CN103193842A - Synthesis method of capecitabine - Google Patents
Synthesis method of capecitabine Download PDFInfo
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- CN103193842A CN103193842A CN2013101415464A CN201310141546A CN103193842A CN 103193842 A CN103193842 A CN 103193842A CN 2013101415464 A CN2013101415464 A CN 2013101415464A CN 201310141546 A CN201310141546 A CN 201310141546A CN 103193842 A CN103193842 A CN 103193842A
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- capecitabine
- trifluoromethanesulfonic acid
- deoxidation
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Abstract
The invention relates to the technical field of synthesis of chemical medicines, and in particular relates to a synthesis method of capecitabine. The synthesis method of the capecitabine comprises the following steps: reacting 5-flucytosine with 5-deoxy-1,2,3-triacetoxy-D-ribose in the presence of a catalyst; performing aftertreatment on the reaction liquid to obtain 2',3'-diacetoxy-5'-deoxy-5-fluorocytidine; adding pentyl chloroformate dropwise into the 2',3'-diacetoxy-5'-deoxy-5-fluorocytidine and pyridine; and performing aftertreatment on the reaction liquid, adding alkaline liquid dropwise and performing treatment to obtain the capecitabine, wherein the catalyst comprises trifluoromethanesulfonic acid and derivatives thereof. The catalyst used in the method can use alpha, beta isomer mixed type 5-deoxy-triacetyl ribose as a raw material and does not need to separate ALFA and BETA isomers; and the generated ALFA type glucoside can be converted into BETA type glucoside, so the production process is simplified and the production cost is reduced.
Description
Technical field
The present invention relates to the chemicals synthesis technical field, particularly a kind of synthetic method of capecitabine.
Background technology
Capecitabine (Capecitabine), chemistry 5 '-deoxidation by name-5-fluoro-N-[(pentyloxy) carbonyl] cytidine, capecitabine itself is cytotoxicity not, and metabolism is 5 FU 5 fluorouracil (5-FU) under the effect of enzyme in vivo, and then the performance antitumor action.High in more normally organizing with the concentration of capecitabine metabolism involved enzyme in tumor tissues, thus make it have selecting cell toxicity to tumour cell, can be used as oral cytotoxicity preparation.Its structural formula is as follows:
The synthetic method of the capecitabine of report has much at present, be raw material with 5-deoxidation-triacetyl ribose and 5-flurocytosine wherein, the synthetic intermediate 2' of elder generation, 3'-diacetoxy-5'-deoxidation-5-fluorine cytidine, the resynthesis capecitabine is 200880116613.4 and 201010177878.4 Chinese invention patent application as application number, but 5-deoxidation-triacetyl ribose has two kinds of isomer of α, β, that usually uses in the reaction is beta isomer, with two kinds of isomer separation purifying, and the cost that needs are very high.All be to use beta isomer at present a lot of technology, this just greatly reduces transformation efficiency, has caused the raising of cost.
Summary of the invention
Be raw material in order to solve in the above prior art with 5-deoxidation-triacetyl ribose and 5-flurocytosine, the synthetic intermediate 2' of elder generation, 3'-diacetoxy-5'-deoxidation-5-fluorine cytidine, the low problem of cost height, transformation efficiency that exists isomer to cause because of 5-deoxidation-triacetyl ribose in the operational path of resynthesis capecitabine, the invention provides and a kind ofly can make 5-deoxidation-triacetyl ribose α simultaneously, the synthetic method beta isomer reaction, that improve the capecitabine of transformation efficiency.
The present invention is achieved by the following measures:
A kind of synthetic method of capecitabine may further comprise the steps:
(1) with 5-flurocytosine and 5-deoxidation-1,2,3-triacetyl oxygen-D-ribose reacts under catalyst action, obtains reaction solution a;
(2) to reaction solution a aftertreatment, collect dichloromethane layer, washing, crystallization, centrifugal, wash, dry, dry 2', 3'-diacetoxy-5'-deoxidation-5-fluorine cytidine;
(3) to 2', drip n-amyl chlorocarbonate in 3'-diacetoxy-5'-deoxidation-5-fluorine cytidine and the pyridine, react to HPLC monitoring K5＜0.05% and obtain reaction solution b;
(4) reaction solution b washing, static separatory, the dichloromethane layer dripping alkali liquid is reacted to HPLC monitoring K6＜0.05%, washing, crystallization, centrifugal, dry capecitabine;
Described 5-deoxidation-1,2,3-triacetyl oxygen-D-ribose is α, the beta isomer mixture, α wherein, the mol ratio of beta isomer is 2.7:1.
