HU206698B - Process for producing n-benzyl-tetrahydro-furane-carboxamide derivatives - Google Patents

Abstract

N-Benzyl-tetra-hydro-furan- carboxy-amides of formula (I) are prepd. from diamino derivs. of formula (II). These are acylated by reactive derivs. of tetra-hydro-furan- carboxylic-acids of formula (III). - In formulae, (I) and (II), R and R1 are each H or 1-4C alkyl gp. or R and R1 are together an ethylene or propylene gp.; n = 2 or 3, provided that when n = 3 and R is a methyl gp., then R1 cannot also be a Me gp.. (1pp Dwg.No.0/0)

Description

The present invention relates to a process for the preparation of a novel compound of formula (I)

For the preparation of N-benzyltetrahydrofuranecarboxamide derivatives, wherein

R ¹ and R ¹ are independently hydrogen, C 1-4 alkyl, or R ¹ together are ethylene or propylene, n is 2 or 3, with the proviso that when n is 3 and R is methyl, R ¹ may have a meaning other than methyl.

The invention encompasses all isomeric and tautomeric forms of the compounds of formula (I). The meaning of variable substituents is not changed throughout the description and will not be given below.

The compounds of formula (I) can be reduced easily, economically and in good yield, to the corresponding pure compound of formula (IV), e.g. can be converted into quinazoline derivatives with known antihypertensive activity, as disclosed in British Patent No. 6,673,613.

The reduction of the compounds of formula (I) to the compound of formula (IV) in a reaction-inert solvent, preferably alcohol, especially methanol, at 25-100 ° C, preferably 3080 ° C, especially 50-60 ° C. on catalytic hydrogenation at a pressure of 0.2 to 7.0 MPa, preferably 5 MPa, on a support with 5-20% palladium on catalyst, preferably 10% palladium on catalyst.

The present invention provides for the acylation of a diamino derivative (H) with a reactive derivative of tetrahydrofuran carboxylic acid (III). The diamino derivatives of formula (II) are known in the literature or by known methods [Chem. Pharm. Bull., 15 (2), 228].

The reactive derivative of tetrahydro-2-furancarboxylic acid of formula (III) is understood to mean, for example, a mixed ester thereof with alkyl formate or aralkyl ester in the presence of triethylamine in the presence of an acid acceptor. Acylation is difficult to accomplish with acid chloride because it is known that tetrahydro-2-furoyl chloride (III) prepared from tetrahydro-2-furancarboxylic acid (III) is readily decomposed. [J. Chem. Soc. 71, 3372 (1949)]. The reaction is carried out in an inert solvent, preferably an apolar or polar aprotic solvent, preferably dioxane, tetrahydrofuran, chloroform or 1,2-dichloroethane, particularly preferably tetrahydrofuran, at -30 to 20 ° C, preferably at -30 ° C. and -20 ° C with a mixed ester at 5 ° C. Coupling with carbonyldiimidazole may also be carried out in an apolar or polar aprotic solvent, preferably benzene, toluene, dioxane, tetrahydrofuran at 20-80 ° C, particularly preferably tetrahydrofuran at 65 ° C.

The compounds of formula (I) are isolated from the reaction mixture by a method known per se, preferably by evaporation followed by filtration of the resulting triethylamine chlorohydrate followed by distillation.

The following examples illustrate the process, but are not intended to limit the process to the examples.

Example 1

To a solution of 4-benzyl-1- (tetrahydrofuroyl) piperazine g (0.11 mol) in tetrahydrofuran-2-carboxylic acid and 80 ml tetrahydrofuran under cooling and stirring, 11.1 g = 15.8 ml (0.11 mol) triethylamine is added dropwise. After stirring for 15 minutes, the reaction mixture was cooled to -30 ° C and at this temperature, a solution of ethyl chloroformate (11.9 g, 10.8 mL, 0.11 mol) in tetrahydrofuran (10 mL) was added dropwise and stirred for a further 10 minutes. A solution of 1-benzylpiperazine (19.4 g, 0.11 mol) in tetrahydrofuran (20 mL) was added dropwise while maintaining the temperature at 5 ° C. After the addition, the mixture was stirred at room temperature for an additional 3 hours until the evolution of carbon dioxide ceased. After filtration of the precipitated triethylamine hydrochloride, the reaction mixture was evaporated and fractionated in vacuo.

24.5 g (81%) of 4-benzyl-1- (tetrahydro-2-furoyl) piperazine are obtained.

fp .; 150-153 ° C (13.33 Pa)

Example 2

4-Benzyl-l- (tetrahydro-2-furoyl) piperazine

In each case, the procedure of Example 1 was repeated except that 80 ml of dioxane was used instead of tetrahydrofuran and the reaction was carried out at -10 ° C instead of 5 ° C.

19.8 g (65%) of the expected product are obtained.

