JPH05247082A - Production of 2'-fluoro-2',3'-dideoxynucleoside and intermediate thereof - Google Patents

Abstract

PURPOSE:To easily, stably obtain in large quantities the subject compound having antiviral activities such as anti-AIDS viral activity by specific means using, as raw material, a readily available dihydroxy-hydroxymethyl-butanolide derivative. CONSTITUTION:The 5-site hydroxyl group of (2S,4S)-2-hydroxy-4- hydroxymethyl-4-butanolide of formula I is first protected and a F atom is introduced into the 2-site of this compound to form a 2-fluoro-5- hydroxypentane-4-olide derivative of formula II (R<4> is protecting group for the hydroxyl group). Thence, this compound is reduced into 2,3-dideoxy-2- fluoropentofuranose of formula III, which is, in turn, condensed with a 5- substituted pyrimidine derivative of formula IV [R<1>-R<2> are each alkyl or phenyl; X is a group having 0, N and other atomic group(s); Y is H, halogen, etc.]. Finally, the resulting a 1-[2,3-dideoxy-2-fluoro-D-pentofuranosyl]pyrimidine derivative of formula V is deprotected, thus obtaining the objective compound of formula VI.

Description

Detailed Description of the Invention

[0001]

[Industrial applications]

The present invention is a compound having antiviral activity such as anti-AIDS virus itself, and at the same time, is a raw material for other pharmaceutically useful related compounds, 2'-fluoro-.
The present invention relates to a method for producing 2 ', 3'-dideoxynucleoside.

[0003]

[Prior Art]

Conventionally, as a method for producing 2'-fluoro-2 ', 3'-dideoxynucleoside, a ribonucleoside derivative is selectively introduced with a fluorine atom at the 2'position and then the 3'hydroxyl group is reductively reduced. Method of desorption [Journal of Medicinal Chemistry (J.Med.Chem.), 1990
Vol. 33, page 2137].

[0005]

[Problems to be Solved by the Invention]

However, in the above-mentioned method, the ribonucleoside derivative obtained from nature is used as a raw material, and when various derivatives are produced, once the non-natural ribonucleoside is produced, the desired 2'-fluoro- It is necessary to lead to a 2 ', 3'-dideoxynucleoside derivative.

Further, when fluorinating, it is necessary to selectively protect only one of the two secondary hydroxyl groups.

Further, there is a problem that a harmful organic tin compound is used in the reductive removal of hydroxyl groups.

The present invention has been made in view of the above circumstances, and a broader range of 2'-fluoro-2 ', 3'-dideoxynucleoside derivatives can be produced by a single method by a simpler production process. The present invention provides a manufacturing method capable of

[0010]

[Means for Solving the Problems]

In order to solve the above problems, the inventors of the present invention have selected a 2,3-dideoxy-2-fluoropentofuranose derivative as an easily available (2S, 4S) -2-hydroxy-4-hydroxy derivative. A method for synthesizing from a methyl-4-butanolide derivative was found, and further, this 2,3-
A dideoxy-2-fluoropentofuranose derivative,
By condensing with a 5-substituted pyrimidine derivative,
It has been found that a 2'-fluoro-2 ', 3'-dideoxynucleoside derivative can be obtained.

That is, the present invention provides (a) the general formula [7],

[0013]

[Chemical 10]

The hydroxyl group at the 5-position of (2S, 4S) -2-hydroxy-4-hydroxymethyl-4-butanolide represented by the formula (6)

[0015]

[Chemical 11]

(Wherein R ⁴ represents a hydroxyl-protecting group), (2S, 4S) -2-hydroxy-
A step of obtaining a 4-hydroxymethyl-4-butanolide derivative, and (b) a step of (a), (2S, 4S) -2.
-Hydroxy-4-hydroxymethyl-4-butanolide derivative [6] with a fluorine atom introduced at the 2-position to give a compound of the general formula [5],

[0017]

[Chemical 12]

