WO2005080351A1 - The preparation and application of a n4-oxycarbonylcytosine derivatives - Google Patents
The preparation and application of a n4-oxycarbonylcytosine derivatives Download PDFInfo
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- WO2005080351A1 WO2005080351A1 PCT/CN2004/000744 CN2004000744W WO2005080351A1 WO 2005080351 A1 WO2005080351 A1 WO 2005080351A1 CN 2004000744 W CN2004000744 W CN 2004000744W WO 2005080351 A1 WO2005080351 A1 WO 2005080351A1
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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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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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
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
Definitions
- N 4 - oxycarbonyl cytosine and derivatives and preparation method TECHNICAL FIELD The present invention belongs to the technical field of pharmaceutical chemistry. Specifically, it relates to N 4 -oxocarbonylcytosine derivative, its preparation method and application. Background technique
- N 4 -oxycarbonylcytosine derivatives are important raw materials for the preparation of fluorocytosine carbamate anticancer drugs.
- Capecitabine is the first fluoropyrimidine carbamate antitumor drug. Its chemical name is 5'-deoxy-5-fluoro-N 4 -pentoxycarbonylcytidine, that is: 5-deoxy-5- fluoro-N 4- (pentyloxycarbony) cytidine. Its structural formula is as follows:
- the invention provides cytosine derivatives of the general formula I:
- R 2 is halogen atom fluorine or iodine, vinyl, ethynyl or halogen, fluorenyl, cycloalkyl, arylcyclofluorenyl Or aromatic heterocyclyl substituted vinyl, ethynyl.
- Another object of the present invention is to provide a method for preparing a cytosine derivative of the general formula I, which is prepared by a condensation reaction of the general formula II and the general formula III.
- R 3 is a halogen atom (such as fluorine, iodine, etc.), a vinyl group, an ethynyl group or a vinyl group, an ethynyl group substituted by a halogen, a fluorenyl group, a cyclofluorenyl group, an arylcycloalkyl group, or an aromatic heterocyclic group.
- X represents a leaving group
- R 4 represents a fluorenyl group, a cyclofluorenyl group, an alkenyl group, an arylfluorenyl group, or an aryl group.
- the condensation reaction of the general formula II and the general formula III can be performed in a solvent such as pyridine, dichloromethane, 1,2-dichloroacetamidine, or water, or in two or more mixed solvents, but Acid acceptors such as triethylamine, pyridine, methylpyridine, alkali metal hydroxides, alkali metal carbonates or phosphates are required.
- the reaction temperature can be varied within a relatively wide range, generally from 20 ° C to -20V, and preferably at about 0 ° C.
- Another object of the present invention is to provide a N 4 -oxycarbonylcytosine derivative of the general formula I, which is represented by the general formula N.
- R 5 is a fluorenyl group, a cycloalkyl group, an alkenyl group, an arylfluorenyl group or an aryl group.
- N-oxycarbonyl-5-fluorocytosine derivatives (general formula IV) are reacted with 5-deoxy-D-ribofuranosyl compounds (general formula V) to prepare fluorine.
- Cytosine carbamate antitumor drugs The synthetic method is an effective way to reduce the cost of such drugs and improve the quality.
- R 6 is a hydrogen atom, an acetyl group or a benzoyl group.
- Yet another object of the present invention is to provide a method for preparing fluorocytosine carbamate antitumor drug capecitabine using N 4 -pentyloxycarbonyl-5 fluorocytosine as a starting material.
- the method includes the following steps:
- N 4 -pentyloxycarbonyl-5-fluorocytosine used as the raw material for the above reaction is obtained by the condensation reaction of 5-fluorocytosine with n-pentyl chloroformate. It is a new compound prepared by the inventors.
- trimethylsiloxane (OSi (CH 3 ) 3 ) trimethylsiloxane (OSi (CH 3 ) 3 ), hexamethyldisilazane (N [Si (CH 3 ) 3 ] 2 ) or sodium iodide and trimethylchlorosiliconium are heated under reflux in anhydrous acetonitrile, dichloromethane, 1,2-dichloroethane, or toluene.
