JPH04217692A - Production of 3'-deoxy-3'-fluorothymidine - Google Patents

Abstract

PURPOSE:To readily mass-produce 3'-deoxy-3'-fluorothymidine in high yield by improving acetylating reaction of 3'-deoxy-3'-fluoro-5'-mesylthymidine. CONSTITUTION:Mesyl group at the 5'-position is acetylated and converted into acetyl group at the 5'-position by selecting an aprotic polar solvent as a reaction solvent and using any of an alkali metallic acetate such as sodium acetate, amine acetates such as tetraalkylammonium acetates and ammonium acetate as an acetylating reagent and deacetylating reaction is then carried out to afford the objective 3'-deoxy-3'-fluorothymidine.

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to a method for producing 3'-deoxy-3'-fluorothymidine, which itself has antiviral and antitumor effects.

0002

BACKGROUND OF THE INVENTION In recent years, it has been known that nucleosides exhibit various physiological activities, and a large number of natural and non-natural nucleosides have been synthesized. Among these nucleosides, methods for synthesizing 3'-deoxy-3'-fluorothymidine, which has attracted attention for its anti-AIDS virus activity, include: (1) 3'-mesylthymidine or 2,3'
- anhydrothymidine and potassium hydrogen fluoride or ammonium fluoride in an ethylene glycol solvent
By heating the reaction at 1°C for 10 to 90 minutes, a yield of 10
A method for synthesizing 3'-deoxy-3'-fluorothymidine at ~14% [Japanese Patent Publication No. 10472/1983], (1) Reacting thymidine and 4-chlorobenzoyl chloride at 5 to 20°C in a pyridine solvent, 5'-( with a yield of 80%
After converting to thymidine (4-chlorobenzoyl), 5'-(4
A method for synthesizing 3'-deoxy-3'-fluorothymidine in a yield of 19.9% by reacting thymidine (chlorobenzoyl) with diethylaminosulfotrifluoride in a methylene chloride solvent at -78°C 68325], ■ 3'-deoxy-3'-fluorothymidine and 3'-deoxy-3' are produced by heating reaction of 2,3'-anhydrothymidine and hydrofluoric acid at 150°C for 90 minutes in a triethylamine solvent. - Method for obtaining a mixture of fluoro-5'-mesylthymidine in a yield of 19% [Zeitsch
rift fur Chemie, Volume 23, No. 3
35 pages (1983)], ■2,3'-Anhydro-
5'-Mesylthymidine was reacted with hydrofluoric acid and aluminum fluoride in dioxane solvent at 170°C, yield 61
After obtaining 3'-deoxy-3'-fluoro-5'-mesylthymidine in %, demesylation with sodium hydroxide is performed to synthesize 3'-deoxy-3'-fluorothymidine in a yield of 46%. Method [Journal fur
Praktische Chemie, No. 315
Vol., p. 895 (1973)]. However, these methods have problems such as low yield, use of expensive reagents, poor reproducibility, and difficult purification methods, and are not suitable as industrial production methods. Other synthetic methods include the 5' of thymidine.
The hydroxyl group at the -position is replaced by a mesyl group (CH3SO), which is an acid-resistant protecting group.
3-), and then fluorinated the 3'-position using hydrofluoric acid to obtain 3'-deoxy-3'-fluoro-5'-mesylthymidine (hereinafter abbreviated as "5'-mesylated product"). and then demesylated to give 3'-deoxy-3'-
A method of using fluorothymidine is known. The demesylation reaction, which is one of the steps in this synthetic method, is usually carried out under alkaline conditions using alkali hydroxide.
Since the mesylated product contains fluorine in its structural formula, which easily reacts with alkali hydroxide, a demesylation reaction using this alkali hydroxide cannot be employed. Therefore 5'
- For the demesylation reaction of the mesylated product, 5'-acetyl-3'-deoxy-3'-fluorothymidine (hereinafter referred to as "5'- 3'-deoxy-3'-
How to obtain fluorothymidine [Nucleic Ac
id Chemistry Part I, 2nd
99-302 (1978)] is used.