(In the above formula, R ⁴ represents a hydroxyl-protecting group), a step of obtaining a 2-fluoro-5-hydroxypentane-4-olide derivative, and (c) step (b) The obtained 2-fluoro-5-hydroxypentane-4-olide derivative [5] is reduced to give the compound represented by the general formula [4]:

[0019]

[Chemical 13]

(In the above formula, R ⁴ represents a hydroxyl-protecting group), a step of obtaining a 2,3-dideoxy-2-fluoropentofuranose derivative and a step of (d) step (c) In addition, the 2,3-dideoxy-2-fluoropentofuranose derivative [4] and the general formula [3],

[0021]

[Chemical 14]

(In the above formula, R ^{1 to} R ³ represent an alkyl group or a phenyl group, which may be the same or different and may be substituted. X represents an oxygen atom or a nitrogen atom. , The nitrogen atom has another atom or atomic group, Y represents a hydrogen atom, a halogen atom, an alkyl group or an alkenyl group, and the alkyl group and the alkenyl group may be substituted with a halogen atom. And a 5-substituted pyrimidine derivative are condensed to give a compound of the general formula [2],

[0023]

[Chemical 15]

(In the above formula, R ⁴ represents a hydroxyl-protecting group. X represents an oxygen atom or a nitrogen atom, and the nitrogen atom has another atom or atomic group. Y represents a hydrogen atom, a halogen atom, 1- [2,3-dideoxy-2-fluoro-D-pentofuranosyl] pyrimidine, which represents an alkyl group or an alkenyl group, and the alkyl group and the alkenyl group may be substituted with a halogen atom. The step of obtaining a derivative, and (e) the step obtained in the step (d), 1-
By subjecting the [2,3-dideoxy-2-fluoro-D-pentofuranosyl] pyrimidine derivative [2] to a deprotection reaction of a protecting group, a compound of the general formula [1],

[0025]

[Chemical 16]

(In the above formula, X represents an oxygen atom or a nitrogen atom, and the nitrogen atom has another atom or an atomic group. Y represents a hydrogen atom, a halogen atom, an alkyl group or an alkenyl group, and an alkyl group. And an alkenyl group may be substituted with a halogen atom).
A method for producing 2'-fluoro-2 ', 3'-dideoxynucleoside, comprising a step of obtaining 2'-fluoro-2', 3'-dideoxynucleoside.

The present invention also provides a specific intermediate compound obtained in steps (b) and (c) of the above-mentioned production method.

The first compound is represented by the general formula [5],

[0029]

[Chemical 17]

(In the above formula, R ⁴ represents a hydroxyl-protecting group).

The second compound is represented by the general formula [4],

[0032]

[Chemical 18]

(In the above formula, R ⁴ represents a hydroxyl-protecting group.)

The production method of the present invention will be described in more detail below.

Represented by the general formula [7] (2S, 4S)-
2-Hydroxy-4-hydroxymethyl-4-butanolide is present in the body fluids of animals, and an increase in blood concentration is observed in fasting rats, and induction of feeding behavior is observed by its administration. Known as an endogenous food-feeding substance [Yu Omura, Nobuaki Shimizu, "Chemistry and Biology",
22, Vol. 4, p. 228, and references therein, O. Uchikaw
a, N.Okukado, T.Sakata, K.Arase, K.Terada, Bull.Chem.So
c. Jpn., 61, 2025 (1988)].

Then, represented by the general formula [7], (2
S, 4S) -2-Hydroxy-4-hydroxymethyl-
Protect the hydroxyl group at the 5-position of 4-butanolide, and use the general formula [6]
The step of obtaining the (2S, 4S) -2-hydroxy-4-hydroxymethyl-4-butanolide derivative represented by is carried out by a usual method.

