CN102424697B - 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound and preparation method thereof - Google Patents
2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound and preparation method thereof Download PDFInfo
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- CN102424697B CN102424697B CN201110330998.8A CN201110330998A CN102424697B CN 102424697 B CN102424697 B CN 102424697B CN 201110330998 A CN201110330998 A CN 201110330998A CN 102424697 B CN102424697 B CN 102424697B
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- deoxidation
- ethanoyl
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- 238000002360 preparation method Methods 0.000 title claims description 16
- 150000001875 compounds Chemical class 0.000 title abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims abstract description 24
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- 238000002425 crystallisation Methods 0.000 claims abstract description 4
- 230000008025 crystallization Effects 0.000 claims abstract description 4
- 239000011737 fluorine Substances 0.000 claims description 31
- 229910052731 fluorine Inorganic materials 0.000 claims description 31
- 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
- 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 17
- 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 17
- BGAWRLZKVIFLKK-GWOFURMSSA-N [(2r,3r,4r,5s)-4,5-diacetyloxy-2-(hydroxymethyl)oxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1O[C@H](CO)[C@@H](OC(C)=O)[C@H]1OC(C)=O BGAWRLZKVIFLKK-GWOFURMSSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- -1 ether compound Chemical class 0.000 claims description 14
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
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- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 238000007344 nucleophilic reaction Methods 0.000 claims description 3
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 241000370738 Chlorion Species 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical group [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
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- 229940006461 iodide ion Drugs 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 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 abstract description 25
- 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 abstract description 25
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- NXEJETQVUQAKTO-PRTGYXNQSA-N [(2r,3r,4r,5s)-4,5-diacetyloxy-2-methyloxolan-3-yl] acetate Chemical compound C[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O NXEJETQVUQAKTO-PRTGYXNQSA-N 0.000 abstract 2
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 230000020477 pH reduction Effects 0.000 abstract 1
- 239000012453 solvate Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
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- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 6
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- KCURWTAZOZXKSJ-IAIGYFSYSA-N 4-amino-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one;hydrochloride Chemical compound Cl.O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 KCURWTAZOZXKSJ-IAIGYFSYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
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- Saccharide Compounds (AREA)
Abstract
The invention relates to a 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound of formula (I) or a solvate thereof. The compound is prepared by using 5-deoxy-1,2,3-tri-O-acetyl-beta-D-ribofuranose as a raw material, carrying out condensation reaction on 5-deoxy-1,2,3-tri-O-acetyl-beta-D-ribofuranose and protected 5-flucytosine under the activation of iodotrimethylsilane to obtain a reaction product, and carrying out deprotection, acidification and crystallization. According to the invention, a novel intermediate for synthesizing Capecitabine is developed, one pot process is adopted for reacting to obtain the 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound, and high-purity Capecitabine can be further synthesized by using the 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound as a key intermediate. The compound has the characteristics of clear structure, high purity and stable quality. The use of the compound to synthesize Capecitabine can reduce reaction steps, control process cost, and reduce environmental pollution.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, particularly, the present invention relates to 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine salt compounds and preparation method thereof, this compounds is the key intermediate of preparing antineoplastic medicine capecitabine.
Background technology
In antitumor and antiviral, there is a large amount of nucleoside compounds to be applied to clinical, their principles based on metabolism antagonism, produce resistant effect by disturbing or suppressing nucleic acid replication viral, tumour cell.Conventionally having bioactive nucleosides need to have 5-hydroxyl to exist, by being played a role by phosphorylated in vivo.And remove 5-hydroxyl, can produce a series ofly to the biochemical and significant compound of physiological Study, because they can not be participated in nucleic acid by phosphorylated, thereby reach, reduce toxicity, improve optionally object.Therefore, the anticarcinogen that the ucleosides of take is parent nucleus, because the targeting of its effect is good, toxicity is low, occupies critical role at anticarcinogen species.In order to develop wide spectrum, efficient, low cytotoxic drug, 5-deoxynucleoside compounds has caused the very big interest of people, and conducts extensive research, as 5-deoxidation-5-FU nucleosides, 5-deoxythymidine, 5-Desoxyadenosine etc.And have some and be applied clinically, obtained good therapeutic effect, as 5-'-Deoxy-5-fluorouridine, capecitabine, gemcitabine etc.
