JPH0692988A - Method for synthesizing 2,2'-anhydroarabinosylthymine derivative - Google Patents

Abstract

PURPOSE:To obtain a compound simply and in high yield useful as an antiviral agent by reacting a specific arabinoaminooxazoline with an alpha- bromomethylacrylic ester and subjecting the reaction product to ring closure reaction with potassium t-butoxide. CONSTITUTION:Arabinoaminooxazoline of formula I is reacted with an alpha- bromomethylacrylic acid of formula II (R is methyl or ethyl) to give an adduct of arabinoaminooxazoline-alpha-bromomethylacrylic ester of formula III and then the adduct is subjected to ring closure with potassium t-butoxide to give 2,2'- anhydroarabinosylthymine of formula TV and arabinosylthymine of formula V or the adduct of formula III is subjected to ring closure with sodium methoxide to give 2,2'-anhydro-5,6-dihydrouridine of formula VI, from which a 2,2'-anhydroarabinosylthymine derivative useful as an antiviral agent is obtained in high yield.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for synthesizing a 2,2'-anhydroarabinosylthymine derivative useful as an antiviral agent or a synthetic intermediate thereof.

[0002]

2. Description of the Related Art Many thymine-based nucleoside derivatives have an antiviral action like arabinosylthymine, and some have been put to practical use as an antiviral agent (for example, a therapeutic agent for AIDS) like azidothymidine. is there.
Most of these thymine-based nucleoside derivatives are synthesized by a chemical synthesis method, except for thymidine which is a component of DNA.

As a method for synthesizing a thymine-based pyridine nucleoside derivative, a method by a condensation reaction between thymine and a saccharide derivative such as ribose, arabinose or deoxyribose has been known. However, in this method, the reaction step becomes long and the selectivity of the reaction is often low,
There is a drawback that the yield of the desired product is low.

There is also a method in which uridine or thymidine obtained from nature is used as a starting material and chemical exchange is carried out to synthesize a desired thymine-based nucleoside derivative. But,
In these chemical exchange methods, the starting material uridine or thymidine is expensive and the production cost is high.

On the other hand, after arabinoaminooxazoline is synthesized from arabinose and cyanamide, it is reacted with an acetylene derivative such as cyanoacetylene,
A method of synthesizing 2,2'-anhydrocytidine, arabinosylcytidine or 2,2'-anhydrouridine which is an anticancer agent has been reported [Robert A. Robert A. Sanchez et al., Journal of
Molecular Biology (J. Mol. Biol.), 4
7 , 531-543 (1970); Journal of Organic Chemistry (J. Org. Chem.), 38 ,.
593 (1973)]. However, in this method, since an acetylene derivative is used, it is impossible to synthesize a 5-position-substituted pyridine nucleoside derivative such as a thymine derivative.

Therefore, recently, a method of reacting arabinoaminooxazoline with β-methylmethylmethacrylate in the presence of triethylamine-diethylaminopyridine to synthesize a thymidine derivative (see Japanese Patent Laid-Open No. 2-59598), or arabiamine After protecting the hydroxyl group of nonaminooxazoline with an organosilicon compound such as a t-butyldimethylsilyl group, it is reacted with methyl methacrylate and the resulting adduct is dehydrogenated with dichlorodicyanoquinone to produce a thymine derivative. Has been published (see US Pat. No. 5,077,403).

[0007]

However, the above-mentioned method for synthesizing a thymidine derivative or a thymine derivative requires a long reaction time and a low yield, or requires protection of a hydroxyl group of arabinoaminooxazoline and a special dehydrogenating agent. It has drawbacks such as

The inventors of the present invention have conducted extensive studies in view of the above circumstances, and as a result, have found a method for synthesizing a thymine-based nucleoside derivative from arabinoaminooxazoline obtained from arabinose and cyanamide in a high yield with a simple operation without using a protecting group. I came up with the idea and completed the present invention.

[0009]

That is, 2,2 'of the present invention
-A synthetic method of anhydroarabinosyl thymine derivative is represented by the following formula IV:

[Chemical 9] The arabinoaminooxazoline represented by the following formula V:

[Chemical 10] [Wherein R represents a methyl group or an ethyl group] and is reacted with an α-bromomethylacrylic acid ester to give the following formula VI:

[Chemical 11] An arabinoaminooxazoline-α-bromomethylacrylic acid ester adduct represented by the formula: wherein R represents a methyl group or an ethyl group is obtained, and then the adduct is closed with potassium t-butoxide to give Formula I:

[Chemical 12] 2,2'-anhydroarabinosyl thymine represented by the following formula III:

[Chemical 13] Arabinosyl thymine represented by the following formula II or by cyclizing the adduct with sodium methoxide.

