Triethylamine → (1R)-1-({4-[(3,4-Dihydro-2H-chromen-7-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione hydrochloride

HRID 1943233Notes

Reaction equation

HRID 1943233 reaction equation
[ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([CH:42]=O)[CH:40]=2)[CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[O:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([CH2:42][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:8][CH2:9]3)[CH:40]=2)[CH2:35][CH2:34][CH2:33]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 5049666Sodium triacetoxyborohydride2×HCID 602097343,4-dihydro-2H-1-benzopyran-7-carbaldehyde2×HCID 66658412(1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride

Product 1

HCID 68597820(1R)-1-({4-[(3,4-Dihydro-2H-chromen-7-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione hydrochlorideYield 26%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6212ChloroformSolvent2×

Procedure

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%).

Workup

  1. customat rt
  2. additionwas added dropwise at rt
  3. stirringThe reaction mixture was stirred at rt for 1 h
  4. stirringthe reaction mixture was stirred at rt overnight
  5. additiona mixture of product
  6. stirringthe reaction stirred at rt for 6 h
  7. customThe reaction was quenched with NaHCO3 (aq) (20 ml)
  8. extractionextracted with 20% MeOH/DCM (3×30 ml)
  9. dry with materialThe combined organic layers were dried over MgSO4
  10. filtrationfiltered
  11. customevaporated
  12. customchromatographed (0-50% MeOH/DCM)

Sources & evidence

ORD record
ord-07b72f015dad4cf6a2981de290d67021
Source dataset
uspto-grants-2013_03
Patent number
US08389524B2

Reaction notes

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