Capecitabine (capecitabine), the chemistry fluoro-N-[(pentyloxy of 5 '-deoxidation-5-by name) carbonyl] cytidine(C, a kind of novel 5-fluor-uracil (5-FU) prodrug of Shi You Switzerland Hoffmann-Laroche company research and development, it has structure design and unique activate mechanism cleverly, has successfully improved its antineoplastic specificity.Capecitabine is a kind of new oral fluorocytidine class medicine, no cytotoxicity own, under the effect of enzyme, metabolism is 5 FU 5 fluorouracil (5-FU) in vivo, and then performance antitumor action, is clinically mainly used in treating advanced breast cancer, knot/rectum cancer and other solid tumor.Recently there are some researches show, capecitabine is combined irinotecan advanced CRC good effect, untoward reaction is light, can be used for treating Metastatic Colorectal Cancer.1998 first in U.S. listing, is uniquely up to now through the oral fluorouracil medicine ，Yi of the FDA approval U.S., Canada, Sweden and Discussion on Chinese Listed, to sell, and at present domesticly by Shanghai Roche Group, is produced, and Bing Youduojia research unit is developing.
Domestic and international many research institutions study and improve the synthetic route of capecitabine, mainly from reducing synthesis step, simplifying the operation, improve productive rate, consider to use inexpensive, low toxicity raw material, feed change proportioning reaches and reduces raw material use, thereby make technique simplify angle, studies.Synthesize capecitabine has several different methods at present, and its route of synthesis is different different because of starting raw material, selects different starting raw materials, can prepare different intermediates, and synthesis route, processing condition are as adopted the complete differences such as reagent, and its effect also can be different.In numerous synthetic routes, all 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine (III) is as the key intermediate of synthetic this medicine.
In document [Drug of Future 21,1996,358-360] and CN93112894.3, reported the synthetic method of this intermediate.Reaction process is as shown in Scheme 1:
Route 1
The method is with 5-deoxidation-1, and 2,3-, tri--O-ethanoyl-β-D-RIBOSE is raw material, under the effect of tin tetrachloride with protection 5-flurocytosine react generation 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine.In building-up process, the solution that the mode of employing underpressure distillation obtains containing intermediate (III) directly carries out lower step building-up reactions.Owing to having used tin tetrachloride as condensing agent in reaction, its toxicity is large, price is high, and noble metal can take in the next step, owing to intermediate not being carried out to purifying, thereby caused in the next step impurity too much, be unfavorable for the raising of end product quality
In addition, document [Bioorganic & Medicinal Chemistry 8 (2000): 1697-1706] and [< < synthetic chemistry > > 2008,16 (1) 120-122 methods] also used identical synthetic method, only aftertreatment is slightly variant.
Separately have patent CN101128472A also to adopt above synthetic route, be characterized in having used trifluoroacetic acid as condensing agent, the method adopts one kettle way, directly obtains crude product, but increased the subsequent processing steps of product purification after continuous dosing.
In addition, patent US7365488/CN1035617, US2009020754 reported with trimethylchlorosilane-sodium iodide activation 5-deoxidation-1, after 2,3-, tri--O-ethanoyl-β-D-RIBOSE with 5-flurocytosine direct reaction, as shown in Scheme 2:
Route 2
In this method, after employing trimethylchlorosilane and sodium iodide displacement, carry out again nucleophilic reaction, there is the problems such as reaction yield is low, and operating process is loaded down with trivial details, poor product quality.
In above synthetic method; all 2 '; 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine is as the key intermediate of preparing capecitabine; but all there is severe reaction conditions, the shortcoming such as agents useful for same is special, yield is lower, product purity is low, poor stability, thereby brought problems to the follow-up building-up reactions of capecitabine.
Summary of the invention
For the deficiency of above background technology, the inventor, through research, finds a kind of low toxic and environment-friendly type processing method of synthetic this intermediate salt compounds, with this method synthesize 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine salt compounds; And using this compound as the further synthesize capecitabine of key intermediate, can directly obtain highly purified capecitabine product.
The midbody compound that the object of this invention is to provide a kind of synthesize capecitabine: 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine salt compounds, its formula is suc as formula shown in (I):
Wherein, X is negatively charged ion, and X is preferably: acetate ion, nitrate ion, trifluoroacetic ions, benzene sulfonamide acid ion, chlorion, bromide anion or iodide ion.
Compound (I) exists with non-solvated form or solvation form (comprising hydrate forms).Hydration can realize in preparation process, or can gradually occur as the hygroscopic result of initial anhydrous product.