(2S, 4S) represented by the general formula [6]
R ⁴ used in the protection of the 5-position of the hydroxyl group of 2-hydroxy-4-hydroxymethyl-4-butanolide derivative (general formula (2), the general formula (4), R ⁴ in the general formula [5] The same ) Is, for example, an aralkyl group such as a benzyl group or a trityl group, or an acyl group such as an acetyl group, a propionyl group, a pivaloyl group or a benzoyl group, an alkyloxycarbonyl group such as an ethoxycarbonyl group, or an aryloxy group such as a phenoxycarbonyl group. A carbonyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, a triorganosilyl group such as a t-butyldiphenylsilyl group or the like, or when these protecting groups have a phenyl group, an alkyl group, a halogen atom or a halogen atom is used as the substituent. Atom, nitro group,
Although it has an alkoxy or the like, it is not particularly limited.

From the (2S, 4S) -2-hydroxy-4-hydroxymethyl-4-butanolide derivative [6] of step (b) to 2-fluoro-5-hydroxypentane-4.
In the step of obtaining the -olide derivative [5], a usual method of performing a substitution reaction involving steric inversion from a hydroxyl group to a fluorine atom is used.

For example, (2S, 4S) -2-hydroxy-4-hydroxymethyl-4-butanolide derivative [6]
Middleto using fluorinated sulfur derivative for
n et al. [Journal of Organic Chemistry (J.Org.Chem.), 1975, vol. 40, p. 574], or the method of Liota et al., in which a hydroxyl group is once methanesulfonylated and then reacted with a fluoride ion. [Journal of American Chemical Society (J.Am.Chem.
Soc.), 1974, Vol. 96, page 2250], etc. to introduce a fluorine atom into the second position.

The conversion of the 2-fluoro-5-hydroxypentane-4-olide derivative [5] to the 2,3-dideoxy-2-fluoropentofuranose derivative [4] in the step (c) is carried out by a usual method. Be seen.

For example, using a di (isobutyl) aluminum hydride for the lactone carbonyl group, JP-A-64-9
It is converted by reduction by the method disclosed in Japanese Patent Publication No. 8 (Bristol-Myers Co., Ltd.).

On the other hand, 5 used in step (d)
The -substituted pyrimidine derivative [3] is a pyrimidine base 2
It is obtained by silylating the carbonyl group at the 4-position and the X group at the 4-position and introducing a triorganosilyl group.

The silylation of the 5-substituted pyrimidine derivative [3] can be carried out according to, for example, the method of Forbruggen et al. [Chem. Ber., Chem. Ber., 1981, Vol. 114, No. 12].
[Page 34]].

That is, it can be obtained by a method of adding trimethylsilyl chloride to a hexamethyldisilazane suspension of pyrimidine base and heating under reflux in an argon gas atmosphere, but the method is not particularly limited to this.

As the pyrimidine base, thymine, uracil, cytosine obtained by decomposing from naturally occurring nucleic acid, those obtained by synthesizing these bases by a usual method, or those not derived from natural products In addition, other pyrimidine bases that are completely obtained by synthesis can be used.

The triorganosilyl group of the 5-substituted pyrimidine derivative [3] introduced by silylation is used as a usual protecting group for a hydroxyl group or an amino group, for example, a trimethylsilyl group, a t-butyldimethylsilyl group, It is a phenyldimethylsilyl group and the like, but is not particularly limited.

X in the general formula [3] represents an oxygen atom or a nitrogen atom. This nitrogen atom has a hydrogen atom or an atom or atomic group such as an alkyl group or an acyl group.

Y is a hydrogen atom, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, an alkyl group or an alkenyl group, which may be substituted with a halogen atom.

The condensation reaction between the 2,3-dideoxy-2-fluoropentofuranose derivative [4] and the 5-substituted pyrimidine derivative [3] in the step (d) is carried out by the 2,3-dideoxy-2-fluoropentofuranose derivative. [4] is carried out as it is, or after the derivative having the 1-position activated is prepared.

