JPS63275597A - Production of dideoxycytidine, intermediate therefore and production thereof - Google Patents

Abstract

NEW MATERIAL:A cytidine derivative expressed by formula I (R<1> is protecting group for the 5'-position of nucleoside; X is halogen). EXAMPLE:5'-O-t-Butyldimethylsilyl-2'-deoxycytidine. USE:A propagation inhibitor or retroviruses, such as HIV (Human Immunodeficiency Virus), which is a cause for AIDS (Acquired Immunodeficiency Syndrome). PREPARATION:A cytidine derivative expressed by formula II (R<2> is alkanesulfonyl or arenesulfonyl) is reacted with a metallic halide.

Description

DETAILED DESCRIPTION OF THE INVENTION The invention is directed to antiviral agents, such as acquired immunodeficiency syndrome (
2' and 3, which are expected to be used as various medicines such as AIDS) therapeutic agents.
The present invention relates to a method for inexpensively and easily producing '-dideoxycytidine or its precursor, an intermediate for producing the same, and a method for producing the same.

BACKGROUND OF THE INVENTION The above 2/, 3/-dideoxycytidine has reverse transcriptase inhibitory activity and is effective against HIV (Humanl + nmunodef1), which is the cause of acquired immunodeficiency syndrome (AIDS).
It is expected to be a drug that suppresses the proliferation of retroviruses such as ci@ney Vlrus).

Conventionally, the production method involves deoxygenating the 2' or 3' position of nucleosides, but prior to the reaction, a protecting group is selectively introduced into the 4-position amino group or the 5'-position hydroxyl group. Must be 2' or 3
For example, (A) 2 is difficult to cause the 8N2 reaction at the '' position due to large steric hindrance, and the chemical instability of nucleosides makes it impossible to use extreme reaction conditions or reactants. After protecting the amino group at the 4-position of '-deoxycytidine with a 47zoyl group, mesyl groups were introduced into the hydroxyl groups at the 3' and 5' positions, and treatment with sodium hydroxide resulted in 3/, S
/-oxetane, and then converted to 27,3/-dideoxy-2'-cytidiene with potassium t-butoxide,
This was hydrolyzed using palladium-carbon, and 196
7, 32.817), (6) After protecting the amino group at the 4-position of cytidine with an acetyl group, it was converted into a 2',5'-di〇-acetyl-3'-turoheptad with acetyl bromide. , a method of hydrogenolyzing this using palladium-carbon and obtaining the desired product through deprotection (Chew, Pharm, Bull, 1974
#221128) (C) Protect the amine group at the 4-position of 2'-deoxycytidine with a penzoyl group and the hydroxyl group at the 5'-position with a p-methoxytrityl group, and then hydrogenate) IJium, carbon disulfide, and iodide Treatment with methyl to give a 3'-0-dentate compound, which is reduced with tributyltin hydride and then deprotected to obtain the desired product (Bioorg Khim, 1
(Refer to 983.9.52), (b) Uridine is led to 27.3/-dideoxyuridine by a chemical method, the hydroxyl group at the 5' position is protected with an acyl group, and the reaction is performed with IH-1,2,4-) lyazole. After converting the 4-triazolylpyrimidine derivative to a 4-triazolylpyrimidine derivative, this is treated with aqueous ammonia and then methanolic ammonia to obtain the desired product (J, M+ed, C
Hem, 1987.30°440) has been proposed.

Problems to be Solved by the Invention The above-mentioned methods that have been proposed so far have disadvantages such as a large number of steps, unsatisfactory yields, and the use of expensive reactants. Therefore, it is desired to develop a method for producing 2',3'-dideoxycytidine that is inexpensive, simple, and industrially advantageous.

Means for Solving the Problems The present inventor conducted intensive studies to develop a method for obtaining the desired product in a high yield in a short process using inexpensive and highly safe reactants, and as a result, the following cytidine derivatives were developed. We have discovered that the above-mentioned problems can be solved by using it as an intermediate for producing ρ, and based on this discovery, we have completed the present invention. This intermediate can be used, for example, as follows.