- alkyl used in the present invention refers to a straight or branched fluorenyl group having 1 to 19 carbon atoms: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl , Tetradecyl, pentadecyl, hexadecyl, heptadecyl, or nonadecyl;
- Cyclomethyl means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
- Alkenyl means an unsubstituted or substituted alkenyl group having 3 to 19 carbon atoms, allyl, butenyl, 3-methyl-2-butenyl, 1-methyl-2- Propenyl, hexenyl, decenyl, undecenyl, tridecenyl, pentadecenyl, heptenyl, undecenyl, or 2-phenylvinyl;
- Alkyl means an unsubstituted or substituted arylfluorenyl, such as benzyl, 1-phenylethyl, methylbenzyl or phenethyl;
- Aryl means an unsubstituted or substituted aryl, such as phenyl, benzyl, xylyl or ethylphenyl;
- Vinyl, ethynyl substituted with halogen, fluorenyl, cycloalkyl, arylcyclofluorenyl or arylheterocyclyl means 1-chlorovinyl, 2-bromovinyl, 1-chloro-2-bromo Vinyl, 2-styryl, 1-propynyl, 1-butynyl, 1-pentynyl, 1-hexynyl, 3,3-dimethyl-1-butynyl, cyclopentylacetylene Radical, cyclohexylethynyl, phenylethynyl, 3-phenyl-1-propynyl, pyridine-2 -ethynyl or imidazole-2-ethynyl.
Abstract
The present invention related to a new N4-oxycarbonylcytidine derivative and its preparation. The present invention disclosed a new N4-oxycarbonylcytidine derivation represented by general formula (1), and provided the preparation of the fluorocytidine amino format which is used antiturnour medicine such as capecitabine by the starting meterial of N4-pentyloxycarbonyl-5-fluorocytidine.
Description
N4—氧羰基胞嘧啶衍生物及制备方法与应用 技术领域 本发明属于药物化学技术领域。 具体涉及 N4—氧羰基胞嘧啶衍生 物及制备方法与应用。 背景技术 N 4 - oxycarbonyl cytosine and derivatives and preparation method TECHNICAL FIELD The present invention belongs to the technical field of pharmaceutical chemistry. Specifically, it relates to N 4 -oxocarbonylcytosine derivative, its preparation method and application. Background technique
N4—氧羰基胞嘧啶衍生物是制备氟胞嘧啶氨基甲酸酯类抗癌药物 的重要原料。 N 4 -oxycarbonylcytosine derivatives are important raw materials for the preparation of fluorocytosine carbamate anticancer drugs.
卡培他滨是第一个氟代嘧啶氨基甲酸酯类抗肿瘤药物， 其化学名 为 ： 5' - 脱 氧 -5- 氟 - N4- 戊 氧 羰 基 胞 苷 ， 即 ： 5 -deoxy-5-fluoro-N4- (pentyloxycarbony) cytidine。 其结构式如 下： Capecitabine is the first fluoropyrimidine carbamate antitumor drug. Its chemical name is 5'-deoxy-5-fluoro-N 4 -pentoxycarbonylcytidine, that is: 5-deoxy-5- fluoro-N 4- (pentyloxycarbony) cytidine. Its structural formula is as follows:
目前文献及专利报道的卡培他滨的合成路线主要有三种， 现列举 如下：
Scheme 1： There are three main synthetic routes of capecitabine in the literature and patent reports, which are listed below: Scheme 1:
参考文献： US005476932 References: US005476932
Scheme 3 Scheme 3
rn
rn
本发明提供了通式 I的胞嘧啶衍生物： The invention provides cytosine derivatives of the general formula I:
( I ) (I)
式中 为烷基、 环垸基、 链烯基、 芳垸基或芳基； R2为卤素原子 氟或碘， 乙烯基， 乙炔基或被卤素、 垸基、 环烷基、 芳环垸基或芳杂 环基所取代的乙烯基、 乙炔基。 本发明的另一目的是提供了通式 I的胞嘧啶衍生物的制备方法， 该方法以通式 II与通式 III进行缩合反应制备而得。 In the formula: alkyl, cyclofluorenyl, alkenyl, arylfluorenyl or aryl; R 2 is halogen atom fluorine or iodine, vinyl, ethynyl or halogen, fluorenyl, cycloalkyl, arylcyclofluorenyl Or aromatic heterocyclyl substituted vinyl, ethynyl. Another object of the present invention is to provide a method for preparing a cytosine derivative of the general formula I, which is prepared by a condensation reaction of the general formula II and the general formula III.