0003

[Problems to be Solved by the Invention] The conventional acetylation reaction of a 5'-mesylated product in acetic anhydride uses about 100 times the amount of acetic anhydride relative to the 5'-mesylated product, and requires a long reaction time. Due to the heating, the reactants are markedly colored, a large amount of side reactants are produced, and the yield of the 5'-acetylated product is extremely low. Therefore, since column chromatography, which is inefficient for purification, is essential, it is difficult to industrially produce large quantities of 5'-acetylated products.

0004

[Means for Solving the Problems] As a result of repeated studies on efficient acetylation of 5'-mesylated products, the present inventors found that 5'-mesylated products, alkali metal salts of acetate, amine acetates, and acetic acid Focusing on the fact that acetylation proceeds easily in a solvent that dissolves both acetylation reagents selected from the group consisting of ammonium, we selected an aprotic solvent as the reaction solvent, thereby eliminating the need for acetic anhydride. We have discovered the acetylation conditions of the present invention that do not. In other words, as shown in the formula below, the present invention provides 5'-
The mesylated product is reacted with an acetylating reagent selected from the group consisting of alkali metal acetates, amine acetates, and ammonium acetate in an aprotic polar solvent to form a 5'-acetylated product, and then the 5' The target 3'-deoxy-3' is obtained by eliminating the acetyl group at the -position.
- fluorothymidine is obtained. (Margin below)

[
0005

[Chemical formula 1] 3'-deoxy-3'-fluorothymidine

[0006]
The 5'-mesylated compound that is the raw material of the present invention is Nuclei
c Acid Chemistry Part
I, p. 299 (1978), after reacting thymidine with mesyl chloride in a pyridine solvent to give 3',5'-dimesylthymidine,
2, by reacting with sodium hydroxide in ethanol solvent.
It can be obtained by preparing 3'-anhydro-5'-mesylthymidine and then reacting it with aluminum fluoride in a 0.1% hydrofluoric acid dioxane solvent under heating. The acetylation reagent used in the present invention is an acetic acid alkali metal salt,
These are amine acetates and ammonium acetate. Specifically, alkali metal acetates include lithium acetate, sodium acetate, potassium acetate, etc., and amine acetates include acetic acid =
Examples include tetraalkylammonium acetic acid such as tetramethylammonium, tetraethylammonium acetate, tetrapropylammonium acetate, and tetrabutylammonium acetate. As the reaction solvent, an aprotic polar solvent is used, and examples thereof include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and hexamethylphosphoric triamide, but are not limited thereto. 5' of the present invention
The acetylation reaction of the -mesylated product requires a minimum equimolar amount of the acetylating reagent relative to the 5'-mesylated product, and usually 1.4 to 3 times the mole is optimal. Excessive use of the acetylating reagent is not preferred because the reaction system becomes acidic. The amount of aprotic polar solvent is sufficient as long as the 5'-mesylated compound is dissolved, and the reaction will proceed even if a part of the acetylating reagent is in a suspended state, but usually 5'-mesylated It is preferable that the amount is equal to or more than the body weight. The reaction temperature may be 50° C. or higher and is preferably carried out at a temperature lower than the boiling point of the reaction solvent. At temperatures below 50°C, the acetylation reaction progresses extremely slowly, and when the temperature approaches the boiling point of the reaction solvent, the reactants may become colored.
-130°C is the most preferred temperature range. The reaction time varies depending on the reaction temperature, the type of reaction solvent, and the type of acetylating reagent, but at 110°C, it takes 10 to 120 minutes. After the reaction is completed, the reaction product may be used as it is in the next step of deacetylation reaction, or it may be used in the deacetylation reaction in the form of a reaction concentrate obtained by removing the reaction solvent from the reaction product under reduced pressure. In addition, the 5'-acetylated product can be extracted from the reactant or reaction concentrate with an organic solvent, and the concentrate after distilling off the solvent can be used as it is, or the concentrate can be deacetylated after purification treatment such as decolorization with activated carbon. It can also be used in reactions. Next, the 5'-acetylated product thus obtained is subjected to a known acetyl group elimination reaction, for example, by standing or stirring in ammonia-saturated methanol at 0°C to room temperature [Nucleic Acid Chemist
ry Part I, page 299 (1978)]
The deacetylation ends. After the reaction is completed, decolorization treatment is performed using activated carbon to obtain crude 3'-deoxy-3'- as gray-white crystals.
Fluorothymidine is obtained and further purified by a recrystallization method using water, a lower alcohol, or ethyl acetate, or after the reaction solvent is distilled off from the reaction solution under reduced pressure, it is treated with a synthetic adsorbent to obtain 3'-Deoxy-3'-fluorothymidine is adsorbed, then eluted with an alcohol-water mixture,
By performing purification treatment by distilling off the solvent and recrystallizing using water and lower alcohol, 3'-deoxy-3'- is produced in the form of white powder or white granular crystals with a purity of 99.8% or more.
Fluorothymidine can be obtained in a high yield of 70% or more.

