butanamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 3 l three necked flask fitted with mechanical stirrer and reflux condenser, under inert atmosphere, 89.7 g (322 mmoles, 1 eq) of {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl methanesulfonate 37 are dissolved in 300 ml of acetonitrile. 27.3 g (419 mmoles, 1.3 eq) of sodium azide are added in one portion, with 150 ml of acetonitrile. The mixture is brought to reflux in 20 min, and stirred overnight. 3.1 g (48 mmoles, 0.2 eq) of sodium azide are added and reflux continued for a total of 44 hours. After cooling down to 10° C., the mixture is filtered, the precipitate washed with 3×50 ml of acetonitrile and the combined organic fractions concentrated to dryness to give 77.3 g of crude 32. It is crystallised from 150 ml of ethyl acetate at 10° C. to give 60 g of pure 32, 82%. Alternatively, (2S)-2-[4-(fluoromethyl)-2-oxo-1-pyrrolidinyl]butanamide 44, (2S)-2-[2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 39, (2S)-2-[2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 40, (2S)-2-[2-oxo-4-(1H-1,2,4-triazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 55, 2-[2-oxo-4-(1H-1,2,3-triazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 56, (2S)-2-{4-[(isopropylsulfanyl)methyl]-2-oxo-1-pyrrolidinyl}butanamide 24, (2S)-2-[2-oxo-4-pyrrolidinylmethyl)-1-pyrrolidinyl]butanamide 15, (2S)-2-[2-oxo-4-(4-thiomorpholinylmethyl)-1-pyrrolidinyl]butanamide 17, are prepared in similar ways, from activated alcohol derivatives, such as mesylates, tosylates or halides. reflux condenser to reflux in 20 min reflux continued for a total of 44 hours the mixture is filtered the precipitate washed with 3×50 ml of acetonitrile the combined organic fractions concentrated to dryness to give 77.3 g of crude 32 It is crystallised from 150 ml of ethyl acetate at 10° C. to give 60 g of pure 32, 82%

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100 mg (0.23 mmol) of 2-[(2-bromopyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide is heated in 1 ml of dioxane with 89 mg (0.28 mmol) of cesium carbonate, 24 mg (0.69 mmol) of butyramide, 4.7 mg (0.0046 mmol) of dipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphos under a cover gas and in a moisture-free environment for 25 hours to a bath temperature of 90° C. It is then mixed with 20 ml of methylene chloride, suctioned off and concentrated by evaporation. The residue is chromatographed on silica gel first with hexane, then with hexane:ethyl acetate=8:2 and then with hexane:ethyl acetate=1:1 as an eluant. 45 mg (42% of theory) of 2-[(2-butyrylamino-pyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide with a melting point of 173° C. is obtained. concentrated by evaporation The residue is chromatographed on silica gel first with hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100 mg (0.23 mmol) of 2-[(2-bromopyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide is heated in 1 ml of dioxane with 89 mg (0.28 mmol) of cesium carbonate, 24 mg (0.69 mmol) of butyramide, 4.7 mg (0.0046 mmol) of dipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphos under a cover gas and in a moisture-free environment for 25 hours to a bath temperature of 90° C. It is then mixed with 20 ml of methylene chloride, suctioned off and concentrated by evaporation. The residue is chromatographed on silica gel first with hexane, then with hexane:ethyl acetate=8:2 and then with hexane:ethyl acetate=1:1 as an eluant. 45 mg (42% of theory) of 2-[(2-butyrylamino-pyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide with a melting point of 173° C. is obtained. concentrated by evaporation The residue is chromatographed on silica gel first with hexane

