JPS5927359B2 - Production method of cytidine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides O2,2'-anhydro-1-(3',5'-
The present invention relates to a new method for producing di-O-acyl-β-D-arabinofuranosyl)cytosine salts.

All of the above target compounds of the present invention are antileukemia agents.

It is a pharmaceutical compound useful as an antitumor agent. Conventionally, O2,
A method for synthesizing 2'-anhydro-1-(3',5'-di-O-acyl-β-D-arabinofuranosyl)cytosine salts is, for example, a method in which cytidine is reacted with a fatty acid halide [Chemical & Pharmaceutical Journal, Volume 22, Page 128 (1974)]
, O2, 2'-anhydro 1-(3'|5'-di-O-acetyl) obtained by reacting 2'-anhydro(β-D-arabinofuranosyl)cytosine with acetic anhydride and bromine Method for catalytic reduction of β-D-arabinofuranosyl-5-bromocytosine [Journal of
Meditinal Chemistry, Volume 15, Page 1218 (1
972)], ← O2, 2'-anhydro 1-(3'-0-acyl-β-D-arabinofuranosyl)cytosine obtained by reacting cytidine with α-acyloxyacyl halide, is converted into acyl halide. A method of further acylating with (JP-A-49-132084) is known.

However, among these methods, method (2) allows synthesis of the target compound from cytidine in one step, but the yield is low. In addition, the methods of the same and (No) require a step of synthesizing the starting compound O",2'-anhydro-1-(β-D-arabinofuranosyl)cytosine or its 3'-0-acyl derivative, The reaction operations are also complicated, and none of the above methods is satisfactory as an industrial method for producing the target compound.As a result of various studies, the present inventors have found that cytidine and organic acid By reacting the anhydride with boron trifluoride in the presence of boron trifluoride, the desired O2,2'-
Anhydro 1-(3'|5'-G-O-acyl-β
It has been found that -D-arabinofuranosyl)cytosine salts can be synthesized with good yield.

According to the present invention, the O2,2'-anhydro-1-(3',5'-di-0-acyl-β-D-arabinofuranosyl)cytosine salts of the target compound combine cytidine and an organic acid anhydride. It can be synthesized by reacting in the presence of boron fluoride.

In the present invention, the reaction between cytidine and an organic acid anhydride is preferably carried out in the presence of boron trifluoride in a suitable solvent. Examples of the organic acid anhydride serving as one of the raw materials include acetic acid, propionic acid, pivalic acid, stearic acid,
Acid anhydrides of saturated aliphatic linear to branched carboxylic acids having 2 to 30 carbon atoms such as palmitic acid and lignoceric acid; acid anhydrides of aryl group-substituted aliphatic carboxylic acids such as phenyl acetic acid and phenyl butyric acid; , acid anhydrides of aromatic carboxylic acids such as benzoic acid, α-naphthoic acid, β-naphthoic acid,
Acid anhydrides of aryl group-substituted or unsubstituted aliphatic carboxylic acids such as crotonic acid, acrylic acid, methacrylic acid, cinnamic acid, cyclopropanecarboxylic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid, adamantane-1-carboxylic acid Suitable examples include acid anhydrides of isoalicyclic carboxylic acids, and any of these reacts with cytidine to yield the corresponding target compound. The boron trifluoride present in this reaction system can be used either by itself or as a complex of boron trifluoride with ether, acetonitrile, etc., and complexes of boron trifluoride and ether are particularly preferred. Boron trifluoride or its complex is preferably present in an amount of about 1 to 10 moles, particularly about 3 moles, per mole of cytidine. The reaction is carried out at 0 to 150°C, especially 80 to 100°C.
The reaction proceeds suitably at around 0.degree. C., and as the reaction solvent, for example, acetic acid, acetonitrile, dioxane, etc. can be used as appropriate. The thus generated 02,27-anhtrow 1-(3',
5'-di-10-acyl-β-D-arabinofuranosyl)
Cytosine salts can be easily isolated, for example, by using a residue obtained by distilling off the solvent from the reaction-completed solution by known purification operations such as washing with an appropriate solvent and recrystallization.

Example 1 Cytidine 59 was suspended in acetonitrile 150a, and boron trifluoride/ether complex 7.8m was suspended in it.
Add 1.

While stirring and refluxing, 50 ml of acetonitrile solution containing 6.31 ml of acetic anhydride was added dropwise over 10 minutes. After dripping 5
Reflux for a minute and remove the solvent under reduced pressure. Add 200 d of ether to the resulting residue to crystallize it, and take it by mouth. By washing the crystals with isopropanol and recrystallizing them from ethanol, 02,2/-anhydro1-(3
',51-di-10-acetyl-β-D arabinofuranosyl)cytosine HBF4 salt 5.79% is obtained. Yield 70%
. Dissolve 2.09 of this product in 10ml of water, and use Diaion S.
Connect to a column filled with 50 ml of A-11B (C type).

After washing this column with 100 ml of water, the flow-through and washing liquid were combined and concentrated under reduced pressure to obtain
1.69% of D-arabinofuranosyl)cytosine hydrochloride is obtained. Yield 92%o Example 2 4.09 ml of cytidine was suspended in 120 ml of acetonitrile, and 6.2 ml of boron trifluoride/ether complex was suspended.
Add 1.

While stirring and refluxing, a solution of 40TfL1 acetonitrile containing 9.2f1 pivalic anhydride was added dropwise over 5 minutes. After the dropwise addition, the mixture was refluxed for 5 minutes, and then the solvent was distilled off under reduced pressure. The resulting residue was crystallized with 50 ml of ether and taken by mouth to give 02,2/-Anchtrow 1-(3/,
5/-di-10pivaloyl-β-D-arabinofuranosyl)cytosine HBF4 salt 7.09 is obtained. Yield 88%.
Example 3 1.09 cytidine to 15 ml of acetonitrile
Suspend in water and add 1.56 ml of boron trifluoride/ether complex.

While stirring and refluxing, a solution of 10 ml of acetonitrile containing 2.89 g of benzoic anhydride was added dropwise over 10 minutes. After the dropwise addition, the mixture was refluxed for 5 minutes, and then the solvent was distilled off under reduced pressure.

The resulting residue is crystallized by adding a small amount of ether and ethanol, and taken by mouth to obtain 02,2'-anthro-1-(3/,51-di-10-benzoyl-β-D-arabinofuranosino). (c) Cytosine/HBF4 salt 1.79
get. Yield: 79% Examples 4 to 12 Compounds shown in Table 1 below can be synthesized by reacting in accordance with Examples 1 to 3.

Claims (1)

[Claims] 1 O^2,2'-anhydro-1-(3',5'-di-O-acyl-β-), which is characterized by reacting cytidine and an organic acid anhydride in the presence of boron trifluoride. Method for producing D-arabinofuranosyl) cytosine salts.