JPS60252493A - Preparation of cytidine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound which is an important synthetic intermediate for citicoline (cytidine diphosphocholine) useful as a medicine industrially and advantageously in high yield, by condensing a specific cytosine derivative with a specific saccharide derivative in the presence of a Lewis acid. CONSTITUTION:A compound expressed by formula I (R<1> is acyl derived from >=3C carboxylic acid), e.g. N<4>-butyrylcytosine, is condensed with a compound expressed by formula II (X is halogen; R<2>-R<4> are acyl derived from carboxylic acid) in the presence of a Lewis acid, preferably a metal halide, e.g. tin tetrachloride, in a halogenated hydrocarbon solvent, preferably dichloromethane at room temperature -100 deg.C for 1-30hr to give the aimed compound expressed by formula III. The compound expressed by formula II is preferably a compound in which R<2>-R<4> are acetyl and X is Br, e.g. 2,3,5-tri-O-acetylribofuranosyl bromide.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel method for producing cytidine derivatives useful as synthetic intermediates for pharmaceuticals.

Conventional technology: Cytidine is a type of cytidine that is currently used as a medicine.
It is an important compound as a raw material for the synthesis of choline diphosphate (generic name: nticoline).

Conventionally, there are many known methods for synthesizing pyrimidine nucleosides such as cytidine by condensation reactions between pyrimidine and Kinuta, but the most commonly used method is to synthesize pyrimidine nucleosides such as cytidine by condensation reactions with pyrimidine and Kinuta. This method involves the condensation of sugars [Japanese Patent Publication No. 52-955]. However, in this method, the silyl group in the pyrimidine is easily hydrolyzed with water and is sensitive to moisture, and when an acetyl/l' group is used as a sugar protecting group, 2 ', 3' + 5') U
Since O'-acetylcytidine is soluble in water, the extraction rate into the organic layer becomes low in the post-treatment after the reaction, which is not satisfactory.

Problems to be Solved by the Invention The present invention provides an industrially advantageous process for producing cytidine derivatives that overcomes the drawbacks of the prior art described above.

Means for Solving the Problems The present invention provides a compound represented by the formula [wherein R1 represents an acyp group derived from a ponic acid having 3 or more carbon atoms] and a compound represented by the formula [wherein, X represents a halogen, R2, R3 and R4 represent a Vμ group derived from a ponic acid]! This is a method for producing a compound represented by [in the formula, each symbol has the same meaning as above], which involves condensation in the presence of canic acid.

The carboxylic acid-derived acyl group having 3 or more carbon atoms as R1 in the above formulas (I) and (I[) may be aliphatic or aromatic, linear or branched, such as globiony, Butyryl/L/, Isogutyryl, Hegisanoyl/L/, 2-ethylhexanoyl, Octanoyl,
Decanoy/l/, Valmitoil.

Alkanoyl having 3 to 16 carbon atoms, particularly 4 to 8 carbon atoms, and Bency ρ are preferred.

The halogen in formula (I[) may be any of fluorine, chlorine, bromine, iodine, etc., and chlorine and bromine are particularly preferred. Also, R2, R3 and R
The force μ as 4 is an acid-derived acid p group with a carbon number of 2
Among the alkanoylneu μ of about 6 to 6, acetyp is preferred.

The condensation reaction between compound (1) and compound (n) is carried out in a solvent in the presence of ρ isic acid. It is usually advantageous to use 1 to 1.27 p of (II) per mole of (1). - As the canic acid, metal halides such as tin tetrachloride, titanium tetrachloride, antimony pentachloride, aluminum chloride, ferric chloride, zinc chloride, diμconium tetrachloride, and P-toμesis/lephonic acid.

Preferred are nonurphonic acid derivatives such as trifluoromethanesulfonic acid-trimethylphosiliester ρ. As a solvent, dichloromethane, 1.
2-dichloroethane, chloroform, 1,2-dichloropropane, I,? , 2°2-tetrachloroethane and other halogenated hydrocarbons are preferred. Reaction conditions are room temperature to 1
00°C for about 1 to 30 hours is preferable.