Another object of the present invention has been to provide the preparation method of the reaction of compound " cooking-pot type " shown in formula (I); the method is with 5-deoxidation-1; 2; 3-tri--O-ethanoyl-β-D-RIBOSE is raw material; under Iodotrimethylsilane activation, carry out condensation reaction with the 5-flurocytosine of protection, reaction product obtains compound shown in formula (I) after deprotection, acidizing crystal.This preparation process is as shown in Scheme 3:
Route 3
A further object of the present invention is to provide the method for preparing capecitabine by such intermediate.
Concrete technical scheme of the present invention is: a kind of 2 ', the preparation method of 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine salt compounds, is characterized in that comprising the following steps:
(1), the preparation of iodide
With 5-deoxidation-1,2,3-, tri--O-ethanoyl-β-D-RIBOSE is raw material, in organic solvent, carries out nucleophilic reaction with Iodotrimethylsilane, obtains the reaction solution containing iodide; Described reaction raw materials 5-deoxidation-1, the mol ratio of 2,3-, tri--O-ethanoyl-β-D-RIBOSE and Iodotrimethylsilane is 1: 1～10, preferred molar ratio is 1: 1～5; Temperature of reaction is-50～50 ℃, is preferably-30～30 ℃; Reaction times is 3～24 hours, is preferably 3～10 hours.Consumption of organic solvent is 1～50 (proportioning of 2,3-, tri--O-ethanoyl-β-D-RIBOSE and organic solvent is 1: 1～20 (w/v) for w/v, i.e. reaction raw materials 5-deoxidation-1), and optimum proportion is 3～20 (w/v).Described organic solvent can be for halohydrocarbon be as methylene dichloride, chloroform, tetracol phenixin, ether compound is as tetrahydrofuran (THF), dioxane, isopropyl ether, amides is as dimethyl formamide, N,N-DIMETHYLACETAMIDE, ketone compounds, as acetone, mibk, pentanone, can be also binary, the ternary mixed solvent of above-mentioned solvent; Wherein, be preferably halogenated hydrocarbon or amides.
(2), condensation reaction
According to a conventional method 5-flurocytosine is carried out to conservation treatment, then with containing the reaction solution of iodide, carry out that condensation is protected 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine, i.e. intermediate (II); After reaction finishes, do not need to process and can directly carry out the next step.Wherein, can select silylating reagent to protect 5-flurocytosine, as hexamethyldisilazane, N, two (TMS) ethanamides of O-, two (TMS) trifluoroacetamide etc.; 5-flurocytosine and 5-deoxidation-1, the mol ratio of 2,3-, tri--O-ethanoyl-β-D-RIBOSE is 1～20: 1, optimum proportion is 1～10: 1; Setting-up point scope is-50～50 ℃, is preferably-30～30 ℃; Reaction times is 3～24 hours, preferably 3～10 hours.
(3), prepare compound (I)
Under the temperature condition of-50～50 ℃, in the above-mentioned reaction solution that contains intermediate (II), add alcohol compound to carry out deprotection, and then add acidic medium to generate compound (I); The separated organic phase of removing, adds alkaline reagents to regulate pH to 1.0～7.0 (being preferably pH2.0～6.0), then adds polar organic solvent crystallization in the aqueous phase solution obtaining; Finally by processing such as filtering, wash and be dry, obtain the compound (I) of purity >=98.0%.
Wherein, deprotection alcohol compound particular methanol used or Virahol; Described intermediate (II) is 1: 1～100 with the mol ratio of alcohol compound, and optimum proportion is 1: 1～50;
Described intermediate (II) is 1: 1～50 with the mol ratio of acidic medium, and optimum proportion is 1: 1～20; Described acidic medium can be selected hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, trifluoracetic acid, alkyl benzene sulphonate (ABS), nitric acid, acetic acid etc., preferably hydrochloric acid, Hydrogen bromide and hydroiodic acid HI.
Described bases reagent is mineral alkali or organic bases, as alkali and alkaline earth metal ions oxyhydroxide, as sodium hydroxide, potassium hydroxide, alkali and alkaline earth metal ions carbonate is as sodium carbonate, calcium carbonate, salt of wormwood, alkali and alkaline earth metal ions supercarbonate is as sodium bicarbonate, saleratus etc., and organic bases is as methylamine, triethylamine, Tributylamine, aniline etc.; The preferred sodium carbonate of described bases reagent mineral alkali, sodium bicarbonate, saleratus etc., organic bases is preferably triethylamine or Tributylamine etc.
