JPH11246590A - Production of trifluoromethyluracil derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain the subject derivative useful as a medicine, etc., as carcinostatic agent, antiviral agent, etc., by reacting a fluorosulfonyldifluoroacetic acid ester with a halogenated uracil in the presence of a copper catalyst in an organic solvent. SOLUTION: A fluorosulfonyldifluoroacetic acid alkyl ester represented by the formula FSO2 CF2 COOR (R is a 1-5C alkyl-) (e.g. methyl fluorosulfonyldifluoroacetate) is reacted with a halogenated uracil derivative represented by formula I (R<1> is a protecting group of nitrogen atom or H; R<2> is a monovalent substituent group having hetero atom; X is halogen) (e.g. 3',5'-di-Oacetyl-5-iodo-2'-deoxyuridine) in the presence of a copper (I)halide [e.g. copper (I) bromide] or metal copper in an organic solvent (e.g. dimethylformamide) to provide the objective trifluoromethyluracil derivative represented by formula II in good reproducibility while suppressing production of a by-product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a trifluoromethyluracil derivative useful as a medicine.

[0002]

2. Description of the Related Art Trimethyluracil and its derivatives are expected to be useful as pharmaceuticals, particularly as anticancer agents and antiviral agents, and various methods for synthesizing trifluoromethyluracil derivatives have been developed.

Examples of the synthesis of trifluoromethyluracil derivatives reported so far include (1) a method of reacting an iodouridine derivative with CF ₃ Br in the presence of metallic copper (JP-A-2-72190); (2) A method of reacting an iodouridine derivative with CF ₃ I in the presence of copper metal (Kobayashi, J. Chem. Soc. Perkin Trans., 1,2755-276)
1 (1980)), (3) CF ₃ N (N → O)
Method of reacting SO ₂ CF ₃ to introduce a —CF ₃ group (U
memoto, Bull.Chem.Soc.Japan., 59,447-452 (1986)),
(4) trifluoroacetic acid-XeF ₂
A method of introducing a group -CF ₃ by reacting (Tanabe, J. Org.
Chem., 53, 4582-4585 (1988)).

[0004]

However, the conventional synthesis method has the following problems as an industrial production method: the reaction is not easy, the raw material is difficult to procure, and the yield of by-products is low. Was.

[0005]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above-mentioned problems, and comprises a method of converting a compound represented by the following formula 1 and a uracil halide derivative represented by the following formula 2 into a halogenated compound. Provided is a method for producing a trifluoromethyluracil derivative represented by the following formula 3, wherein the reaction is carried out in an organic solvent in the presence of copper (I) or metallic copper. However, the symbols in the formula have the following meanings. R: an alkyl group having 1 to 5 carbon atoms. R ¹ : a protecting group for a nitrogen atom or a hydrogen atom. R ² : a monovalent substituent having a hetero atom. X: halogen atom.

[0006]

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[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound represented by the formula 1,
R represents an alkyl group having 1 to 5 carbon atoms, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an n-pentyl group, and a sec-butyl group, particularly preferably a methyl group. .

The uracil halide derivative used in the present invention is represented by Formula 2. In the formula, R ¹ represents a protecting group for a nitrogen atom or a hydrogen atom, and specific examples of the protecting group for a nitrogen atom include:
Acetyl, n-propionyl, pivaloyl, benzoyl, p-phenylbenzoyl, benzyl, p
-Methoxybenzyl group, trityl group, 4,4'-dimethoxytrityl group, methoxyethoxymethyl group, aryloxycarbonyl group, benzyloxycarbonyl group, t-butoxycarbonyl group and the like.

R ² represents a monovalent substituent having a hetero atom, and is preferably a pentasaccharide derivative residue represented by the following formula 4. However, the symbols in the formula have the following meanings. R ³ , R ⁴ , R ⁵ : may be the same or different, and each represents a hydrogen atom, a halogen atom, or —OR ⁶
(Here, R ⁶ represents a protecting group for a hydroxyl group, a hydrogen atom, or a halogen atom.) Further, when two or more —OR ⁶ are present in Formula 4, they may be the same or different, and two R ⁶ may form a ring together.

[0010]

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When R ⁶ is a protecting group for a hydroxyl group, specific examples of R ⁶ include acyl groups such as acetyl group, n-propionyl group, pivaloyl group, benzoyl group, and p-phenylbenzoyl group, benzyl group, p-methoxybenzyl group, trityl group, 4,4′-dimethoxytrityl group,
Examples include a methoxyethoxymethyl group, an aryloxycarbonyl group, a tetrahydrofuranyl group, a methyl group, a t-butyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, a triisopropylsilyl group, and a diphenylmethylsilyl group. preferable. When R ³ , R ⁴ and R ⁵ are halogen atoms,
A fluorine atom is preferred.