(Vl) [IV) (
III) (1) [:l)
(V) Note that R1 represents a protecting group for the da-position of the nucleoside, R2d represents methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, p-toluenesulfonyl, etc., and X represents a halodef atom such as an iodine atom or a bromine atom, respectively. .

According to the present invention, in order to produce 3'-dideoxycytidine (V), l-dideoxycytidine (CM) is used as a starting material, and only the hydroxyl group at the da-position is selectively protected while the amino group at the 4-position is left unprotected. 1, which is commonly used in the field of nucleic acid chemistry as
It is desirable to use a protective group for the hydroxyl group, such as 1-butyldimethylsilyl, trityl, methoxytrityl, dimethoxytrityl, etc.), and then in a basic solvent (such as pyridine, lutidine, collidine, etc.). 30
Alkanesulfonyl chloride, alkanesulfonic anhydride or 7V-chloride at room temperature (preferably -20°C)
7th is treated with *nyl (mt t, < t [methanesulfonyl chloride, trifluoromethanesulfonic anhydride, ethanesulfonyl chloride, [p-)luenesulfonyl, etc.] to selectively convert only the hydroxyl group at the 3' position to sulfonyl. and then a polar non-grotic solvent (e.g. acetone, methyl ethyl ketone, diethyl ketone, diethyl ketone, dibutyl ketone, acetonitrile, propionitrile, butyronitrile, dimethylformamide, dimethyl aptamide, etc.)
1 to 20 equivalents (preferably 5 equivalents) of halo r
Metal chloride or ammonium chloride (e.g. lithium iodide, sodium iodide, potassium iodide, ammonium iodide, tetratstylammonium iodide, lithium bromide, sodium bromide, potassium bromide, ammonium bromide) After coexistence with Na, 2-butylammonium bromide and heating under reflux to form the corresponding 3'-iodine compound, a catalyst such as 5- or 10% Noradium on carbon or radium-barium sulfate, or radium-calcium carbonate is added. The process involves reductive denologonization at room temperature and under a hydrogen stream at normal pressure, followed by removal of the 5'-protecting group to lead to the desired product.

Next, the present invention will be explained with reference to examples. In addition, the melting point (m
p) #'iMeasured using a model 510 melting point meter manufactured by Ki Corporation and is uncorrected. Infrared absorption spectrum (rIRJ
) used a JASCO Corporation fRIR-800 spectrometer. The ultraviolet absorption spectrum (hereinafter abbreviated as "UV") was measured using a U-3200m spectroscopic needle manufactured by Hitachi. 1
H nuclear magnetic resonance spectra (hereinafter abbreviated as r'HNMRJ) were measured using FX-400 (400 MHz) manufactured by JEOL Ltd. or EM-380 (90 MHz) manufactured by aVarian. Chemistry-/7 is (CI(,)4St (O
ppm) was used as an internal standard and expressed as a δ value. Mass spectrometry was performed using GX-300 manufactured by JEOL Ltd. Analytical silica gel thin J-chromatography (hereinafter abbreviated as "TLC") is manufactured by Merck & Co., Ltd. Key-W 60F2
, 4 pre-coated plates (thickness 0.25 tm) were coated with ethanol, p-anisaldehyde, concentrated sulfuric acid, and acetic acid.
After soaking in a 0:5:5:1 (volume ratio) mixture, color was developed on a hot plate. For column chromatography, Merck's Kiesel 6 was inactivated by adding 6 g (by weight) of water.
0 (70-230mesh) was used.

Example 2'-deoxycytidine hydrochloride (26.37 g, 100
dish net) and imidazole (21,2 g, 312 mmo
t-Butyldimethylsilyl chloride (15,
A solution of 67,9,104 mmol) in dry dimethylformamide (50 mg) was added and stirred at the same temperature for 3 hours. Water (200 d) was added to the reaction mixture and the temperature was gradually raised to room temperature. This was mixed with hexa/-ethyl acetate (1:1,250m
), the aqueous layer was poured into water (1.5 t) and cooled on ice. Remove the resulting scuttling and wash it with cold water and then with ether.
It was dried over phosphorus pentoxide under reduced pressure (50° C.) overnight.

