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

HRID 1943183Notes

Reaction equation

HRID 1943183 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: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.ClCCl.CO>[ClH:1].[S: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 574231152,3-Dihydro[1,4]oxathiino[2,3-c]pyridine-7-carbaldehydeHCID 68600205HCID 68600205, compound

Product 1

HCID 68599143(1R)-1-({4-[(2,3-Dihydro-[1,4]oxathiino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochlorideYield 90%

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 (160 mg, 0.428 mmol) (for a preparation see Example 13(k) or 15(d)) in chloroform (10 ml) and methanol (0.400 ml) under argon at room temperature was treated with triethylamine (0.179 ml, 1.283 mmol) and stirred for 0.25 h at room temperature (everything went into solution). 2,3-Dihydro[1,4]oxathiino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 60) (77 mg, 0.428 mmol) was then added and the reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (272 mg, 1.283 mmol) was then added and the reaction was stirred at room temperature. After 1.5 h there was still some imine present by LCMS so 1 equivalent of sodium triacetoxyborohydride was added. After 1 h sat NaHCO3 (50 ml) was added followed by 20% methanol/dichloromethane (80 ml) and the aqueous 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 MgSO4, 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 yellow foam (179 mg, 90%).

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 there was still
  5. waitAfter 1 h sat
  6. extractionthe aqueous 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 MgSO4
  10. filtrationfiltered
  11. customevaporated
  12. customto afford 215 mg of crude product which
  13. customwas purified by silica chromatography

Sources & evidence

ORD record
ord-22af976f321b4368bc36a0f0c0d551a7
Source dataset
uspto-grants-2013_03
Patent number
US08389524B2

Reaction notes

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