As the active group at the 1-position, for example, halogen atom such as fluorine atom, chlorine atom, bromine atom, alkyloxy group such as methoxy group, aryloxy group such as phenoxy group, acetyloxy group, An acyloxy group such as a propionyloxy group, a pivaloyloxy group, a benzoyloxy group, an alkyloxycarbonyloxy group such as an ethoxycarbonyloxy group, an aryloxycarbonyloxy group such as a phenoxycarbonyloxy group, or these groups have a phenyl group. If
Examples of the substituent include those having an alkyl group, a halogen atom, a nitro group, an alkoxy group, and the like, but are not particularly limited.

In the condensation reaction, the 5-substituted pyrimidine derivative [3] is used in an equivalent amount or more with respect to the 2,3-dideoxy-2-fluoropentofuranose derivative [4] without catalyst or in the presence of Lewis acids. Done below.

Examples of the Lewis acids include trimethylsilyltrifluoromethanesulfonate, tin tetrachloride, titanium tetrachloride and the like.

The condensation reaction is carried out, for example, at ambient temperature in an aprotic solvent such as chloroform, methylene chloride,
1,2-dichloroethane in acetonitrile,
When a Lewis acid is used, it is used in an amount that works effectively as a catalyst, for example, 20 mol% to 10 equivalents, and the reaction is usually completed in 24 hours.

After that, if necessary, after treatment with an aqueous sodium hydrogen carbonate solution and after treatment such as extraction of an organic solvent, purification is carried out by a known method such as chromatography.

As a result, the desired 1- [2,3-dideoxy-2-fluoro-D-pentofuranosyl] pyrimidine derivative [2] is obtained.

1- [2,3-dideoxy-of step (e)
Deprotection of the 2-fluoro-D-pentofuranosyl] pyrimidine derivative [2] can be carried out by a known method.

However, the specific reaction for deprotection varies depending on the type of protecting group.

For example, when the protecting group is a triorganosilyl group, deprotection can be performed in tetra (n-butyl) ammonium fluoride and tetrahydrofuran.

In the case of an aralkyl group, the benzyl group can be deprotected by reducing it with a catalytic hydrogenation catalyst in a hydrogen gas atmosphere, and treating the trityl group in acetic acid.

In the case of an acyl group, deprotection can be carried out by alkali hydrolysis, alcoholysis, ammonolysis or the like.

In the case of an aryloxycarbonyl group and an alkyloxycarbonyl group, deprotection can be carried out in the same manner as in the acyl group.

The reaction mixture obtained by the above deprotection reaction is separated by crystallization or chromatography to obtain the desired pure 2'-fluoro-2 ', 3'.
-Dideoxynucleoside [1] can be obtained.

[0063]

Example 1

The process for producing 2'-fluoro-2 ', 3'-dideoxyuridine will be described below as an example of the present invention.

Step (a): Production of (2S, 4S) -2-hydroxy-4-hydroxymethyl-4-butanolide derivative [6]

Ribonolactone 1.03 g (6.75 mmol)
Was dissolved in 16 ml of pyridine, and 2.04 g (16.89 mmol) of pivaloyl chloride was slowly added dropwise thereto under ice-water cooling, and then the mixture was stirred at room temperature for 30 minutes. 3.09 g (26.98 mmol) of mesyl chloride was gradually added dropwise to the above reaction solution under ice-water cooling, and then the mixture was stirred at room temperature for 3 hours. The obtained reaction solution was poured into ice water and extracted with diethyl ether, and then the ether layer was washed with 1N hydrochloric acid, a sodium hydrogen carbonate aqueous solution, water, a saturated copper sulfate aqueous solution, and water in this order.
The extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure.
Then, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) and recrystallized from a mixed solvent of hexane: diethyl ether to give a compound of the general formula

1.26 g of the compound represented by [9] (yield from starting material 62.8%) was obtained.

[0067]

[Chemical 19]

General formula

Compound represented by [9] 6.93
g (23.23 mmol) was dissolved in 70 ml of ethyl acetate, 0.70 g of 10% palladium-carbon was added thereto, and the mixture was stirred in a hydrogen gas atmosphere at room temperature for 2 hours. Then
Palladium-carbon was removed by filtration from the reaction solution, and the solvent was distilled off from the filtrate under reduced pressure. Then, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 6:
The product was purified using 1) and recrystallized from a hexane: diethyl ether mixed solvent to obtain 7.16 g of a compound represented by the following general formula [8].

