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

HRID 1943182Notes

Reaction equation

HRID 1943182 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.[S:32]1[C:40]2[CH:39]=[C:38]([CH:41]=O)[N:37]=[CH:36][C:35]=2[O: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.ClCCl>[ClH:1].[S:32]1[C:40]2[CH:39]=[C:38]([CH2:41][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:37]=[CH:36][C:35]=2[O:34][CH2:33]1

Participants

9

Reactant 5

HCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride2×HCID 59254367[1,3]Oxathiolo[5,4-c]pyridine-6-carbaldehydeHCID 68600205HCID 68600205, compound

Product 1

HCID 68596287(1R)-1-({4-[([1,3]Oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochlorideYield 93%

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 (165 mg, 0.441 mmol) in chloroform (10 ml) and methanol (0.4 ml) at room temperature under argon was treated with triethylamine (0.184 ml, 1.323 mmol) and stirred for 0.25 h (the suspension turned into a solution). [1,3]Oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144 Example 61) (73.7 mg, 0.441 mmol) was then added and the reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (280 mg, 1.323 mmol) was then added and the reaction was stirred at room temperature. After 1.5 h LCMS showed that there was still some imine present in the mixture so 1 eq of sodium triacetoxyborohydride was added. After 1 h saturated NaHCO3 (50 ml) was added followed by 20% methanol/dichloromethane (80 ml) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted again twice with 20% methanol/dichloromethane (2×80 ml). The combined organic extracts were dried on magnesium sulphate, filtered and evaporated to afford 215 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 yellow solid (185 mg, 93%).

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 1.5 h LCMS showed that there
  5. additionwas added
  6. extractionthe aqueous layer was extracted
  7. customseparated from the organic layer
  8. extractionThe aqueous layer was extracted again twice with 20% methanol/dichloromethane (2×80 ml)
  9. customThe combined organic extracts were dried on magnesium sulphate
  10. filtrationfiltered
  11. customevaporated
  12. customto afford 215 mg of crude product which
  13. customwas purified by silica chromatography

Sources & evidence

ORD record
ord-a1ca7ed78cdc47f49c87a11fe54aaf86
Source dataset
uspto-grants-2013_03
Patent number
US08389524B2

Reaction notes

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