[Chemical 14] 2,2'-anhydro-5,6-dihydrouridine represented by

In the compounds represented by the above formulas, an arabinoaminooxazoline-α-bromomethylacrylic acid ester adduct represented by the formula VI and 2,2'-anhydro-5,6-dihydrouridine represented by the formula II. All other compounds are known, and, for example, JP-A-2-
59598, United States Patent No. 507740.
No. 3, specification, JP-A-3-86897, chemicals
Abstracts (Chemical abstracts), 113 , 19
90; 113: 41229b, C-SELECTS: CARBOHYDRATES (Chemical Aspects) [CA Selec
ts: Carbohydrates (Chemical Aspects)], another edition (Issue
) 11, 1992, p. 18, 116: 194801.
u.

The arabinoaminooxazoline represented by the formula IV and the α-bromomethylacrylic ester represented by the formula V, which are the starting materials, can be synthesized by known methods.

The arabinoaminooxazoline-α-bromomethylacrylic acid ester adduct represented by the formula VI obtained as a result of the above reaction is a novel compound. Therefore, the present invention also relates to an arabinoaminooxazoline-α-bromomethylacrylic acid ester adduct represented by the formula VI [wherein R represents a methyl group or an ethyl group].

The adduct of formula VI and potassium t-
The reaction with butoxide or sodium methoxide can be carried out in a polar solvent such as t-butanol or methanol. Reaction conditions such as reaction temperature, reaction time, stirring state during reaction, reaction atmosphere, etc. are appropriately selected.

The adduct of formula VI is potassium t-
When the ring is closed with butoxide, the desired 2,2'-anhydroarabinosylthymine of formula I and arabinosylthymine of formula III as well as the adduct of formula VI as a by-product are obtained. Of the following formula VII in which the ester group moiety of

[Chemical 15] The compound represented by is produced in a considerable amount. Therefore, the reaction mixture may be separated and purified by an appropriate and appropriate separation / purification means such as column chromatography to obtain the desired substance.

The 2,2'-anhydroarabinosylthymine represented by the formula I can be converted to the arabinosylthymine represented by the formula III by hydrolysis (eg, treatment with aqueous ammonia).

On the other hand, when the adduct represented by the formula VI is cyclized with sodium methoxide, the desired formula II is obtained.
2,2'-anhydro-5,6-dihydrouridine represented by can be obtained. In this case as well, the target substance may be obtained by using the conventional appropriate separation / purification means. 2,2'-anhydro-5 represented by formula II
6-dihydrouridine is a novel compound. Therefore, the present invention further relates to 2,2'-anhydro-
It relates to 5,6-dihydrouridine.

The target substance can be confirmed by conventional analysis / identification means such as melting point measurement, IR, UV, NMR, and mass spectral analysis.

[0018]

The desired 2,2'-anhydroarabinosylthymine derivative can be obtained easily and in high yield by cyclizing the adduct represented by the formula VI with potassium t-butoxide or sodium methoxide. To be

[0019]

The present invention will be described in more detail with reference to the following examples.

I. Synthesis of starting materials I-1. Arabinoaminooxazoline (represented by Formula IV
The compound was added to the conventional synthetic method to improve the yield. The present synthesis method will be described below.

A mixture of 3.07 g of D-arabinose, 1.01 g of cyanamide and 0.13 g of potassium carbonate was added to 20 ml of dimethylformamide at 50 ° C. for 18 hours.
The mixture was heated and stirred for an hour. The reaction mixture was cooled to room temperature, 12 ml of ethyl acetate was slowly added dropwise to the reaction solution, and the mixture was allowed to stand for 1 hour and then at 4 ° C. for 1 hour. The generated crystals were separated by filtration, washed with ethyl acetate and then with diethyl ether, and dried under reduced pressure to obtain 3.43 g (yield 96%) of arabinoaminooxazoline as white crystals. Melting point: 170-171 ° C.

I-2. α-Bromomethylacrylic acid S
Synthesis of ter (compound represented by formula V) was synthesized by the following method or.