Reaction formula is as follows:
Described catalyzer is trifluoromethanesulfonic acid and derivative thereof.
Described catalyzer is trifluoromethanesulfonic acid, triflate or trifluoromethanesulfonic acid estersil.
Described catalyzer is trifluoromethanesulfonic acid, trifluoromethanesulfonic acid methyl esters, trifluoromethanesulfonic acid ethyl ester or trifluoromethanesulfonic acid silanol ester.
Described catalyzer is with the trifluoromethanesulfonic acid optimum.
The 0.001-1.20 that described catalyzer trifluoromethanesulfonic acid consumption is the 5-flurocytosine molar weight doubly.
The more excellent consumption of described catalyzer trifluoromethanesulfonic acid is 0.01-1.0 times of 5-flurocytosine molar weight.
The 0.1-1.0 that the optimum consumption of described catalyzer trifluoromethanesulfonic acid is the 5-flurocytosine molar weight doubly.
Beneficial effect of the present invention:
The catalyzer that uses in the synthetic method of the present invention can use α, and beta isomer mixed type 5-deoxidation-triacetyl ribose is raw material, need not separate α, beta isomer; The α type glucosides that generates can also be converted into β type glucosides simultaneously, synthesis technique is simplified, and production cost reduces.
Embodiment
For a better understanding of the present invention, further specify below in conjunction with specific embodiment.
(1) with toluene (206 g) HMDS (79.38 g) .5-flucytosine (59.58 g). ammonium sulfate (2.4g) drops into 1000 milliliters of reaction flasks, stirring is warming up to backflow, about 2 hours molten clear, refluxed 1 hour again, and decompression and solvent recovery (about 80 ℃) is to doing, be cooled to below 30 ℃, add methylene chloride (1010.26g) 5-deoxidation-1,2,3-triacetyl oxygen-D-ribose is α, beta isomer mixture (120g), α wherein, the mol ratio of beta isomer is 2.7:1, be cooled to 20 ℃, drip trifluoromethanesulfonic acid (8.372ML), control＜25 ℃, dripped complete in about 2 hours, 25 ℃ of insulation reaction 12 hours get reaction solution a;
(2) reaction solution a changes 2000 milliliters of reaction flasks over to and adds sodium bicarbonate (232.64g), drips water (400g), drips complete in about 1-2 hour, stirred 1 hour, static layering is collected dichloromethane layer, water adds methylene chloride (500 g), stirs static layering 30 minutes, collect dichloromethane layer, add methylene chloride again (500 g), stirred static layering 30 minutes, collect dichloromethane layer, combined dichloromethane, 4% sodium hydrogen carbonate solution (200 g) is washed (25 ℃), and water (200 g) is washed, the reclaim under reduced pressure methylene dichloride is to doing, add ethanol (284.04 g), rising temperature for dissolving is cooled to 0-5 ℃ of crystallization, be incubated 2-3 hour, centrifugal, ethanol is washed, and dries, 65 ℃ dry 2', 3'-diacetoxy-5'-deoxidation-5-fluorine cytidine 100g; Yield: 67.4%;
(3) with methylene dichloride (663.3g), pyridine (41.27g), 2', 3'-diacetoxy-5'-deoxidation-5-fluorine cytidine (100g) drops into 1000 milliliters of reaction flasks, is cooled to-5-0 ℃, drips n-amyl chlorocarbonate (69.68g), temperature control＜5 ℃, dripped in about 1-1.5 hour and finish ,-5-5 ℃ is incubated 2-3 hour to react completely (HPLC monitoring K5＜0.05% is considered as terminal point), gets reaction solution b;
(4) reaction solution b adds water (300g) and washes, static separatory, dichloromethane layer adds saturated sodium bicarbonate solution (300g) to be washed, and static separatory, dichloromethane layer add methyl alcohol (79.18g), be cooled to-20--15 ℃, the solution of dropping sodium (16g) water (50g), temperature control＜-10 ℃ were dripped and to be finished in about 1 hour, insulation reaction 2-3 hour to react completely (HPLC monitors K6＜0.05%), drip concentrated hydrochloric acid (about 35g), temperature control＜-5 ℃, accent PH4.0, reaction solution changes 2000 milliliters of reaction flasks over to, add water (300g) methylene dichloride (663.3g), stir 10 minutes (temperature control 20-25 ℃), static separatory, dichloromethane layer is washed (300gx2) again twice, filter the reclaim under reduced pressure methylene dichloride to doing (45 ℃ of temperature controls), add ethyl acetate (500g), it is molten clear to heat up, be cooled to 0-5 ℃, be incubated 2-3 hour, centrifugal, ethyl acetate is washed, dry, 40 ℃ dry finished product 96.2g.Yield: 86.3%.