(II) (III)
通式 II中 R3为卤素原子 （如氟， 碘等）， 乙烯基， 乙炔基或被卤 素、 垸基、 环垸基、 芳环烷基或芳杂环基所取代的乙烯基、 乙炔基； 通式 III中 X代表离去基团， R4代表垸基、 环垸基、 链烯基、 芳 垸基或芳基。 (II) (III) In the general formula II, R 3 is a halogen atom (such as fluorine, iodine, etc.), a vinyl group, an ethynyl group or a vinyl group, an ethynyl group substituted by a halogen, a fluorenyl group, a cyclofluorenyl group, an arylcycloalkyl group, or an aromatic heterocyclic group. In the general formula III, X represents a leaving group, and R 4 represents a fluorenyl group, a cyclofluorenyl group, an alkenyl group, an arylfluorenyl group, or an aryl group.
通式 II与通式 III的缩合反应， 可以在一种溶剂如吡啶、 二氯甲 烷、 1， 2-二氯乙垸或水中进行， 也可以在二个或二个以上混合溶剂中 进行， 但需存在酸性接受体如三乙胺、 吡啶、 甲基吡啶、 碱金属氢氧 化物、 碱金属碳酸盐或磷酸盐。 反应温度可以在较宽范围内变化， 一 般为 20°C〜- 20V , 最好在 0°C左右进行。 The condensation reaction of the general formula II and the general formula III can be performed in a solvent such as pyridine, dichloromethane, 1,2-dichloroacetamidine, or water, or in two or more mixed solvents, but Acid acceptors such as triethylamine, pyridine, methylpyridine, alkali metal hydroxides, alkali metal carbonates or phosphates are required. The reaction temperature can be varied within a relatively wide range, generally from 20 ° C to -20V, and preferably at about 0 ° C.
按上述方法制备的化合物可以用一般的技术 （例如蒸发、 过滤、 提取、 沉淀、 重结晶以及合并使用这些方法） 分离和纯化。 本发明的又一目的是提供了通式 I的 N4—氧羰基胞嘧啶衍生物, 以通式 N表示。 Compounds prepared as described above can be isolated and purified using general techniques (e.g., evaporation, filtration, extraction, precipitation, recrystallization, and a combination of these methods). Another object of the present invention is to provide a N 4 -oxycarbonylcytosine derivative of the general formula I, which is represented by the general formula N.
0 0
HN, O HN, O
Η Η
(IV) (IV)
通式 IV中 R5为垸基、 环烷基、 链烯基、 芳垸基或芳基。 通式（I )所示的新衍生物中 N -氧羰基 -5-氟胞嘧啶衍生物（通式 IV)与 5-脱氧 -D-呋喃核糖类化合物（通式 V)反应， 可制备氟胞嘧啶 氨基甲酸酯类抗肿瘤药物。 该合成方法是降低该类药物合成成本、 提 高质量的有效途径。
In Formula IV, R 5 is a fluorenyl group, a cycloalkyl group, an alkenyl group, an arylfluorenyl group or an aryl group. Among the new derivatives represented by the general formula (I), N-oxycarbonyl-5-fluorocytosine derivatives (general formula IV) are reacted with 5-deoxy-D-ribofuranosyl compounds (general formula V) to prepare fluorine. Cytosine carbamate antitumor drugs. The synthetic method is an effective way to reduce the cost of such drugs and improve the quality.
(V) (V)
通式 V中 R6为氢原子、 乙酰基或苯甲酰基。 In Formula V, R 6 is a hydrogen atom, an acetyl group or a benzoyl group.
