Process for preparing dihydrofuranone derivatives

Abstract: The present invention provides a process for preparing dihydrofuranone derivative of the fornula (III): wherein R¹ and R³ are individually lower alkyl, and R² is hydrogen or lower alkyl, by reacting a dihydrofuranone derivative of the formula (I): wherein R¹ is as defined above, with a malonic acid derivative of the formula (II): wherein R² and R³ are as defined above, in the presence of an alkalimetal alkoxide and/or an alkalimetal hydroxide.

Description: The present invention relates to an industrially advantageous process for preparing a dihydrofuranone derivative of formula (III) : wherein R 1 and R 3 , which may be the same or different, each represent lower alkyl, and R 2 is hydrogen or lower alkyl, which is useful as an intermediate for the synthesis of pilocarpine and analogues thereof. Pilocarpine is useful for the treatment of glaucoma. The present invention provides a process for preparing a dihydrofuranone derivative of formula (III) as defined above which comprises reacting a dihydrofuranone derivative of formula (I) : wherein R 1 is as defined above, with a malonic acid derivative of formula (II) : wherein R 2 and R 3 are as defined above, in the presence of an alkali metal alkoxide and/or an alkali metal hydroxide. With respect to the dihydrofuranone derivative of formula (I) and the malonic acid derivative of formula (II) used as starting materials in the present invention, and to the product dihydrofuranone derivative of formula (III), those compounds in which R 1 is ethyl, R 2 is methyl and R 3 is t-butyl have been disclosed in Tetrahedron 28 : 967 (1972). In this reference, a method of preparing a dihydrofuranone derivative of formula (III) by reacting a dihydrofuranone derivative (I) with a malonic acid derivative (II) in the presence of sodium hydride has been described. However, such a method has problems and is industrially disadvantageous because of the inflammability of sodium hydride used and the possibility of explosion of hydrogen gas generated during the reaction. The present invention provides an industrially advantageous process for preparing the dihydrofuranone derivative of formula (III) by reacting a dihydrofuranone derivative (I) with a malonic acid derivative (II) in high yield and without fear of explosion and inflammation. The inventors have surprisingly found that the dihydrofuranone derivative of formula (III) can be obtained without fear of inflammation and explosion by using a metal alkoxide and/or a metal hydroxide instead of the sodium hydride used in the abovementioned prior method. The starting compounds, dihydrofuranone derivative (I) and malonic acid derivative (II) , used in the present process, may be prepared in an analogous way as in the above mentioned reference. The term "lower alkyl" in the definitions of R 1 , R 2 and R 3 includes straight and branched chain alkyls, for example, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl and t-butyl. The substituent R 2 denotes a hydrogen atom in addition to lower alkyl. The present process may usually be carried out in the presence of an inert solvent, for example ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-diethoxyethane, 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, xylene; and amides such as formamide, dimethylformamide, N-methylpyrrolidone. Tetrahydrofuran, toluene and dimethylformamide are preferred. Examples of alkali metal alkoxides are sodium methoxide, sodium ethoxide, sodium t-butoxide and potassium t-butoxide. Sodium ethoxide, sodium t-butoxide and potassium t-butoxide are preferred. As an alkali metal hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide may be mentioned. Sodium hydroxide and potassium hydroxide are preferred. The abovementioned compounds may be used alone or in combinations thereof. These compounds can be used safely due to their lack of inflammability. In the practice of the present invention, the malonic acid derivative (II) is generally used in an amount of 0.1-5 mol, preferably 0.5-1.2 mol, per mol of the starting dihydrofuranone derivative (I), and the alkali metal alkoxide and/or alkali metal hydroxide is generally used in an amount of 0.1-5 mol, preferably 0.5-1.2 mol, per mol of the starting dihydrofuranone derivative (I). The amount of the solvent used is usually 2-100 times, preferably 5-30 times, the weight of the starting dihydrofuranone derivative (I). The reaction is generally conducted at -30°C to +150°C, preferably at 3°C to +80°C, for 1 minute to 10 hours, preferably for 10 minutes to 5 hours. After completion of the reaction, the reaction mixture is worked up in a conventional way to give the desired dihydrofuranone derivative (III) product. The invention is further illustrated by the following Examples. Example 1 1.41 g(0.015 mol) of sodium t-butoxide and 10 ml of toluene were placed in a 100 ml reactor equipped with a thermometer and a dropping funnel, and the mixture was stirred at room temperature for 30 minutes under N 2 . To the mixture, a solution of 4.00 g(0.015 mol) of di-t-butyl acetamidomalonate in 30 ml of toluene was added dropwise at room temperature, followed by heating at 60°C for 2 hours. The reaction mixture was cooled on ice, and a solution of the compound (I) (R 1 is ethyl, prepared from 2.52 g (0.015 mol) of (+)-homopilopic acid according to the method described in Tetrahedron 28: 967, 1972) in 10 ml of toluene was added while maintaining the temperature below 10°C. After the addition, the reaction mixture was stirred for an additional hour. To the mixture thus obtained, 20 ml of ice-water was added and the toluene layer was removed. The aqueous layer was extracted with 30 ml of ethyl acetate, and the combined organic layer was washed with saturated sodium chloride solution and dryed over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give an oil which was diluted with isopropyl alcohol to a volume of 100 ml. A 5 ml aliquot of this solution was diluted with isopropyl alcohol to a volume of 25 ml. This solution was analyzed by a HPLC column (column: R-SIL-5-06 S-5 60A, YMC, eluent: n-hexane/isopropyl alcohol 9:1, internal standard: 1-acetylaminoadamantane). The yield of the desired dihydrofuranone derivative (III) was 70 %. The remainder of the reaction mixture was purified by silicagel column chromatography (eluent: n-hexane/acetone 3:1), and the resultant solid was recrystallyzed from n-hexane/acetone 3:1 to give 3.77 g (yield 60%) of the dihydrofuranone derivative (III) wherein R 1 is ethyl, R 2 is methyl and R 3 is t-butyl as white crystals. The 1 H-NMR and mass spectrum (molecular ion peak 428) of the crystals are identical with those of the authentic sample. Example 2 The procedure of Example 1 was followed using (±) homopilopic acid instead of (+)-homopilopic acid. Yield: 70 % (HPLC). Example 3 The procedure of Example 1 was followed using 0.652 g (0.015 mol) of sodium hydroxide in 2 ml of H 2 O as a base, and a solution of di-t-butyl acetamidomalonate in toluene which had previously been dehydrated by azeotropic distillation. Yield: 49 % (HPLC). Example 4 The procedure of Example 1 was followed using dioxane instead of toluene. Yield: 51 % (HPLC). Example 5 The procedure of Example 1 was followed using dimethylformamide instead of toluene. Yield: 34 % (HPLC). Example 6 The procedure of Example 1 was followed using 1.06 g of sodium ethoxide instead of sodium t-butoxide. Yield: 42 % (HPLC). Example 7 The procedure of Example 1 was followed using 1.06 g of sodium ethoxide instead of sodium t-butoxide and dry THF instead of toluene. Yield: 62 % (HPLC). Example 8 The procedure of Example 1 was followed except that 1.06 g of sodium ethoxide was used instead of sodium t-butoxide and the heating after the addition of the solution of di-t-butyl acetamidomalonate in toluene was effected at 90°C instead of 60°C. Yield: 32 % (HPLC). Example 9 The procedure of Example 1 was followed using 1.06 g of sodium ethoxide instead of sodium t-butoxide and also using a solution of 4.00 g (0.015 mol) of di-t-butyl acetamidomalonate in 90 ml of toluene. Yield: 18 % (HPLC). Example 10 The procedure of Example 1 was followed using 1.06 g of sodium ethoxide instead of sodium t-butoxide and also using a solution of 4.00 g (0.015 mol) of di-t-butyl acetamidomalonate in 20 ml of toluene. Yield: 32 % (HPLC). Example 11 The procedure of Example 1 was followed using 1.74 g of potassium t-butoxide instead of sodium t-butoxide. Yield: 49 % (HPLC).