[0007]

[Examples] The present invention will be illustrated below with reference to Examples. Example 1 3.22 g (10 mmol) of 3'-deoxy-3'-fluoro-5'-mesylthymidine is dissolved in 10 ml of dimethyl sulfoxide. Add 1 part of sodium acetate to this solution.
．． Add 64g (20mmol) and heat at 110°±5°C.
Heat with stirring for 0 minutes. After the reaction was completed, dimethyl sulfoxide was distilled off from the reaction mixture under reduced pressure to obtain about 5 g of a pale brown oil as a residue. This light brown oil gave the same retention time in high performance liquid chromatography as the standard 5'-acetyl-3'-deoxy-3'-fluorothymidine, and gave the same Rf value in thin layer chromatography. Ta. In addition, in the nuclear magnetic resonance spectrum, the peak with a δ value of 3.25 ppm attributed to the mesyl group disappeared, and the generation of a peak with a δ value of 2.09 ppm attributed to the acetyl group was confirmed. −
It was confirmed that it was 3'-deoxy-3'-fluorothymidine. Next, 60 ml of ammonia saturated methanol solution was added to this light brown oil, and after stirring at room temperature for about 2 hours,
Methanol was distilled off under reduced pressure to obtain a light reddish brown oil. Add 10 ml of water to this reddish-brown oil, heat and dissolve, then add activated carbon to decolorize and filter while hot. Add this to 10 m of boiling water.
The mixture is combined with the previous filtrate and the water is distilled off under reduced pressure. After adding 10 ml of water to the residue and dissolving it under heating, it was left to stand at room temperature overnight to obtain 2.0 g (8.2 mmol) of 3'-deoxy-3'-fluorothymidine in the form of white granular crystals. Yield 82%.

Analysis value (1) 3'-deoxy-3'-fluoro-5'-mesylthymidine Melting point: 165-166°C 1H-nuclear magnetic resonance spectrum (DMSO-
d6) δ (ppm) = 1.77 (s, 3H
,CH3)
2.39 (m, 2H, H-2'×2)
3.25(s,3H,CH3
SO2-)
4.38 (m, 1H, H-4')
4.42(m, 2H, H-5'×
2) 5.3
7 (dd, JHH=4.0HZ, JHF=52.2HZ
，
1H,H-3')
6.24 (dd, J=8.6HZ,
J=6.0HZ, 1H,
H-1')
7.51(s, 1H
,6-H) 11
．． 40(brS, 1H, >NH) 13C-
Nuclear magnetic resonance spectrum (DMSO-d6)
δ (ppm) = 11.94 (CH3)
36.08 (d, J=20.
7HZ, 2'-C)
36.76(CH3SO2-)
68.83 (d, J=11
．． 2HZ,5'-C)
81.39 (d, J=26.9HZ, 4'-
C) 84.
45 (1'-C)
93.86 (d, J=176.6HZ, 3'-C
) 110.37
(5-C) 13
5.88 (6-C)
150.80 (2-C)
160.98 (4-C)