Example 3

4-Benzyl-1- (tetrahydro-2-fluoryl) -piperazine

In each case, the procedure of Example 1 was followed, except that 80 ml of 1,2-dichloroethane was used instead of tetrahydrofuran and the reaction was carried out at 20 ° C instead of 5 ° C.

22.3 g (74%) of the title compound are obtained.

Example 4

4-Benzyl-l- (tetrahydro-2-furoyl) homopiperazine

In each case, the procedure of Example 1 was followed except that 20.9 g (0.11 mole) of 1-benzyl-homopiperazine was used in place of 1-benzylpiperazine.

27.6 g (87%) of 4-benzyl-1- (tetrahydro-2-furoyl) -homopiperazine are obtained.

Mp: 161-163 ° C (10.64 Pa)

Example 5

N- [3- (N-methyl-N-benzyl) aminopropyl] -tetrahidro2-furancarboxamide

In each case, the procedure of Example 1 was followed, except that 19.6 g (0.11 mole) of N-benzyl-N-methyl-1,3-diaminopropane was replaced by 1-benzylpiperazine and 80 ml of tetrahydrofuran. ml of chloroform was used.

25.4 g (83%) of the title compound are obtained.

Mp: 167-170 ° C (2.66 Pa)

HU 206 698 Β

Example 6

4-Benzyl-l- (tetrahydro-2-furoyl) homopiperazine

To a solution of 32.4 g (0.2 mol) of carbonyldiimidazole in 200 ml of tetrahydrofuran was added dropwise 23.2 g (0.2 mol) of tetrahydrofuran-2-carboxylic acid at room temperature and the mixture was heated at 40 ° C for 3/4 hours. After cooling to room temperature, a solution of 38.1 g (0.2 mol) of 1-benzyl-homopiperazine and 40 ml of tetrahydrofuran was added dropwise and the mixture was refluxed for 3 hours. After evaporation of the solvent, 200 ml of 1N sodium hydroxide are added to the residue and extracted with 2 x 100 ml of chloroform. The combined organic layers were re-extracted with water (100 mL), dried over sodium sulfate, then removed in vacuo and the residue fractionated in vacuo.

51.6 g (89%) of 4-benzyl-1- (tetrahydro-2-furoyl) -homopiperazine are obtained.

Example 7

4-Benzyl-l- (tetrahydro-2-furoyl) piperazine

In each case, the procedure of Example 6 was followed, except that 35.3 g (0.2 mole) of 1-benzylpiperazine was substituted for 1-benzyl-homopiperazine and 240 ml of dioxane was used instead of tetrahydrofuran.

46.3 g (84%) of 4-benzyl-1- (tetrahydro-2-furoyl) piperazine are obtained.

Example 8

N- [3- (N-methyl-N-benzyl) aminopropyl] -tetrahidro2-furancarboxamide

In each case, the procedure of Example 6 was followed except that 35.7 g (0.2 mole) of N-benzyl-N-methyl-1,3-diaminopropane and 250 tetrahydrofuran were substituted for 1-benzyl-homopiperazine. ml of benzene was used.

Yield: 41.2 g (74.5%) of N- [3- (N-methyl-N-benzyl) aminopropyl] -tetrahydro-2-furancarboxamide.

Example 9

N- (tetrahydro-2-furoyl) piperazine

To a solution of 4-benzyl-1- (tetrahydro-2-furoyl) -piperazine (54.9 g, 0.2 mol) in methanol (250 mL) was added 10% palladium on carbon (5 g) followed by autoclaving at 5 MPa and 50 ° C. hydrogenated. After uptake of the calculated amount of hydrogen, the reaction mixture was filtered, washed with methanol (2 x 50 ml) and then removed in vacuo. The residual crude product was fractionated in vacuo.

33.6 g (92%) of N- (tetrahydro-2-furoyl) -piperazine are obtained.

Mp: 123-125 ° C (26.66 Pa)

Example 10

N- (tetrahydro-2-furoyl) piperazine

In all cases, the procedure of Example 9 was followed, except that 250 ml of ethanol was used instead of methanol and the reaction was carried out at 25 'C instead of 50' C and at 0.2 MPa.

Yield: 27.3 g (75%) of the title compound.

Claims (3)

PATENT CLAIMS A process for the preparation of a novel N-benzyltetrahydrofuranecarboxamide derivative of formula (I) wherein R and R * are each independently hydrogen or C 1-4 alkyl, or R and R ¹ taken together are ethylene or propylene, n is 2 or 3, with the proviso that when n is 3 and R is methyl , ^R1 does not represent methyl group - preparation, characterized in that a (Π) is acylated diamino derivative (III) tetrahydro-furan-carboxylic acid is reacted with a reactive derivative thereof. Process according to Claim 1, characterized in that the reaction is carried out in an apolar or polar aprotic solvent, preferably tetrahydrofuran. Process according to claim 1, characterized in that the reaction is carried out between -30 and +20 'C.