IL116656A

IL116656A - 4-Amino-1, 3, 3a, 4, 7, 7a- hexahydroisoindole compounds

Info

Publication number: IL116656A
Application number: IL11665692A
Authority: IL
Original assignee: Bayer Ag
Priority date: 1991-06-22
Filing date: 1992-06-19
Publication date: 1996-10-31
Also published as: IL116656A0

Description

Ui>NHN iTnVpn-a7,7, ,a3,3>l-^>>3N- JiiaiMJi 4-Amino-l,3,3a,4,7,7a-hexahydroisoindole compounds Bayer Aktiengesellschaft C.100390 in which R and R' denote hydrogen or methyl.

These compounds are useful as intermediates for preparing the pharmaceutically active derivatives which are described and claimed in Israel patent specification No. 102261, from which this application is divided.

The following examples are used as a non-limiting illustration of the invention.

Example A 4-Methylamino- 1 , 3 , 3a , 4 , 7 , 7a-hexahydroisoindole Method I: 14.4 g (60 mmol) of 70 % strength 1- ( tert . -butyloxy-carbonylamino ) -1 , 3-butadiene [J. Org. Chem. 43., 2164 (1978)], as a solution in 30 ml of absolute tetrahydro- furan, are added dropwise to 10.1 g (60 mmol) of N-tri-methylsilylmaleimide [J. Org. Chem. 4.0, 24 (1975)] in 30 ml of absolute tetrahydrofuran, which have been initially introduced into the reaction vessel. When the exothermic reaction has subsided, the mixture is boiled under reflux cooling for a further hour.

The cooled reaction mixture is then added dropwise, under nitrogen, to 7.6 g (0.2 mol) of lithium aluminium hydride in 200 ml of absolute tetrahydrofuran, which have been initially introduced into the reaction vessel. The mixture is then boiled under reflux cooling for 14 hours. 7.6 g of water in 23 ml of tetrahydrofuran, 7.6 g of 10 % strength sodium hydroxide solution and 22.8 g of water are then added dropwise in succession to the cooled reaction mixture. The salts are filtered off and the filtrate is concentrated in vacuo. The residue (10.3 g) is distilled at 87eC/0.8 mbar. 1 The distillate is taken up in 80 ml of absolute pentane, the mixture is filtered and the product is crystallised by cooling to -70 °C.

Yield: 3.3 g, melting point: 72 - 82 eC.

Treatment with an eguimolar amount of 2N hydrochloric acid gives 4-methylamino-l,3,3a,4,7/7a-hexahydro-iso-indole dihydrochloride of melting point 265-268 °C (from methanol ) .

Method II: a) 4 - ( t ert . - Buty loxyc arbony1 amino )-l,3-dioxo- 1 , 3 , 3a , 4 , 7 , 7a-hexahydroisoindole 48.0 g (0.5 mol) of maleimide are initially introduced into the reaction vessel as a solution in 200 ml of absolute tetrahydrofuran, and 120 g (0.5 mol) of approximately 70 % strength l-(tert.- butyloxycarbonylamino) -1 , 3-butadiene are added dropwise as a solution in 500 ml of absolute tetrahydrofuran, the temperature being kept at 20 to 30 eC. The mixture is subsequently stirred overnight at room temperature. It is then concentrated and the residue is recrystallised from ethyl acetate. 57 g of product having a melting point of 177 to 182 °C are obtained. A further 13 g of melting point 158 to 160 °C are obtained from the mother liquor. b) 4-Methylamino-l , 3,33,4,7, 7a-hexahydroisoindole 27.1 g (0.71 mol) of lithium aluminium hydride in 300 ml of absolute tetrahydrofuran are initially introduced into the reaction vessel, under nitrogen, and a solution of 57 g (0.21 mol) of 4-(tert.- butyloxycarbonylamino ) -1 , 3-dioxo-l , 3 , 3a , 4 , 7 , 7a- hexahydroisoindole in 570 ml of absolute tetrahydro- furan is added dropwise. The mixture is then boiled under reflux cooling overnight. After cooling, 27.1 g of water in 82 ml of tetrahydrofuran, 27.1 g of 10 % strength sodium hydroxide solution and 81.3 g of water are added dropwise to the batch in succession. The salts are filtered off with suction and washed with tetrahydrofuran and the filtrate is concentrated in vacuo. The residue is distilled under a high vacuum.