Described polar organic solvent is rudimentary ketone, lower alcohols, ethers or their mixed solvent.Wherein, lower alcohols is as Virahol, ethanol, propyl carbinol, and rudimentary ketone is as acetone, pentanone, mibk, and rudimentary ethers is as binary, the ternary mixed solvent of tetrahydrofuran (THF), isopropyl ether, dioxane etc. or above-mentioned solvent.
The present invention synthesize 2 '; 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine salt compounds is the intermediate of preparing capecitabine; employing one kettle way preparation, with this intermediate, under alkaline medium, react with chloro-formic ester obtain 2 ', the fluoro-N of 3 '-O-diacetyl-5 '-deoxidation-5-
4-(penta oxygen carbonyl)-fluorine cytidine, sloughs protecting group and is capecitabine.
Beneficial effect of the present invention has been to develop the new intermediate of synthesize capecitabine; adopt " one kettle way " reaction obtain 2 '; 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine salt compounds; in preparation process, avoid using special reagent as tin tetrachloride etc., abandoned the method for traditional distillation crystallization.This type of compound products structure is clear and definite, has high, the stay-in-grade characteristic of chemical purity, under normal temperature, stores and is 2 years.With this compounds, carry out the next step synthesize capecitabine, can reduce reactions steps, control process costs, reduce environmental pollution.
Through evidence; synthetic 2 '; the method agents useful for same raw material of 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine salt compounds is cheap and easy to get; the gentle easily control of processing condition; reaction yield is up to 80～95%; without specific installation, product purity high (HPLC detects purity >=98.0%), steady quality, be applicable to suitability for industrialized production.
Embodiment
Be below the compounds of this invention (I) and the specific embodiment of preparing capecitabine with (I), embodiment only, for the preferred embodiment of the present invention is more specifically described, is not used in technical scheme of the present invention is limited.The test conditions adopting in following examples and reagent, all available corresponding test conditions mentioned above and reagent substitute to realize the present invention's object.
Embodiment 1:
2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine hydrochloride synthetic
(1), the protective reaction of 5-flurocytosine
In dry 3L glass reaction bottle, connect tail gas (ammonia) absorption unit and return line standby, add 300ml methylene dichloride, 100g (0.775mol) 5-flurocytosine, 140ml hexamethyldisilazane, 0.5ml Iodotrimethylsilane, is warming up to 70～80 ℃, back flow reaction 10～15 hours, feed liquid is molten clear.
(2) iodide is synthetic
In another reaction flask, drop into 500ml methylene dichloride, 5-deoxidation-1,2,3-, tri--O-ethanoyl-β-D-RIBOSE 201g, is cooled to 0 ℃, adds Iodotrimethylsilane 145ml, is incubated 0 ℃ of reaction 5 hours.
(3) the 5-flurocytosine reaction solution of protection is joined in iodide reaction solution, under room temperature, react 3～5 hours.Then in feed liquid, add Virahol 60ml, separate out white-yellowish solid.Then in feed liquid, add 10% hydrochloric acid 380ml, be stirred to solid and dissolve completely.Layering, discards dichloromethane layer, adds gac 10g in water layer, after decolouring 30 minutes, filters.In filtrate, add triethylamine, regulate material liquid pH 1.5～2.0, separate out solid.Stir and continue to add triethylamine after 30 minutes, regulate pH to 5.0～5.5, then in feed liquid, add acetone 1500ml.Filter, washing with acetone, vacuum-drying at 50 ℃, obtain off-white color 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine hydrochloride 258g, 191.5～194 ℃ of mp, purity 99.0%, yield 91.0%.
Mass：m/z?365.72[m
++z]
1HNMR：δ1.33(d，3H)，1.45(s，6H)，4.01(q，1H)，4.7(d，1H)，4.9(d，1H)，5.7(s，1H)，7.5-7.8(2H)，7.9(d，1H)
Embodiment 2
2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine hydrobromate synthetic
(1), in 2L glass reaction bottle, add 200ml methylene dichloride, under stirring, add 52g 5-flurocytosine, 100ml N, two (TMS) ethanamides of O-, are warming up to 30～40 ℃, react 3～5 hours, feed liquid is completely molten clear.
(2) in another reaction flask, drop into methylene dichloride 300ml, 5-deoxidation-1,2,3-, tri--O-ethanoyl-β-D-RIBOSE 104g, is cooled to 0 ℃, adds Iodotrimethylsilane 85ml, is incubated 0～5 ℃ of reaction 3～5 hours.