The cytidine derivative (II[) thus produced can be isolated from the reaction solution by conventional means such as solvent extraction and chromatography.

Of the cytidine derivatives (N) thus obtained, R', R
2.This is a new compound that has not been described in any literature except when R3 and R4 are all benzoyl.Since the compound is water-insoluble, it can be extracted quantitatively with an organic solvent, making it extremely easy to purify. It has characteristics.

Cytidine derivatives (III) obtained by the method of the present invention
) is a known hydrolysis method using acali [for example, "
79, 506 ON (1957)] or a similar method thereto. In this case, the compound (II) does not need to be purified, and it is convenient to subject the crude product to the reaction.

Compound (I) used as a raw material in the method of the present invention
) can be easily produced, for example, by the method described in "Research μ Opza Chemical Society, 1956, p. 2384" or a method analogous thereto.

Compound (n) is, for example, “Nucleic Ands”.
Research, Vol. 3, pp. 1387-1399 (1976
The method described in ``Research Op the American Chemical Society'', Vol. 79, 50.
60 (195γ) or a method analogous thereto.

EXAMPLES The present invention will be explained in more detail by Examples and Reference Examples below, but these are not intended to limit the present invention.

Example 1 5.66 ft of dried guanosine was suspended in 30 ml of acetic acid, 25 ft of acetyl bromide was added, and the mixture was stirred at room temperature for 16 hours. The precipitate was removed in an oven, and the p solution was dried under reduced pressure at a bath temperature of 50°C or less. The residue was dissolved in 50 yl of toluene and dried under reduced pressure to obtain 2,3.5-)di-0-acetyl lipofonone lupromide as a light brown candy-like substance. 1 crystal,
It was dissolved in 200 ml of 2-dichloroethane, 2.9 f of N-butyryrho cytosine and then 2 ml of tin tetrachloride were added and stirred at 50°C for 13 hours. The reaction solution was washed three times with ice water 2001, and the organic M was dried under reduced pressure to obtain H4-butylene μm2'.
, 3', 5'-)so0-acetiμcytidine was obtained as a light brown candy-like substance. Yield: 10f0 This product is converted into methanol.
/l' 50 tptl, dissolved in sodium hydroxide 3
．． Add 10g1 of an aqueous solution of 311 and heat at 50°C.

Stir for 2 hours. The reaction solution was dried under reduced pressure, and INN was added to the residue.
Hydrochloric acid 1 note 0 It was adsorbed on rum. After washing the column with water, add concentrated ammonia water 2
The eluate was eluted with 5096 ethanol containing 96, and the eluate was dried under reduced pressure. The residue was dissolved in water, passed through a column of DOWEX-1 (trade name, Dow Chemical Company product, OH type) IO*J, and washed with water. Combine the passing liquid and washing liquid and dry under reduced pressure.
When 20w1'ft of methanol was added to the residue, it once dissolved, and then 2.4g of colorless needle crystals of ntidine were precipitated. Melting point +
2 1 9 -220°C redundancy analysis value: C9 H1
3N3, 05 as C (J5) H (%) N (%) Calculated value 44.44 5.39 17.28 Actual value 4
4.58 5.41 +7.05 Example 2 2.3.5-)so0-acetyllipopnosy μpromide prepared from 710 M'l of guanosine and l(4-isobutylpropylene) Luciton 362■ and 1-
1, Dissolved in 25 ml of 2-dichloroethane, added 0.3 tttl of tin tetrachloride, and stirred at 50"C for 3 hours. The reaction solution was washed three times with 25 rsl of ice water, and the organic layer was dried under reduced pressure. /20g column and eluted with chloroform containing 1% methano-/I/1%.The main fraction was dried under reduced pressure to give N-isobutylene/I'-2'.
．． 3'. 5'-)So-0-acetylcytidine was obtained as a colorless syrupy substance. Yield 6404.