(28,83,li+, 8l%) rnp'1OEy-
'1oq-D.

Production s'-o-t-butyldimethylsilyl-2'-deoxycytidine (5,129,15 mmo
Methanesulfonyl chloride (3,0911°27 mmol) was added to a solution of dry pyridine (120d) at -30°C.
was added and stirred at -20°C for 14 hours.

Water (3 iJ) was added to the reaction mixture, and the mixture was further stirred for 1 hour and gradually heated to room temperature. The gum-like material obtained by removing soot using a rotary evaporator at 30°C or lower was dissolved in chloroform (200m), washed with saturated sodium bicarbonate solution (1001d), then with saturated saline (SOgoX2), and then poured onto magnesium sulfate. Dry and shrink. The title compound was obtained by azeotroping the remaining pyridine with toluene-methanol (1:1, 50i1X3) (8.63.9,99.8
%). This was used in the next reaction without purification.

Product spectral data IR (KBr tablets) 3375.3200.1730.
1680.1620°1530, 1500.1480.
1420.1360.1290.1260°1180,
1130.1080.940.840.790.53C
krn.

'HNMR (CDCA,) Jo, 11 (s, 6H, 8
1(CH3)2), 0.90(m, 9H, 5l-t-
C4H,), 2.0-2.8(m, 2H,2H-2
'), 3.10(s,3H,CH35O2)t3
．． 90 (ms 2H, 2H-5'), 4.35 (m,
IHtH-4'), 5.18(me IH,H-3
'), 6.20 (dd, p6.8Hz, IH.

H-1') e 6.45 (d, Q7.5Hz,
IH, H-5), 7.15 (br, @, 2H
.

NH2) −7,85(d −L=7.5Hz −I
H-H-6).

5'-Q-t-butyldimethylsilyl-3'-0-methanesulfonyl-2'-deoxycytidine (1,269, 3,00 mn5 ol) prepared as described above was ground in a mortar in a solution of methyl ethyl ketone (20 aA). Sodium iodide (2,251, 15 rnmol) was added to make a homogeneous solution under ultrasonic irradiation, and the mixture was heated (100°C) and stirred. After refluxing for 12 hours, chloroform ( 10011Lt) was added and washed with saturated saline (8017).The aqueous layer was washed with chloroform (2
011j x 2), and the combined organic layers were dried over magnesium sulfate.

The residue (1,31N) obtained by concentration was used as it was in the next reaction.

Silica gel chromatography (M@OH-CHCts
-1:50-1:30) Spectral data of the title compound purified by: IR (KBr tablet) 3370.3200.1640.
1520.1490°1410.1360,1290,
1260.1200,1140,1120°1060,
1030.840.790.540cPR.

Ms(FD, m/*) 452 (M”+1
).

'HNMR (CDC2,) δ0.13 (easy, 6H,
5l(CH,)2), 0.92(@,9H,5i-t-
C4H,)j2.4-2.9(m, 2H#2H-2')
13.95 (rn, 2H12H-5'), 4.1-4.
3 (rn12H, H-4', H-3'), 5.82 (d
, LA8. OHz -I H, H-5) e 6.0
3 (m -I H* H-1'), 7.20 (b
rl, 2H, NH2), 7.90 (d, J=8.0
Hz, IH, H-6).

s'-o-t-butyldimethylsilyl-3'-iodo-2/,3/-nobuoxy-1-β-D-xylofuranosylcytosine (1,31 Jl, about 3 mmol, crude product obtained in the previous step) material), lO% no arm carbon (25
0■), triethylamine (1#) and ethanol (
The mixture of 50 m) was stirred vigorously at 30° C. for 1 hour under a hydrogen atmosphere at normal pressure. The reaction mixture was passed through an upper tube 545, the catalyst was removed from P, and the 9F solution was concentrated. The residue was soaked in chloroform (looy) and saturated sodium bicarbonate solution (50dX2)
and dried over magnesium sulfate. The residue obtained by concentration (0.93i>t) was used in the next reaction.

