Triethylamine → (1R)-1-({4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochloride

HRID 1943187Notes

Reaction equation

HRID 1943187 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]=[N: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[CH:40]=[C:39]([CH:42]=O)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.CO.C(Cl)Cl>[ClH:1].[ClH:1].[O:32]1[C:41]2[CH:40]=[C:39]([CH2:42][NH:3][CH:4]3[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:6][CH2:5]3)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1

Participants

9

Reactant 5

HCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride2×HCID 218736682,3-Dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehydeHCID 68600205HCID 68600205, compound

Product 1

HCID 68598115(1R)-1-({4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochlorideYield 71%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6212ChloroformSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochloride (70 mg, 0.187 mmol) in chloroform (5 ml) and methanol (0.2 ml) at room temperature under argon was treated with triethylamine (0.078 ml, 0.561 mmol) and stirred for 0.25 h. Everything went into solution; 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144 Example 2(c) or WO03/087098 Example 19(d))) (30.9 mg, 0.187 mmol) was then added and the reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (119 mg, 0.561 mmol) was then added and the reaction was stirred at room temperature. After 1.5 h 1 eq more of sodium triacetoxyborohydride was added. After 1 h sat NaHCO3 (50 ml) was added followed by 20% MeOH/DCM (50 ml) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted again twice with 20% MeOH/DCM (2×50 ml). The combined organic extracts were dried on MgSO4, filtered and evaporated to afford 90 mg of crude product which was purified by silica chromatography using a 0-20% methanol/dichloromethane gradient to afford the free base of the title compound as a pale yellow gum (60 mg, 71%).

Workup

  1. additionwas then added
  2. stirringthe reaction was stirred at room temperature for 0.5 h
  3. stirringthe reaction was stirred at room temperature
  4. waitAfter 1 h sat
  5. extractionthe aqueous layer was extracted
  6. customseparated from the organic layer
  7. extractionThe aqueous layer was extracted again twice with 20% MeOH/DCM (2×50 ml)
  8. customThe combined organic extracts were dried on MgSO4
  9. filtrationfiltered
  10. customevaporated
  11. customto afford 90 mg of crude product which
  12. customwas purified by silica chromatography

Sources & evidence

ORD record
ord-18fff56600eb4891aba37029fc53cd1d
Source dataset
uspto-grants-2013_03
Patent number
US08389524B2

Reaction notes

Loading…