Elemental analysis value: C (%) as C engineering 9H25N3 o9
H (%) N (%) Calculated value 51.93 5.73 9.56 Actual value 5L
57 5.46 9.23 Example 3 Prepared according to Example 1 from 710 g of guanosine. .2ml and 25g of 1,2-dichloroethane? The mixture was stirred at room temperature for 24 hours. After the reaction solution was treated according to Example 2, the obtained product was recrystallized with ethanol-μ5at to obtain H4-octanoyl m1. t. 700q of colorless needle-like crystals of 5'-tri-acetylcytidine were obtained. Melting point: 139-140℃ Elemental analysis value "23" C (%) as 33N3 09
H (%) N (*) Calculated value 55.75 6.71 8.48 Actual value 55
．． 89 6.87 8.19 Example 4 Prepared from guanosine r1ayny according to Example 1 L7
'c2,3,5-)so0-acetylribofuranone p-glomide and H4-(2-ethylhexanoyl/I/)
V) Dissolve Syn 474η in 25 m of 1,2-dichloroethane, add 0.2 yt of titanium tetrachloride, and make 50"0.3
I stirred the time. 25 tll of ice water was added to the reaction solution, the mixture was shaken, and the precipitated gel was removed using gold celite. After washing the organic layer with water, it was dried under reduced pressure, and the residue was
It was adsorbed onto a column of f and eluted with chloroform containing methanol/L'+96'.

The main fraction was dried under reduced pressure and N'-(2-ethylphexanoyl
)-g, 3', 5'-) ley O-acetyptinthidine was obtained as a colorless candy-like substance. Yield 54011f Elemental analysis value “23” 33H309 as C(*) H(%) N(
%) Calculated value 55,75 6.71 8.48 Actual value 55
．． 88 6.89 8.26 Example 5 H4 was produced from guanosine 710q according to Example 1.
, 3.5-tri〇-acetyl ρ ribofrudge µ promide, - 〇 〇 〇 - 〇 〇 - 〇 〇cytosine 〇 osy, antimony pentachloride 0.2 C and chloromethane 40 g J for 6 hours. The reaction solution was treated according to Example 4, and H4-
Bapmitoys'-1+3',5'-)so0-acetylcytidine was obtained as a colorless candy-like substance. Yield 4501
1v Elemental analysis value: C (%) as C31H49M309
H (%) H (%) Calculation a 61.26 B, 13 6.91 Actual value 61
．． 03 8.34 6.67 Example 6 Guanosine 71 (from IF to jillm according to Example 1)
2,3.5-1-so0-acety~LibovufnoVf
i/promide and H4-penceyμctocin 430 cuttotrifluoromethaneμphonic acid-trimethytyl Vsuester N0.45ml and 1,2-dichloropropane 25v
The mixture was stirred for 5 hours at 50° C.

The reaction solution was treated according to Example 2, and 1q-Henzoi/
L'-2', 3', 5'-) ly O-acetiμcytidine was obtained as a colorless candy-like substance. Yield 5609 Elemental analysis value “22H23N3 o, as C(H6) H(9
6) N (96) Calculated value 55.81 4,90 8.88 Actual value 55
．． 57 4.62 8.62 Example 7 Ether 30txe was saturated with hydrogen chloride? The mixture was left in the refrigerator for 4 days.The reaction solution was completely dried under reduced pressure, and the residue was poured into a refrigerator.
Dissolve in 20 ml of ene and dry under reduced pressure at a bath temperature of 50°C or less.
2,3.5-) Lio-pency plipo7lanosyρ chloride was obtained as a colorless candy-like substance. Dissolve the crystal in 50 g of 1,2-dichloroethane, add 500 ml of H4-gropioni IvV tocin and 0.5 Mζ of tin tetrachloride to 50 g.
℃.

Stirred for 5 hours. The reaction solution was diluted with ice water at 10°C.
! 1 wash, and the organic layer was dried under reduced pressure. Remove the residue with silica μ3
It was adsorbed onto a 0F column and eluted with chloroform. Main molecule [! ! I was dried under reduced pressure to obtain H4-globioni ρ-2'
, 450q of white powder of 3',5'-tri0-bencyiμcytidine was obtained.