本发明的再一目的是提供了以 N4—戊氧羰基一 5 氟胞嘧啶为起始 原料制备氟胞嘧啶氨基甲酸酯类抗肿瘤药物卡培他滨的方法， 该方法 包括下列步骤： Yet another object of the present invention is to provide a method for preparing fluorocytosine carbamate antitumor drug capecitabine using N 4 -pentyloxycarbonyl-5 fluorocytosine as a starting material. The method includes the following steps:
用作上述反应原料的 N4-戊氧羰基 -5-氟胞嘧啶是由 5-氟胞嘧啶与 氯甲酸正戊酯缩合反应而得， 是由本发明人制备的一种新化合物， 对 该化合物的羰基保护可用三甲基硅氧垸（ OSi (CH3) 3)、六甲基二硅氮烷
( N[Si (CH3) 3]2 )或碘化钠与三甲基氯硅垸在无水乙腈、二氯甲烷、 1，2 -二氯乙垸或甲苯中进行加热回流。 N 4 -pentyloxycarbonyl-5-fluorocytosine used as the raw material for the above reaction is obtained by the condensation reaction of 5-fluorocytosine with n-pentyl chloroformate. It is a new compound prepared by the inventors. For carbonyl protection, trimethylsiloxane (OSi (CH 3 ) 3 ), hexamethyldisilazane (N [Si (CH 3 ) 3 ] 2 ) or sodium iodide and trimethylchlorosiliconium are heated under reflux in anhydrous acetonitrile, dichloromethane, 1,2-dichloroethane, or toluene.
本发明所应用的术语 "烷基"是指有 1〜19个碳原子的直链或带 支链的垸基： 甲基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 仲丁基、 叔丁基、 戊基、 异戊基、 新戊基、 己基、 异己基、 庚基、 辛基、 壬基、 癸基、 十一垸基、 十二烷基、 十三烷基、 十四烷基、 十五垸基、 十六 垸基、 十七垸基或十九垸基； The term "alkyl" used in the present invention refers to a straight or branched fluorenyl group having 1 to 19 carbon atoms: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl , Tetradecyl, pentadecyl, hexadecyl, heptadecyl, or nonadecyl;
"环垸基"是指环丙基、 环丁基、 环戊基或环己基； "Cyclomethyl" means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
"链烯基"是指有 3〜19个碳原子的未取代或取代的链烯基， 烯 丙基、 丁烯基、 3-甲基- 2-丁烯基、 1-甲基 -2-丙烯基、 己烯基、 癸烯 基、 十一碳烯基、 十三碳烯基、 十五碳烯基、 十七碳烯基、 十九碳烯 基或 2-苯基乙烯基； "Alkenyl" means an unsubstituted or substituted alkenyl group having 3 to 19 carbon atoms, allyl, butenyl, 3-methyl-2-butenyl, 1-methyl-2- Propenyl, hexenyl, decenyl, undecenyl, tridecenyl, pentadecenyl, heptenyl, undecenyl, or 2-phenylvinyl;
"芳烷基"是指未取代或取代的芳垸基， 例如苄基、 1-苯基乙基、 甲基苄基或苯乙基； "Aralkyl" means an unsubstituted or substituted arylfluorenyl, such as benzyl, 1-phenylethyl, methylbenzyl or phenethyl;
"芳基"是指未取代或取代的芳基， 例如苯基、 苯甲基、 二甲苯 基或乙基苯基； "Aryl" means an unsubstituted or substituted aryl, such as phenyl, benzyl, xylyl or ethylphenyl;
"被卤素、 垸基、 环烷基、 芳环垸基或芳杂环基所取代的乙烯基、 乙炔基"是指 1-氯乙烯基、 2-溴乙烯基、 1-氯- 2-溴乙烯基、 2-苯乙烯 基、 1-丙炔基、 1-丁炔基、 1-戊炔基、 1-己炔基、 3， 3-二甲基 -1-丁炔 基、环戊乙炔基、环己乙炔基、苯乙炔基、 3-苯基 -1-丙炔基、吡啶 -2 - 乙炔基或咪唑 -2-乙炔基。 "Vinyl, ethynyl substituted with halogen, fluorenyl, cycloalkyl, arylcyclofluorenyl or arylheterocyclyl" means 1-chlorovinyl, 2-bromovinyl, 1-chloro-2-bromo Vinyl, 2-styryl, 1-propynyl, 1-butynyl, 1-pentynyl, 1-hexynyl, 3,3-dimethyl-1-butynyl, cyclopentylacetylene Radical, cyclohexylethynyl, phenylethynyl, 3-phenyl-1-propynyl, pyridine-2 -ethynyl or imidazole-2-ethynyl.
