CN104628804A - Synthesis method of capecitabine impurity acetyl condensate - Google Patents
Synthesis method of capecitabine impurity acetyl condensate Download PDFInfo
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- CN104628804A CN104628804A CN201510047814.5A CN201510047814A CN104628804A CN 104628804 A CN104628804 A CN 104628804A CN 201510047814 A CN201510047814 A CN 201510047814A CN 104628804 A CN104628804 A CN 104628804A
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- condensate
- capecitabine
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- flurocytosine
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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 invention relates to a synthesis method of a capecitabine impurity acetyl condensate, which comprises the following steps: (1) adding toluene, hexamethyldisilazane and methanesulfonic acid into 5-fluctyosine to complete concentration, adding triacetyl ribose and dichloromethane, dropwisely adding a tin tetrachloride dichloromethane solution, reacting, regulating the pH value, extracting, and concentrating to obtain a condensate; (2) adding chloro-formic acid, n-amyl ester, dichloromethane and pyridine into the obtained condensate, and concentrating to obtain grease; (3) adding acetic anhydride into the condensate, refluxing, distilling off the acetic anhydride, adding trichloromethane for extraction, and concentrating the trichloromethane layer to obtain grease; and (4) passing the grease through a silica gel column, eluting with ethyl acetate and petroleum ether in a ratio of 1:1-9:1 for separation, collecting the end product, and concentrating to obtain the capecitabine impurity acetyl condensate. The method can obtain the capecitabine acetyl condensate with higher purity. When the capecitabine acetyl condensate is used as a known impurity in quality analysis of capecitabine, the analysis is more accurate. The method has the advantages of mild preparation conditions, simple steps, stable product quality and high purity.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to the acetyl condenses impurity 2' of the medicine capecitabine of mammary cancer, the rectum cancer, colorectal carcinoma and cancer of the stomach, the synthetic method of the fluoro-N4-of 3'-O-carbonyl-5'-deoxidation-5-[(pentyloxy) carbonyl] cytosine(Cyt).
Background technology:
Capecitabine is the prodrug of a kind of novel 5-Fluracil developed by Roche Holding Ag of Switzerland, has selectively acting to tumour cell, can as oral cytotoxic agent.
Capecitabine itself and no cytotoxicity, but can be converted into through three steps under the effect of enzyme in vivo there is Cytotoxic 5-Fluracil.Organize high with the concentration compared with normal of capecitabine metabolism involved enzyme in tumor tissues, thus make it have the selecting cell toxicity to tumour cell.Be applicable to taxol and include the further treatment of advanced primary that anthracycline antibiotics chemotherapy regimen fails to respond to any medical treatment or 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.
Because the biological activity because of capecitabine is strong, its acetyl condenses also has certain biological activity, controls its content, is of great importance to improving the quality of products.Its structural formula of capecitabine acetylactone is: the fluoro-N4-of 2', 3'-O-carbonyl-5'-deoxidation-5-[(pentyloxy) carbonyl] cytosine(Cyt) core is sweet.
The patent documentation prepared about capecitabine is many, all describe in detail the preparation technology of capecitabine, but not have record about the synthesis of impurity, analysis, detection, to realize the control to drug quality.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of capecitabine impurity acetyl condenses " 2'; the fluoro--N4-of 3'-O-carbonyl-5'-deoxidation-5* [(pentyloxy) carbonyl] cytosine(Cyt) ", obtain the highly purified isomer impurities compound as the medicine capecitabine impurity analysis of mammary cancer, the rectum cancer, colorectal carcinoma and cancer of the stomach by the method.
Synthetic method of the present invention comprises the following steps:
I, to 5-flurocytosine
Add toluene, hmds and methylsulfonic acid, react 5 ~ 8h under 50 ~ 110 DEG C of conditions, reacted rear concentration of reaction solution.Add triacetyl ribose and methylene dichloride again, be cooled to-10 ~ 0 DEG C, drip tin tetrachloride dichloromethane solution.Dropwise reaction 5 ~ 12h.React rear sodium bicarbonate aqueous solution or triethylamine adjust ph 4 ~ 5, through methylene dichloride or chloroform extraction, after concentrated, obtain condenses;
Wherein, the add-on of hmds, methylsulfonic acid and triacetyl ribose is respectively 2 ~ 9 and 1 ~ 10 of 5-flurocytosine quality, 2 ~ 12
2, positive penta fat of chloroformic acid is added in the condenses obtained to step 1
Methylene dichloride and pyridine ,-20 ~ 25 DEG C of reaction 1 ~ 4h, with salt acid for adjusting pH value 4 ~ 6, layering, organic layer reconcentration obtains oily matter;
Wherein, chloroformic acid isoamyl fat add-on is be 1 ~ 3 with 5-flurocytosine mass ratio used in step 1, and it is 7 ~ 4 and 1 ~ 3 that the add-on of methylene dichloride and pyridine is respectively 5-flurocytosine mass volume ratio;
3, add acetic anhydride, reflux 2-20h in the condenses obtained to step 2, steam acetic anhydride, add water and chloroform extraction in decompression, concentrated trichloromethane layer obtains oily matter.
