of the present invention, but those skilled in the art should know, without departing from the principles and spirit of the present invention, can make change to these exemplary embodiments, scope of the present invention is limited by claim and equivalent thereof.
Claims (10)
1. a preparation method for capecitabine, said method comprising the steps of:
The preparation of the fluoro-N-of (1) 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine
With 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine is raw material, at methylene dichloride, ethylene dichloride, acetonitrile, N, under any one organic solvent in dinethylformamide and basifier exist, carry out acylation reaction with n-amyl chlorocarbonate and generate the fluoro-N-of 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine; Extracting in water, merges organic phase; Concentrating under reduced pressure organic phase is to flowing out without distillate, add isopropyl ether, acetonitrile to oily matter, after normal temperature all dissolves, crystallization behind slow cooling to 0～5 ℃, obtain the fluoro-N-of white powder 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine;
(2) preparation of capecitabine crude product
The white powder 2 ' that step (1) is obtained, under the fluoro-N-of 3 '-bis--O-ethanoyl-5 '-deoxidation-5-(n-pentyl oxygen carbonyl) cytidine room temperature, join in any one organic solvent in methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) to dissolving, reaction under alkaline solution exists, after completion of the reaction, use concentrated hydrochloric acid to regulate pH value to 2-6, then dichloromethane extraction is twice, obtain organic phase, extracting in water, merge organic phase, concentrating under reduced pressure organic phase, to thickness, adds toluene crystallization, suction filtration, toluene wash, obtain capecitabine crude product;
(3) capecitabine crude product refining
Under room temperature, capecitabine crude product to the solution that uses methylene dichloride dissolving step (2) to obtain is clarified, and adds toluene crystallization, suction filtration, and toluene wash, obtains capecitabine.
2. the preparation method of capecitabine according to claim 1, is characterized in that, in described step (1), acylation reaction temperature is-5 ℃～-10 ℃.
3. the preparation method of capecitabine according to claim 1, is characterized in that, any one organic solvent in described step (1) in methylene dichloride, ethylene dichloride, acetonitrile, DMF is methylene dichloride.
4. the preparation method of capecitabine according to claim 1, is characterized in that, in described step (1), basifier is pyridine, triethylamine or salt of wormwood.
5. the preparation method of capecitabine according to claim 4, is characterized in that, in described step (1), basifier is pyridine.
6. the preparation method of capecitabine according to claim 1, is characterized in that, any one organic solvent in described step (2) in methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) is methyl alcohol.
7. the preparation method of capecitabine according to claim 1, is characterized in that, in described step (2), alkaline solution is sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide.
8. the preparation method of capecitabine according to claim 7, is characterized in that, in described step (2), alkaline solution is sodium hydroxide.
9. the preparation method of capecitabine according to claim 1, is characterized in that, in described step (2), using concentrated hydrochloric acid to regulate pH value is 4.5-4.6.