(3) the 5-flurocytosine reaction solution of protection is joined in iodide reaction solution, under room temperature, react 3～6 hours.Then in feed liquid, add methyl alcohol 50ml, separate out white-yellowish solid.In feed liquid, add 20% Hydrogen bromide 300ml, be stirred to solid and dissolve completely.Layering, abandons or adopts dichloromethane layer, adds gac 10g in water layer, after decolouring 30 minutes, filters.In filtrate, add triethylamine, regulating material liquid pH is 1.5～2.0, separates out solid.Stir 30 minutes, continue to add triethylamine, regulate pH to 5.5～6.0, then in feed liquid, add Virahol 1000ml.Filter, washed with isopropyl alcohol, vacuum-drying at 50 ℃, obtain yellow-white 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine hydrobromate solid 144g, 194～196 ℃ of mp, purity 98.5%, yield 88%.
Mass：m/z?410.19[m
++z]
1HNMR：δ1.33(d，3H)，1.45(s，6H)，4.01(q，1H)，4.7(d，1H)，4.9(d，1H)，5.7(s，1H)，7.5-7.8(2H)，7.9(d，1H)
Embodiment 3
2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine hydriodate synthetic
(1), in 2L glass reaction bottle, connect tail gas (ammonia) absorption unit standby, logical nitrogen replacement 5min, add 200ml methylene dichloride, under stirring, add 65g 5-flurocytosine, 92ml hexamethyldisilazane, 0.2ml Iodotrimethylsilane, system is warming up to 60～70 ℃, reacts 10～15 hours, and feed liquid is completely molten clear.
(2) in another reaction flask, drop into methylene dichloride 300ml, 5-deoxidation-1,2,3-, tri--O-ethanoyl-β-D-RIBOSE 130g, is cooled to 0 ℃, adds Iodotrimethylsilane 110ml, is incubated 0 ℃ of reaction 3～5 hours.
(3) the 5-flurocytosine reaction solution of protection is joined in iodide reaction solution, under room temperature, react 3～5 hours.Then in feed liquid, add Virahol 50ml, separate out white-yellowish solid.Then in feed liquid, add 30% hydroiodic acid HI 350ml, be stirred to solid and dissolve completely.Layering, abandons or adopts dichloromethane layer, adds gac 10g in water layer, after decolouring 30 minutes, filters.In filtrate, add triethylamine, regulate material liquid pH 2.0～2.5, separate out solid.Stir 30 minutes, continue to add triethylamine, regulate pH to 5.5～6.0, then in feed liquid, add acetone 1200ml.Filter, washing with acetone, vacuum-drying at 50 ℃, obtain yellow-white 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine hydriodate solid 201g, 197～199.5 ℃ of mp, purity 98.5%, yield 89.0%.
Mass：m/z?457.20[m
++z]
1HNMR：δ1.33(d，3H)，1.45(s，6H)，4.01(q，1H)，4.7(d，1H)，4.9(d，1H)，5.7(s，1H)，7.5-7.8(2H)，7.9(d，1H)
Synthesizing of capecitabine
Embodiment 4
By methylene dichloride 150ml, 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine hydrogen salt hydrochlorate 36g joins in reaction flask, stirs, and adds triethylamine 15g under room temperature, is stirred to solid and dissolves completely.Then be cooled to-15 ℃; Add n-amyl chlorocarbonate 20g, in adition process, control temperature not higher than-10 ℃.After adding ,-10 ℃ of insulation reaction, after 3～5 hours, after having reacted, add the washing of 500ml purified water, separate organic phase.Distillation organic phase, remaining yellow oily liquid; Then add methyl alcohol 200ml, add 10% sodium hydroxide to regulate pH10.0～12.0, react after 2 hours, add Virahol 1500ml, separate out white solid, 50 ℃ of vacuum-dryings, obtain capecitabine 31g, yield 87%.