Combination of ethyl α-bromomethyl acrylate
Forming paraformaldehyde 32.0 g, water 73ml and 1N
After stirring a mixed solution containing 3 ml of phosphoric acid at 90 ° C. for 1 hour, 59.9 g of diethyl phosphorous oxyacetate was added to the aldehyde aqueous solution prepared by cooling to room temperature. While maintaining the solution at 35-40 ° C in a water bath, potassium carbonate 40.2
An aqueous solution prepared by dissolving g in 40 ml of water was slowly added dropwise.
After reacting at 40 ° C. for 10 minutes, the mixture was cooled in an ice bath, extracted with diethyl ether, and the organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution. Then, the organic phase was dried using anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain an oily crude product of α-hydroxymethyl acrylate. Next, this ethyl α-hydroxymethylacrylate crude product was dissolved in 300 ml of diethyl ether, cooled to −10 ° C. in an ice-salt bath, and 57 g of phosphorus tribromide was slowly added dropwise while stirring. After completion of dropping, -10
The reaction was carried out at 30 ° C. for 30 minutes and then at room temperature for 2.5 hours with stirring. Water was added to the reaction mixture while cooling with ice to stop the reaction, and then the product was extracted with n-hexane, and the organic phase was washed with saturated brine. After drying the organic phase with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure,
The residue was distilled under reduced pressure to obtain 27.4 g (yield 55%) of ethyl α-bromomethylacrylate. Boiling point: 72-77 ° C / 9 mmHg ¹ H-NMR spectrum (δ, ppm): 6.43,
5.95 (2H, J = 7.8Hz, = CH 2); 4.2
8 (2H, J = 7.1Hz, -CH 2 -); 4.19
_{(2H, -CH 2 Br);} 1.34 (3H, J = 7.1
Hz, -CH ₃₎

Combination of methyl α-bromomethyl acrylate
In a 100 ml pressure resistant container, methyl acrylate 17.6
g, paraformaldehyde 15.5 g, and diazabicyclooctane 1.1 g were added, and the mixture was reacted at 95 ° C. for 1 hour while stirring. After cooling the reaction solution to room temperature, 47% hydrobromic acid-
100 g of concentrated sulfuric acid mixture was added, and the mixture was reacted at room temperature for 1 day while stirring. Next, n-hexane was added to the reaction solution to extract the product, and the organic phase was washed successively with water, a saturated sodium hydrogen carbonate aqueous solution and saturated saline. After drying the organic phase using anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain 8.9 g of methyl α-bromomethylacrylate (yield 17%).

II. Arabinoaminooxazoline-α-
With bromomethyl acrylic acid ester (ethyl ester)
Synthesis of Additive (Compound represented by Formula VI) 1.0 g of arabinoaminooxazoline was suspended in 5 ml of dimethylacetamide, 1.3 ml (1.87 g) of ethyl α-bromomethylacrylate was added, and the mixture was allowed to stand at room temperature for 18 hours. It was stirred. Then, 15 ml of methylene chloride was added to the reaction liquid, and the mixed liquid was added dropwise to 100 ml of n-hexane while stirring. 2.0 g of the adduct as a white precipitate (yield 95
%) Was obtained. Melting point: 150-151.6 ° C. ¹ H-NMR spectrum (δ, ppm): 6.54,
6.12 (2H, d, = CH 2); 6.06 (1H,
d, 1'-H); 5.34 (1H, d, 2'-H);
4.58 (1H, d, 3'-H); 4.39 (2H,
_{s, -CH 2 -); 4.28} (1H, 4'-H); 4.
_{26 (2H, q, -CH 2} -); 3.59 (2H, d,
5'-H); 1.31 (1H , t, -CH 3) Mass spectrum (FD): 287 (M- Br) + m / z IR spectrum ^(cm -): 1698,1298,12
71

III. 2,2'-anhydroarabinoshi
Rutimine (a compound of formula I) and arabinosyl
Synthesis of thymine (compound represented by formula III) Prepared from arabinoaminooxazoline-α-bromomethylethyl acrylate adduct 1.69 g dried under reduced pressure, potassium metal 600 mg and t-butanol 30 ml under a nitrogen atmosphere. A t-butanol solution of potassium t-butoxide was added, and the mixture was stirred at room temperature for 1 day. 80 ml of methanol was added to the reaction mixture, the solvent was partially distilled off, and the precipitate was filtered. The filtrate was subjected to silica gel column chromatography (eluent: 15% methanol / methylene chloride) to separate and purify the reaction product, and 354 mg of 2,2'-anhydroarabinosylthymine (yield 32%) and arabinosyl were obtained. 163 mg of thymine was obtained (14% yield). 2,2′-Anhydroarabinosylthymine Melting point: 210 ° C. ¹ H-NMR spectrum (δ, ppm): 7.79 (1
H, s, 6-H); 6.53 (1H, d, 1'-H);
5.45 (1H, d, 2'-H); 4.66 (1H,
m, 3'-H); 4.40 (1H, m, 4'-H);
3.55 (1H, d, 5'-H); 1.96 (3H,
s, 5-CH ₃ ) Mass spectrum (FD): 241 (MH) ⁺ m / z arabinosylthymine Melting point: 242.5-244 ° C. ¹ H-NMR spectrum (δ, ppm): 7.70 ( 1
H, s, 6-H); 6.18 (1H, d, 1'-H);
4.43 (1H, dd, 2'-H); 4.15 (1H,
dd, 3'-H); 4.01-3.80 (3H, m,
4'-H, 5'-H); 1.91 (3H, s, 5-CH
₃ ) Mass spectrum (FD): 258 (M) ⁺ m / z

