| 26% |
Stage #1: (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride With triethylamine In methanol; chloroform at 20℃; for 0.25h;
Stage #2: 3,4-Dihydro-2H-benzopyran-7-carbaldehyde In methanol; chloroform at 20℃; for 1h;
Stage #3: With water; sodium tris(acetoxy)borohydride; sodium hydrogencarbonate more than 3 stages; |
50
Example 50; (lR)-l-({4-[(3,4-Dihydro-2H-chromen-7-ylmethyl)amino]-l- piperidinyl}methyl)- 1 ,2-dihydro-4H,9H-imidazo [ 1 ,2,3-//] -1 ,8-naphthyridine-4,9- dione hydrochloride; A solution of (IR)- 1 - [(4-amino- 1 -piperidinyl)methyl] - 1 ,2-dihydro-4η,9η- imidazo[l,2,3-ij]-l,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see example 5A(j)) (188 mg, 0.503 mmol) and triethylamine (0.175 ml, 1.256 mmol) in chloroform (4.5 ml) and methanol (0.5 ml) at rt was stirred at rt for 15 min then 3,4- dihydro-2H-chromene-7-carbaldehyde (for a synthesis see WO2007067511 Example 19 (chromane-7-carbaldehyde)) (68 mg, 0.419 mmol) in chloroform (2 ml) was added dropwise at rt. The reaction mixture was stirred at rt for 1 h then sodium triacetoxyborohydride (444 mg, 2.096 mmol) was added in one portion and the reaction mixture was stirred at rt overnight. LCMS showed a mixture of product, some residual aldehyde. Additional sodium triacetoxyborohydride (267 mg, 1.258 mmol) was added and the reaction stirred at rt for 6 h. The reaction was quenched with NaHCO3 (aq) (20 ml) and extracted with 20% MeOH/DCM (3 x 30 ml). The combined organic layers were dried over MgSO4, filtered, evaporated and chromatographed (0-50% MeOH/DCM) to deliver the free base of the title compound as a pale yellow clear oil (49 mg, 0.11 mmol, 26%). 1H NMR δH CDCl3, (400MHz) 1.28-1.42 (m, 2H), 1.78-1.87 (m, 2H), 1.97-2.01 (m, 2H), 2.17-2.31 (m, 2H), 2.47-2.55 (m, IH), 2.62-2.68 (m, 2H), 2.74-2.77 (m, 2H), 2.95 (d, IH), 3.07 (dd, IH) 3.71 (m, 2H), 4.17 (t, 2H), 4.35 (dd, IH), 4.56 (dd, IH), 4.96-5.02 (m, IH), 6.23-6.31 (m, 2H), 6.72 (s, IH), 6.77 (dd, IH), 6.98 (d, IH), 7.47-7.50 (m, 2H). MS (ES+) m/z 447 (MH+).The free base of the title compound in 2 ml DCM was treated with one equivalent of IM HCl in diethyl ether and then evaporated to give the title compound as the mono- HCl salt as a pale orange powder (51 mg, 25%). LCMS was consistent with product. |
| 49 mg |
Stage #1: (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride With triethylamine In methanol; chloroform at 20℃; for 0.25h;
Stage #2: 3,4-Dihydro-2H-benzopyran-7-carbaldehyde In methanol; chloroform at 20℃; for 1h;
Stage #3: With methanol; sodium tris(acetoxy)borohydride In chloroform at 20℃; |
50 Example 50 (1R)-1-({4-[(3,4-Dihydro-2H-chromen-7-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-4H,9H-imidazo[1,2,3-if]-1,8-naphthyridine-4,9-dione hydrochloride
A solution of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see example 5A(j)) (188 mg, 0.503 mmol) and triethylamine (0.175 ml, 1.256 mmol) in chloroform (4.5 ml) and methanol (0.5 ml) at rt was stirred at rt for 15 min then 3,4-dihydro-2H-chromene-7-carbaldehyde (for a synthesis see WO2007067511 Example 19 (chromane-7-carbaldehyde)) (68 mg, 0.419 mmol) in chloroform (2 ml) was added dropwise at rt. The reaction mixture was stirred at rt for 1 h then sodium triacetoxyborohydride (444 mg, 2.096 mmol) was added in one portion and the reaction mixture was stirred at rt overnight. LCMS showed a mixture of product, some residual aldehyde. Additional sodium triacetoxyborohydride (267 mg, 1.258 mmol) was added and the reaction stirred at rt for 6 h. The reaction was quenched with NaHCO3 (aq) (20 ml) and extracted with 20% MeOH/DCM (3×30 ml). The combined organic layers were dried over MgSO4, filtered, evaporated and chromatographed (0-50% MeOH/DCM) to deliver the free base of the title compound as a pale yellow clear oil (49 mg, 0.11 mmol, 26%). 1H NMR δH CDCl3, (400 MHz) 1.28-1.42 (m, 2H), 1.78-1.87 (m, 2H), 1.97-2.01 (m, 2H), 2.17-2.31 (m, 2H), 2.47-2.55 (m, 1H), 2.62-2.68 (m, 2H), 2.74-2.77 (m, 2H), 2.95 (d, 1H), 3.07 (dd, 1H) 3.71 (m, 2H), 4.17 (t, 2H), 4.35 (dd, 1H), 4.56 (dd, 1H), 4.96-5.02 (m, 1H), 6.23-6.31 (m, 2H), 6.72 (s, 1H), 6.77 (dd, 1H), 6.98 (d, 1H), 7.47-7.50 (m, 2H). MS (ES+) m/z 447 (MH+). |
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