Claims: A process for preparing a dihydrofuranone derivative of formula (III): wherein R 1 and R 3 , which may be the same or different, each represent lower alkyl, and R 2 is hydrogen or lower alkyl, which comprises reacting a dihydrofuranone derivative of formula (I): wherein R 1 is as defined above, with a malonic acid derivative of formula (II): wherein R 2 and R 3 are as defined above, in the presence of an alkali metal alkoxide and/or an alkali metal hydroxide. A process according to claim 1 wherein the molar ratio of (II) to (I) is from 0.5 to 1.2:1. A process according to claim 1 or 2 wherein the amount of alkali metal alkoxide and/or hydroxide is from 0.5 to 1.2 mol per mol of (I). A process according to claim 1, 2 or 3 wherein the reaction temperature is from 3° to 80°C.

Inventors: IMUTA JUNICHI, KIHARA NORIAKI, ORI AIICHIRO, IMUTA, JUNICHI, KIHARA, NORIAKI, ORI, AIICHIRO, IMUTA, JUNICHI, C/O MITSUI PETROCHEMICAL IND., LTD, Kihara, Noriaki, c/o MITSUI PETROCHEMICAL IND. LTD, Ori, Aiichiro, c/o MITSUI PETROCHEMICAL IND., LTD
Applicants: IWAKI SEIYAKU KK, IWAKI SEIYAKU CO., LTD.
Application year: 1991
Main classification: C07D307
IPC codes: C07D307