CN102993254A - Preparation method of xeloda intermediate 5'-deoxy-2', 3'-O-isopropylidene-5-fluorocytidine - Google Patents
Preparation method of xeloda intermediate 5'-deoxy-2', 3'-O-isopropylidene-5-fluorocytidine Download PDFInfo
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- CN102993254A CN102993254A CN2012105824507A CN201210582450A CN102993254A CN 102993254 A CN102993254 A CN 102993254A CN 2012105824507 A CN2012105824507 A CN 2012105824507A CN 201210582450 A CN201210582450 A CN 201210582450A CN 102993254 A CN102993254 A CN 102993254A
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- isopropylidene
- fluorine cytidine
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- cytidine
- fluorine
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Abstract
The invention provides a preparation method of a xeloda intermediate 5'-deoxy-2', 3'-O-isopropylidene-5-fluorocytidine. The preparation method includes steps: 1) dissolving 5-fluorocytidine in acetone, adding p-toluenesulfonic acid and 2,2-dimethoxy propane, adding a saturated sodium bicarbonate solution after a reaction by stirring, and recrystallizing to obtain 2',3'-O-isopropylidene-5-fluorocytidine; 2)placing the 2',3'-O-isopropylidene-5-fluorocytidine and bromination sulfoxide in dimethylformamide to obtain oily matter, dissolving the oily matter in ethyl acetate, adding normal hexane devitrification into the filter liquor to obtain 5'-bromo-2',3'-O-isopropylidene-5-fluorocytidine through devitrification; and 3)dissolving the 5'-bromo-2',3'-O-isopropylidene-5-fluorocytidine in carbinol, adding triethylamine and palladium-carbon to recrystallize to obtain the 5'-deoxy-2', 3'-O-isopropylidene-5-fluorocytidine. According to the preparation method, raw materials are easy to obtain, and preparation cost is reduced.
Description
Technical field
The present invention relates to medicine, be a kind of capecitabine intermediate 5 '-deoxidation-2 ', 3 '-preparation method of O-isopropylidene-5-fluorine cytidine.
Background technology
The chemistry of capecitabine is by name 5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl]-born of the same parents' (pyrimidine nuclear) glycosides, it is oral fluorinated pyrimidine carbamate series antineoplastic medicament, and this medicine is mainly used in the treatment of advanced primary or metastatic breast cancer, the rectum cancer, colorectal carcinoma and cancer of the stomach.Because capecitabine is a target therapeutic agent, has stronger antitumor action, therefore lower toxic side effect is used widely in the various solid tumor chemotherapy such as mammary cancer, coton and rectal cancer.Because this medicine import price is expensive, China also began oneself this medicine of production in recent years, and for this reason, those skilled in the art provide the preparation method of more multiple capecitabine and intermediate thereof.
Published these methods are all passed through intermediate a(hydroxyl protecting group R
1, R
2Can be identical or different) with n-amyl chlorocarbonate reaction, through selectivity slough on the five-ring 2 ', the protecting group of 3 ' position finally obtains capecitabine.The general structure of intermediate a is as follows:
In addition; in the prior art among the capecitabine preparation technology on the five-ring the employed protecting group of hydroxyl also different, such as ethanoyl, phenyl, 2,2-dimethoxypropane etc.; those skilled in the art further study discovery, and all there is some deficiency in these methods in production.With 2; the 2-Propanal dimethyl acetal is as the capecitabine intermediate of hydroxyl protecting group; protecting group is easily sloughed; be easy to suitability for industrialized production, about the intermediate 5 of this method '-deoxidation-2 ', 3 '-preparation method of O-isopropylidene-5-fluorine cytidine; at Chinese pharmaceutical chemistry magazine report was arranged once; the method is 5-fluorine cytidine through 2 ', the isopropyl methylene radical protection of 3 ' position, 5 ' iodo remove hydroxylation and hydrogenation reduction and obtain 5 '-deoxidation-2 ', 3 '-O-isopropylidene-5-fluorine cytidine.But, the deficiency of this method is: the triphenyl phosphorous acid ester methyl-iodide compound that iodo goes hydroxylating to adopt can not be bought in market, must prepare separately when producing, and preparation cost is higher, cause the target product cost higher, failed so far industrial application.
Summary of the invention
The purpose of this invention is to provide a kind of intermediate 5 of capecitabine '-deoxidation-2 ', 3 '-preparation method of O-isopropylidene-5-fluorine cytidine, the raw material that its adopts is easy to get, and preparation cost is reduced, thereby has solved the deficiency that prior art exists.
