DK145058B - PROCEDURE FOR MANUFACTURING FTORAFUR - Google Patents

Description

/ ftfel

<19) DENMARK

(12) PUBLICATION MANAGEMENT mi 145058 B

PATENT AND TRADEMARKET DIRECTORATE

(21) Application No. 3687/79 (B1) IntCI. * C 07 0 £ 05/04 (22) Filing Day 3 · Sep. 1979 (24) Race day 16 · Oct. 1 977 (41) Aim. available Sep 3 1979 (44) Presented 1 Aug 6 1982 (86) International application no.

(86) International Filing Day (85) Continuation Day - (62) Stock Application No. ^ 9 ^ / 77

(30) Priority 12 Oct. 1976, 50071 IL

(71) Applicant ABIC LTD., Ramat-Gan, IL.

(72) Inventor Uri Michael, IL: Zabar _SaBBon, IL: Eva ^ choenberger, IL.

(74) Plougmann & Vingtoft Patent Bureau.

(54) Proceedings for the preparation of ftorafur.

The present invention relates to a particular process for the preparation of N - (2'-furanidyl) -5-fluoro-uracil (hereinafter referred to as "ftorafur").

Ftorafur is a very important anticancer compound and has heretofore been prepared particularly by the alkylation of 5-fluorouracil or one of its derivatives, e.g. the mercuric complex or the silyl or stannyl-Ό derivatives. However, to date, no completely satisfactory alkylating agent has been found to carry out this process.

The most frequently described alkylating agent used for this purpose is 2-chloro-furanidine (cf. Japanese Patent Application No. 51-008282). However, the use of this chloride has certain disadvantages: 1. No completely satisfactory process is known for its preparation. All known methods, e.g. those described in H. Gross, Chem. Ber. 9_5, page 83 (1962), H. Paulsen et al., Chem.Ber. 108, 2279 (1975) and H. Normant Compt. troughs. Ac. Sc. 228 (1949), page 102, has certain disadvantages, e.g. that they yield low yields, are technically complicated, etc.

2. Certain chloroethers are highly carcinogenic, and the use of this volatile compound can therefore be dangerous for the people who deal with them.

3. Both in the preparation of the compound and in the final step of preparing ftorafur, HCl is present which is highly undesirable due to the strongly corrosive properties of this acid.

Also known are some methods by which 2-chloro-furanidine 'is replaced by 2-acyloxy-, 2-aryloxy- or certain 2-lower alkoxy-furanidines, cf. eg. Belgian Patent No. 807,556 and Japanese Patent No. 50-50 384.

Neither is the use of these compounds completely satisfactory, which is due to the following: 1. a. Their method of preparation either comprises the use of highly undesirable starting materials, e.g. peroxides as described by S.O. Lawesson. Archives of Chemistry 17, 475 (1961).

b. Or their method of manufacture includes rather complicated work-up procedures for insulating the compound.

2. Furthermore, the reaction with 5-fluoro-uracil or with 2,4-bis-trialkylsilyl) -5-fluoro-uracil (hereinafter referred to as "silylated 5-fluoro-uracil") is very often undesirable by-products, e.g.

1 3 N, N-bis- (2 * -furanidyl-5-fluoro-uracil), cf. Japanese Patent Specification No. 50-50384.

3 Since the starting compounds must be isolated before they can be reacted further, they cannot be used in situ, ie. in a "one-pot" approach.

It has now been found that the above disadvantages can be largely overcome by reacting bis-2-furanidyl ether with silylated 5-fluoro-uracil in the presence of a Friedel-Crafts type catalyst in an inert organic solvent. .

The process according to the invention is characterized by the characterizing part of claim 1.

The alkylation reaction can be carried out at temperatures between -20 and + 120 ° C. However, the reaction is preferably carried out at room temperature.

An "inert organic solvent" herein means a solvent which does not react with any of the reactants and which can dissolve at least one of the starting materials. As suitable solvents, e.g. mention is made of dioxane, tetrahydrofuran, dihydrofuran and other ethers, acetone, methyl ethyl ketone and other ketones, acetonitriles, dimethylformamide, chlorinated hydrocarbons and hydrocarbons.

Suitable Friedel-Crafts type catalysts include certain Lewis, acids, e.g. SnCl ^, BF ^ or TiCl₂ or NaX. Preferably up to molar amounts of the catalyst are used.

The method according to the invention has many advantages. It gives a very high yield. It can be carried out as a "one-pot" approach in that bis-2-furanidyl ether can be prepared in situ by reacting 2,3-dihydrofuran with water in the presence of a catalytic amount of an acidic catalyst at a pH below 2, 5, and the resulting mixture containing bis-2-furanidyl ether can be reacted directly with silylated 5-fluorouracil by the process of the invention. Furthermore, as has been shown, and as has been confirmed by the high yields, no undesirable side reactions occur.