(2) 5'-acetyl-3'-deoxy-3'-fluorothymidine Melting point: 99-100°C 1H-nuclear magnetic resonance spectrum (DMSO=
d6) δ (ppm) = 1.90 (d, J =
1.22HZ, 3H, CH3)
2.09(s,3H,CH3CO-
) 2.23
(m, 1H, 2'-H)
2.62 (m, 1H, 2'-H)
4.36 (m, 2H
,5'-H)
4.37 (m, 1H, 4'-H)
5.18 (dd, JHH=5.
3HZ, JHF=51.6HZ,
3'-H)
6.30 (
dd, J=8.8HZ, J=55HZ, 1'-H)
7.22(d,
J=1.22HZ, 6-H)
9.21 (brS, 1H, >NH)
13C-Nuclear Magnetic Resonance Spectrum (DMSO-
d6) δ (ppm) = 12.43 (CH3
) 20.5
5(CH3CO-)
38.12 (d, J=21.3HZ, 2'-C
) 63.4
4 (d, J=10.2HZ, 5'-C)
82.37 (d, J=26
．． 7HZ, 4'-C)
85.47 (1'-C)
93.44 (d, J=180.
6HZ, 3'-C)
111.57 (5-C)
134.83 (6-C)
150.41 (2-C)
163.82 (4-C)
170.32 (
CH3CO-)

(3) 3'-deoxy-3'-fluorothymidine melting point:
177-179°C 1H-Nuclear Magnetic Resonance Spectrum (DMSO-
d6) δ (ppm) = 1.77 (d, J =
1.1Hz, CH3)
2.30 (m, 2H, H-2'x2)
3.64 (m, 2
H, H-5'×2)
4.13 (td, JHH=4.0HZ, JHF
=27.8Hz,
1H,H-4')
5.29 (dd
, JHH=4.0HZ, JHF=54.2HZ,

1H,H-3')
6.20 (dd, J=5.9HZ, J=9.
1HZ, 1H,
H-1')
7.69 (d, J=1.1H
Z, 1H, H-6)
11.31 (brS, 1H, >NH)
13C-Nuclear Magnetic Resonance Spectrum (DMSO-d6)
δ (ppm) = 12.16 (CH3)
36.94 (d, J
=20.3Hz, 2'-C)
60.94 (d, J=11.1HZ,
5'-C)
83.89 (1'-C)
84.94 (d, J=23.0Hz, 4'
-C) 95
．． 03 (d, J=174.4HZ, 3'-C)
110.00 (5-C)
136.04 (
6-C) 150
．． 82 (2-C)
164.03 (4-C) Ratio [α] (26°/
D) -7.0° (c=1.0, DMSO)

[0011]
Example 2 3.22 g (10 mmol) of 3'-deoxy-3'-fluoro-5'-mesylthymidine is dissolved in 10 ml of N,N-dimethylformamide. Add 1.96 g (20 mmol) of potassium acetate to this solution and mix at 110°±5
Heat with stirring at 0.degree. C. for 60 minutes. After the reaction, N,N-dimethylformamide was distilled off under reduced pressure, and 30% of water was added to the residue.
ml was added and extracted twice with 50 ml of ethyl acetate. The ethyl acetate layer was washed twice with 30 ml of water, dried over anhydrous sodium sulfate, then ethyl acetate was distilled off under reduced pressure, and the residue was dissolved in methanol. 1.4 g of activated carbon is added to this solution to decolorize it, and then filtered, and the filtrate is concentrated to obtain a residue. The residue was treated with ammonia-saturated methanol in the same manner as in Example 1, and then purified to yield 1.8 g of 3'-deoxy-3'-fluorothymidine (7.38 m m ) as white granular crystals.
ol) was obtained. Yield 73.8%. The analytical values are the same as for 3'-deoxy-3'-fluorothymidine obtained in Example 1.

Example 3 644 g (2 mol) of 3'-deoxy-3'-fluoro-5'-mesylthymidine is dissolved in 1 liter of N,N-dimethylformamide. 308 g (4 mol) of ammonium acetate was added to this solution, and the mixture was heated at 110°±5° C. for 2 hours with stirring. After the reaction was completed, N,N-dimethylformamide was distilled off from the reaction mixture under reduced pressure to obtain about 1 kg of brown oil as a residue. This brown oil was obtained from Example 1.
From the results of high performance liquid chromatography, thin layer chromatography, and nuclear magnetic resonance spectroscopy similar to those described above, it was confirmed that it was 5'-acetyl-3'-deoxy-3'-fluorothymidine. Next, 6 liters of ammonia-saturated methanol solution was added to this brown oil, and after stirring at room temperature for about 2 hours, methanol was distilled off under reduced pressure, and about 1 liter of ammonia-saturated methanol solution was added.
I got kg. Next, after dissolving this brown oil in 10 liters of water, this solution was added to the synthetic adsorbent Sepabead SP207 (
(Registered Trademark) 10 liters for adsorption. Next, after washing by passing 30 liters of water through this synthetic adsorbent, 50%
30 liters of methanol-water mixture and 10 liters of methanol were passed through the solution in sequence for elution and washing. This methanol-
The water mixture eluate was concentrated to dryness under reduced pressure to obtain about 450 g of crude crystals of 3'-deoxy-3'-fluorothymidine as a white solid as a residue. Next, 2 liters of water was added to this white solid, and after heating and dissolving with stirring, the mixture was stirred overnight at room temperature, and 3'-deoxy-3'-fluorothymidine 4 was dissolved in white powdery crystals.
10 g (1.68 mol) was obtained. Yield 84%. The analytical values are the same as for 3'-deoxy-3'-fluorothymidine obtained in Example 1.