The present invention is achieved through the following technical solutions for achieving the above object: the intermediate 5 of capecitabine '-deoxidation-2 ', 3 '-preparation method of O-isopropylidene-5-fluorine cytidine, comprise the steps:
1. getting 5-fluorine cytidine is dissolved in the acetone, then add tosic acid, add again 2,2-dimethoxypropane, stirring reaction is 2 hours under the room temperature, then add saturated sodium bicarbonate solution and make reaction solution be weakly alkaline, filter, filtrate is concentrated into dried, with re-crystallizing in ethyl acetate obtain 2 ', 3 '-O-isopropylidene-5-fluorine cytidine, wherein 5-fluorine cytidine: acetone: tosic acid: the mol ratio of 2,2-dimethoxypropane is 1:67.5:1.3-1.5:4.9-5.1;
2. get 2 ', 3 '-O-isopropylidene-5-fluorine cytidine and thionyl bromide place dimethyl formamide, stirring at room reaction 2-2.5 hour, behind the evaporate to dryness oily matter, oily matter is dissolved in 35-45 ℃ the ethyl acetate, filter, filtrate adds normal hexane, the cooling crystallization, obtain 5 after the filtration '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine, wherein 2 ', 3 '-mol ratio of O-isopropylidene-5-fluorine cytidine and thionyl bromide is 1:1.1-1.2;
3. with 5 '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine is dissolved in the methyl alcohol, add triethylamine and palladium carbon, logical hydrogen reducing reaction 1-2 hour, reacting liquid filtering, filtrate is concentrated into dried, use re-crystallizing in ethyl acetate, obtain 5 '-deoxidation-2 ', 3 '-O-isopropylidene-5-fluorine cytidine, wherein 5 '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine: triethylamine: the weight ratio of palladium carbon is 3:1:0.15-0.2.
Step 2 in 2. ', 3 '-mol ratio of O-isopropylidene-5-fluorine cytidine and thionyl bromide is 1:1.1; Step 5 described in 3. '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine: triethylamine: the weight ratio of palladium carbon is 3:1:0.2.
The 5-fluorine cytidine of step described in 1.: acetone: tosic acid: the mol ratio of 2,2-dimethoxypropane is 1:67.5:1.3:4.9; Step 5 described in 3. '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine: triethylamine: the weight ratio of palladium carbon is 3:1:0.15.
Described a kind of capecitabine intermediate 5 '-deoxidation-2 ', 3 '-preparation method of O-isopropylidene-5-fluorine cytidine, comprise the steps:
1. getting 5-fluorine cytidine 39g is dissolved in the 750ml acetone, add tosic acid 42.6g, add again 2,2-Propanal dimethyl acetal 94.3ml, stirring reaction is 2 hours under the room temperature, then adds saturated sodium bicarbonate solution and makes reaction solution be weakly alkaline, filter, filtrate is concentrated into dried, with re-crystallizing in ethyl acetate obtain 2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g;
2. get 2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g and thionyl bromide 33.6g add in the 500ml dimethyl formamide, stirring at room reaction 2 hours, get oily matter behind the evaporate to dryness, oily matter is dissolved in the ethyl acetate of 45 ℃ of 500mL, filter, filtrate adds the 1.5L normal hexane, the cooling crystallization, obtain 5 after the filtration '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g;
3. with 5 '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g is dissolved in the 400ml methyl alcohol, adds triethylamine 13.7g and palladium carbon 2.7g, logical hydrogen reaction 1 hour, with re-crystallizing in ethyl acetate obtain 5 '-deoxidation-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 29g.
Capecitabine intermediate 5 of the present invention '-deoxidation-2 ', 3 '-preparation method of O-isopropylidene-5-fluorine cytidine in the palladium content of employed palladium carbon be 10.0%.
Capecitabine intermediate 5 of the present invention '-deoxidation-2 ', 3 '-synthetic route of O-isopropylidene-5-fluorine cytidine is as follows:
5 '-deoxidation-2 ', 3 '-structural formula of O-isopropylidene-5-fluorine cytidine is as follows:
Capecitabine intermediate 5 provided by the invention '-deoxidation-2 '; 3 '-preparation method of O-isopropylidene-5-fluorine cytidine, so that hydroxyl protecting group easily removes, be easy to suitability for industrialized production; solved the more deficiency that exists in the prior art; adopt bromo-reaction to go hydroxylation, in going hydroxylated process, use thionyl bromide as removing hydroxylated raw material; preparation cost is significantly reduced; and reduced simultaneously foreign matter content, after testing, purity reaches 98.8%.
