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Hydrochloric Acid → tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamate

HRID 705271
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 705271
CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=O)=O.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[OH:41].Cl.C(=O)(ON1C(=O)CCC1=O)OC(C)(C)C.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O.O1CCOCC1.CCOC(C)=O>[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@H:9]1[CH2:8][C@@H:7]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[C@@H:6]([N:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]2=[O:41])[C@@H:11]([CH3:12])[CH2:10]1.[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@@H:9]1[CH2:8][C@H:7]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[C@H:6]([N:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]2=[O:41])[C@H:11]([CH3:12])[CH2:10]1
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

12

Edukt 6

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 83168Carbonic acid, 1,1-dimethylethyl 2,5-dioxo-1-pyrrolidinyl esterHCID 516892Sodium BicarbonateHCID 86705223(1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate
HCID 178516071
HCID 178516071, Verbindung

Produkt 2

HCID 86705232tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamateAusbeute 8 %HCID 86705233tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamateAusbeute 9 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 312751,4-DioxaneLösungsmittelHCID 57417360Sodium chloride; waterLösungsmittel

Reaktionsbedingungen

Temperatur
70 °C

Versuchsvorschrift

To a solution of (1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) Cs2CO3 (3.0 equiv.) in DMF (0.15 M) was added pyridin-2-ol (1.0 equiv). The mixture was stirred at 70° C. for 5 hrs. The reaction was worked up with EtOAc and Brine. The organic layer was concentrated and was treated with 4N HCl (30.0 equiv.) in Dioxane for 2 hrs at which time the volatiles were removed in vacuo. The redisue was dissolved in THF (0.15 M) and tert-butyl 2,5-dioxopyrrolidin-1-yl carbonate (1.5 equiv.) was added, followed by DIEA (3.0 equiv.). After stirring at rt for 3 hrs, the reaction was quenched with sat. NaHCO3 and extracted with EtOAc. The organic layer was washed with Brine, dried over Na2SO4 and concentrated. The crude was purified by prep HPLC to yield two major peaks. The fractions of the first product peak was combined and neutralized with sat. NaHCO3 and extracted with EtOAc. The organic layer was washed with Brine, dried over Na2SO4 and concentrated. Purification was completed via SFC (20% (MeOH with 10% DEA), 100 mL/min, AD column) to yield tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamate (8% yield, 99% ee) and tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamate (9% yield, 99% ee). LC/MS (m/z)=399.2 (MH+), Rt=0.60 min. 1H NMR (400 MHz, <dmso>) δ ppm 0.72 (s, 3 H), 1.30 (s, 9 H), 1.63-1.81 (m, 2 H), 1.89-2.00 (m, 2 H), 2.02-2.18 (m, 2 H), 3.04-3.13 (m, 1 H), 4.03-4.12 (m, 1 H), 4.91-5.02 (m, 1 H), 5.04-5.13 (m, 2 H), 6.17-6.26 (m, 1 H), 6.31-6.41 (m, 1 H), 6.98-7.07 (m, 1 H), 7.32-7.41 (m, 2 H), 7.68-7.74 (m, 1H), 7.74-7.82 (m, 1 H), 7.85-7.90 (m, 1 H). The fractions of the second product peak was combined and neutralized with sat. NaHCO3 and extracted with EtOAc. The organic layer was washed with Brine, dried over Na2SO4 and concentrated. Purification was completed via SFC (20% (MeOH with 10% DEA), 100 mL/min, AD column) to yield tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(pyridin-2-yloxy)cyclohexyl)carbamate (14% yield, 99% ee) and tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(pyridin-2-yloxy)cyclohexyl)carbamate (15% yield, 99% ee). LC/MS (m/z)=399.2 (MH+), Rt=0.65 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.95 (d, J=6.65 Hz, 3 H), 1.35-1.78 (m, 12 H), 1.97-2.08 (m, 2 H), 2.76 (t, J=11.93 Hz, 1 H), 3.72 (br. s., 2 H), 3.88 (d, J=4.70 Hz, 1 H), 5.43 (d, J=7.43 Hz, 1 H), 5.59 (br. s., 1H), 6.79-6.94 (m, 2H), 7.08 (d, J=5.09 Hz, 1 H), 7.56-7.65 (m, 1 H), 7.98-8.17 (m, 3 H).

Aufarbeitung

  1. concentrationThe organic layer was concentrated
  2. customwere removed in vacuo
  3. dissolutionThe redisue was dissolved in THF (0.15 M)
  4. stirringAfter stirring at rt for 3 hrs
  5. customthe reaction was quenched with sat. NaHCO3
  6. extractionextracted with EtOAc
  7. washThe organic layer was washed with Brine
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated
  10. customThe crude was purified by prep HPLC
  11. customto yield two major peaks
  12. extractionextracted with EtOAc
  13. washThe organic layer was washed with Brine
  14. dry with materialdried over Na2SO4
  15. concentrationconcentrated
  16. customPurification

Quellen und Nachweise

ORD-Eintrag
ord-b38ea8c692ad4ca69fbf56f4b5c10a45
Quelldatensatz
uspto-grants-2015_11
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09173883B2

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