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Example 54: W-[(1S)-2-(Dimethylamino)-1-phenylethyl]-3-[(6-ethylpyrimidin-4-yl)amino]-6,6- dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide. EPO <DP n="69"/>Preparation of I(H): 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrroIo[3,4-c]pyrazoIe-2,5(4H,6H)- dicarboxylate.The synthetic route of compound I(H) can be found in Scheme 1 under the "Detailed Description" of this application. The detailed synthetic condition of for the preparation of I(H) can be found in U.S. Patent Application Publication No. 2003/0171357 and PCT Publication WO 02/12242, the disclosure of which are incorporated herein by reference.Preparation of compound 54a: ethyl 3-amino-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)- carboxylate dihydrochloride. EPO <DP n="70"/>To a stirred slurry of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazoIe-1,5- dicarboxylate (l(H),~30.0 g, 92.5 mmol) in ethanol (200 mL)was drop wise added HCI 4 M solution in hexanes (116 mL) drop wise. The resulting clear solution was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to a residue and stirred with hexane (250 mL) for 10 min. The solid product was collected by filtration, washed with hexane (100 mL) and dried under vacuum at 40 0C for 15 h to get ethyl 3-amino-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate dihydrochloride (54a, 27.0 g, 98.5 %) as white solid. 1H NMR (300MHz, dmso-d6): delta 1.31 (td, J=7, 1.3Hz, 3H), 1.59 (s, 6H), 4.09 (t, J=3.7Hz, 2H), 4.36 (qd, J=7.2, 1.2Hz, 2H), 10.12 (br s, 2H). Preparation of compound 54c: benzyl [(1S)-2-(dimethylamino)-2-oxo-1-phenylethyl]-carbamate. To a mixture of (2S)-[(benzy.oxy)carbonyljamino}(phenyl)acetic acid (54b, 196 g, 688 mmol), HBTU (261 g, 688 mmol), and dichloromethane (2.8 L) were added sequentially potassium carbonate (285 g, 2.06 mol) and dimethylamine hydrochloride (84.1 g, 1031 mmol). The reaction mixture was heated at 40 C overnight. After cooling to room temperature, the solids were filtered, washed with ethyl acetate (2x500 mL) and the filtrate concentrated to a residue. Water (1L) was added to the residue and the solution kept in an ultrasonic cleanser for 2 hours. The precipitated solids were collected and washed with water (4*300 mL), hexane (2x500 mL), and dried under vacuum for 24 hours. The solid crude product was dissolved in chloroform (300 mL) and un-dissolved solids were filtered off. The filtrate was concentrated to dryness and the residue dissolved in hexane/ethyl acetate (2:1) (250 mL) and allowed to stand at room temperature overnight. The resulting crystals were collected by filtration, washed with hexane/ethyl acetate (3:1) (100 mL) and dried in high vacuum at 40 C for 24 hours to give compound 54c (100.0 g, 47 %) as a white crystalline solid. 1H NMR (CDCI3) delta: 2.88 (s, 3H), 2.98 (s, 3H), 5.01 (d, J = 12.2 Hz, 1H), 5.11 (d, J = 12.2 Hz, 1 H), 5.58 (d, J = 7.5 Hz, 1 H), 6.37 (d, J = 7.2 Hz, 1 H), 7.32 (m, 10H). Preparation of Compound 54d: (2S)-2-amino-Lambda/,Lambda/-dimethyl-2-phenylacetamide. To a solution of 54c (80.0 g, 256 mmol) in ethanol (1.2 L) was added a slurry of Pd/C (10%, 9.0 g) in ethyl acetate (50 mL). The reaction mixture was shaken in Parr-apparatus under hydrogen (40 psi) overnight. The catalyst was removed by filtration through celite. The filter pad was washed with ethanol (2x200 mL) and the combined filtrate was concentrated to give 54d (40.2 g, 88%) as a white solid. 1H NMR (CDCI3) delta: 2.85 (s, 3H), 2.99 (s, 3H), 4.72 (s, 1 H), 7.33 (m, 5H). Preparation of Compound 54e: N-[(2S)-2-amino-2-phenylethyl]-N,N-dimethylamine.A flask containing dry THF (2300 mL) under a nitrogen atmosphere was chilled by an ice-water bath. Lithium aluminum hydride pellets (59.0 g, 1555 mmol) were added. To this LAH suspension, a solution of amide 54d (123.0 g, 691 mmol) in dry THF (800 mL) was slowly added over approximately 1 hour. The resulting reaction mixture was heated at reflux for 5 hours, then cooled to 10 C. The cooled reaction mixture was slowly quenched with saturated sodium sulfate solution (380 mL) and stirred overnight. The precipitated solids were filtered off and washed with ethyl acetate (4x500 mL). The filtrate was concentrated to a residue that was purified on silica gel column (10% methanol, 5% triethylamine in chloroform) to afford 54e (66.7 g, 59%) as a light yellow liquid. 1H NMR (CDCI3) delta: 2.24 (dd, J = 3.6, 12.1 Hz, 1 H), 2.29 (s, 6H), 2.47 (dd, J = 10.6, 12.1 Hz, 1H), 4.07 (dd, J = 3.6, 10.4 Hz, 1H), 7.24 (m, 1 H), 7.37 (m, 4H). Preparation of Compound 54f: N-[(2S)-2-isocyanato-2-phenylethyl]-N,N-dimethylamine hydrochloride. EPO <DP n="71"/>To a cooled (0 C) and stirred solution of triphosgene (27.1 g, 91.32 mmol) in DCM (250 ml.) was drop wise added a solution of diisopropylethyl amine (23.6 g, 182.26 mmol) in DCM (50 ml_) over a period of 20 min. A solution of N-[(2S)-2-amino-2-phenylethyl]-N,N-dimethylamine (54e, 15.0 g, 91.32 mmol) in DCM (10... |
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Preparation of Compound 46c: N-[(2S)-2-amino-2-phenylethyl]-N,N-dimethylamine; A flask containing dry THF (2300 mL) under a nitrogen atmosphere was chilled by an ice-water bath. Lithium aluminum hydride pellets (59.0 g, 1555 mmol) were added. To this LAH suspension, a solution of amide 46b (123.0 g, 691 mmol) in dry THF (800 mL) was slowly added over approximately 1 hour. The resulting reaction mixture was heated at reflux for 5 hours, then cooled to 10 C. The cooled reaction mixture was slowly quenched with saturated sodium sulfate solution (380 mL) and stirred overnight. The precipitated solids were filtered off and washed with ethyl acetate (4×500 mL). The filtrate was concentrated to a residue that was purified on silica gel column (10% methanol, 5% triethylamine in chloroform) to afford 46c (66.7 g, 59%) as a light yellow liquid. 1H NMR (CDCl3) delta: 2.24 (dd, J=3.6, 12.1 Hz, 1H), 2.29 (s, 6H), 2.47 (dd, J=10.6, 12.1 Hz, 1H), 4.07 (dd, J=3.6, 10.4 Hz, 1H), 7.24 (m, 1H), 7.37 (m, 4H). |