经实验证明， 本发明路线可大大降低生产成本， 所获得的产品质 量可靠、 性能稳定。 具体实施方式 实施例 1 N4-戊氧羰基- 5-氟胞嘧啶的制备 在冰盐浴冷却和惰性气氛下， 向 250mL四口烧瓶中加入 180mL 1， 2-二氯乙烷、 10mL无水吡啶和 13g( 0. lmol ) 5-氟胞嘧啶， 当反
应液温度降到 20 - 20 °C时， 在搅拌下滴加氯甲酸正戊酯 18mL ( 0. 12mol ) , 滴加速度要保证反映液温度不超过 5°C。 滴加完毕， 在该温度范围内继续反应 2小时。 减压浓缩到总体积约 lOmL, 向浓缩 液中加入 50mL正己垸， 室温下搅拌 30分钟。 过滤， 将所得滤饼用蒸 馏水洗涤 2 4次， 每次 50mL。 将所得白色固体产品于 65Ό进行快速 真空干燥。收率： 78% mp: 108 109 C IR: 1653 (VN-C=0-) 1743 (V— 2959 NMR(ppm) 0. 8 (3H, C5'— H)， 1. 33 (4H, C3'— H C4'— H)， 1. 65 ( 2H, C2'- H) 3. 3 (1H C6-H) 4. 3 (2H C _H) 8. 0 (1H, N1 -H) 8. 4 (1H, N4 - H)；元素分析： 计算值 C 49. 38%， H 5. 83% , Ν 17. 28%， F 7. 82% ； 实测值 C 49. 13% H 5. 87% N 17. 34% F 7. 71% 实施例 2 2' , 3' -二- 0-乙酰基 -5' -脱氧 -5-氟 -N4-戊氧羰基胞苷的 制备 将 N4-戊氧羰基 -5-氟胞嘧啶 24. 3g ( 0. lmol ) 悬浮在 50mL甲苯 和六甲基二硅氮垸 8g ( 0. 05mol )中， 在氮气氛下加热回流， 用薄层 色谱法跟踪反应， 展开剂为甲醇：氯仿 =1 : 6， 在 254nm紫外下显色。 The experiment proves that the route of the present invention can greatly reduce the production cost, and the obtained product has reliable quality and stable performance. DETAILED DESCRIPTION Example 1 Preparation of N 4 -pentyloxycarbonyl-5-fluorocytosine In a 250-mL four-necked flask, 180 mL of 1, 2-dichloroethane and 10 mL of anhydrous were added under cooling in an ice-salt bath under an inert atmosphere. Pyridine and 13 g (0.1 mol) 5-fluorocytosine, when When the temperature of the reaction solution drops to 20-20 ° C, 18 mL (0.12 mol) of n-amyl chloroformate is added dropwise with stirring, and the dropping speed must be ensured that the temperature of the reflection solution does not exceed 5 ° C. After the dropwise addition was completed, the reaction was continued in this temperature range for 2 hours. The solution was concentrated under reduced pressure to a total volume of about 10 mL, 50 mL of n-hexane was added to the concentrate, and the mixture was stirred at room temperature for 30 minutes. After filtration, the obtained filter cake was washed with distilled water 24 times, 50 mL each time. The resulting white solid product was quickly vacuum dried at 65 Torr. Yield: 78% mp: 108 109 C IR: 1653 (V N - C = 0- ) 1743 (V— 2959 NMR (ppm) 0.8 (3H, C 5 '— H), 1. 33 (4H, C 3 '— HC 4 ' — H), 1. 65 (2H, C 2 '-H) 3. 3 (1H C 6 -H) 4. 3 (2H C _H) 8. 0 (1H, N 1- H) 8. 4 (1H, N 4 -H); Elemental analysis: Calculated values C 49. 38%, H 5. 83%, Ν 17. 28%, F 7. 82%; Found C 49. 13% H 5. 87% N 17. 34% F 7. 71% Example 2 Preparation of 2 ', 3'-di-0-acetyl-5'-deoxy-5-fluoro-N 4 -pentoxycarbonylcytidine the N 4 - pent-oxycarbonyl-5-fluoro cytosine 24. 3g (0. lmol) was suspended (0. 05mol) was heated under reflux in 50mL of toluene under a nitrogen atmosphere and hexamethyl silazane embankment 8g, with a thin The reaction was followed by layer chromatography, and the developing solvent was methanol: chloroform = 1: 6, and the color was developed under ultraviolet light of 254 nm.
