KR100834711B1 - A method of synthesizing n-acyl-5'-deoxy-5-fluoroucytidine derivers - Google Patents

Abstract

A method for preparing an N-acyl-5-deoxy-5-fluoroucytidine derivative is provided to synthesize a final target material easily and rapidly from a 5'-deoxy-5-fluoroucytidine compound. A method for preparing an N-acyl-5-deoxy-5-fluoroucytidine derivative comprises the steps of: (a) reacting a compound represented by a formula(II) with ditrichloromethyl carbonate at a temperature of 0-60 deg.C in the presence of an inactive organic solvent and an organic alkali to obtain a compound represented by a formula(III); (b) reacting the compound of the formula(III) with R-O-CO-X at a temperature of -30 to 20 deg.C in the presence of an inactive organic solvent and an organic alkali to obtain a compound represented by a formula(IV); and (c) putting the compound of the formula(IV) in a mixture solvent consisting of an organic solvent and water at a temperature of -30 to 30 deg.C to hydrolyze selectively a protected lactone which is introduced into a hydroxy group of a saccharide portion, thereby preparing a compound represented by a formula(I), wherein R is C1-6 linear or branched alkyl, C3-12 cycloalkyl, C1-6 alkenyl, C1-6 aralkyl or an aryl such as phenyl, naphthyl, anthryl and phenanthryl; and X is halide, anhydride, or multianhydride.

Description

Method for synthesizing N-acyl-5'-deoxy-5-fluoroucytidine derivers

The present invention relates to a process for preparing an N-acyl-5'-deoxy-5-fluorocytidine compound and its derivatives.

N-acyl-5'-deoxy-5-fluorocytidine derivative compound (I), which is the following structural formula I compound, shows the possibility of anti-cancer effect [Japanese Journal of Cancer Research, Vol. 81, pp. 188-195 (1990).

WO 2005-049031 and US 2005-119337 describe capecitabine, in which R is an n-amyl group, has a wide range of anticancer effects.

European Patent Publication No. EP0316704A and Chinese Patent Publication No. CN1035675 disclose that the structure I compound can be obtained from 5'-deoxy-5-fluorocytidine, but the prior arts are acyl, isopropylidene, It is necessary to introduce a protecting group to the hydroxy group of the saccharide portion by a method such as silylation, to introduce the acyl group to the amino group, and to remove the protecting group from the saccharide. Difficult to apply Moreover, since the acyl group of the amino group is accompanied by side reactions, there is a problem in that the separation is complicated and purification is required.

Chinese Patent Publication No. CN1035675 discloses another method, which simplifies the manufacturing process, but adopts the same group to both the protecting group introduced into the saccharide portion and the acyl group introduced to the amino group, thereby providing an expensive acylation reagent ( The consumption of acylating agent) in large quantities has a problem of high cost.

Accordingly, an object of the present invention is to provide a simple and efficient method for producing an N-acyl-5'-deoxy-5-fluorocytidine derivative compound.

In order to achieve the above object, the present invention provides a method for preparing an N-acyl-5'-deoxy-5-fluorocytidine derivative which is the following structural formula I compound.

Wherein R represents an alkyl, cycloalkyl, alkenyl, aralkyl or aryl group.

The present invention is a preparation method using 5'-deoxy-5-fluorocytidine as a starting material, and the present invention is described in detail below.

The present invention introduces a protected cyclic group into the hydroxy group of the saccharide moiety, an acyl group into the amino group moiety, and then hydrolyzes the cyclic lactone from the saccharide to obtain the compound of formula (I). In three steps, the present invention can produce the final product N-acyl-5'-deoxy-5-fluorocytidine derivative having high productivity and high efficiency suitable for industrial production.

The reaction process according to the present invention is as follows.

Wherein R is an alkyl, cycloalkyl, alkenyl, aralkyl or aryl group.

The present invention is straight chain alkyl or branched alkyl having 1 to 22 carbon atoms (C ₁ to C ₂₂ ) when the substituent R is alkyl, and preferably methyl, ethyl, isopropyl, butyl, isobutyl or amyl and the like. Alkyl containing lower paraffin hydrocarbons having 1 to 6 carbon atoms (C ₁ to C ₆ ).

In the present invention, when the substituent R is cycloalkyl, cycloalkyl having 3 to 12 carbon atoms (C ₃ to C ₁₂ ) such as cyclopropyl, cyclobutyl, cyclopentyl or adamantaneyl is preferable.