[0069]

[Chemical 20]

Compound 1 represented by the above general formula [8]
0.55 g was dissolved in 53.7 ml of methanol, 53.7 ml of 10% sodium hydroxide aqueous solution was added to this solution, and the mixture was stirred at room temperature for 20 hours. Then, under ice-water cooling, 1N hydrochloric acid was gradually added dropwise to this reaction solution to give an acidic solution. Then, the solvent was distilled off from the reaction solution under reduced pressure,
Silica gel column chromatograph (ethyl acetate)
To give an oily compound (2) represented by the general formula [7].
S, 4S) -2-Hydroxy-4-hydroxymethyl-
4-butanolide (4.53 g, yield 97.6%) was obtained. Then, the necessary amount of (2S, 4S) -2-hydroxy-4-hydroxymethyl-4-butanolide was obtained by carrying out the series of steps described above. Next, the (2S, 4S)-
To a solution of 4.63 g (35.0 mmol) of 2-hydroxy-4-hydroxymethyl-4-butanolide in 30 ml of N, N-dimethylformamide was added 2.40 g of imidazole at 0 ° C.
(35.2 mmol) was added, and 10.5 ml (41.0 mmol) of t-butylchlorodiphenylsilane was slowly added dropwise. After the dropping was completed, the mixture was stirred under anhydrous conditions at room temperature for 2.4 hours. After completion of the reaction, the solution was poured into water and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 2).
˜1: 1) and the desired product, 5- (t-butyldiphenylsilyloxy) -2-hydroxypentane-
8.98 g (24.2 mmol) of 4-olide was obtained. (Yield 6
9%)

Step (b): Preparation of 5- (t-butyldiphenylsilyloxy) -2-fluoropentane-4-olide [5]

Sulfur trifluoride diethylamine complex 3.5
A solution of 6 g (22.0 mmol) in 20 ml of anhydrous methylene chloride was added to the 5- (t-butyldiphenylsilyloxy) -2-obtained in step (a) at -78 ° C under an atmosphere of argon gas.
Hydroxypentane-4-olide 7.43 g (20.0 mm
30 ml of anhydrous methylene chloride solution of ol) was added dropwise. After the dropping was completed, the temperature was slowly raised to room temperature, and the mixture was further stirred for 2.5 hours. After completion of the reaction, the reaction solution was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 7: 1) to obtain the desired product, 5- (t-butyldiphenylsilyloxy) -2-fluoropentane-4-olide 4. .4
4 g (11.9 mmol) were obtained. (Yield 60%) The physical data of the obtained product are as follows.

Melting point: 119.0-122.5 ° C. (n-hexane-methylene chloride) Optical rotation: [α] _D + 51.3 ° (c1.17, CHCl 3)
₃ , 29 ° C.) ¹ H-NMR (CDCl ₃ ): δ 7.67-7.59 (4H, m, aromatic H) 7.50-7.38 (6H, m, aromatic H) 5.50 (1H, dt, J = 52.8, 8.2 Hz, H-
2) 4.75-4.68 (1H, m, H-4) 3.92 (1H, dt, J = 11.5, 1.9Hz, H-
5) 3.61 (1H, dd, J = 11.4, 1.7Hz, H-
5) 2.78-2.45 (2H, m, H-3) 1.05 (3H, s, t-Bu) IR (KBr): ν (cm ^-1 ) 1798 (s), 1193.
(M), 1112 (s), 1094 (s), 1081
(M), 704 (s), 505 (m), 491 (m)

Step (c): 5-O- (t-butyldiphenylsilyl) -2,3-dideoxy-2-fluoro-
Production of D-erythro-pentofuranose [4]