Embodiment 5
By methylene dichloride 200ml, 2 ', 3 '-bis--O-ethanoyl-5 '-deoxidation-5-fluorine cytidine hydriodate 68g joins in reaction flask, stirs, and adds pyridine 24g under room temperature, is stirred to solid and dissolves completely.Then be cooled to-10 ℃; Add n-amyl chlorocarbonate 44g, in adition process, control temperature not higher than 0 ℃.Add rear 0 ℃ of insulation reaction after 1～2 hour, after having reacted, with the washing of 500ml purified water, the washing of 300ml saturated nacl aqueous solution, adds methyl alcohol 200ml in organic phase after washing, then adds 10% sodium hydroxide to regulate pH10.0～12.0, react and add methylene dichloride 200ml after 2 hours, feed liquid layering, water layer discarded then adds Virahol 1200ml in organic layer, separate out white-yellowish solid, 50 ℃ of vacuum-dryings, obtain capecitabine 47.2g, yield 90%.
Claims (4)
1. a 2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine salt compounds preparation method, is characterized in that, described 2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine salt compounds is as shown in logical formula I:
Wherein, X is acetate ion, nitrate ion, trifluoroacetic ions, benzene sulfonamide acid ion, chlorion, bromide anion or iodide ion;
Described preparation method comprises the following steps:
(1), the preparation of iodide
With 5-deoxidation-1,2,3-, tri--O-ethanoyl-β-D-RIBOSE is raw material, in organic solvent, carries out nucleophilic reaction with Iodotrimethylsilane, obtains the reaction solution containing iodide; Described 5-deoxidation-1, the mol ratio of 2,3-, tri--O-ethanoyl-β-D-RIBOSE and Iodotrimethylsilane is 1:1～10; Temperature of reaction is-50～50 ℃; Reaction times is 3～24 hours; Described organic solvent is binary, the ternary mixed solvent of halohydrocarbon, ether compound, amides, ketone compounds or above-mentioned solvent, described 5-deoxidation-1, the ratio of 2,3-, tri--O-ethanoyl-β-D-RIBOSE and organic solvent is 1:1～20(w/v);
(2), condensation reaction
5-flurocytosine is carried out to conservation treatment, then containing the reaction solution of iodide, carry out the 2' that condensation is protected, 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine with step (1); Described 5-flurocytosine and 5-deoxidation-1, the mol ratio of 2,3-, tri--O-ethanoyl-β-D-RIBOSE is 1～20:1; Setting-up point scope is-50～50 ℃; Reaction times is 3～24 hours;
(3), prepare 2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine salt compounds
Under the temperature condition of-50～50 ℃, in the reaction solution of step (2), add alcohol compound to carry out deprotection, and then add acidic medium to generate 2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine salt compounds; The separated organic phase of removing, adds alkaline reagents to regulate pH to 1.0～7.0, then adds polar organic solvent crystallization in the aqueous phase solution obtaining; Finally by filtering, wash and the dry 2' that obtains purity >=98.0%, 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine salt compounds; Described acidic medium is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, trifluoracetic acid, alkyl benzene sulphonate (ABS), nitric acid or acetic acid; The 2' of described protection, the mol ratio of 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine and alcohol compound is 1:1～100; The 2' of described protection, the mol ratio of 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine and acidic medium is 1:1～50.
2. preparation method as claimed in claim 1, is characterized in that, in described step (1), and 5-deoxidation-1, the mol ratio of 2,3-, tri--O-ethanoyl-β-D-RIBOSE and Iodotrimethylsilane is 1:1～5; Temperature of reaction is-30～30 ℃; Reaction times is 3～10 hours; Described organic solvent is halogenated hydrocarbon or amides, described 5-deoxidation-1, the ratio of 2,3-, tri--O-ethanoyl-β-D-RIBOSE and organic solvent is 1:3～20(w/v).
3. preparation method as claimed in claim 1 or 2, is characterized in that, described step (2) adopts silylating reagent to protect 5-flurocytosine; In described step (2), 5-flurocytosine and 5-deoxidation-1, the mol ratio of 2,3-, tri--O-ethanoyl-β-D-RIBOSE is 1～10:1; Setting-up point scope is-30～30 ℃; Reaction times is 3～10 hours.
4. preparation method as claimed in claim 1 or 2, it is characterized in that, in described step (3), described alcohol compound is methyl alcohol or Virahol, the 2' of described protection, the mol ratio of 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine and alcohol compound is 1:1～50; The 2' of described protection, the mol ratio of 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine and acidic medium is 1:1～20; Described alkaline reagents is mineral alkali or organic bases; Described polar organic solvent is rudimentary ketone, lower alcohols, ethers or their mixed solvent; Described lower alcohols is Virahol, ethanol or propyl carbinol, and described rudimentary ketone is acetone, pentanone or mibk, and described ethers is tetrahydrofuran (THF), isopropyl ether or dioxane.
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