The present invention is a substituted or unsubstituted group having 2 to 22 carbon atoms (C ₂ to C ₂₂ ) when the substituent R is alkenyl, and lower alkenyl having 1 to 6 carbon atoms (C ₁ to C ₆ ) Preferred, for example, allyl, butenyl, amylene or hexane. When R is substituted alkenyl, preference is given to lower allyl or aryl groups.

The present invention is a substituted or unsubstituted aryl group when the substituent R is aryl. So-called aryl refers to mononuclear aryl such as phenyl and multinuclear aryl such as naphthyl, anthryl and phenanthryl. Both types can be substituted at the same position. When R is substituted mononuclear aryl, preferred groups are lower paraffinic hydrocarbons having 1 to 6 carbon atoms (C ₁ to C ₆ ), halogen, lower alkoxy, nitro group, nitrile group, acetyl, carbamoyl or lower carbaalcohol. It is carbalkoxy. All of the aryl groups mentioned above may include heteroatomics which may be selected from nitrogen, oxygen or sulfur. And these atoms are unsubstituted or substituted by the group. And when R is a mononuclear heteroaryl group, it is a thienyl, methylthienyl, furan group or nitro-furan group. Preferred multinuclear aryl groups are naphthyl, biphenyl, pyrrolyl, methylpyrrolyl, imidazole, pyrazolyl, pyridyl, pyridyl, methylpyri Diyl (methylpyridyl) or pyrazinyl, and the like.

The present invention refers to aryl of lower alkyl when the substituent R is aralkyl. Herein, the aryl group means the same as above and lower alkyl having 1 to 6 carbon atoms (C ₁ to C ₆ ). In addition, the aryl groups mentioned are substituted or unsubstituted. Preferred unsubstituted aralkyl is benzyl. Substituted aralkyls are methylbenzyl, benzyl fluoride, benzyl chloride, methoxy benzyl, dimethoxy benzyl, and nitro-benzyl. ), Phenylethyl, pyridine methyl, 3-indolol methyl or 1-phenylethyl.

The preparation process according to the invention starts with 5'-deoxy-5-fluorocytidine, which is a compound of formula II. Its structural formula is as follows.

The formula II compound is a preparation example of 5-gemcitabine from 5-flucitosin (5-Flucytosin) [chempharm. Bull, the twenty-sixth volume, the tenth issue 2990 (1978), is a compound known to be prepared from 5'-deoxy-5-gemcitabine.

Structural Formula III compounds and Structural Formula IV compounds are important intermediates that are novel compounds of the present invention. The structural formula of compound III is as follows.

Formula III compounds are prepared by the reaction of triphosgene with the above formula II compounds in the presence of organic alkalis and inert organic solvents. Inert organic solvents are ionic or nonionic inert solvents, for example halohydrocarbons such as DMF, acetonitrile, toluene, chloroform, pyridine, lutidine, methyl-sulfoxide or dichloromethane, with dichloromethane being preferred. .

The organic alkali is triethylamine, tributylamine, pyridine, N, N-dimethylaminopyridine, lutidine or N-methyl monofoline, preferably pyridine.

The reaction temperature is 0 ° C to 60 ° C, preferably 20 ° C to 50 ° C, and most preferably 25 ° C to 40 ° C.

The present invention introduces tripphosgen as a reagent to convert hydroxy groups to protected cyclic lactone groups in the sugar moiety. The reagents have advantages such as suitable reaction conditions, high selectivity, high volume, low cost in the preparation method according to the present invention.

The structural formula of compound IV is as follows.

The compound of formula IV is prepared by the reaction of the following formula (1) which is a compound of an inert organic solvent under the organic alkali.

<Formula 1>

R-O-CO-X

Wherein R is an alkyl, cycloalkyl, alkenyl, aralkyl or aryl group, X is an activated group such as halide, anhydride, multianhydride or methylsulfonyl Related to sulfated alkyl, sulfated aryl, methylbenzene sulfonyl. When X is associated with a halide, it is a bromide, fluoride or chloride.

Inert organic solvents in the reaction are ionic or nonionic inert solvents, for example halohydrocarbons such as DMF, acetonitrile, toluene, chloroform, pyridine, lutidine, methyl-sulfoxide or dichloromethane ), Preferably dichloromethane.

The organic alkali in the reaction is also triethylamine, tributylamine, pyridine, N, N-dimethylaminopyridine, lutidine or N-methyl monopoline, preferably pyridine.

The reaction temperature is carried out at -30 ° C to 20 ° C, preferably -10 ° C to 10 ° C, and most preferably at 0 ° C.