R ³ , R ⁴ and R ⁵ are preferably a hydrogen atom or —OR ⁶ when R ⁶ is an acetyl group.
X is preferably a chlorine atom, a bromine atom or an iodine atom, particularly preferably an iodine atom.

As the uracil halide derivative represented by the formula 2, a compound represented by the following formula 2a is preferable. However, X, R ³ , R ⁴ and R ⁵ in the formula 2a have the same meaning as described above. Specific examples of Formula 2a include the compounds in Table 1.

[0014]

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The copper (I) halide is preferably copper (I) bromide or copper (I) iodide. Copper (I) bromide, copper (I) iodide, or metallic copper used in the present invention preferably has a purity of 95 to 99.9999%. Copper (I) halide or metallic copper may be refined before the reaction to improve the purity. Copper halide (I)
Alternatively, metallic copper is preferably used in an amount of 0.0001 to 100 times, more preferably 0.001 to 10 times, the weight of the uracil halide derivative represented by the formula (2).

In the present invention, the compound represented by the formula 1 and the uracil halide derivative represented by the formula 2 are reacted in the presence of copper (I) halide or metallic copper. The compound represented by the formula 1 is preferably used in a molar amount of 0.1 to 50 times, more preferably 1 to 10 times the molar amount of the uracil halide derivative represented by the formula 2.

The reaction is performed in an organic solvent. As the organic solvent, an aprotic polar solvent is preferable. Particularly, from the viewpoint of yield, N, N-dimethylformamide (DMF), 1,3
-Dimethyl-2-imidazolidinone (DMI), 1-methyl-2-pyrrolidinone (NMP), dimethylsulfoxide (DMSO), sulfolane, dimethylacetamide, or hexamethylphosphoric triamide (HM
PA) and the like are preferred. The amount of the organic solvent is 0.1 to 1000 with respect to the uracil halide derivative represented by the formula 2.
Double weight is preferable, and 1 to 200 times weight is particularly preferable.

In the reaction of the present invention, the halogen atom (X) in the formula 2 is trifluoromethylated. The trifluoromethylation reaction can be performed at normal pressure. The reaction temperature is preferably from 0 ° C to about the solvent reflux, and particularly preferably from 20 ° C to the solvent reflux. The reaction time is preferably 0.1 to 100 hours, particularly 0.5 to 100 hours.
50 hours is preferred. The reaction is preferably performed in an atmosphere of an inert gas such as argon or nitrogen.

In the production method of the present invention, a trifluoromethyluracil derivative represented by the formula 3 is produced. When a protecting group for a nitrogen atom or a protecting group for a hydroxyl group is present in Formula 3, a deprotection reaction may be performed as necessary.
As the method and conditions of the deprotection reaction, the methods and conditions employed in ordinary organic synthesis methods can be employed. Further, when the trifluoromethyluracil derivative represented by the formula 3 is desired to have high purity, purification may be performed. Examples of the purification method include a distillation method, a chromatographic method, and a method based on a combination thereof.

The trifluoromethyluracil derivative represented by the formula 3 produced by the present invention can be used as a drug such as an anticancer drug or an antiviral drug. As the trifluoromethyluracil derivative represented by the formula 3, a compound represented by the following formula 3a is preferable. However, R ³ , R ⁴ and R ⁵ in the formula 3a have the same meaning as described above.

[0021]

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Specific examples of the formulas 2a and 3a include the compounds shown in Table 1. However, the column of X in Table 1 relates only to the compound 2a. Ph in Table 1 represents a phenyl group.

[0023]

[Table 1]

[0024]

EXAMPLES Example 1 3 ′, 5′-Di-O-acetyl-5-trifluoromethyl-2′-deoxyuridine (wherein R ¹ in the formula 3a is a hydrogen atom, and R ³ and R ⁴ are — Example of Synthesis of OCOCH ₃ and R ⁵ is a Hydrogen Atom) In a 200 ml four-necked flask, 3 ′, 5′-di-O—
Acetyl-5-iodo-2'-deoxyuridine (formula 2
9.50 g (21.7 mmol) of a compound in which X in a is an iodine atom, R ¹ is a hydrogen atom, R ³ and R ⁴ are —OCOCH ₃ , and R ⁵ is a hydrogen atom.
l), copper (I) iodide 0.99 g (5.2 mmol),
9.59 g of methyl fluorosulfonyldifluoroacetate
(49.9 mmol) and 70 m of DMF as a solvent
and stirred at 100 ° C. for 3 hours under a nitrogen gas atmosphere. After completion of the reaction, the reaction solution was filtered, and the filtrate was poured into ice water. Ether and ethyl acetate were added for extraction, and the organic layer was washed with water and dried.

