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

HRID 879185

反応式

HRID 879185 の反応式
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

参加物

12

反応物 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 methanesulfonateHCID 178516071HCID 178516071、化合物

生成物 2

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

試薬・触媒・溶媒 4

HCID 6228Dimethylformamide溶媒HCID 8857Ethyl Acetate溶媒HCID 312751,4-Dioxane溶媒HCID 57417360Sodium chloride; water溶媒

反応条件

温度
70 °C

実験手順

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 residue 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, 3H), 1.30 (s, 9H), 1.63-1.81 (m, 2H), 1.89-2.00 (m, 2H), 2.02-2.18 (m, 2H), 3.04-3.13 (m, 1H), 4.03-4.12 (m, 1H), 4.91-5.02 (m, 1H), 5.04-5.13 (m, 2H), 6.17-6.26 (m, 1H), 6.31-6.41 (m, 1H), 6.98-7.07 (m, 1H), 7.32-7.41 (m, 2H), 7.68-7.74 (m, 1H), 7.74-7.82 (m, 1H), 7.85-7.90 (m, 1H). 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, 3H), 1.35-1.78 (m, 12H), 1.97-2.08 (m, 2H), 2.76 (t, J=11.93 Hz, 1H), 3.72 (br. s., 2H), 3.88 (d, J=4.70 Hz, 1H), 5.43 (d, J=7.43 Hz, 1H), 5.59 (br. s., 1H), 6.79-6.94 (m, 2H), 7.08 (d, J=5.09 Hz, 1H), 7.56-7.65 (m, 1H), 7.98-8.17 (m, 3H).

後処理

  1. concentrationThe organic layer was concentrated
  2. customwere removed in vacuo
  3. dissolutionThe residue 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

出典と根拠

ORDレコード
ord-9b5816f2bf3f4cb0a13bbba3b38aea5a
出典データセット
uspto-grants-2015_03
特許番号
US08987457B2

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