Embodiment
The intermediate 5 of capecitabine of the present invention '-deoxidation-2 ', 3 '-preparation method of O-isopropylidene-5-fluorine cytidine, step is as follows:
1. getting 5-fluorine cytidine is dissolved in the acetone, then add tosic acid, add again 2,2-dimethoxypropane, stirring reaction is 2 hours under the room temperature, then add saturated sodium bicarbonate solution and make reaction solution be weakly alkaline, filter, filtrate is concentrated into dried, with re-crystallizing in ethyl acetate obtain 2 ', 3 '-O-isopropylidene-5-fluorine cytidine, wherein 5-fluorine cytidine: acetone: tosic acid: the mol ratio of 2,2-dimethoxypropane is 1:67.5:1.3-1.5:4.9-5.1;
2. get 2 ', 3 '-O-isopropylidene-5-fluorine cytidine and thionyl bromide place dimethyl formamide, stirring at room reaction 2-2.5 hour, behind the evaporate to dryness oily matter, oily matter is dissolved in 35-45 ℃ the ethyl acetate, filter, filtrate adds normal hexane, the cooling crystallization, obtain 5 after the filtration '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine, wherein 2 ', 3 '-mol ratio of O-isopropylidene-5-fluorine cytidine and thionyl bromide is 1:1.1-1.2;
3. with 5 '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine is dissolved in the methyl alcohol, add triethylamine and palladium carbon, logical hydrogen reducing reaction 1-2 hour, reacting liquid filtering, filtrate is concentrated into dried, use re-crystallizing in ethyl acetate, obtain 5 '-deoxidation-2 ', 3 '-O-isopropylidene-5-fluorine cytidine, wherein 5 '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine: triethylamine: the weight ratio of palladium carbon is 3:1:0.15-0.2.
Preferred scheme is: step 2 in 2. ', 3 '-mol ratio of O-isopropylidene-5-fluorine cytidine and thionyl bromide is 1:1.1; Step 5 described in 3. '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine: triethylamine: the weight ratio of palladium carbon is 3:1:0.2.
The 5-fluorine cytidine of step described in 1.: acetone: tosic acid: the mol ratio of 2,2-dimethoxypropane is 1:67.5:1.3:4.9; Step 5 described in 3. '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine: triethylamine: the weight ratio of palladium carbon is 3:1:0.15.
Embodiment 1:Step is as follows:
1. get 5-fluorine cytidine 26.4g(0.1mol) be dissolved in the 500ml acetone, add tosic acid 24g(0.13mol), add again 2,2-dimethoxypropane 60ml(0.49mol), stirring reaction is 2 hours under the room temperature, then adding saturated sodium bicarbonate solution makes reaction solution be weakly alkaline, filter, filtrate is concentrated into dried, with re-crystallizing in ethyl acetate obtain 2 ', 3 '-O-isopropylidene-5-fluorine cytidine 27g, yield 90%.
2. get 2 ', 3 '-O-isopropylidene-5-fluorine cytidine 27g(0.09mol) and thionyl bromide 21g(0.1mol) add in the 300ml dimethyl formamide, stirring at room reaction 2 hours gets oily matter behind the evaporate to dryness, oily matter is dissolved in the ethyl acetate of 35 ℃ of 300mL, filter, filtrate adds the 1L normal hexane, the cooling crystallization, obtain 5 after the filtration '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 27g, yield 82.2%.
3. with 5 '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 27g(0.074mol) be dissolved in the 250ml methyl alcohol, add triethylamine 9g (0.089mol) and palladium carbon 1.35g(palladium content 10.0%), logical hydrogen reaction 2 hours, with re-crystallizing in ethyl acetate obtain 5 '-deoxidation-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 19g, yield 90%, purity: 98.8% (HPLC area normalization method).
Embodiment 2: step is as follows:
1. get 5-fluorine cytidine 39g(0.15mol) be dissolved in the 750ml acetone, add tosic acid 42.6g(0.225mol), add again 2,2-dimethoxypropane 94.3ml (0.765mol), stirring reaction 2h under the room temperature, then adding saturated sodium bicarbonate solution makes reaction solution be weakly alkaline, filter, filtrate is concentrated into dried, with re-crystallizing in ethyl acetate obtain 2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g, yield 90.1%.
2. get 2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g(0.135mol) add in the 500ml dimethyl formamide with thionyl bromide 33.6g (0.162mol), stirring at room reaction 2h gets oily matter behind the evaporate to dryness, oily matter is dissolved in the ethyl acetate of 45 ℃ of 500mL, filter, filtrate adds the 1.5L normal hexane, the cooling crystallization, obtain 5 after the filtration '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g, yield 83%.
3. with 5 '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g(0.112mol) be dissolved in the 400ml methyl alcohol, add triethylamine 13.7g (0.136mol) and palladium carbon 2.7g(palladium content 10.0%), logical hydrogen reaction 1 hour, with re-crystallizing in ethyl acetate obtain 5 '-deoxidation-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 29g, yield 90.8%, purity: 98.9% (HPLC area normalization method).