Example 4 322 g (1 mol) of 3'-deoxy-3'-fluoro-5'-mesylthymidine was dissolved in 500 g of dimethyl sulfoxide.
ml, add 266 g (2 mol) of tetramethylammonium acetate to this solution, and stir at 110°±5°C for 30
Heat with stirring for minutes. After the reaction was completed, dimethyl sulfoxide was distilled off from the reaction mixture under reduced pressure to obtain about 500 g of a brown oil as a residue. This brown oil was confirmed to be 5'-acetyl-3'-deoxy-3'-fluorothymidine from the results of high performance liquid chromatography, thin layer chromatography, and nuclear magnetic resonance spectroscopy similar to those in Example 1. . Next, 3 liters of ammonia-saturated methanol solution was added to this brown oil, and after stirring at room temperature for about 2 hours, methanol was distilled off under reduced pressure, and about 50 liters of ammonia-saturated methanol solution was added to the brown oil.
Obtained 0g. Next, after dissolving this brown oil in 5 liters of water, the synthetic adsorbent Diaion HP20 (registered trademark) 5 was added.
Pass the liquid through the liter to absorb it. Next, this synthetic adsorbent was treated in the same manner as in Example 3, and 195 g (0.80 mol.
) was obtained. Yield 80%. The analytical value is 3'- obtained in Example 1.
Identical to deoxy-3'-fluorothymidine.

Comparative Example 3 0.5 g (1.6 mmol) of deoxy-3'-fluoro-5'-mesylthymidine was dissolved in 60 ml of acetic anhydride, and 0.5 g (5.1 mmol) of potassium acetate was added to this solution.
mol) was added and heated at 130-135°C for 2 hours with stirring. After the reaction was completed, acetic anhydride was distilled off under reduced pressure, and the dark reddish brown residue was dissolved in 125 ml of chloroform.
Wash with 100ml of water, and remove the chloroform layer with activated carbon.
．． 1 g to decolorize and dry using magnesium sulfate. Then, chloroform was distilled off to obtain 0.73 g of a reddish-brown oil as a residue. As a result of analyzing this reddish brown oil by high performance liquid chromatography, 27 peaks were detected, among which 5'-acetyl-3'-deoxy-3'
- The content of fluorothymidine was 20% (area ratio).

[0015]

Effects of the Invention The method for producing 3'-deoxy-3'-fluorothymidine of the present invention is useful as a compound that itself has antiviral and antitumor effects, and is particularly useful for producing 3'-deoxy-3'-fluorothymidine, which is an anti-AIDS drug. Deoxy-3'-azidothymidine (A
3'- which shows stronger anti-AIDS virus activity compared to ZT)
This method can stably supply deoxy-3'-fluorothymidine in a high yield, simply and in large quantities, and is suitable as an industrial production method.

Claims (1)

[Claims] Claim 1. A method for producing 3'-deoxy-3'-fluorothymidine, in which 3'-deoxy-3'-fluoro-5'-mesylthymidine is treated in an aprotic polar solvent with an alkali metal salt of acetate, an acetic acid a step of reacting with an acetylating reagent selected from the group consisting of amines and ammonium acetate to obtain 5'-acetyl-3'-deoxy-3'-fluorothymidine;
A method for producing 3'-deoxy-3'-fluorothymidine, which comprises the step of deacetylating deoxy-3'-fluorothymidine to obtain 3'-deoxy-3'-fluorothymidine.