Bis-2-furanidyl ether can be obtained from the above reaction mixture by distillation if desired.

Examples 1 to 5 and 9 illustrate the process of the invention, while Examples 6-8 illustrate the preparation of bis-2-furanidyl ether.

Example 1.

16.80 g (0.240 mole) of 2,3-dihydrofuran is slowly added with stirring to a pH 2.0 buffered aqueous solution (1.8 ml, 0.100 mole) while maintaining the temperature at 60 - 65 ° C. . When the addition is complete, the reaction mixture is further stirred at 65 ° C for 1/2 hour, then cooled to room temperature and the volatiles removed by heating to 50 ° C under reduced pressure. In this way, 16.50 g of colorless residue is obtained. Add 1,900 g of the crude addition product with stirring to a mixture of stannous chloride (0.65 ml; 5.5 millimoles) and anhydrous dioxane (20 ml) followed by silylated 5-fluorouracil (2.740 g; 10.0 millimoles). The reaction mixture is stirred at room temperature for 3 hours and then evaporated under reduced pressure. Then 20 ml of isopropanol is added and the reaction mixture is stirred at room temperature for 10 minutes. After removal of the isopropanol by distillation, the resulting crude product is taken up in acetone / petroleum ether and filtered through a layer of silica gel. Phorafur (1.840 g, mp 158-160 ° C) and unreacted 5-fluorouracil (0.100 g) are thus obtained. Further recrystallization of chlorobenzene (55 ml) is obtained by pure phtorafur (1.780 g; 96% of theory), mp 169-170 ° C.

5 1Λ5058

Example 2.

1,600 g of crude addition product of water to 2,3-dihydrofuran (prepared as described in Example 1) is added with stirring to a mixture of 0.65 ml (5.5 millimoles) of stannous chloride and 20 ml of anhydrous toluene. Immediately, 2.700 g (10.0 millimoles) of silylated 5-fluorouracil are added and the reaction is stirred for 3 hours at room temperature. 5 ml of isopropanol are added and after 10 minutes stirring at room temperature 25 ml of chloroform are added. The resulting mixture is extracted with small portions of a 5% aqueous 1 ° C solution (until a pH of 7 - 7.5 is obtained). The aqueous phase is extracted with 4 x 5 ml CHCl 3. The combined organic phases are dried over MgSO 4 and the solvents are removed by distillation under reduced pressure. The. the resulting residue is treated with 20 ml of boiling chlorobenzene and filtered hot, and the filtrate is evaporated to ca. half the volume, cool and dilute with 10 ml of petroleum ether. Suction filtration yields 1,720 g (86% of theory) of ftorafur with a melting point of 168 - 169 ° C.

Example 3

Add 1,600 g of crude addition product of water to 2,3-dihydrofuran (prepared as described in Example 1) with a mixture of 0.710 g (5.0 millimoles) of boron trifluoride etherate and 20 ml of anhydrous dioxane, after which silylated 5-fluorouracil ( 2.740 g, 10.0 millimoles). The reaction mixture is stirred for 3 hours at room temperature and then worked up as described in Example 1. 0.200 g of unreacted 5-fluorouracil and 1.580 g (93% of theory) of ftorafur are isolated.

Example 4

2,400 g of crude addition product of water to 2,3-dihydrofuran (prepared as described in Example 1) are added with stirring to a mixture of 0.30 ml (2.6 millimoles) of stannous chloride, 25 ml of anhydrous dioxane and 2.740 g (10.0 millimol) of silylated 5-fluorouracil. The reaction is stirred at room temperature for 2 hours, then 3 ml of isopropanol is added and the mixture is stirred for a further 5 minutes. The volatile components of the mixture are removed under reduced pressure.

The oil obtained as the residue is dissolved in 20 ml of chloroform and stirred for 15 minutes with 15 ml of a 15% 1 s aqueous 2 CO 2 solution. The phases are separated, and the organic phase is extracted once again with 3 ml of the 15% aqueous 1 CO 2 solution. The combined alkaline solutions are acidified to pH 3 and extracted with 10 x 5 ml of chloroform. The combined organic phases are dried over MgSO4 and evaporated to dryness. 1.840 g (92% of theory) of phorafur are obtained, m.p. 160 - 161 ° C.