IV. 2,2'-anhydroarabinosyl
Arabinosyl from thymine (a compound of formula I)
Synthesis of thymine (compound represented by formula III) 2,2'-anhydroarabinosylthymine 20 mg
It was added to 1 ml of M ammonia water and reacted at 70 ° C. for 14 hours. The reaction solution was concentrated and then recrystallized from water to obtain arabinosyl thymine 14 mg (yield 65%).

V. 2,2'-anhydro-5,6-dihi
Synthesis of Drouridine (Compound represented by Formula II) 157 mg of arabinoaminooxazoline-α-bromomethylacrylic acid ethyl adduct was dissolved in 1 ml of methanol. A methanol solution of sodium methoxide prepared from 12 mg of sodium metal and 2 ml of methanol was added to this solution, and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction solution, silica gel column chromatography (eluent:
The reaction product was separated and purified by subjecting to 15% methanol / methylene chloride) to obtain 62 mg (yield 53%) of 2,2'-anhydro-5,6-dihydrouridine. Melting point: 155-157 ° C. ¹ H-NMR spectrum (δ, ppm): 6.07 (1
H, d, J = 5.3 Hz, 1'-H); 5.32 (1
H, d, 2'-H); 4.57 (1H, m, 3'-
H); 4.32 (1H, m, 4'-H); 3.92-
_{3.5 (6H, -CH 2 O-,} 5'-H, 6-CH
_{2 -); 3.88 (3H,} s, -OCH 3); 3.14
-2.98 (1H, m, 5- H) Mass spectrum (FD): 273 (M- H) + m / z UV _{spectrum: λ max 273nm (ε = 3.0} × 10
³ )

[0029]

As described above, the method for synthesizing the 2,2'-anhydroarabinosyl thymine derivative of the present invention is the arabinoaminooxazoline-derived from arabinoaminooxazoline and α-bromomethylacrylic acid ester. The α-bromomethylacrylic acid ester adduct was treated with potassium t-
Ring closure with butoxide to give 2,2'-anhydroarabinosylthymine and arabinosylthymine, or ring closure of the adduct with sodium methoxide to 2,2'-anhydro-5. In order to obtain 6-dihydrouridine, it is possible to obtain the target substance with a high yield by a simple operation without the need of using a protecting group or a special reaction reagent, as compared with the conventional synthesis method of a thymine-based nucleoside derivative.

Further, 2,2'-anhydro-5,6-dihydrouridine is useful as a substance having a novel antiviral activity or a synthetic intermediate thereof. Furthermore, the arabinoaminooxazoline-α-bromomethylacrylic acid ester adduct is also useful as a novel intermediate in the synthesis of thymine-based nucleoside derivatives.

Claims (3)

[Claims] 1. The following formula IV: The arabinoaminooxazoline represented by the following formula V: [Wherein R represents a methyl group or an ethyl group] and reacted with an α-bromomethylacrylic acid ester to give the following formula VI: An arabinoaminooxazoline-α-bromomethylacrylic acid ester adduct represented by the formula: wherein R represents a methyl group or an ethyl group is obtained, and then the adduct is closed with potassium t-butoxide to give Formula I: 2,2'-anhydroarabinosyl thymine represented by the following formula III: An arabinosyl thymine represented by the following formula is obtained, or the adduct is cyclized with sodium methoxide to give the following formula II: A method for synthesizing a 2,2′-anhydroarabinosylthymine derivative, which comprises obtaining 2,2′-anhydro-5,6-dihydrouridine represented by 2. The following formula VI: [In the formula, R represents a methyl group or an ethyl group] arabinoaminooxazoline-α
-Bromomethyl acrylate adduct. 3. The following formula II: 2,2'-anhydro- characterized by being represented by
5,6-dihydrouridine.