The add-on of acetic anhydride is respectively 1 ~ 9 of 5-flurocytosine mass volume ratio.
4, step 3 gained oily matter is crossed silicagel column ethyl acetate and sherwood oil in proportion 1:1 ~ 9:1 wash-out be isolated, collect end product, concentrated, obtain off-white color compound.
High purity capecitabine acetyl condenses 2' is confirmed as, the fluoro--N4-of 3'-O-carbonyl-5'-deoxidation-5* [(pentyloxy) carbonyl] cytosine(Cyt) after adopting nucleus magnetic resonance to analyze structure to step 4 gained off-white color compound.After adopting high performance liquid chromatograph to carry out purity testing, its purity is greater than 99.0%.
Positively effect of the present invention obtains the higher capecitabine acetyl condenses of purity.It can be used as known impurities in the mass analysis of capecitabine, specify impurity position in sample, investigate impurity and sample room resolution, make analytical procedure more accurate.Mild condition of the present invention, synthesis step is simple, constant product quality, and experimental implementation is simple, prepares sample purity higher.
Embodiment:
Embodiment 1
Taking 5-flurocytosine 25.0g puts in 500ml three-necked bottle, adds toluene 55ml wherein, hmds 2ml, and 110 DEG C of reflux 6.5h, have reacted rear concentration of reaction solution.Add triacetyl ribose 26.0g again and methylene dichloride 200ml is cooled to-10 ~ 0 DEG C, drip the mixing solutions of tin tetrachloride 20ml and methylene dichloride 50ml, reaction 8h, pH to 4 ~ 5 are regulated with sodium bicarbonate aqueous solution, use dichloromethane extraction twice again, merge organic phase, after concentrated by rotary evaporation, obtain condenses.
In condenses, add the positive penta fat 30mlg of chloroformic acid, methylene dichloride 100ml, pyridine 20ml ,-15 DEG C of reaction 2h, regulate pH4-6 with hydrochloric acid, layering, organic layer concentrates to obtain oily matter.
In oily matter, add acetic anhydride 100ml, reflux 15h, steam acetic anhydride in decompression, add water 450ml and trichloromethane 400ml and extract, 200ml washes three times.Concentrated trichloromethane layer obtains oily matter, through dichloromethane extraction, obtains oily matter after concentrated.
Finally cross silicagel column ethyl acetate and sherwood oil 1:1 to carry out wash-out and be isolated, collect end product, concentrate drying obtains the higher off-white color compound of purity.
1H-NMR（400MHz，CDCl
3）δ0.1.0~1.07（t，3h），1.20(t,3H)，1.29（d，2H），1.34~1.36（d，4H），1.57（d，2H），4.08（d，2H），4.55（d，2H），4.59~4.60（s，2H），5.94（d，2H），6.93（m，1H）8.0（s，1H）。Liquid phase purity 99%.
Embodiment 2
Taking 5-flurocytosine 30.5g puts in 500ml three-necked bottle, adds toluene 65ml wherein, hmds 3ml, and 110 DEG C of reflux 6.5h, have reacted rear concentration of reaction solution.Add triacetyl ribose 39.6g again and methylene dichloride 200ml is cooled to-5 ~ 5 DEG C, drip the mixing solutions of tin tetrachloride 25ml and methylene dichloride 50ml, reaction 9h, pH to 4 ~ 5 are regulated with sodium bicarbonate aqueous solution, use dichloromethane extraction twice again, merge organic phase, after concentrated by rotary evaporation, obtain condenses.
In condenses, add the positive penta fat 32ml of chloroformic acid, methylene dichloride 100ml, pyridine 20ml ,-10 DEG C of reaction 4h, regulate pH4-6 with hydrochloric acid, layering, water layer methylene dichloride 20ml extracting twice, merge organic phase.Once, organic layer concentrates to obtain oily matter in 30ml washing.
In oily matter, add acetic anhydride 155ml, reflux 10h, steam acetic anhydride in decompression, add water 450ml and trichloromethane 400ml and extract, 200ml washes three times.Concentrated trichloromethane layer obtains oily matter, through dichloromethane extraction, obtains oily matter after concentrated.