A solution of 2.04 g (5.48 mmol) of 5- (t-butyldiphenylsilyloxy) -2-fluoropentane-4-olide obtained in step (b) in 20 ml of anhydrous tetrahydrofuran was added under argon atmosphere to-. At 78 ° C., 11 ml (11 mmol) of a toluene solution containing 1.0 mol of di (isobutyl) aluminum hydride per liter were added dropwise. After completion of dropping, the mixture was stirred as it was for 3 hours. After the reaction was completed, after adding a small amount of water to the reaction solution, the temperature was raised to room temperature,
Anhydrous magnesium sulfate was added. The resulting solid was filtered off using Celite, and the solvent was evaporated under reduced pressure to give a residue. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1),
1.93 g (5.16 mmol) of -O- (t-butyldiphenylsilyl) -2,3-dideoxy-2-fluoro-D-erythro-pentofuranose were obtained. (Yield 94
%) The physical data of the obtained product are as follows.

Melting point: 67.5-68.5 ° C. (n-hexane-diethyl ether) Optical rotation: [α] _D −6.9 ° (c 0.91, CHCl ₃ ,
29 ° C.) ¹ H-NMR (CDCl ₃ ): δ7.72-7.64 (4H, m, aromatic H) 7.50-7.35 (6H, m, aromatic H) 5.39 (1H, t, J = 7.6 Hz, H-1) 4.99 (1H, dd, J = 52.6, 4.1 Hz, H-
2) 4.52 (1H, tt, J = 7.7, 2.6Hz, H-4) 3.88 (1H, dd, J = 11.1, 2.7Hz, H-)
5) 3.63 (1H, d, J = 7.8Hz, OH) 3.49 (1H, dd, J = 11.1, 2.4Hz, H-
5) 2.34 (1H, dddd, J = 42.8, 14.7, 8.
0, 4.2 Hz, H-3) 2.13 (1H, ddd, J = 25.1, 14.7, 7.4
Hz, H-3) 1.07 (3H, s, t-Bu) IR (KBr): ν (cm ^-1 ) 3394 (w), 1429
(M), 1112 (s), 1058 (m), 1044
(M), 992 (m), 704 (s), 509 (m)

Step (d): Preparation of 1- [5-O- (t-butyldiphenylsilyl) -2,3-dideoxy-2-fluoro-D-erythro-pentofuranosyl] uracil [2]

5-O- (t-butyldiphenylsilyl) -2,3-dideoxy-2-fluoro-D-obtained in step (c)
erythro-pentofuranose 315mg (0.84mm
ol) in 10 ml of anhydrous methylene chloride, 0.50 ml (5.3 mmol) of acetic anhydride and 10 mg of 4- (N, N-dimethylamino) pyridine were added, and the mixture was stirred overnight under anhydrous conditions.
After completion of the reaction, the reaction solution was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 8: 1),
1-O-acetyl-5-O- (t-butyldiphenylsilyl) -2,3-dideoxy-2-fluoro-D-er
352 mg of ythro-pentofuranose (0.84 mmo)
l) got. (Yield 100%) The physical data of the obtained product are as follows.

¹ H-NMR (CDCl ₃ ): δ7.72-7.65 (4H, m, aromatic H) 7.48-7.35 (6H, m, aromatic H) 6.37 (0.1H, 0.1H, dd, J = 4.1, 1.7 Hz, H-1
minor) 6.30 (0.9H, d, J = 10.4Hz, H-1 majo
r) 5.40-4.96 (1H, m, H-2) 4.58-4.44 (1H, m, H-4) 3.84-3.68 (1.9H, m, H-) 5) 3.60 (0.1H, dd, J = 11.3, 2.9Hz, H-
5 minor) 2.45-2.11 (2.3H, m, H-3, Ac mino
r) 1.90 (2.7H, s, Ac major) 1.06 (3H, s, t-Bu)

