JP3005422B2 - Method for producing 2'-deoxy-5-trifluoromethyl-β-uridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a 1- (2'-deoxy-.beta.-D-erythro-pentofuranosyl) -5-trifluoromethyluracil derivative having an antitumor effect and an antiviral effect.

[0002]

2. Description of the Related Art A 1- (2'-deoxy-β-D-erythro-pentofuranosyl) -5-trifluoromethyluracil derivative (trifluorothymidine derivative) is related to uridine and thymidine which are bases of nucleic acids. Therefore, it is a compound that has been attracting attention for a long time. Since it has an antitumor effect and an antiviral effect in particular, many production methods have been studied as pharmaceuticals or important raw material intermediates thereof. It is well known that in synthetic organic chemistry in the field, the method of producing nucleic acid bases differs greatly depending on the type of nucleic acid base, and a better production method must be considered for each base.
For example, Nucleic Acids Research
h 12 6827 (1984) and Nucleosi
des & Nucleotides, 8 549
(1989), etc., nucleobases such as uracil, fluorouracil, thymine, and trifluorothymine each have significantly different properties depending on the substituent at the 5-position, and their glycosylation reactions In the manufacturing method, each unique manufacturing method must be considered. In particular, with respect to 5-trifluoromethyluridine, which is the object of the present invention, the chemical properties of uridine and thymidine are greatly different due to the influence of the trifluoromethyl group, and a satisfactory result cannot be obtained by a known similar reaction. In addition, in the synthesis of a 2′-deoxy form of a sugar moiety, the selectivity of α and β during glycosylation is low by a usual method,
It was difficult to establish a practical method for producing the required β-form.

[0003] Conventional methods for producing 1- (2'-deoxy-β-D-erythro-pentofuranosyl) -5-trifluoromethyluracil derivative include (1) nucleoside-2'-deoxyribose transferase. A method of exchanging nucleobases from thymidine and 5-trifluoromethyluracil by, for example, [M. G. FIG. Stout, et al. ,
Methods Carbhydr. Res. ,
7, 19 (1976)], (2) a method of reacting the 5-position halogen atom of a 1- (2′-deoxy-β-D-erythro-pentofuranosyl) -5-halouracil derivative with trifluoromethyl copper or the like [ Y. Kobayashi, e
t. al. , J. et al. C. S. PerkinTrans
I, 2755 (1980)], (3) a method of subjecting a thymidine derivative and trifluoroacetic acid to an electrolytic reaction [L. Hei
n, et. al. , DE 119423 (197
6)], (4) 5-trifluoromethyl-2,4-bis (trimethylsilyloxy) pyrimidine and methyl 2-
A method of reacting a deoxy-D-erythro-pentofuranoside derivative in the presence of an acid catalyst [Japanese Patent Application Laid-Open No. 62-50023]
9], (5) 5-trifluoromethyl-2,4-bis (trimethylsilyloxy) pyrimidine and 3,5-di-
O- (p-chlorobenzoyl) -2-deoxy-α-D
-Reaction of erythro-pentofuranosyl chloride in the presence of a zinc chloride catalyst [JP-A-2-289595, H
etherocycles, 31, 569 (1990)]
Etc. have been reported.

[0004] However, the method (1) has a drawback in that it is difficult to isolate and purify the target substance from the reaction system and is difficult to apply to mass production. In the method (2), the reaction intermediate is air or the like. Very sensitive to the reaction conditions and yields are difficult,
The method (3) has drawbacks in that the yield and current efficiency are poor, and an electrolytic facility that can withstand trifluoroacetic acid is required. In the method (4), a mixture of α- and β-derivatives whose products are difficult to separate is used. Β to be obtained as
The isolation yield of the derivative is extremely low, and the method (5) requires a large excess of 5-trifluoromethyl-2,4-bis (trimethylsilyloxy) pyrimidine which is an expensive raw material. In order to obtain a more practical yield of the target product, it is necessary to use zinc chloride as a catalyst, which is hygroscopic and insoluble in a solvent and is difficult to handle, and has disadvantages such as reproducibility and a large problem in industrialization. I have. Furthermore, when expensive 5-trifluoromethyl-2,4-bis (trimethylsilyloxy) pyrimidine is reacted in an equimolar amount or less, the β selectivity is extremely reduced, and the required β derivative has a large yield. It causes a decline. Thus, in any of the conventional production methods, the 1- (2′-deoxy-β-D-erythro-pentofuranosyl) -5-trifluoromethyluracil derivative, which is important as a pharmaceutical or a raw material intermediate thereof, can be obtained reliably and reliably. It is not suitable for inexpensive mass production, and it has been desired to establish a more improved and useful production method.