The structural formula of the compound I which is an objective compound of this invention is as follows.

The compound of formula I can be obtained with high efficiency and high yield by selectively hydrolyzing the protected lactone introduced into the hydroxy group of the saccharide portion in a mixed solvent consisting of water-soluble organic solvent containing low concentration of inorganic alkali and water. .

The soluble solvent used to prepare the above formula I compound is alcohol, ether, THF, dioxane or acetone selected from methanol, ethanol, propanol, butyl alcohol, isopropanol, preferably ether.

The ratio of soluble solvent and water is 1: 9 to 9: 1, preferably 4: 6 to 6: 4, most preferably 5: 5.

The inorganic alkali is a sodium hydroxide group or potassium hydroxyl group used at a concentration of 0.1 M to 1.0 M, with 0.5 M being preferred.

The reaction temperature is -30 ℃ to 30 ℃, the suitable temperature is 0 ℃ to 1 ℃, the best results can be obtained at 5 ℃.

In order to explain the present invention more clearly, the following examples are given, and the content is not limited thereto.

Example 1 Preparation of Compound III

57.3 g (0.233 mol) of Compound II was dissolved in 400 ml of anhydrous dichloromethane, then 76.0 ml (0.932 mol) of pyridine was added and added dropwise to 100 ml solution of dichloromethane containing 75.3 g (0.256 mol) of triphosgen at room temperature. Next, the temperature of the solution is raised to 40 ° C. and reacted for 2 hours with stirring.

Then, the reaction was confirmed by TLC (EtOAc / Petroleum ester = 1: 7), the reaction solution was added to 1000 ml of water, separated, and the organic layer was washed with saturated sodium bicarbonate solution, and the aqueous layer was washed with 2 ml of 500 ml of dichloromethane. Extract once. The organic layer was taken, dried over anhydrous sodium sulfate, extracted, filtered and circulated distilled to give 56.2 g of a yellowish oily compound III. (Yield: 89.0%)

Example 2 Preparation of Compound III

61.2 g (0.25 mol) of compound II are dissolved in 400 ml anhydrous dichloromethane, and then 122 g of N, N-dimethylaminopyridine (1 mol) is added. Then, the mixture is added dropwise to 100 ml dichloromethane solution containing 75.3 g (0.256 mol) of triphosgene at room temperature, and then the reaction mixture is stirred for 2 hours while increasing the temperature of the compound to 30 ° C. After completion of the reaction by TLC (EtOAc / petroleum ester = 1: 7), the reaction solution was poured into 1000 ml of water, separated, washed with saturated sodium hydrogen carbonate solution, and the aqueous layer was extracted twice with 500 ml of dichloromethane. . The organic layer was taken, dried over anhydrous sodium sulfate, extracted, filtered and cyclic distilled to yield 63.7 g of a yellowish oily compound III. (Yield: 94.0%)

Example 3 Preparation of Compound IV

After dissolving 56.2 g (0.207 mol) of compound III in 1000 ml anhydrous dichloromethane, 27.7 ml pyridine (0.340 mol) was added thereto, cooled to 0 ° C, and at this temperature, N-amyl chloroformate 93.2 g (0.62 mol) was added dropwise, followed by stirring for 2 hours while increasing the temperature of the compound to room temperature.

TLC (EtOAc / petroleum ester = 1: 7) confirms the completion of the reaction, and the solvent is evaporated under reduced pressure. The reaction product was added to 2000 ml of a mixed solution of ether and saturated sodium hydrogen carbonate (1: 1), and the organic layer was washed with saturated sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and distilled to give 59.3 g of a white solid compound. Obtain an IV (Yield: 74.4%).

Example 4 Preparation of Compound IV

63.7 g (0.235 mol) of compound III was dissolved in 1000 ml anhydrous dichloromethane, and 41.5 g (0.304 mol) of N, N-dimethylaminopyridine was added thereto, cooled to 0 ° C., and en-amyl chloroformate (N -amyl chloroformate) 52.9g (0.353mol) is added dropwise, and the mixture is stirred for 2 hours while increasing the temperature of the compound to room temperature. TLC (EtOAc / petroleum ester = 1: 7) confirms the completion of the reaction, and the solvent is evaporated under reduced pressure. The reaction product was added to 2000 ml of a mixture of ether and saturated sodium hydrogen carbonate solution (1: 1), and the organic layer was washed with saturated sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and distilled off to obtain 76.8 g of a white solid compound. Obtain an IV (Yield: 85.0%)

