Triethylamine → (1R)-1-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochloride

HRID 1943223Notes

Reaction equation

HRID 1943223 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:37]2=[CH:38][N:39]=[C:40]([CH:42]=O)[CH:41]=[C:36]2[CH2:35][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.C(Cl)Cl.CO>[ClH:1].[O:32]1[C:37]2=[CH:38][N:39]=[C:40]([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)[CH:41]=[C:36]2[CH2:35][CH2:34][CH2:33]1

Participants

9

Reactant 5

HCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride2×HCID 566403113,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehydeHCID 68600205HCID 68600205, compound

Product 1

HCID 68600610(1R)-1-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochlorideYield 87%

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 (for a preparation see Example 13(k) or 15(d)) (50 mg, 0.100 mmol) in chloroform (4 ml) and methanol (0.200 ml) at room temperature under nitrogen was treated with triethylamine (0.042 ml, 0.301 mmol) and stirred for 0.25 h (the suspension turned into a solution). 3,4-Dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(e)) (16.35 mg, 0.100 mmol) was then added and the reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (67.1 mg, 0.301 mmol) was then added and the reaction was stirred at room temperature. After 3 h there was still some starting material so 30 mg of sodium triacetoxyborohydride were added. After 1 h a saturated aqueous solution of sodium bicarbonate (25 mL) was added followed by 20% methanol/DCM (25 mL) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted again twice with 20% methanol/DCM (2×25 mL). The combined organic layers were dried on sodium sulphate, filtered and evaporated to afford 60 mg of crude product. The crude product was purified by silica chromatography (0-20% MeOH/DCM) to afford the free base of the title compound as a yellow solid (39 mg, 87%).

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 3 h there was still
  5. extractionthe aqueous layer was extracted
  6. customseparated from the organic layer
  7. extractionThe aqueous layer was extracted again twice with 20% methanol/DCM (2×25 mL)
  8. customThe combined organic layers were dried on sodium sulphate
  9. filtrationfiltered
  10. customevaporated
  11. customto afford 60 mg of crude product
  12. customThe crude product was purified by silica chromatography (0-20% MeOH/DCM)

Sources & evidence

ORD record
ord-1a2e3221cd2842c59a1c3c8110cebdd5
Source dataset
uspto-grants-2013_03
Patent number
US08389524B2

Reaction notes

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