Claims (4)
- The intermediate 5 of capecitabine '-deoxidation-2 ', 3 '-preparation method of O-isopropylidene-5-fluorine cytidine, it is characterized in that: comprise the steps:1. getting 5-fluorine cytidine is dissolved in the acetone, then add tosic acid, add again 2,2-dimethoxypropane, stirring reaction is 2 hours under the room temperature, then add saturated sodium bicarbonate solution and make reaction solution be weakly alkaline, filter, filtrate is concentrated into dried, with re-crystallizing in ethyl acetate obtain 2 ', 3 '-O-isopropylidene-5-fluorine cytidine, wherein 5-fluorine cytidine: acetone: tosic acid: the mol ratio of 2,2-dimethoxypropane is 1:67.5:1.3-1.5:4.9-5.1;2. get 2 ', 3 '-O-isopropylidene-5-fluorine cytidine and thionyl bromide place dimethyl formamide, stirring at room reaction 2-2.5 hour, behind the evaporate to dryness oily matter, oily matter is dissolved in 35-45 ℃ the ethyl acetate, filter, filtrate adds normal hexane, the cooling crystallization, obtain 5 after the filtration '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine, wherein 2 ', 3 '-mol ratio of O-isopropylidene-5-fluorine cytidine and thionyl bromide is 1:1.1-1.2;3. with 5 '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine is dissolved in the methyl alcohol, add triethylamine and palladium carbon, logical hydrogen reducing reaction 1-2 hour, reacting liquid filtering, filtrate is concentrated into dried, use re-crystallizing in ethyl acetate, obtain 5 '-deoxidation-2 ', 3 '-O-isopropylidene-5-fluorine cytidine, wherein 5 '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine: triethylamine: the weight ratio of palladium carbon is 3:1:0.15-0.2.
- The intermediate 5 of capecitabine according to claim 1 '-deoxidation-2 ', 3 '-preparation method of O-isopropylidene-5-fluorine cytidine, it is characterized in that: step 2 in 2. ', 3 '-mol ratio of O-isopropylidene-5-fluorine cytidine and thionyl bromide is 1:1.1; Step 5 described in 3. '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine: triethylamine: the weight ratio of palladium carbon is 3:1:0.2.
- The intermediate 5 of capecitabine according to claim 1 '-deoxidation-2 ', 3 '-preparation method of O-isopropylidene-5-fluorine cytidine, it is characterized in that: the 5-fluorine cytidine of step described in 1.: acetone: tosic acid: the mol ratio of 2,2-dimethoxypropane is 1:67.5:1.3:4.9; Step 5 described in 3. '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine: triethylamine: the weight ratio of palladium carbon is 3:1:0.15.
- Capecitabine intermediate 5 according to claim 1 '-deoxidation-2 ', 3 '-preparation method of O-isopropylidene-5-fluorine cytidine, it is characterized in that: comprise the steps:1. getting 5-fluorine cytidine 39g is dissolved in the 750ml acetone, add tosic acid 42.6g, add again 2,2-Propanal dimethyl acetal 94.3ml, stirring reaction is 2 hours under the room temperature, then adds saturated sodium bicarbonate solution and makes reaction solution be weakly alkaline, filter, filtrate is concentrated into dried, with re-crystallizing in ethyl acetate obtain 2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g;2. get 2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g and thionyl bromide 33.6g add in the 500ml dimethyl formamide, stirring at room reaction 2 hours, get oily matter behind the evaporate to dryness, oily matter is dissolved in the ethyl acetate of 45 ℃ of 500mL, filter, filtrate adds the 1.5L normal hexane, the cooling crystallization, obtain 5 after the filtration '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g;3. with 5 '-bromo-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 41g is dissolved in the 400ml methyl alcohol, adds triethylamine 13.7g and palladium carbon 2.7g, logical hydrogen reaction 1 hour, with re-crystallizing in ethyl acetate obtain 5 '-deoxidation-2 ', 3 '-O-isopropylidene-5-fluorine cytidine 29g.
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Cited By (1)
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| CN109761743A (en) * | 2019-02-15 | 2019-05-17 | 浙江永太科技股份有限公司 | The preparation method of 2- methyl -3,4,5- trifluorobromobenzene |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109761743A (en) * | 2019-02-15 | 2019-05-17 | 浙江永太科技股份有限公司 | The preparation method of 2- methyl -3,4,5- trifluorobromobenzene |
| CN109761743B (en) * | 2019-02-15 | 2021-04-30 | 浙江永太科技股份有限公司 | Preparation method of 2-methyl-3, 4, 5-trifluorobromobenzene |
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