10. the preparation method of capecitabine according to claim 1, is characterized in that, in described step (2) and step (3), the crystallization time is 2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310647451.XA CN103601777A (en) | 2013-12-04 | 2013-12-04 | Preparation method of capecitabine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310647451.XA CN103601777A (en) | 2013-12-04 | 2013-12-04 | Preparation method of capecitabine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103601777A true CN103601777A (en) | 2014-02-26 |
Family
ID=50120055
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310647451.XA Pending CN103601777A (en) | 2013-12-04 | 2013-12-04 | Preparation method of capecitabine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103601777A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
| CN106496294A (en) * | 2016-09-21 | 2017-03-15 | 齐鲁天和惠世制药有限公司 | A kind of method for preparing micro powder type capecitabine |
| CN117229341A (en) * | 2023-11-07 | 2023-12-15 | 成都苑东生物制药股份有限公司 | Capecitabine crystal form I and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010065586A2 (en) * | 2008-12-02 | 2010-06-10 | Dr. Reddy's Laboratories Ltd. | Preparation of capecitabine |
| CN101993463A (en) * | 2009-08-19 | 2011-03-30 | 成都康弘药业集团股份有限公司 | Preparation method of capecitabine and intermediate thereof |
-
2013
- 2013-12-04 CN CN201310647451.XA patent/CN103601777A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010065586A2 (en) * | 2008-12-02 | 2010-06-10 | Dr. Reddy's Laboratories Ltd. | Preparation of capecitabine |
| CN101993463A (en) * | 2009-08-19 | 2011-03-30 | 成都康弘药业集团股份有限公司 | Preparation method of capecitabine and intermediate thereof |
Non-Patent Citations (1)
| Title |
|---|
| 陈言德等: "5"-脱氧-5-氟-N-［（戊氧基）羰基］胞苷-2"，3"-二乙酸酯的合成改进", 《精细化工中间体》, vol. 40, 31 December 2010 (2010-12-31), pages 37 - 42 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN104926901B (en) * | 2015-06-15 | 2018-04-20 | 广安凯特制药有限公司 | A kind of synthetic method of capecitabine key intermediate |
| 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 |
| CN106478751B (en) * | 2015-09-02 | 2020-06-26 | 正大天晴药业集团股份有限公司 | Preparation method of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytosine nucleoside |
| CN106496294A (en) * | 2016-09-21 | 2017-03-15 | 齐鲁天和惠世制药有限公司 | A kind of method for preparing micro powder type capecitabine |
| CN106496294B (en) * | 2016-09-21 | 2018-10-30 | 齐鲁天和惠世制药有限公司 | A method of preparing micro powder type capecitabine |
| CN117229341A (en) * | 2023-11-07 | 2023-12-15 | 成都苑东生物制药股份有限公司 | Capecitabine crystal form I and preparation method thereof |
| CN117229341B (en) * | 2023-11-07 | 2024-02-09 | 成都苑东生物制药股份有限公司 | Capecitabine crystal form I and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104024262B (en) | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof | |
| CN103601777A (en) | Preparation method of capecitabine | |
| CN102417491A (en) | Method for preparing cabazitaxel by taking 10-deacetylate-baccatin III as raw material | |
| CN105712984A (en) | Preparation method of Azilsartan | |
| CN103755628B (en) | The synthetic method of the iodo-5-bromopyridine of 2-amino-3- | |
| CN103570702A (en) | Method for industrial preparation of raltitrexed and novel raltitrexed crystal form for pharmacy | |
| CN102321086B (en) | Synthesizing method of adenine | |
| CN103242251B (en) | Preparation method of letrozole | |
| CN102976998A (en) | Method for synthesizing 3-(5-chloro-2-phenoxy-phenyl)-1-methyl-pyrrolidine-2, 4-diketone | |
| CN102731436A (en) | Preparation and refining method of repaglinide | |
| CN102225954B (en) | Method for purifying platinum | |
| CN111943937A (en) | Synthesis method of triphenyl candesartan | |
| CN104109182B (en) | A kind of method preparing gemcitabine hydrochloride | |
| CN103360326A (en) | Method for refining Gefinitib crystal form I | |
| CN103554136B (en) | Preparation method of cefmenoxine hydrochloride dry powder | |
| CN103113294A (en) | Synthesizing method of rebamipide | |
| CN106883227B (en) | The method for preparing ergometrine by ergot fermentation waste | |
| CN103739635B (en) | A kind of purification process of mannose triflate intermediate | |
| CN104402910B (en) | Thiazole pyridine compound and preparation method thereof | |
| CN103058950A (en) | Preparation method of febuxostat | |
| CN110229111B (en) | Ambroxol impurity and preparation method and application thereof | |
| CN101993464A (en) | Preparation method of capecitabine | |
| CN106336401A (en) | Refining method for avanafil | |
| CN102532125A (en) | Synthesis method for aztreonam compound | |
| CN108690000A (en) | A kind of process for purification of avanaphil |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140226 |
|
| RJ01 | Rejection of invention patent application after publication |