当硅垸保护反应完全后， 降温到室温， 加入 150mL二氯甲垸。 在 冰浴下加入 5-脱氧 -1 2, 3-三- 0-乙酰基 -D-呋喃核糖 31. 2g ( 0. 12mol ) 和 无水 SnCl4 31. 2g ( 0. 12mol )， 加料完毕， 在室温下反应过夜。 加入 50 g碳酸氢钠并滴加 50mL水， 继续室温下搅拌 1小时， 过滤。 滤液用 4%碳酸氢钠溶液洗涤 3次， 每次 25mL。有机层用无水硫酸钠干 燥后进行减压浓縮， 得淡黄色油状物。 收率： 76% 实施例 3 5' -脱氧 -5-氟- N4-戊氧羰基胞苷（卡培他滨）的制备 将 44. 3g ( 0. lmol ) 2' , 3' -二- 0-乙酰基 -5' -脱氧 -5-氟- Ν4-戊 氧羰基胞苷溶于 50 mL甲醇中， 在室温下通入氨气， 搅拌反应过夜。 反应结束， 浓缩至干。 将残余物溶于 50 mL乙酸乙酯中， 将浆液冷却 到 0°C， 陈化 1小时， 将晶体回收， 用 2X 20mL正己垸：乙酸乙酯 =1 : 1
冷却液洗涤，在真空下将超白产物一卡培他滨于 40°C干燥过夜。收率:
After the silamidine protection reaction was completed, the temperature was lowered to room temperature, and 150 mL of dichloromethane was added. Add 31.2 g (0.12 mol) of 5-deoxy-1 2, 3-tri-0-acetyl-D-ribofuranose and 31.2 g (0.12 mol) of anhydrous SnCl 4 in an ice bath. The reaction was allowed to proceed at room temperature overnight. 50 g of sodium bicarbonate was added and 50 mL of water was added dropwise, stirring was continued at room temperature for 1 hour, and filtration was performed. The filtrate was washed 3 times with 4% sodium bicarbonate solution, 25 mL each time. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a pale yellow oil. Yield: 76% Example 3 Preparation of 5'-deoxy-5-fluoro-N 4 -pentoxycarbonylcytidine (capecitabine) 44.3 g (0.1 mol) 2 ', 3' -di- O-acetyl-5 '- deoxy-5-fluoro - Ν 4 - pentyloxycarbonyl cytidine was dissolved in 50 mL of methanol, ammonia gas at room temperature, and stirred overnight. The reaction was completed and concentrated to dryness. The residue was dissolved in 50 mL of ethyl acetate, the slurry was cooled to 0 ° C, aged for 1 hour, and the crystals were recovered, and 2X 20 mL of hexane: ethyl acetate = 1: 1 The coolant was washed and the ultra-white product, capecitabine, was dried under vacuum at 40 ° C overnight. Yield:
Claims
权 利 要 求 Rights request
-种胞嘧啶衍生物， 其特征在于该衍生物具有下列通式 I -A cytosine derivative, characterized in that the derivative has the following general formula I
( I ) (I)
式中 ^为烷基、 环垸基、 链烯基、 芳垸基或芳基； 为[¾素原子 氟或碘， 乙烯基， 乙炔基或被卤素、 烷基、 环垸基、 芳环烷基或芳杂 环基所取代的乙烯基、 乙炔基。 In the formula, ^ is an alkyl group, a cyclofluorenyl group, an alkenyl group, an arylfluorenyl group or an aryl group; it is a fluorine atom or iodine, a vinyl group, an ethynyl group, or a halogen, an alkyl group, a cyclofluorenyl group, or an arylcycloalkane group. A vinyl or ethynyl group substituted by a radical or arylheterocyclyl.
2. —种通式 I的胞嘧啶衍生物的制备方法， 其特征在于该方法为将通 式 II与通式 III的化合物进行缩合反应，反应需在酸性接受体三乙胺、 吡啶、 甲基吡啶、 碱金属氢氧化物、 碱金属碳酸盐或磷酸盐存在下， 在溶剂吡啶、 二氯甲垸、 1， 2—二氯乙垸或水， 或在二个及二个以上的 混合溶剂中， 于 20°C〜一 20°C进行。 氧羰基胞嘧啶衍生物，其特征在于该方法具有下列通式 IV： 2. —A method for preparing a cytosine derivative of the general formula I, which is characterized in that the method is a condensation reaction of a compound of the general formula II and a compound of the general formula III. In the presence of pyridine, alkali metal hydroxide, alkali metal carbonate or phosphate, in the solvent pyridine, methylene chloride, 1,2-dichloroacetamidine or water, or in a mixed solvent of two or more Medium, at 20 ° C ~ 20 ° C. Oxycarbonyl cytosine derivatives, characterized in that the method has the following general formula IV:
(IV) (IV)
通式 IV中 R5为垸基、 环烷基、 链烯基、 芳垸基或芳基 <
R 5 in Formula IV is fluorenyl, cycloalkyl, alkenyl, arylfluorenyl or aryl <
4. 一种 N4—氧羰基胞嘧啶衍生物在制备氟胞嘧啶氨基甲酸酯类抗肿瘤 药物中的应用。 4. Application of an N 4 -oxycarbonylcytosine derivative in the preparation of fluorocytosine carbamate antitumor drugs.
5. 一种氟胞嘧啶氨基甲酸酯类抗肿瘤药物卡培他滨的制备方法， 其特 征在于该方法以 N4—戊氧羰基一 5 氟胞嘧啶为原料， 先用三甲基硅氧 烷、 六甲基二硅氮烷或碘化钠与三甲基氯硅垸在无水乙腈、 二氯甲烷 或甲苯中进行加热回流， 对羰基保护， 再与 5-脱氧 -1， 2, 3-三 -0-乙酰 基 -D-呋喃核糖反应生成胞苷，在氯气氛下经过氨气一甲醇液水解后制 得。 5. A method for preparing capecitabine, a fluorocytosine carbamate antitumor drug, characterized in that the method uses N 4 -pentyloxycarbonyl-5 fluorocytosine as a raw material, and first uses trimethylsiloxane , Hexamethyldisilazane or sodium iodide and trimethylchlorosiliconium in anhydrous acetonitrile, dichloromethane or toluene under heating and reflux to protect the carbonyl group, and then with 5-deoxy-1, 2, 3- Tri-0-acetyl-D-ribofuranose reacts to produce cytidine, which is prepared by hydrolysis of ammonia-methanol solution in a chlorine atmosphere.
6.根据权利要求 5所述的一种氟胞嘧啶氨基甲酸酯类抗肿瘤药物卡培 他滨的制备方法，其特征在于其中所述的 N4—戊氧羰基一 5—氟胞嘧啶 是由 5—氟胞嘧啶与氯甲酸正戊酯縮合制得。 The method for preparing capecitabine, a fluorocytosine carbamate antitumor drug according to claim 5, characterized in that the N 4 -pentyloxycarbonyl 5-fluorocytosine is composed of 5-Fluorocytosine and n-amyl chloroformate condensed.