Finally, purification is carried out by column chromatography (carrier: silica gel, eluent (volume ratio) is ethanol / chloroform = 1/30), 3 ', 5'-di-
4.21 g (yield 51%) of O-acetyl-5-trifluoromethyl-2'-deoxyuridine was obtained. The spectral data of the obtained compound are shown below. ¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.05 (s, 3H), 2.10 (s, 3H), 2.3
0-2.60 (m, 2H), 4.20-4.50 (m, 3H), 5.10-5.35 (m, 1H), 6.10-
6.40 (dd, 1H, J = 8Hz), 8.00 (1H, s), 9.30 (brs, 1H). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ) δ (ppm): -67.0. MS m / e: 380 (M ⁺ ).

Example 2 3 ', 5'-di-O-acetyl-5-trifluoromethyl-2'-deoxyuridine (R ¹ in the formula 3a is a hydrogen atom, and R ³ and R ⁴ are -OCOCH ₃ and a compound in which R ⁵ is a hydrogen atom) 3 ′, 5′-di-O- was reacted in the same manner as in Example 1 except that copper (I) iodide was changed to metallic copper. Acetyl-5-trifluoromethyl-2′-deoxyuridine was converted to 4.35.
g (yield 53%).

Example 3 2 ′, 3 ′, 5′-Tri-O-acetyl-5-trifluoromethyl-uridine (wherein R ¹ in the formula 3a is a hydrogen atom, and R ³ , R ⁴ and R ⁵ are Example of synthesis of compound which is —OCOCH ₃ ) In Example 1, 2 ′, 3 ′, instead of 3 ′, 5′-di-O-acetyl-5-iodo-2′-deoxyuridine
Using 5'-tri-O-acetyl-5-iodouridine, 2 ', 3', 5'-tri-O-acetyl-5-trifluoromethyl-uridine was obtained in the same reaction. ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ) δ (ppm): −68.0.

Example 4 5'-O-acetyl-2 ', 3'-dideoxy-5-trifluoromethyl-uridine (R ¹ in the formula 3a is a hydrogen atom, R ³ is -OCOCH ₃ , Synthesis Example of R ⁴ and R ⁵ are hydrogen atoms) In Example 1, 5′-O-acetyl-2 is used instead of 3 ′, 5′-di-O-acetyl-5-iodo-2′-deoxyuridine. Using ', 3'-dideoxy-5-iodouridine, 5'-O-acetyl-2', 3'-
Dideoxy-5-trifluoromethyl-uridine was obtained. ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ) δ (ppm): -66.3.

[0029]

According to the production method of the present invention, a target trifluoromethyluracil derivative can be synthesized using readily available raw materials and reagents without employing special reaction procedures and conditions. The method of the present invention is a method that can be adopted as a large-capacity method, has good reproducibility of the reaction, and suppresses the generation of by-products. Therefore, the method is useful as an industrial production method.

Claims (5)

[Claims] 1. A compound represented by the following formula 1 and a uracil halide derivative represented by the following formula 2 are reacted in an organic solvent in the presence of copper (I) halide or metallic copper. A method for producing a trifluoromethyluracil derivative represented by the following formula 3. Embedded image However, the symbols in the formula have the following meanings. R: an alkyl group having 1 to 5 carbon atoms. R ¹ : a protecting group for a nitrogen atom or a hydrogen atom. R ² : a monovalent substituent having a hetero atom. X: halogen atom. 2. The method according to claim 1, wherein the copper (I) halide is copper (I) bromide or copper (I) iodide. 3. The method according to claim 1, wherein the organic solvent is an aprotic polar solvent. 4. The method according to claim 1, wherein R is a methyl group. 5. The method according to claim 1, wherein R ² is a pentasaccharide derivative residue represented by the following formula 4: Embedded image However, the symbols in the formula have the following meanings. R ³ , R ⁴ ,
R ⁵ : may be the same or different, and each represents a hydrogen atom, a halogen atom, or —OR ⁶ (here, R ⁶
Represents a protecting group for a hydroxyl group, a hydrogen atom, or a halogen atom. ). When two or more —OR ⁶ are present in Formula 4, they may be the same or different, and
R ^{6 's} may together form a ring.