[0005]

SUMMARY OF THE INVENTION The present inventors have solved the problems of the prior art and have found it easy and inexpensive to use 1- (2'-deoxy-β-D-erythro-pentofuranosyl) -5-trifluoro. As a result of intensive studies to establish a method for producing a methyluracil derivative, as shown below, when reacting with a copper compound as a catalyst, chloroform was used as a solvent,
In addition, in the presence of fluorine ions, the reaction proceeds surprisingly with very high selectivity and yield, and even in the case of stoichiometrically equimolar, which is economically very effective, and is sufficiently satisfactory. We have found that we have obtained results and completed the present invention.

[0006]

That is, the present invention relates to 5-trifluoromethyl-formula represented by the formula (1)
2,4-bis (trimethylsilyloxy) pyrimidine and

[0007]

Embedded image 2-deoxy-α-D-erythro-pentofuranosyl chloride derivative represented by the formula (2)
X is a halogen atom, preferably a chlorine atom, and X ¹ and X ² each independently represent hydrogen or a halogen atom represented by a chlorine atom)

[0008]

Embedded image 1- (2′-deoxy-β-D-erythro-pentofuranosyl represented by the formula (3), wherein the reaction is carried out in a chloroform solvent using a copper compound as a catalyst in the presence of fluorine ions. ) -5-trifluoromethyluracil derivative.

[0009]

Embedded image 5-trifluoromethyl-2,4-bis (trimethylsilyloxy) of the formula (1) used as a raw material in the present invention
Pyrimidine can be easily synthesized from a known compound, 5-trifluoromethyluracil, by a known method. [T. A. Khawaja, et a
l. , J. et al. Med. Chem. , 12, 543 (196
9). ]. 3,5-di-O- (p-chlorobenzoyl) which is a typical example of the other raw material used in the present invention.
2-Deoxy-α-D-erythro-pentofuranosyl chloride can be synthesized in several steps by a known method using 2-deoxyribose, which is easily available, as a starting material. [For example, J. J. Fox, et. a
l. , J. et al. Am. Chem. Soc. , 83, 4066
(1961) et al. ].

The stoichiometric ratio of the raw materials used in the present invention is 3,5-di-O- (p-chlorobenzoyl) -2-deoxy-α-D-erythro-pentofuranosyl chloride, 0.5 equivalent or more of fluoromethyl-2,4-bis (trimethylsilyloxy) pyrimidine,
It is not more than 2 equivalents, and is economically desirably in the range of equivalents or less.

The catalyst used in this reaction is cupric chloride,
An easy-to-handle copper compound having low hygroscopicity, such as cupric fluoride, can be used. Further, as the fluorine ion, in the case of a copper fluoride, the copper ion itself is used, and in other cases, the purpose can be achieved by adding a fluoride such as cesium fluoride or potassium fluoride. The amount of the copper compound used is
3,5-di-O- (p-chlorobenzoyl) as a raw material
-2-Deoxy-α-D-erythro-pentofuranosyl chloride can be used in a range of 0.01 equivalent or more to 1 equivalent or less, but 0.05 equivalent or more,
The range of 0.5 equivalent or less is most preferable. The amount of fluorine ions is not particularly limited, but is usually 0.0
It is 5 to 3 equivalents, preferably 0.1 to 2 equivalents. The solvent used in this reaction is chloroform, and the use of other solvents reduces β selectivity in particular. The reaction temperature ranges usually from -40 ° C or higher to the boiling temperature of the solvent, preferably -1.
0 ° C. or higher and room temperature or lower. Reaction time is usually 0.5 to 4
8 hours.