0.1 ml of trimethylsilyl chloride was added to a suspension of 180 mg (1.61 mmol) of uracil in 5 ml of hexamethyldisilazane, and the mixture was heated under reflux for 30 minutes under an argon gas atmosphere. When the suspended crystals were completely dissolved, after cooling to room temperature, the low boiling point substances were distilled off under reduced pressure in a vacuum pump to obtain an oily residue. The obtained residue was previously obtained, 1-O-acetyl-5-O- (t-butyldiphenylsilyl) -2,3-dideoxy-2-fluoro-D-.
erythro-pentofuranose 55.5 mg (0.13
3 mmol) of anhydrous 1,2-dichloroethane (1 ml) was added, and under an argon gas atmosphere, 5.5 ml (1.5 mmol) of anhydrous 1,2-dichloroethane solution containing 51 μl of trimethylsilyltrifluoromethanesulfonate per ml was slowly added, and the mixture was stirred at room temperature. Stir overnight. After completion of the reaction, the reaction solution was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by thin layer preparative chromatography (n-hexane: ethyl acetate = 1: 1). Obtained purified product 48.7 mg
Is 1- [5-O- (t-butyldiphenylsilyl)-
2,3-dideoxy-2-fluoro-β-D-eryt
[uro-pentofuranosyl] uracil (β form) and its α
It was a mixture of bodies and the ratio was β: α = 6: 4.
(Yield 78%) The physical data of the obtained product are as follows.

¹ H-NMR (CDCl ₃ ): δ 9.35 (0.4H, br, NH minor) 9.28 (0.6H, br, NH major) 7.97 (0.6H, d, J =) 8.1Hz, H-6 major) 7.67-7.61 (4H, m, aromatic H) 7.48-7.33 (6.4H, m, aromatic H, H-
6 minor) 6.15 (0.4H, dd, J = 20.0, 2.8Hz, H-
1'minor) 6.08 (0.6H, d, J = 16.7Hz, H-1 'majo
r) 5.74 (0.4H, d, J = 8.2Hz, H-5 minor) 5.45-5.07 (1.6H, m, H-5 major, H-)
2 ') 4.62-4.42 (1H, m, H-4') 4.25 (0.6H, dd, J = 12.1, 2.0Hz, H-
5'major) 3.91 (0.4H, dd, J = 11.4, 3.2Hz, H-
5'minor) 3.77 (0.6H, dd, J = 12.2, 2.4Hz, H-
5'major) 3.68 (0.4H, dd, J = 11.4, 3.6Hz, H-
5'minor) 2.50-2.05 (2H, m, H-3 ') 1.09 (1.8H, s, t-Bu major) 1.07 (1.2H, s, t-Bu minor) )

Step (e): 2'-fluoro-2 ',
Production of 3'-dideoxyuridine [1]

1- [5-O-obtained in step (d)
(T-Butyldiphenylsilyl) -2,3-dideoxy-2-fluoro-D-erythro-pentofuranosyl] uracil 164 mg (0.35 mmol) in tetrahydrofuran 5 ml solution, 1 mol of tetra (n-butyl) per liter 0.4 ml (0.4 mmol) of a tetrahydrofuran solution containing ammonium fluoride was added, and the mixture was stirred under anhydrous conditions at room temperature for 60 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was analyzed by a high performance liquid chromatograph (fixed layer: YMC A-363, OD
S, diameter 30 mm × length 250 mm; mobile phase: acetonitrile: water = 10: 90, flow rate 10 ml / min; detection: ultraviolet absorption, λ = 254 nm), and 2′-fluoro-
36 mg of 2 ', 3'-dideoxyuridine (0.16 mmo
l) got. (Yield 45%) The physical data of the obtained product are as follows.