Example 5

Add 1,600 g of crude addition product of water to 2,3-dihydrofuran (prepared as described in Example 1) to a solution of 1,880 g (12.5 millimoles) of sodium iodide in anhydrous acetonitrile (20 ml), and immediately thereafter add 2,740 g (10.0 millimoles) of silylated 5-fluorouracil. The reaction mixture is refluxed and stirred for 4 hours.

The volatiles are removed under reduced pressure (45 - 50 ° C / 30 mm Hg). 20 ml of isopropanol is added to the oil recovered as the residue and the resulting mixture is stirred for 10 minutes at room temperature, then concentrated in vacuo. The resulting crude product is filtered through a layer of silica gel. 0.169 g of unreacted 5-fluorouracil and 1,700 g of ftorafur are obtained. By recrystallization from chlorobenzene, 1.560 g (90% of theory) of pure phoraphor were obtained, m.p. 168-170 ° C.

Example 6

52.5 g (0.750 millimoles) of 2,3-dihydroprane are added with stirring to 5.4 ml (0.300 mol) of dilute phosphoric acid (pH 1) while maintaining the temperature at 60-65 ° C. The reaction mixture is further heated to 65 ° C for 1/2 hour. The reaction mixture is cooled and the volatiles removed by heating to 50 ° C under reduced pressure. The colorless oily residue (49.0 g) is washed with 3 ml of 25% aqueous 1 CO 2 solution, then washed with 2x2 ml of an aqueous saturated sodium chloride solution, dried over magnesium sulfate and filtered. The resulting oil (46.0 g) is distilled under reduced pressure through a 2.5 cm x 12.5 cm adiabatic column filled with Podbielniak's Heli Pak 3013 spirals (0.125 cm x 0.250 cm). In this way, 19.5 g of a compound which is bis-2-furanidyl ether is obtained, boiling point 93 - 95 ° C / 32 mm Hg; NMR spectrum (in CDCl2); <5 = 1.90 ppm (complext center), <5 = 3.53 ppm (complext center) and δ = 5.40 ppm (complext center) in the ratios · 4: 2: 1, respectively.

IR Spectrum (δ-pure (δ, u): 3.40 - 3.50 (sharp doublet); 6.85 - 6.95 (sharp doublet); 7.30; 7.50; 8.45; , 00; 9.30; 9.70; 10.00 (wide); 10.80 (wide); 11.70 (wide).

The major ions in the compound's mass spectrum are at the following mass units: 41, 57, 71, 87 and 114.

Example 7

33.6 g (0.480 mol) of 2,3-dihydrofuran are added with stirring to a suspension of acid-washed Amberlite IR-120 (H) (0.5 g) in 3.6 ml (0.200 mol) of water while maintaining the temperature at 60 ° C. . When the addition is complete, the mixture is allowed to cool (30 ° C) and stirred further for 12 hours. The pure bis-2-furanidyl ether (11.4 g) is isolated as described in Example 6.

Example 8.

33.6 g (0.48Q mol) of 2,3-dihydrofuran are slowly added with stirring to a pH 2.0 solution (3.6 ml, 0.200 mol) while maintaining the temperature at 60 - 63 ° C. When the addition is complete,

Claims (3)

In the reaction mixture, the reaction mixture is further heated to 65 ° C for 0.5 hour. The pure bis-2-furanidyl ether (12.5 g) is isolated as described in Example 6. Example 9. 0. 65 ml. (5.5 millimoles) of stannous chloride is added with stirring to 20 ml of freshly distilled dioxane. To the resulting stirred mixture is added 0.948 g (6.0 millimoles) of bis-2-furanidyl ether prepared as described in Example 6, and then 2,740 g (10.0 millimoles) of silylated 5-fluorouracil are added. The reaction mixture is stirred for 3 hours at room temperature, then evaporated under reduced pressure (50 - 55 ° C / 30 mm Hg). The residue is then added 20 ml of isopropanol and, after stirring for a few minutes at room temperature, the isopropanol is removed by distillation in vacuo. The crude reaction mixture is put on a silica gel column. Ftorafur (1.490 g, mp 159 - 160 ° C) is first eluted with a 4: 6 mixture of acetone: petroleum ether (bp 40 - 60 ° C), and then 5-fluorouracil - (0, 320 g) is eluted. Recrystallization of isopropanol (35 ml) afforded pure phtorafur (1.420 g, 94% of theory), m.p. 169-170 ° C. Claims. Process for the preparation of ftorafur, characterized in that bis-2-furanidyl ether is reacted with silylated 5-fluorouracil in the presence of a Friedel-Crafts type catalyst in an inert organic solvent. Process according to claim 1, characterized in that the Friedel-Crafts type catalyst is a Lewis acid. Process according to claim 2, characterized in that the catalyst is SnCl 2, BF 2 or TiCl 2.