Finally cross silicagel column ethyl acetate and sherwood oil 1:1 to carry out wash-out and be isolated, collect end product, concentrate drying obtains the higher off-white color compound of purity.Liquid phase purity 99%.
Claims (1)
1. a synthetic method for capecitabine impurity acetyl condenses, comprises the following steps:
(I) to 5-flurocytosine
Add toluene, hmds and methylsulfonic acid, 5 ~ 8h is reacted under 50 ~ 110 DEG C of conditions, react rear concentration of reaction solution, then added triacetyl ribose and methylene dichloride, be cooled to-10 ~ 0 DEG C, drip tin tetrachloride dichloromethane solution, dropwise reaction 5 ~ 12h, react rear sodium bicarbonate aqueous solution or triethylamine adjust ph 4 ~ 5, through methylene dichloride or chloroform extraction, condenses is obtained after concentrated
Wherein, the add-on of hmds, methylsulfonic acid and triacetyl ribose is respectively 2 ~ 9 and 1 ~ 10 of 5-flurocytosine quality, 2 ~ 12;
(2) positive penta fat of chloroformic acid is added in the condenses obtained to step (1)
Methylene dichloride and pyridine ,-20 ~ 25 DEG C of reaction 1 ~ 4h, with salt acid for adjusting pH value 4 ~ 6, layering, organic layer reconcentration obtains oily matter;
Wherein, chloroformic acid isoamyl fat add-on is be 1 ~ 3 with 5-flurocytosine mass ratio used in step 1, and it is 7 ~ 4 and 1 ~ 3 that the add-on of methylene dichloride and pyridine is respectively 5-flurocytosine mass volume ratio;
(3) add acetic anhydride, reflux 2-20h in the condenses obtained to step (2), steam acetic anhydride, add water and chloroform extraction in decompression, concentrated trichloromethane layer obtains oily matter,
The add-on of acetic anhydride is respectively 1 ~ 9 of 5-flurocytosine mass volume ratio;
(4) step (3) gained oily matter is crossed silicagel column ethyl acetate and sherwood oil in proportion 1:1 ~ 9:1 wash-out be isolated, collect end product, concentrated, obtain the 2' of off-white color compound proterties, the fluoro--N4-of 3'-O-carbonyl-5'-deoxidation-5* [(pentyloxy) carbonyl] cytosine(Cyt).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566419A (en) * | 2015-12-28 | 2016-05-11 | 上海金和生物技术有限公司 | Capecitabine preparation method |
| CN108864231A (en) * | 2018-07-27 | 2018-11-23 | 上海葆隆生物科技有限公司 | A kind of impurity of capecitabine and preparation method thereof |
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| CN1896089A (en) * | 2005-07-15 | 2007-01-17 | 上海奥锐特国际贸易有限公司 | Synthesis of N-acyl-5'-desoxy-5-flucytogly derivative |
| WO2011010967A1 (en) * | 2009-07-23 | 2011-01-27 | Scinopharm Taiwan Ltd. | Process for producing flurocytidine derivatives |
| CN103524583A (en) * | 2013-10-30 | 2014-01-22 | 山东铂源药业有限公司 | 2',3'-O-carbonyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine synthesis method |
| CN103570781A (en) * | 2012-07-02 | 2014-02-12 | 国药一心制药有限公司 | Industrialized preparation method for capecitabine |
| CN103601777A (en) * | 2013-12-04 | 2014-02-26 | 哈药集团制药总厂 | Preparation method of capecitabine |
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2015
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Patent Citations (6)
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| CN1896089A (en) * | 2005-07-15 | 2007-01-17 | 上海奥锐特国际贸易有限公司 | Synthesis of N-acyl-5'-desoxy-5-flucytogly derivative |
| WO2011010967A1 (en) * | 2009-07-23 | 2011-01-27 | Scinopharm Taiwan Ltd. | Process for producing flurocytidine derivatives |
| CN103570781A (en) * | 2012-07-02 | 2014-02-12 | 国药一心制药有限公司 | Industrialized preparation method for capecitabine |
| CN103897005A (en) * | 2012-12-27 | 2014-07-02 | 鲁南制药集团股份有限公司 | Method for synthesizing capecitabine by continuous operations |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566419A (en) * | 2015-12-28 | 2016-05-11 | 上海金和生物技术有限公司 | Capecitabine preparation method |
| CN108864231A (en) * | 2018-07-27 | 2018-11-23 | 上海葆隆生物科技有限公司 | A kind of impurity of capecitabine and preparation method thereof |
| CN114685584A (en) * | 2018-07-27 | 2022-07-01 | 上海葆隆生物科技有限公司 | Impurities of capecitabine and preparation method thereof |
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