SE451723B - 4-AMINOPYRAZOLIDE INGREDIENTS USED AS INTERMEDIATES FOR THE PREPARATION OF N- (4-PYRAZOLIDINYL) BENZAMIDES - Google Patents

Description

451 723 R? may represent, for example, hydroxy cyano, nitro, amino, fluoro, chloro, bromo, trifluoromethyl, lower alkyl, lower alkoxy, sulfamoyl or acetamido, I-4 I wherein R 3 is suitably the same or different groups and n represents 0, 1, 2 or 3.

The antiemetic properties were determined using a modification of the method described by Chen and Enxor, J. Pharmac.

Exp. Ther. go, 245-250 (1950) and Leonard-and-co-workers, J. Phar- mac. Exp. Ther. lâí, 339-345 (1966).

The gastric emptying activity was determined by the following procedure. She Spraque-Dawlay rats weighing from 117-221 g were allowed to starve for 24 hours in individual sieve-bottomed cages with water ad libitum.

The animals were arranged in groups of eight. At time zero, 9 mg / kg of the test compound was administered intraperitoneally to the rats in 5% acacia (0.4 ml / 100 g body weight). The control group received acacia alone, 4 ml / kg intraperitoneally. Thirty minutes after dosing, the rats were given orally by gavage 3 ml of a test target consisting of methylcellulose, to which had been added broth, casein, powdered sugar and corn starch to give a semi-solid homogeneous paste. 60 minutes after the test goal (after a total time of 90 minutes), the rats were killed by cervical dislocation, laparotomized and the stomach removed. The full stomach was weighed on an analytical balance scale after which it was cut and emptied, after which the empty stomach was weighed. The difference between full and empty stomach weight represented the amount of food remaining in the stomach and was subtracted from the weight of 3 ml of the test meal, whereby the amount of the meal emptied from the stomach was obtained during the test period.

In the present application, lower alkyl groups refer to 1-4 carbon atoms.

In the present application the term "lower cycloalkyl" refers to primary cyclic alkyl groups containing from 4 to 12 carbon atoms and includes such groups as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopentyl, ethylcyclohexyl and the like. J) The term "lower alkyl "includes straight or branched chains having 45 to 72 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, tertiary butyl, amyl, isoamyl, n-hexyl, n-heptyl and n-octyl groups Lower alkoxy groups have the form O-lower alkyl.

The term "phenyl lower alkyl" includes such groups as benzyl, phenethyl, phenpropylphenmethylbenzyl and the like.

Thus, the present invention relates to novel 4-amino-1,2-hydrocarbyl-pyrazolidines (II). The compounds of formula II have the formula: R 2 N 2 N 2 wherein R represents lower alkyl, lower cycloalkyl or phenyl lower alkyl, wherein R 1 represents lower alkyl and R 2 represents hydrogen or phenyl.

The compounds of formula II wherein R 2 represents hydrogen are prepared by heating a mixture of 4-halo-1,2-hydrocarbylpyrazolidine and concentrated ammonium hydroxide in a steel bomb at a temperature of from about 125 to about 200 ° C for several tim- mar.

The compounds of formula II wherein R2 represents phenyl are prepared. by reacting a 1,2-hydrocarbyl-4-arylsulfonyloxy-pyrazolidine and aniline or a substituted aniline together with a suitable solvent. 1,2-Hydrocarbyl-4-arylsulfonylogy-pyrazolidine is generally prepared by reacting the sodium salt of 1,2-hydrocarbyl-4-pyrazolidinol with benzenesulfonyl chloride or p--tolylsulfonyl chloride in a dry aprotic solvent such as toluene. The 1,2-hydrocarbyl-4-pyrazolidinols from which the respective 4-aminopyrazolidinols are prepared are either shown in or can be prepared; by the procedure set forth in U.S. Pat. No. 3,660,426.

The preparation of the hensanido compounds of formula I can be effected by contacting a 4-amino-1,2-hydrocarbylpyrazolidine II with an appropriately substituted benzoyl chloride III according to the reaction scheme as follows: AI cooc1 - RI i 'i 3 ..' <3) NH. R R-N / 3 NWC-Cï f * _ N + \\ (R) n .__) R_å | Where R, R 1, R 2 and R 3 and n are previously defined and where R 3 cannot be primary amine.