¹ H-NMR (CD ₃ OD): δ 8.10 (1 H, d, J = 8.1 Hz, H-6) 5.95 (1 H, d, J = 17.4 Hz, H-1 ′) 5.66 (1H, d, J = 8.1Hz, H-5) 5.35-5.13 (1H, m, H-2 ') 4.48-4.39 (1H, m, H-4) ') 4.00 (1H, dd, J = 12.5, 2.6Hz, H-
5 ') 3.70 (1H, dd, J = 12.5, 3.2Hz, H-
5 ') 2.35-2.11 (2H, m, H-3')

[0085]

【The invention's effect】

According to the present invention, 2'-fluoro-2 ', 3', which is a compound having an anti-AIDS virus action itself and is a raw material for other pharmaceutically useful related compounds.
-The dideoxynucleoside can be easily synthesized, and a large amount can be stably supplied.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Katsuya Matsumoto, 6-2 Umegaoka, Midori-ku, Yokohama-shi, Kanagawa, Japan Institute of Life Sciences, Tobacco Inc. (72) Hajime Matsushita 6-2, Umegaoka, Midori-ku, Yokohama-shi, Kanagawa Japan Tobacco Inc. Life Science Research Institute

Claims (3)

[Claims] (A) General formula [7]: The hydroxyl group at the 5-position of (2S, 4S) -2-hydroxy-4-hydroxymethyl-4-butanolide represented by the following general formula [6]: (In the above formula, R ⁴ represents a hydroxyl-protecting group), a step of obtaining a (2S, 4S) -2-hydroxy-4-hydroxymethyl-4-butanolide derivative, and (b)
(2S, 4S) -2-hydroxy-obtained in step (a)
By introducing a fluorine atom into the 2-position of the 4-hydroxymethyl-4-butanolide derivative, the compound represented by the general formula [5], (In the above formula, R ⁴ represents a hydroxyl-protecting group), a step of obtaining a 2-fluoro-5-hydroxypentane-4-olide derivative, and (c) obtained in step (b), Two
The -fluoro-5-hydroxypentane-4-olide derivative is reduced to give a compound represented by the general formula [4]: (In the above formula, R ⁴ represents a hydroxyl-protecting group), a step of obtaining a 2,3-dideoxy-2-fluoropentofuranose derivative represented by the formula (d), obtained in the step (c),
A 2,3-dideoxy-2-fluoropentofuranose derivative and a compound represented by the general formula [3]: (In the above formula, R ^{1 to} R ³ represent an alkyl group or a phenyl group, which may be the same or different and may be substituted. X represents an oxygen atom or a nitrogen atom, and a nitrogen atom. Has another atom or atomic group.Y
Represents a hydrogen atom, a halogen atom, an alkyl group or an alkenyl group, and the alkyl group and the alkenyl group may be substituted with a halogen atom. ) Is condensed with a 5-substituted pyrimidine derivative to give a compound represented by the general formula [2]: (In the above formula, R ⁴ represents a hydroxyl-protecting group. X represents an oxygen atom or a nitrogen atom, and the nitrogen atom has another atom or atomic group. Y represents a hydrogen atom, a halogen atom, an alkyl group or An 1- [2,3-dideoxy-2-fluoro-D-pentofuranosyl] pyrimidine derivative represented by an alkenyl group, the alkyl group and the alkenyl group may be substituted with a halogen atom. Step, (e) 1- [2,3-, obtained in step (d)
By subjecting a dideoxy-2-fluoro-D-pentofuranosyl] pyrimidine derivative to a deprotection reaction of a protecting group, a compound of the general formula [1] (In the above formula, X represents an oxygen atom or a nitrogen atom, and the nitrogen atom has another atom or an atomic group. Y represents a hydrogen atom, a halogen atom, an alkyl group or an alkenyl group, and an alkyl group and an alkenyl group. Is optionally substituted with a halogen atom.) 2′-fluoro-2 ′, 3′-dideoxynucleoside represented by the formula 2′-fluoro-2 ′, Process for producing 3'-dideoxynucleoside. 2. General formula [5], embedded image (In the above formula, R ⁴ represents a hydroxyl-protecting group.) A compound represented by the formula: 3. A compound represented by the general formula [4]: (In the above formula, R ⁴ represents a hydroxyl-protecting group.) A compound represented by the formula: