WO2005080351A1 - The preparation and application of a n4-oxycarbonylcytosine derivatives - Google Patents

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

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:

There are three main synthetic routes of capecitabine in the literature and patent reports, which are listed below: Scheme 1:

参考文献： Drugs of the Future 1996， 21 (4) : 358〜360 Scheme 2：

References: Drugs of the Future 1996, 21 (4): 358 ~ 360 Scheme 2:

References: US005476932

 Scheme 3

rn

参考文献： Bioorganic & Medicinal Chemistry 8 (2000) : 1697〜1706 发明内容 本发明所要解决的技术问题在于研究设计以 N⁴—戊氧羰基一 5— 氟胞嘧啶为原料制备卡培他滨的方法。

References: Bioorganic & Medicinal Chemistry 8 (2000): 1697 ~ 1706 Summary of the Invention The technical problem to be solved by the present invention is to study and design a method for preparing capecitabine using N ⁴ -pentyloxycarbonyl-5-fluorocytosine as a raw material.

 The invention provides cytosine derivatives of the general formula I:

(I)

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) 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.

 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.

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

HN, O

Η

(IV)

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)

In Formula V, 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:

以 N⁴-戊氧羰基 -5-氟胞嘧啶与 5-脱氧 -1， 2, 3-三- 0-乙酰基 -D -呋 喃核糖反应生成胞苷， 经过氨气一甲醇液的水解得卡培他滨产品。

The reaction of N ⁴ -pentyloxycarbonyl-5-fluorocytosine with 5-deoxy-1, 2, 3-tri-0-acetyl-D-ribofuranose produces cytidine, which is obtained by hydrolysis of ammonia-methanol solution. Betabine products.

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.

 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;

 "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;

 "Aralkyl" 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.

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.

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

Rights request -A cytosine derivative, characterized in that the derivative has the following general formula I

(I)  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. —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) R _{5 in} Formula IV is fluorenyl, cycloalkyl, alkenyl, arylfluorenyl or aryl < 4. Application of an N ⁴ -oxycarbonylcytosine derivative in the preparation of fluorocytosine carbamate antitumor drugs. 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.

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. 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;  "Cycloalkyl" 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;  "Aralkyl" means an unsubstituted or substituted aralkyl, 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.