Acetic Acid → ((3aS,5S,6aR)-5-((3S,4S)-3-Methoxytetrahydro-2H-pyran-4-ylamino)hexahydro-2H-cyclopenta[b]furan-3a-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone

HRID 1747148Notes

Reaction equation

HRID 1747148 reaction equation
Cl.Cl.[NH2:3][C@@H:4]1[CH2:11][C@H:7]2[O:8][CH2:9][CH2:10][C@@:6]2([C:12]([N:14]2[CH2:23][CH2:22][C:21]3[N:20]=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[CH:17][C:16]=3[CH2:15]2)=[O:13])[CH2:5]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:46][O:47][C@H:48]1[C:53](=O)[CH2:52][CH2:51][O:50][CH2:49]1>ClCCCl.C(Cl)Cl.ClCCCl>[CH3:46][O:47][C@H:48]1[C@@H:53]([NH:3][C@@H:4]2[CH2:11][C@H:7]3[O:8][CH2:9][CH2:10][C@@:6]3([C:12]([N:14]3[CH2:23][CH2:22][C:21]4[N:20]=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[CH:17][C:16]=4[CH2:15]3)=[O:13])[CH2:5]2)[CH2:52][CH2:51][O:50][CH2:49]1

Participants

7

Reactant 4

HCID 176Acetic Acid2×HCID 5049666Sodium triacetoxyborohydrideHCID 11320949(R)-3-methoxydihydro-2H-pyran-4(3H)-one3×HCID 86708148((3aS,5S,6aR)-5-Aminohexahydro-2H-cyclopenta[b]furan-3a-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone dihydrochloride

Product 1

HCID 60148505((3aS,5S,6aR)-5-((3S,4S)-3-Methoxytetrahydro-2H-pyran-4-ylamino)hexahydro-2H-cyclopenta[b]furan-3a-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 220203331,2-Dichloroethane methylene chlorideSolvent

Conditions

Temperature
16 °C

Procedure

To a mixture of the product of Step K (the free base) (619.7 g, 1.74 mol) in 1,2-dichloroethane/CH2Cl2 (˜10 L) was added acetic acid (glacial, 180 mL) and the mixture was cooled to 16° C. Solid Na(OAc)3BH (463 g, 2.18 mol) was added and the suspension was stirred for 5-10 min. A solution of (R)-3-methoxydihydro-2H-pyran-4(3H)-one (prepared as described in Intermediate 1, 213 g, 1.63 mol) in 1,2-dichloroethane (1.75 L) was added over 20 min and the resulting mixture was stirred at rt overnight. Additional acetic acid, (R)-3-methoxytetrahydro-4H-pyran-4-one (28 g) and Na(AcO)3BH were added until TLC showed the reaction was complete. The reaction was quenched with saturated aqueous NaHCO3, the organic layer was separated and the aqueous layer was back-extracted with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. Purification was affected by chromatography with MeOH (7N NH3) in CH2Cl2. The collected enriched isomer was further purified using chiral chromatography on chiralpak AD column using a mixture of heptanes/EtOH/isopropyl alcohol to provide the product of Step L.

Workup

  1. stirringthe resulting mixture was stirred at rt overnight
  2. customThe reaction was quenched with saturated aqueous NaHCO3
  3. customthe organic layer was separated
  4. extractionthe aqueous layer was back-extracted with CH2Cl2
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried (Na2SO4)
  7. customevaporated under reduced pressure
  8. customPurification
  9. customwas further purified
  10. additiona mixture of heptanes/EtOH/isopropyl alcohol

Sources & evidence

ORD record
ord-4f796fec416845d0b582fc9ab4a448d2
Source dataset
uspto-grants-2015_10
Patent number
US09150532B2

Reaction notes

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