The title compound was subjected to chromatography on silica gel (deactivated by adding triethylamine) and eluted with methanol and chloroform (1:30-1.15).
Kutle Data IR (KBr Tablets) 3270.3130.1670.
1620.1530°1490, 1410.1280.
1260.1100.11080cPR-@ (FD,
Melon/See) 325 (M”).

'HNMR(CDC1,)a O,10(s, 6H,
5i(CH3)2), o, 9°(@, 9H, 8l-t
-C4H,), 1.8-2.6(m, 4H, 2H-2
'e2H-3') 13.70 (dd, Q3 t 1
1Hz e IH, H-5'), 3.9-4.2(
rat 2H,H-5'.

H-4''), 5.67(d, p7.5Hs,
IHtH-5>, 6.00 (dd, ?2, 7H
z, IH, H-1') t 6.65 (br s
, 2H, NH3), 7.97 (d, L=7.
5Hz * I H, H-6).

Preparation of H2'e 3'-Did@oxyeytidin@ s'-o-t-butyldimethylsilyl 2/,3/-dideoxycytidine (0,93N) prepared as described above.

Approximately 3 mmol) of dry tetrahydrofuran (20 mmol
) Add 1M tetrabutylammonium fluoride tetrahydro 7 run bath I11.) to the solution. (3,3ysl, 3.3
r+unot) and stirred at 20°C for 20 minutes. The syrupy substance obtained by concentration was soaked in distilled water (50 ml) and washed with ether (501114X3). The aqueous layer was concentrated and the residue was subjected to Avicel (30JI) column chromatography (
3X 2051) K 86 of n-butanol and water
:14 mixture to give the title compound (458R9, 72%
) was obtained.

IR (KBr tablet) 3400.3220.3200.
1650.1620°1530* 1500- 14
10* 1290* 1180- 1100t
1070 Crlt-'.

Ms (FD, S’g) 211 (fly).

'HNMR (D20) δ1.8-2.6 (m, 4
H, 2H-2', 2H-3').

3.85 (rn, 2H* 2H-5')-4,25
(m -IHt H-4') t 5,9-6.1 (
m-2H=H-5? H-1') *7.92
(d-J; 7.5Hz-IH-H-6).

Effects of the Invention As is clear from the above, according to the present invention, by using 2'-dideoxycytidine as a starting material, pharmaceuticals such as 2/, 3/-dideoxycytidine, which is an antiviral agent, can be produced inexpensively, extremely easily, and in high yields. The present invention is useful in the pharmaceutical industry.

Claims (5)

[Claims] (1) Cytidine derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [I]. However, in the formula, R^1 represents a protecting group for the 5' position of the nucleoside, and X represents a halogen atom. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A general formula characterized by subjecting the cytidine derivative represented by [I] to a reductive dehalogenation reaction ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ II] A method for producing a cytidine derivative. However, during the ceremony,
R^1 represents a protecting group for the 5' position of the nucleoside, and X represents a halogen atom. (3) The manufacturing method according to claim 2, wherein the protective group at the 5' position is removed by a reductive dehalogenation reaction and then a deprotection reaction. (4) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [III] A general formula characterized by reacting the cytidine derivative represented by the formula with a metal halide ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] A method for producing a cytidine derivative represented by However, during the ceremony,
R^1 is a protecting group for the 5' position of the nucleoside, R^2 is an alkanesulfonyl group or an arenesulfonyl group,
Each X represents a halogen atom. (5) The cytidine derivative represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [III] is derived from the cytidine derivative represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IV] A manufacturing method according to claim 4. However, in the formula, R
^1 represents a protecting group for the 5' position of the nucleoside.