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 3 l three necked flask fitted with mechanical stirrer and reflux condenser, under inert atmosphere, 89.7 g (322 mmoles, 1 eq) of {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl methanesulfonate 37 are dissolved in 300 ml of acetonitrile. 27.3 g (419 mmoles, 1.3 eq) of sodium azide are added in one portion, with 150 ml of acetonitrile. The mixture is brought to reflux in 20 min, and stirred overnight. 3.1 g (48 mmoles, 0.2 eq) of sodium azide are added and reflux continued for a total of 44 hours. After cooling down to 10° C., the mixture is filtered, the precipitate washed with 3×50 ml of acetonitrile and the combined organic fractions concentrated to dryness to give 77.3 g of crude 32. It is crystallised from 150 ml of ethyl acetate at 10° C. to give 60 g of pure 32, 82%. Alternatively, (2S)-2-[4-(fluoromethyl)-2-oxo-1-pyrrolidinyl]butanamide 44, (2S)-2-[2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 39, (2S)-2-[2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 40, (2S)-2-[2-oxo-4-(1H-1,2,4-triazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 55, 2-[2-oxo-4-(1H-1,2,3-triazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 56, (2S)-2-{4-[(isopropylsulfanyl)methyl]-2-oxo-1-pyrrolidinyl}butanamide 24, (2S)-2-[2-oxo-4-pyrrolidinylmethyl)-1-pyrrolidinyl]butanamide 15, (2S)-2-[2-oxo-4-(4-thiomorpholinylmethyl)-1-pyrrolidinyl]butanamide 17, are prepared in similar ways, from activated alcohol derivatives, such as mesylates, tosylates or halides. reflux condenser to reflux in 20 min reflux continued for a total of 44 hours the mixture is filtered the precipitate washed with 3×50 ml of acetonitrile the combined organic fractions concentrated to dryness to give 77.3 g of crude 32 It is crystallised from 150 ml of ethyl acetate at 10° C. to give 60 g of pure 32, 82%

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 3 l three necked flask fitted with mechanical stirrer and reflux condenser, under inert atmosphere, 89.7 g (322 mmoles, 1 eq) of {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl methanesulfonate 37 are dissolved in 300 ml of acetonitrile. 27.3 g (419 mmoles, 1.3 eq) of sodium azide are added in one portion, with 150 ml of acetonitrile. The mixture is brought to reflux in 20 min, and stirred overnight. 3.1 g (48 mmoles, 0.2 eq) of sodium azide are added and reflux continued for a total of 44 hours. After cooling down to 10° C., the mixture is filtered, the precipitate washed with 3×50 ml of acetonitrile and the combined organic fractions concentrated to dryness to give 77.3 g of crude 32. It is crystallised from 150 ml of ethyl acetate at 10° C. to give 60 g of pure 32, 82%. Alternatively, (2S)-2-[4-(fluoromethyl)-2-oxo-1-pyrrolidinyl]butanamide 44, (2S)-2-[2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 39, (2S)-2-[2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 40, (2S)-2-[2-oxo-4-(1H-1,2,4-triazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 55, 2-[2-oxo-4-(1H-1,2,3-triazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 56, (2S)-2-{4-[(isopropylsulfanyl)methyl]-2-oxo-1-pyrrolidinyl}butanamide 24, (2S)-2-[2-oxo-4-pyrrolidinylmethyl)-1-pyrrolidinyl]butanamide 15, (2S)-2-[2-oxo-4-(4-thiomorpholinylmethyl)-1-pyrrolidinyl]butanamide 17, are prepared in similar ways, from activated alcohol derivatives, such as mesylates, tosylates or halides. reflux condenser to reflux in 20 min reflux continued for a total of 44 hours the mixture is filtered the precipitate washed with 3×50 ml of acetonitrile the combined organic fractions concentrated to dryness to give 77.3 g of crude 32 It is crystallised from 150 ml of ethyl acetate at 10° C. to give 60 g of pure 32, 82%