Claims (5)
1. the synthetic method of a capecitabine is characterized in that may further comprise the steps:
(1) with 5-flurocytosine and 5-deoxidation-1,2,3-triacetyl oxygen-D-ribose reacts under catalyst action, obtains reaction solution a;
(2) to reaction solution a aftertreatment, collect dichloromethane layer, washing, crystallization, centrifugal, wash, dry, dry 2', 3'-diacetoxy-5'-deoxidation-5-fluorine cytidine;
(3) to 2', drip n-amyl chlorocarbonate in 3'-diacetoxy-5'-deoxidation-5-fluorine cytidine and the pyridine, react to HPLC monitoring K5＜0.05% and obtain reaction solution b;
(4) reaction solution b washing, static separatory, the dichloromethane layer dripping alkali liquid is reacted to HPLC monitoring K6＜0.05%, washing, crystallization, centrifugal, dry capecitabine;
Described 5-deoxidation-1,2,3-triacetyl oxygen-D-ribose is α, the beta isomer mixture, α wherein, the mol ratio of beta isomer is 2.7:1;
Described catalyzer is the trifluoromethanesulfonic acid or derivatives thereof.
2. synthetic method according to claim 1 is characterized in that described catalyzer is trifluoromethanesulfonic acid.
3. synthetic method according to claim 2 is characterized in that 0.001-1.20 that described catalyzer trifluoromethanesulfonic acid consumption is the 5-flurocytosine molar weight doubly.
4. synthetic method according to claim 2 is characterized in that 0.01-1.0 that described catalyzer trifluoromethanesulfonic acid consumption is the 5-flurocytosine molar weight doubly.
5. synthetic method according to claim 2 is characterized in that 0.1-1.0 that described catalyzer trifluoromethanesulfonic acid consumption is the 5-flurocytosine molar weight doubly.
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| CN2013101415464A CN103193842A (en) | 2013-04-23 | 2013-04-23 | Synthesis method of capecitabine |
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| CN2013101415464A CN103193842A (en) | 2013-04-23 | 2013-04-23 | Synthesis method of capecitabine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113321693A (en) * | 2021-05-25 | 2021-08-31 | 神隆医药（常熟）有限公司 | Preparation method of capecitabine intermediate suitable for industrial production |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005063786A2 (en) * | 2003-12-22 | 2005-07-14 | F.Hoffman-La Roche Ag | Process for fluorocytidine derivatives |
| WO2010017547A1 (en) * | 2008-08-08 | 2010-02-11 | Scinopharm Taiwan Ldt. | Process for making 5-azacytosine nucleosides and their derivatives |
| CN101845070A (en) * | 2010-05-25 | 2010-09-29 | 郑州大学 | Synthesis method of antineoplastic medicine capecitabine |
| CN101899079A (en) * | 2009-05-30 | 2010-12-01 | 鲁南制药集团股份有限公司 | Preparation, separation and purification method of Decitabine |
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- 2013-04-23 CN CN2013101415464A patent/CN103193842A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005063786A2 (en) * | 2003-12-22 | 2005-07-14 | F.Hoffman-La Roche Ag | Process for fluorocytidine derivatives |
| WO2010017547A1 (en) * | 2008-08-08 | 2010-02-11 | Scinopharm Taiwan Ldt. | Process for making 5-azacytosine nucleosides and their derivatives |
| CN101899079A (en) * | 2009-05-30 | 2010-12-01 | 鲁南制药集团股份有限公司 | Preparation, separation and purification method of Decitabine |
| CN101845070A (en) * | 2010-05-25 | 2010-09-29 | 郑州大学 | Synthesis method of antineoplastic medicine capecitabine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113321693A (en) * | 2021-05-25 | 2021-08-31 | 神隆医药（常熟）有限公司 | Preparation method of capecitabine intermediate suitable for industrial production |
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Application publication date: 20130710 |