As an example of glycosylation in the presence of fluoride, an example of a method for producing 3 ', 5'-disubstituted-2'-deoxy-5-fluorouridine is disclosed in JP-A-60-23397.
Although reported in the gazette, nothing is mentioned about the trifluoromethyluridines that are the subject of the present invention, and, as is clear from Comparative Example 2 described later, selectivity and yield other than the chloroform solvent are clear. Both are not satisfactory. Also, Nucleosides & Nuc
As described in Leotides 8549 (1989) and the like, it can be seen that there is a large difference in reactivity depending on the type of halogen ion when performing a glycosylation reaction using a copper compound. That is, the usefulness of reacting a copper compound with fluorine ions in a chloroform solvent is unique to trifluoromethyluridines, and is a major feature of the present invention. This reaction will be described in detail below with reference to examples, but it is inexpensive, has excellent operability and β selectivity, and has remarkable economic significance and technical uniqueness as compared with conventional methods as an industrial production method. It is.

Further, 1- [3 ′,
5′-Di-O- (p-chlorobenzoyl) -2′-deoxy-β-D-erythro-pentofuranosyl] -5-trifluoromethyluracil is prepared by a method known in the literature (for example, alkaline hydrolysis). 1- (2'-deoxy-β-D-
(Erythro-pentofuranosyl) -5-trifluoromethyluracil (trifluorothymidine).

[0014]

The present invention will be described more specifically with reference to the following examples. Reference Example 1 Methyl 2-deoxy-D-erythro-pentofuranosi
De Synthesis of 2-deoxy -D- erythro - pent - scan 52g was stirred for 1 hour at room temperature was added a 1 molar hydrochloric acid methanol solution 3.8ml at room temperature here was dissolved in methanol 1.1 l. 1 g of sodium hydrogen carbonate was dissolved in the reaction solution, and after confirming that it was weakly basic, the solution was concentrated. 100m each of toluene and pyridine
The operation of adding, dissolving and then concentrating the mixture was repeated twice to completely remove methanol. This crude methyl 2-deoxy-α
-D-erythro-pentofuranoside was subjected to the next reaction without being produced as it was.

Reference Example 2 Methyl 3,5-di-O- (p-chlorobenzoyl)-
2-Deoxy-α-D-erythro-pentofuranoside The above crude product was dissolved in 260 ml of pyridine and cooled with ice. To this, 150 g of p-chlorobenzoyl chloride was added dropwise over 1 hour so that the reaction temperature did not exceed 30 ° C. After standing at room temperature overnight, 10 ml of methanol was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 1 liter of water and extracted twice with 500 ml of isopropyl ether. The extract was washed three times with 100 ml of 10% sulfuric acid and dried over magnesium sulfate. The crude product was subjected to the next reaction as an isopropyl ether solution.

Reference Example 3 3,5-di-O- (p-chlorobenzoyl) -2-deo
Xy-α-D-erythro-pentofuranosyl chloride
De destination isopropyl ether solution was cooled to 1/10 amount tori 0 ℃ a. 20 g of hydrochloric acid gas was passed at such a rate that the temperature of the reaction solution was maintained at 8 to 13 ° C. over 40 minutes. After stirring at the same temperature for an additional hour, the desired product was collected by filtration.
The crystals were washed with 20 ml of cold isopropyl ether, washed with 20 ml of hexane and dried in a vacuum dryer at room temperature for 5 hours. Yield 11.75 g (2-deoxy-α
70.5% from D-erythro-pentose). Less than,
This compound is sometimes referred to as compound (2).

Reference Example 4 5-trifluoromethyl-2,4-bis (trimethyl
6.16 g of (ryloxy) pyrimidine 5-trifluoromethyluracil was suspended in 50 ml of hexamethyldisilazane, 0.22 ml of trimethylchlorosilane was added, and the mixture was reacted under heating and reflux for 5 hours.
After the reaction, excess hexamethyldisilazane was distilled off and vacuum distillation was performed to collect all the fractions near 60 ° C. at 1 mmHg. Yield 10.3g. Hereinafter, this compound may be referred to as compound (1).