Elemental analysis value “33”29N309 (CC96)
HC%) HCl2) Calculated value 64.8+ 4.78 6.87 Actual value 64
．． 99 4,95 6.59 Reference Example I V galvanized iron 2fk pyridine 1000d and propionic anhydride 4
．． The mixture was refluxed for 14 hours in a mixture with 699. Precipitation after cooling?
Take the furnace, methanol! The mixture was washed with water and dried to obtain 2.84F white powder of N-propionylcytosine. Melting point 32B-
338°C (decomposition) elemental analysis value: C(96) H(96) N (%) as C7H0N302 Calculated value 50.30 5.43 25.14 Expected value 5
0.42 5.48 25.03 Reference Example 2 Cytosine 2y and pyridine 100r? and 1' Rakuic anhydride5.
In a mixed solution with 7g, it lasted for 19 hours. After cooling, the precipitate was collected by filtration and washed with methanol to obtain 2.8 grams of white powder of N4-butyrintocone. Melting point 329-334'C Elemental analysis value "8" C (%) as 1lN3 o2 ■
(%) N (96) Calculated value 53.03 6.12 23.19 Actual value 5
2.91 6.0+ 23.198 Example 3 10 Oyl of cytosine 21-pyridine and isoacetic anhydride 5.
71 for 2 hours. When the reaction solution was concentrated under reduced pressure, 3.2 g of colorless plate-like crystals of N4-isobutyrylreitothane were precipitated. Melting point 315-320°C (decomposition) Elemental analysis value: 08H, C(96) H as N302
(%) kHz96') Calculated value 53.03 6.12 23.19 Expected value 5
3.25 6.22 2319 Reference Example 4 Cytosine 5.55F, 2-ethyρhexanoylμ chloride 10vtl and total viridis: / in 250 ml, γ0°C
Stirred for 91 hours. The reaction solution was dried under reduced pressure, and the residue was washed with water and then recrystallized from Megno) v100*t to give N4-(2
-ethylhexanoyl) V tosine tm was obtained as colored needle crystals. 8.496 Melting point: 2SO-263℃ Elemental analysis value: C (96) as Cl2H engineering 9'302
I((%>X<96> Calculated value 60.74 8.07 17.71 Actual value 6
0.84 8.04 +7.838 Example 5 Tocin 2.22fk pyridine 100g? and capri)v
v It was refluxed at rKJ for 2 hours in a mixture with chloride 5f.

After cooling, the precipitate was collected by filtration and washed with methanol to obtain 3.56 fk of white powder of N4-octanoylcytosine. Melting point 295
-300″C (decomposition) elemental analysis value” 12H19”30
2 as C (%') U (96) N (3) Calculated value 60.74 8.07 17.71 Actual value 6
0.73 7.99 17.64 was refluxed for 1 hour in a mixture of Example 6 tocin 5.551-pyridine 25 (ly? and palmitoy! chloride 41.25f. After cooling, the precipitate was collected by filtration, and methanol Washing with water gave 17.51! of pale yellow powder of N4-palmitoylntocin.

Melting point 288-29 BiC (decomposition) elemental analysis value 'C20''
As 35”3o2, C(*) a(96)!(th) Calculated value 68.73 10.09 12.02 Actual value
69.22 10.18 11.02 Effects of the Invention According to the present invention, compound (I) and compound (II), which are stable against moisture and easy to handle, are condensed in the presence of a Lewis acid. C, desired cytidine derivative <m>
*Can be obtained with a yield.

Furthermore, the method of the present invention is industrially advantageous in that it does not use mercury salts or the like.

k, h +1- Furthermore, in the method of the present invention, +≠1, R2, R3, and R are required ÷φ! When compound (II) is used, the objective compound (I[) is water-insoluble and can be extracted quantitatively with an organic solvent, so it has the advantage of being extremely easy to purify.

Claims (1)

[Scope of Claims] A compound represented by the formula [wherein R1 represents an acid μ group derived from a ponic acid having 3 or more carbon atoms] and a compound represented by the formula [wherein, 〃Ponic acid-derived a V/I/
A method for producing a compound represented by the formula [in the formula, each symbol has the same meaning as above], which is characterized by condensing the compound represented by the following formula with the following group in the presence of 1-μ isic acid.