7. 根据权利要求 1、 2或 3所述的通式 I、 II、 III和 IV化合物， 其
特征在于其中所述的 "烷基"是指有 1〜19个碳原子的直链或带支链 的烷基： 甲基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 仲丁基、 叔丁 基、 戊基、 异戊基、 新戊基、 己基、 异己基、 庚基、 辛基、 壬基、 癸 基、 十一垸基、 十二垸基、 十三烷基、 十四垸基、 十五垸基、 十六烷 基、 十七烷基或十九垸基； 7. Compounds of general formulae I, II, III and IV according to claim 1, 2 or 3, which It is characterized in that the "alkyl" refers to a straight or branched alkyl group having 1 to 19 carbon atoms: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl , Tetradecyl, pentadecyl, hexadecyl, heptadecyl or nonadecyl;
"环烷基"是指环丙基、 环丁基、 环戊基或环己基； "Cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
"链烯基"是指有 3〜19个碳原子的未取代或取代的链烯基， 烯 丙基、 丁烯基、 3-甲基- 2-丁烯基、 1-甲基 -2-丙烯基、 己烯基、 癸烯 基、 十一碳烯基、 十三碳烯基、 十五碳烯基、 十七碳烯基、 十九碳烯 基或 2-苯基乙烯基； "Alkenyl" means an unsubstituted or substituted alkenyl group having 3 to 19 carbon atoms, allyl, butenyl, 3-methyl-2-butenyl, 1-methyl-2- Propenyl, hexenyl, decenyl, undecenyl, tridecenyl, pentadecenyl, heptenyl, undecenyl, or 2-phenylvinyl;
"芳烷基"是指未取代或取代的芳烷基， 例如苄基、 1-苯基乙基、 甲基苄基或苯乙基； "Aralkyl" means an unsubstituted or substituted aralkyl, such as benzyl, 1-phenylethyl, methylbenzyl or phenethyl;
"芳基"是指未取代或取代的芳基， 例如苯基、 苯甲基、 二甲苯 基或乙基苯基； "Aryl" means an unsubstituted or substituted aryl, such as phenyl, benzyl, xylyl or ethylphenyl;
"被卤素、 垸基、 环烷基、 芳环垸基或芳杂环基所取代的乙烯基、 乙炔基"是指 1-氯乙烯基、 2-溴乙烯基、 1-氯 -2-溴乙烯基、 2-苯乙烯 基、 1-丙炔基、 1-丁炔基、 1-戊炔基、 1-己炔基、 3, 3-二甲基 -1-丁炔 基、环戊乙炔基、环己乙炔基、苯乙炔基、 3-苯基 -1-丙炔基、吡啶 -2 - 乙炔基或咪唑 -2-乙炔基。
"Vinyl, ethynyl substituted with halogen, fluorenyl, cycloalkyl, arylcyclofluorenyl or arylheterocyclyl" means 1-chlorovinyl, 2-bromovinyl, 1-chloro-2-bromo Vinyl, 2-styryl, 1-propynyl, 1-butynyl, 1-pentynyl, 1-hexynyl, 3, 3-dimethyl-1-butynyl, cyclopentylacetylene Radical, cyclohexylethynyl, phenylethynyl, 3-phenyl-1-propynyl, pyridine-2 -ethynyl or imidazole-2-ethynyl.
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| CN200410016472.2 | 2004-02-23 | ||
| CNB2004100164722A CN100383128C (en) | 2004-02-23 | 2004-02-23 | Ramification of N-carbethoxy cytosine and preparation method and application |
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| WO2009071726A1 (en) * | 2007-12-06 | 2009-06-11 | Coll Farma S.L. | Method for the preparation of capecitabine and intermediates used in said method |
| WO2010047866A2 (en) | 2008-08-01 | 2010-04-29 | Dow Agrosciences Llc | Use of 5-fluorocytosine as a fungicide |
| WO2010061402A3 (en) * | 2008-11-25 | 2012-05-10 | Vishwanath Kannan | An improved process for the preparation of capecitabine |
| CN102558262A (en) * | 2010-12-23 | 2012-07-11 | 天津泰普药品科技发展有限公司 | Preparation method of high-purity capecitabine |
| CN103772453A (en) * | 2014-03-04 | 2014-05-07 | 大连大学 | Beta-elemene substituted ethyl peracetylated sugar complex, beta-elemene substituted ethyl sugar complex, and preparation methods and use |
| 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 |
| CN105566419A (en) * | 2015-12-28 | 2016-05-11 | 上海金和生物技术有限公司 | Capecitabine preparation method |
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| AR046077A1 (en) | 2005-11-23 |
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