Example 1 3,5-Di- (p-chlorobenzoyl) -2-deoxy-α-D-erythro-pentofuranosyl chloride 8
69 mg and 656 mg of 5-trifluoromethyl-2,4-bis (trimethylsilyloxy) pyrimidine were dissolved in 8 ml of chloroform. Then, at room temperature, copper fluoride 21
mg was added and stirred at the same temperature for 24 hours. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution, and the mixture was separated. The obtained organic layer was washed with water and dried over magnesium sulfate. When the organic layer is concentrated,
1- [3 ', 5'-di-O- (p-chlorobenzoyl)
-2'-deoxy-D-erythro-pentofuranosyl]
-5-trifluoromethyluracil with a 98% yield
It was obtained as a mixture having a ratio of the isomer to the β-isomer of 1:11. This was recrystallized from ethanol to give pure 1- [3 ', 5'-di-O- (p-chlorobenzoyl) -2'-deoxy-β
-D-erythro-pentofuranosyl] -5-trifluoromethyluracil was obtained. Yield 997 mg (86%) NMR, melting point: consistent with the value described in the literature.

Comparative Example 1 In the same manner as in the method described in JP-A-2-289595, a reaction was carried out using zinc chloride as a catalyst and the molar ratio of the compounds (1) and (2) was 1: 1. The results are shown below. 3,5-di-O- (p-chlorobenzoyl) -2
-Deoxy-α-D-erythro-pentofuranosyl chloride 616 mg, 5-trifluoromethyl-2,4
-Bis (trimethylsilyloxy) pyrimidine 465 m
g was dissolved in 6 ml of chloroform. At room temperature, 19 mg of zinc chloride was added thereto, and the mixture was stirred at the same temperature for 24 hours. After the completion of the reaction, aqueous sodium bicarbonate was added to the reaction solution, and the mixture was separated. The obtained organic layer was washed with water, dried over magnesium sulfate, and then concentrated to give 1- [3 ′, 5′-di-O- (p -Chlorobenzoyl) -2'-deoxy-D-erythro-pentofuranosyl] -5-trifluoromethyluracil was obtained as a mixture having a ratio of α-form to β-form of 1: 3 with a yield of 77%. This was recrystallized from ethanol to give pure 1- [3 ', 5'
-Di-O- (p-chlorobenzoyl) -2'-deoxy-β-D-erythro-pentofuranosyl] -5-trifluoromethyluracil was obtained. Yield 288 mg (35%) NMR, melting point: consistent with the value described in the literature.

Comparative Example 2 Similarly to the method described in JP-A-60-23397, copper fluoride was used as a catalyst and 1,2-dichloroethane was used as a solvent, and the molar ratio of the compounds (1) and (2) was determined. 1: 1
The reaction was performed as follows. The results are shown below. 3,5-
Di-O- (p-chlorobenzoyl) -2-deoxy-α
-D-erythro-pentofuranosyl chloride 530
mg, 5-trifluoromethyl-2,4-bis (trimethylsilyloxy) pyrimidine (400 mg) was dissolved in 1,2-dichloroethane (6 ml). 12 mg of copper fluoride was added thereto at room temperature, and the mixture was stirred at the same temperature for 24 hours. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution, and the mixture was separated. The resulting organic layer was washed with water and dried over magnesium sulfate. The organic layer was concentrated to give 1- [3 ', 5'-di-O- (p-chlorobenzoyl) -2'-deoxy-D-erythro-pentofuranosyl] -5-trifluoromethyluracil at 96%. It was obtained as a mixture having a ratio of α-form and β-form of 1: 1.4 in yield. When this was recrystallized from ethanol, pure 1-
[3 ', 5'-di-O- (p-chlorobenzoyl)-
2′-Deoxy-β-D-erythro-pentofuranosyl] -5-trifluoromethyluracil was obtained. Yield 106 mg (15%) NMR, melting point: consistent with the value described in the literature.