Yield: 19.1 g Example B 4-Amino-1 , 3 , 3a , 4 , 7 , 7a-hexahvdro-isoindole 13.3 g (50 mmol) of 4-tert.-butyloxycarbonylaraino-l,3-dioxo-l,3,3a,4,7,7a-hexahydro-isoindole (from Example A, method II) are stirred in 166 ml of trifluoroacetic acid at room temperature overnight. The trifluoroacetic acid is then distilled off under 10 mbar and the residue is freed from residues of acid at 50° under a high vacuum. It is then taken up in absolute tetrahydrofuran and the mixture is concentrated in vacuo. The residue is taken up in 100 ml of absolute tetrahydrofuran and the mixture is added dropwise to a solution of 11.3 g (0.3 mol) of lithium aluminium hydride in 300 ml of absolute tetrahydrofuran, under nitrogen. The mixture is then boiled under reflux cooling for 16 hours. After cooling, 11.3 g of water in 34 ml of tetrahydrofuran, 11.3 ml of 10 % strength sodium hydroxide solution and 34 ml of water are added dropwise in succession. The precipitate is filtered off with suction and washed with tetrahydrofuran. The filtrate is concentrated and the residue is distilled.

Yield: 2.2 g, content: 92 % (determined by gas chromatography) Boiling point: 70°/0.2 mbar Example C 1 7-Methyl-4-methylamino-1 , 3 , 3a, 4 , 7 , 7a-hexahvdro-isoindole HNCH Analogously to Example A, method I, 21.9 g (0.12 mol) of 1- ( tert . -butyloxycarbonylamino ) -1 , 3-pentadiene are reacted with 20.3 g (0.12 mol) of N-trimethylsilyl-maleimide and the product is then reduced with 15.2 g (0.4 mol) of lithium aluminium hydride. The crude product is recrystallised from tetrahydrofuran.

Yield: 6.2 g, melting point: 106 - 108°C.

Example D 6-Methyl-4-methylamino-l , 3 ,3a ,4,7, 7a-hexahvdro-isoindole a ) 4- ( tert . -Butyloxycarbonylamino ) -1 , 3-dioxo-6-methyl- 1/3,33,4,7, 7a-hexahydro-isoindole Boc 1-tert . -Butyloxycarbonylamino-3-methyl-l , 3-butadiene is reacted in dioxane in accordance with Example A/method Ila.

Melting point: 135 °C b) 6-Methyl-4-methylamino-l, 3 , 3a, 4 , 7 , 7a-hexahydro- isoindole Analogously to Example B, 5.6 g (20 mmol) of the product from Example Ma) are heated under reflux with 2.2 g (60 mmol) of lithium aluminium hydride in 60 ml of tetrahydrofuran for 15 hours. Working up by distillation gives 1.2 g of the product of boiling point 68-71°C/0.2-0.3 mbar.

Example E 4-Amino-7-methyl-l , 3 , 3a , 4 , 7 , 7a-hexahydro-isoindole CH3 a ) 4- ( tert . -Butyloxycarbonylamino ) -1 , 3-dioxo-7-methyl- 1 , 3 , 3a, 4 , 7 , 7a-hexahydro-isoindole CH3 0 1-tert . -Butyloxycarbonylamino-1 , 3-pentadiene is employed in accordance with Example A/method Ila and the reaction product is recrystallised from dioxane. Yield: 79 % Melting point: 208-211°C 4-Amino-7-methyl-l , 3 , 3a , 4 , 7 , 7a-hexahydro-isoindole The product from Example Na) is employed in accordance with Example B to give the free amine as an oil of boiling point 83-92 eC/0.1 mbar, which crystallises on standing-Content: 90 % pure (according to the gas chromato-gram)

Claims

Patent Claims:

1. Substituted 4-amino- l,3,3a,4,7,7a-hexahydroisoindoles of the formula ^ in which R and R' denote hydrogen or methyl.

2. A compound according to claim 1 , substantially as described and exemplified herein. For the Applicants, DR. REINHOLD COHN AND PARTNERS