The compounds of formula I wherein -R 3 is primary amino are generally prepared by catalytic hydrogenation of the precursor compound of formula I, wherein R 3 represents nitro. Alternatively, a compound of formula I may be prepared with R 3 as an acetamido group and this compound is hydrolyzed with dilute acid to form an amino group.

The substituted benzoyl chlorides III, useful in the preparation of N- (4-pyrozolidinyl) benzamides, are either known compounds or can be prepared in a known manner and include but are not limited to the following listed compounds: 2-fluorobenzoyl chloride α-bromobenzoyl chloride 4-bromobenzoyl chloride 3,5-dinitrobenzoyl chloride 3,4-dichlorobenzoyl chloride 3,4-diethoxybenzoyl chloride 3-trifluoromethylbenzoyl chloride 4-tertiary butylbenzoyl chloride 4-butoxybenzoyl chloride I! 1451 723 2,4-Dimethoxybenzoyl chloride 4-methylbenzoyl chloride 4-cyanobenzoyl chloride 2-methoxy-5-sulfamoylbenzoyl chloride 2-methoxy-4-dimethylaminobenzoyl chloride 2-methoxy-4-nitrobenzoyl chloride 2-methoxy-5-oxy-5-oxy-5-oxy-5-methoxy brmobenzoyl chloride 2-methoxy-3-acetamido-5-trifluoromethylbenzoyl chloride. 4-Chloro-1,2-diethylpyrazolidine A solution of triphenylphosphine (52 g; 0.2 mol) in 150 ml of chloroform was treated with chlorine gas, followed by a temperature increase of the mixture to 60 ° until excess chlorine gas appeared over the surface of the mixture. Air was allowed to pass through the mixture until the greenish-yellow gas disappeared. To the cooled (30 ° C) stirred mixture was added dropwise 28.8 g (0.2 mol) of 1,2-diethyl-4-pyrazolidinol at a rate which caused the reaction mixture to drop to 40 ° C. After the addition of the stirred solution, the mixture was refluxed for two hours, cooled to room temperature and extracted with water. The combined aqueous extracts were basified with concentrated sodium hydroxide solution and the basic mixture was extracted with chloroform. The dried chloroform extracts (sodium sulfate) were concentrated under reduced pressure, and the remaining material was distilled at 92-94 ° C / 30 mm Hg to give 24.5 g (75%) of the product.

Analysis; s ~ calculated for c7H'-15N2c1 = c Vs1f, ss ~; «an ~~ 9 ',. 2-9; ~ - N 17,22 nfhånetf -' c 51,45; n 9.30; N 17.29.

Example 1 4-Amino-1,2-diethylpyrazolidine A mixture of 100 g (0.615 mol) of 4-chloro-1,2-diethylpyrazolidine and 200 ml of concentrated ammonium hydroxide in a closed steel container was heated to 150 ° C for about 36 hours. The cooled reaction mixture was extracted with isopropyl ether, the aqueous phase was saturated with potassium carbonate and extracted continuously with 451-723 chloroform for 6 hours. The dried chloroform extract (sodium sulfate) was concentrated under reduced pressure and the residue was distilled at 113-115 ° C / 40 mm Hg to give 40.5 g (45.5%) of the product. Example 2 In 4-amino-1,2-dimethylpyrazolidine A mixture of 300 g (2.22 mol) of 4-chloro-1,2-dimethylpyrazolidine and 600 ml of concentrated ammonium hydronide was heated to 100 ° C for 18 hours in a steel bomb. The cooled mixture was saturated with potassium carbonate and extracted continuously for 18 hours with chloroform. The residual material after concentration of the chloroform extract was distilled at 90-100 ° C / 40 mm Hg to give 73 g of the product.

