Triethylamine → (2R)-2-[(4-{[(5-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]amino}-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochloride

HRID 1943239Notes

Reaction equation

HRID 1943239 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[N:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.C(N(CC)CC)C.[F:46][C:47]1[C:56]2[O:55][CH2:54][CH2:53][O:52][C:51]=2[CH:50]=[CH:49][C:48]=1[CH:57]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CO>[ClH:1].[F:46][C:47]1[C:56]2[O:55][CH2:54][CH2:53][O:52][C:51]=2[CH:50]=[CH:49][C:48]=1[CH2:57][NH: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[N:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1

Participants

8

Reactant 6

HCID 8471TriethylamineHCID 149026Tetrafluoro-m-phenylenediamine dihydrochlorideHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride2×HCID 68598038(2R)-2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochlorideHCID 866421125-Fluoro-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde

Product 1

HCID 68597997(2R)-2-[(4-{[(5-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]amino}-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochlorideYield 45%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A suspension of (2R)-2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochloride (for a preparation see Example 16A(j), amine was converted into dihydrochloride after chiral hplc purification) (51.3 mg, 0.137 mmol) in chloroform (5 ml) and methanol (0.1 ml) at rt under argon was treated with triethylamine (0.057 ml, 0.411 mmol) and stirred at rt for 0.25 h. The solution was then treated with 5-fluoro-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (24.95 mg, 0.137 mmol) and stirred for a further 0.5 h. The solution was then treated with sodium triacetoxyborohydride (174 mg, 0.822 mmol) and stirred at rt for 2 h, more sodium triacetoxyborohydride (174 mg, 0.137 mmol) was added, reaction stirred for a further 1 h, the reaction was then treated with saturated aqueous NaHCO3 (20 ml) and extracted with 20% methanol/DCM (3×20 ml). The combined organic extracts were dried (MgSO4) and chromatographed (0-20% methanol:DCM) to give the free base of the title compound as a white solid (29 mg, 0.062 mmol, 45%,).

Workup

  1. customafter chiral hplc purification) (51.3 mg, 0.137 mmol) in chloroform (5 ml)
  2. stirringstirred for a further 0.5 h
  3. stirringstirred at rt for 2 h
  4. customreaction
  5. stirringstirred for a further 1 h
  6. extractionextracted with 20% methanol/DCM (3×20 ml)
  7. dry with materialThe combined organic extracts were dried (MgSO4)
  8. customchromatographed (0-20% methanol:DCM)

Sources & evidence

ORD record
ord-5f3b45cbe75a404e871a286cbed17285
Source dataset
uspto-grants-2013_03
Patent number
US08389524B2

Reaction notes

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