Comparative Example 3 The reaction results of compounds (1) and (2) are shown below under the condition that only cupric chloride is used as a catalyst and no fluoride ion is present. 7.9 g of 3,5-di-O- (p-chlorobenzoyl) -2-deoxy-α-D-erythro-pentofuranosyl chloride, 5-trifluoromethyl-
5.89 g of 2,4-bis (trimethylsilyloxy) pyrimidine was dissolved in 150 ml of chloroform. This was cooled to 0 ° C., and 0.25 g of cupric chloride was added. After reacting at 0 ° C. for 10 hours, the reaction mixture was poured into 1N hydrochloric acid and separated. The organic layer was washed with water, washed with saturated aqueous sodium hydrogen carbonate and dried over magnesium sulfate. Concentration gave a clear, colorless, hard glass. This was recrystallized from ethanol to give 1-
[3 ', 5'-di-O- (p-chlorobenzoyl)-
2′-Deoxy-β-D-erythro-pentofuranosyl] -5-trifluoromethyluracil was obtained. Yield 3.2 g (30%) NMR, melting point: consistent with literature values.

Examples 2 to 5 The molar ratio of compound (1) to compound (2) was 1.2: 1.
The reaction was carried out under the same reaction conditions as in Example 1 except that the amount was adjusted to be 0 to 0.9: 1.0, and the equivalent number of copper fluoride was adjusted to be 1.0 to 0.1. After completion of the reaction, the reaction solution was treated in the same manner as in Example 1, and expressed in terms of the yield of α-form + β-form, the isolated yield of only β-form and the molar ratio of α-form: β-form to compound (1). Selectivity was determined. Table 1 shows the results.
It is shown in [Table 1].

[0023]

[Table 1]

Example 6 3,5-Di-O- (p-chlorobenzoyl) -2-deoxy-α-D-erythro-pentofuranosyl chloride (7.9 g), 5-trifluoromethyl-2,4-bis 5.89 g of (trimethylsilyloxy) pyrimidine was dissolved in 150 ml of chloroform. This was cooled to -5 ° C, and 2.5 g of cesium fluoride and 0.72 g of cupric chloride were added. After reacting at -5 ° C for 4 hours, the reaction solution was washed with 1N hydrochloric acid, washed with water, washed with saturated aqueous sodium hydrogen carbonate and dried over magnesium sulfate. Concentration gave a clear, colorless, hard glass. This was recrystallized from 15 ml of ethanol to give 1-
[3 ', 5'-di-O- (p-chlorobenzoyl)-
2′-Deoxy-β-D-erythro-pentofuranosyl] -5-trifluoromethyluracil was obtained. Yield 8.4 g (80%) NMR, melting point: consistent with literature values.

[0025]

The effects of the present invention are clear from the above Examples and Comparative Examples. That is, as shown in Example 1 and Comparative Example 1, economically expensive 5-trifluoromethyl-2,4-
When bis (trimethylsilyloxy) pyrimidine was used in an equivalent amount, the method of the present invention showed a high yield of 98% and a high selectivity of αβ selectivity of 1:11.
The usefulness is clearly recognized as compared to 77% of the method of -289595, 1: 3. Further, in the method described in JP-A-60-23397 shown in Comparative Example 2, the αβ selectivity is 1: 1.4, the isolation yield of the required β form is as low as 15%, and the usefulness of chloroform is low. Is shown. Further, as shown in Comparative Example 3, under the condition where no fluorine ion was present, the αβ selectivity was extremely reduced to 1: 2, suggesting the usefulness of the fluorine ion.

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Claims (1)

(57) [Claims] 1. A 5-trifluoromethyl-2,4-bis (trimethylsilyloxy) pyrimidine represented by the formula (1) [Formula 1] and 2-deoxy-α-D-erythro-pentofuranosyl chloride derivative represented by the formula (2)
X represents a halogen atom, and X ¹ and X ² each independently represent a hydrogen atom or a halogen atom). Formula (3) characterized in that the reaction is carried out in a chloroform solvent in the presence of fluorine ions using a copper compound as a catalyst.
A method for producing a 1- (2′-deoxy-β-D-erythro-pentofuranosyl) -5-trifluoromethyluracil derivative represented by Chemical Formula 3. Embedded image