Example 5 Preparation of Compound I

59.3 g (0.154 mol) of Compound IV are dissolved in 500 ml of dioxane / water (1/1), and then 375 ml 0.5 M sodium hydroxide (0.185 mol) is added and reacted at room temperature for 5 minutes. TLC (EtOAc / petroleum ester = 1: 7) After confirming the completion of the reaction, the pH was adjusted to 5-6 by dropwise addition of sulfuric acid and the reaction solution was extracted three times with 500ml dichloromethane / methanol (95/5). The organic layer was taken, dried over anhydrous sodium sulfate, circulated distilled and cooled slowly with ether acetate to give 45.9 g of white crystalline compound I. (Yield: 82.9%)

The present invention is to prepare the intermediate compound (III) and compound (IV) with the 5'-deoxy-5-fluorocytidine compound as a starting material, N-acyl-5'- as the final target easily and quickly Deoxy-5-fluorocytidine derivative compounds can be prepared.

In addition, the present invention can produce the target material in a high yield, it is applicable to industrial scale production.

Claims (9)

(B) reacting the following formula II compound with ditrichloromethyl carbonate in the presence of an inert organic solvent and an organic alkali to give the following formula III compound; Reacting the compound of formula III prepared in step VII with formula 1 below in the presence of an inert organic solvent and an organic alkali to produce the compound of formula IV; And N is prepared by selectively hydrolyzing the protected lactone introduced into the hydroxy group of the saccharide moiety by adding the compound of formula IV produced in step VII to a mixed solvent consisting of an organic solvent and water to prepare a compound of formula I below. A process for preparing an acyl-5'-deoxy-5-fluorocytidine derivative compound.

Wherein R is C ₁ to C ₆ straight or branched alkyl; C ₃ to C ₁₂ cycloalkyl; C ₁ to C ₆ alkenyl; C ₁ to C ₆ aralkyl; Or an aryl group selected from phenyl, naphthyl, anthryl, phenanthryl. <Formula 1> R-O-CO-X Wherein R is C ₁ to C ₆ straight or branched alkyl; C ₃ to C ₁₂ cycloalkyl; C ₁ to C ₆ alkenyl; C ₁ to C ₆ aralkyl; Or an aryl group selected from phenyl, naphthyl, anthryl and phenanthryl, and X is a halide, anhydride, or multianhydride. The method for preparing an N-acyl-5'-deoxy-5-fluorocytidine derivative compound according to claim 1, wherein the compound of formula (I) is prepared from the compound of formula (III) prepared in step (iii).

The organic solvent of claim 1, wherein the organic solvent used in step VII is selected from methanol, ethanol, propanol, butyl alcohol, isopropanol, ether, THF, dioxane or acetone, and the ratio of the mixed solvent of the organic solvent and water is 1: 9 to A process for preparing an N-acyl-5'-deoxy-5-fluorocytidine derivative compound characterized by being 9: 1. 4. The N-acyl-5'-decane according to claim 3, further comprising an inorganic alkali having a sodium hydroxide group or a potassium hydroxyl group used at a concentration of 0.1M to 1.0M in the mixed solvent used in step (iii). Method for preparing oxy-5-fluorocytidine derivative compound. The method for preparing an N-acyl-5'-deoxy-5-fluorocytidine derivative compound according to claim 3, wherein step VII is reacted at -30 ° C to 30 ° C. The method of claim 1, wherein the inert organic solvent of step VII is selected from DMF, acetonitrile, toluene, chloroform, pyridine, lutidine, methyl-sulfoxide or dichloromethane, and the organic alkali is triethylamine, tributylamine, pyridine , N, N-dimethylaminopyridine, lutidine or N-methyl monopoline. The process for preparing N-acyl-5'-deoxy-5-fluorocytidine derivative compound according to claim 6, wherein the step (iii) reacts at -30 ° C to 20 ° C. The method of claim 1, wherein the inert organic solvent of step VII is selected from DMF, acetonitrile, toluene, chloroform, pyridine, lutidine, methyl-sulfoxide or dichloromethane, and the organic alkali is triethylamine, tributylamine, pyridine , N, N-dimethylaminopyridine, lutidine or N-methyl monopoline. A method for preparing a N-acyl-5'-deoxy-5-fluorocytidine derivative compound. 8. The method for preparing an N-acyl-5'-deoxy-5-fluorocytidine derivative compound according to claim 7, wherein step VII is reacted at 0 ° C to 60 ° C.