Example 3 4-Amino-1-benzyl-2-methylpyrazolidine 4-amino-1-benzyl-2-methylpyrazolidine, b.p. 115-125 ° C / 1.0 mm Hg was prepared from 1-benzyl-2-methyl-4-pyrazolidinol according to Preparation 1 and Example 1. 7 Example 4 4-amino-1-cyclohexyl-2-methylpyrazolidine fumarate 4-amino-1-cyclohexyl-2-methylpyrazolidine, b.p. 90-100 ° C / 0.5-1.0 mm Hg was prepared from 1-cyclohexyl-2-methylpyrazolidinol according to Preparation 1 and Example 1. The furamate salt melted at 149-151 ° C.

H Example 5 4-Amino-1-isopropyl-2-methylpyrazolidine 4-amino-1-isopropyl-2-methylpyrazolidine, b.p. 110-115 ° C / 50 mm Hg was prepared from 1-isopropyl-2-methylpyrazolidinol according to Preparation 1 and Example 1.

Example 6 When in Example 1 equimolar amounts of methylamine in methanol were used instead of concentrated ammonium hydroxide, 4-methylamino-1,2-diethylpyrazolidine was obtained. Example 45 7 4-Fluoro-N- (1,2-ethyl-4-pyrazolinyl) benzamide A solution of 10 g (0.026 mol) of 1,2-diethyl-4-phthalimidopyrazolidine maleate in 25 ml of GN hydrochloric acid was refluxed 2 hours, after which the resulting mixture was cooled and filtered, the filter cake was washed with water, which was combined with the acidic solution; The acidic solution was basified with dilute sodium hydroxide and cooled with ice. To the remaining solution was added 8 .2 g (0.052 mol) of p-fluorobenzoyl chloride and the mixture was shaken for 10 minutes The resulting mixture was extracted with chloroform, the chloroform was diluted with an equal volume of isopropyl ether and the resulting solution was extracted with dilute hydrochloric acid.

The acid phase was basified with dilute sodium hydroxide and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The vein residue was crystallized from isooctane-isopropyl ether and recrystallized from isooctane-isopropyl ether containing a few drops of ethyl acetate and clarified by treatment with activated carbon. The product (2.0 g; 29%) melted at 114-11 ° C.

Analysis: Calculated for C 14 H 20 N 3 OF: C 63.38; H 7.607, N 15.84 - Found: C 63.36; H 7.61; N 15.96.

Example 8 3,4,5-Trimethoxy-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide To 10-g (0.09 mol) of 4-amino-1,2-dimethylpyrazolidine in chloroform was added with stirring. 7. g (0.09 mol) of 3,4,5-trimethoxybenzoyl chloride. After stirring for 30 minutes, the solution was extracted with dilute sodium hydroxide. The chloroform solution was dried (sodium sulfate), filtered and the filtrate concentrated. The resulting crystalline material was recrystallized from equal amounts of ethyl acetate and isopropyl ether. The product (12.1 g; 44%) melted at 163-166 ° C.

Analysis; Calculated for c 15 H 23 N 3 O 4 = c 58.24; H 7.49; A 13.58 Erna11et = c 58.20; H 7.45; N 13.19. 4-Nitro-N- (1,2-diethyl-4-pyrazolidinyl) benzamide hydrochloride To a solution of 40.5 g (0.28 mol) of 4-amino-1,2-diethylpyrazolidine in 200 ml of chloroform 52 g (0.28 mol) of p-nitrobenzyl chloride in 200 ml of chloroform were added with stirring. The solution was allowed to stand overnight and then extracted with dilute sodium hydroxide. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized twice from isopropyl ether-ethyl acetate to give 73 g (80%) of the free base. 7 H Analysis: Calculated for C 14 H 20 N 4 O 3: C 57.52; H 6.90; N 19.17 Erhä11et = A. c 57.56; H 6.94; N 18.99.

The base was converted to the hydrochloride salt and crystallized from isopropyl alkenel, melting at 189-191 ° C (dec.).

Analysis: Calculated for c 14 H 21 N 4 O 3 Cl = c 51.14; - H 6.44; N 17.04 Found: C 50.96; H 6.59; N 16.58. + h-

Claims (1)

A 45-amihopyrazolidine has the formula wherein R represents lower alkyl, lower cycloalkyl or phenyl-lower alkyl, wherein R 1 represents lower alkyl and wherein R 2 represents hydrogen or phenyl.