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of butyramide (19.88 g) and 1.3-dichloroacetone (24.14 g) was heated at 130° C. for 1.5 hours. After cooling, the mixture was diluted with water, neutralized with aqueous sodium bicarbonate solution and extracted with ethyl ether. The extract was washed with water, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel with acetone-hexane (1:9) to yield 4-chloromethyl-2-propyloxazole as an oil (10.70 g 35.3%). NMR (CDCl3)δ: 0.97 (3H, t, J=7.5 Hz), 1.79 (2H, sext, J=7.5 Hz), 2.72 (2H, t, J=7.5 Hz), 4.47 (2H, s), 7.53 (1H, s). After cooling extracted with ethyl ether The extract was washed with water dried (MgSO4) concentrated The residue was purified by chromatography on silica gel with acetone-hexane (1:9)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of butyramide (19.88 g) and 1.3-dichloroacetone (24.14 g) was heated at 130° C. for 1.5 hours. After cooling, the mixture was diluted with water, neutralized with aqueous sodium bicarbonate solution and extracted with ethyl ether. The extract was washed with water, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel with acetone-hexane (1:9) to yield 4-chloromethyl-2-propyloxazole as an oil (10.70 g 35.3%). NMR (CDCl3)δ: 0.97 (3H, t, J=7.5 Hz), 1.79 (2H, sext, J=7.5 Hz), 2.72 (2H, t, J=7.5 Hz), 4.47 (2H, s), 7.53 (1H, s). After cooling extracted with ethyl ether The extract was washed with water dried (MgSO4) concentrated The residue was purified by chromatography on silica gel with acetone-hexane (1:9)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[2-(2-,3-dihydro-6-methoxy-1H-inden-3-yl)ethyl]amine was resolved according to the procedure described using L-tartaric acid and was shown to have an enantiomeric excess of ≤90 by 1H NMR. The amine was then converted to the butanamide using n-butyryl chloride according to General Procedure A. m.p. 79°-80° C.; 1H NMR (300 MHz, CDCl3) δ7.08 (d, J=8Hz, 1H), 6.72-6.67 (M, 2H), 5.57 (bs, 1H), 3.76 (s, 3H), 3.86-3.66 (bm, 2H), 3.08 (bm, 1H), 2.89-2.69 (bm, 2H), 2.35-2.27 (m, 1H), 2.13 (t, J=7.5 Hz, 2H), 2.06-2.00 (m, 2H), 1.7-1.54 (bm, 4H), 0.92 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ172.0, 158.8, 148.11, 135.8, 124.9, 112.27, 109.18, 55.48, 42.67, 38.71, 37.98, 34.83, 32.47, 30.55, 19.21, 13.76; IR (KBr) 1632, 1546, 1290 cm-1 ; MS (DCI) 276m/e (MH); Analysis calc'd for C16H21NO1 : C, 78.97; H, 8.70; N, 5.76; found: C, 78.73; H, 8.90; N, 5.76. Analysis calc'd for C16H23N1O2 : C, 73.53; H, 8.87; N, 5.36; found: C, 73.47; H, 8.77; N, 5.13; [α] (25° C., 589 nm, CHCl3)=+4.24.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[2-(2-,3-dihydro-6-methoxy-1H-inden-3-yl)ethyl]amine was resolved according to the procedure described using L-tartaric acid and was shown to have an enantiomeric excess of ≤90 by 1H NMR. The amine was then converted to the butanamide using n-butyryl chloride according to General Procedure A. m.p. 79°-80° C.; 1H NMR (300 MHz, CDCl3) δ7.08 (d, J=8Hz, 1H), 6.72-6.67 (M, 2H), 5.57 (bs, 1H), 3.76 (s, 3H), 3.86-3.66 (bm, 2H), 3.08 (bm, 1H), 2.89-2.69 (bm, 2H), 2.35-2.27 (m, 1H), 2.13 (t, J=7.5 Hz, 2H), 2.06-2.00 (m, 2H), 1.7-1.54 (bm, 4H), 0.92 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ172.0, 158.8, 148.11, 135.8, 124.9, 112.27, 109.18, 55.48, 42.67, 38.71, 37.98, 34.83, 32.47, 30.55, 19.21, 13.76; IR (KBr) 1632, 1546, 1290 cm-1 ; MS (DCI) 276m/e (MH); Analysis calc'd for C16H21NO1 : C, 78.97; H, 8.70; N, 5.76; found: C, 78.73; H, 8.90; N, 5.76. Analysis calc'd for C16H23N1O2 : C, 73.53; H, 8.87; N, 5.36; found: C, 73.47; H, 8.77; N, 5.13; [α] (25° C., 589 nm, CHCl3)=+4.24.

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of butyramide (19.88 g) and 1.3-dichloroacetone (24.14 g) was heated at 130° C. for 1.5 hours. After cooling, the mixture was diluted with water, neutralized with aqueous sodium bicarbonate solution and extracted with ethyl ether. The extract was washed with water, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel with acetone-hexane (1:9) to yield 4-chloromethyl-2-propyloxazole as an oil (10.70 g 35.3%). NMR (CDCl3)δ: 0.97 (3H, t, J=7.5 Hz), 1.79 (2H, sext, J=7.5 Hz), 2.72 (2H, t, J=7.5 Hz), 4.47 (2H, s), 7.53 (1H, s). After cooling extracted with ethyl ether The extract was washed with water dried (MgSO4) concentrated The residue was purified by chromatography on silica gel with acetone-hexane (1:9)