Ammonia → (R)-4-Hydroxy-7-(1-hydroxy-2-(2-(6-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)hexylthio)ethylamino)ethyl)benzo[d]thiazol-2(3H)-one formate

HRID 471235Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 471235
[O:1]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][N:21]([CH2:29][C@H:30]([OH:42])[C:31]3[C:39]4[S:38][C:37](=[O:40])[NH:36][C:35]=4[C:34]([OH:41])=[CH:33][CH:32]=3)[C:22](=[O:28])[O:23]C(C)(C)C)[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1.[CH:43]([C:46]1[S:47][CH:48]=[C:49]([C:51](O)=[O:52])[N:50]=1)([CH3:45])[CH3:44].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:22]([OH:28])=[O:23].[OH:41][C:34]1[C:35]2[NH:36][C:37](=[O:40])[S:38][C:39]=2[C:31]([C@@H:30]([OH:42])[CH2:29][NH:21][CH2:20][CH2:19][S:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:9]2[CH2:8][CH2:7][C:6]3([O:1][CH2:2][CH2:3][N:4]([C:51]([C:49]4[N:50]=[C:46]([CH:43]([CH3:45])[CH3:44])[S:47][CH:48]=4)=[O:52])[CH2:5]3)[CH2:11][CH2:10]2)=[CH:32][CH:33]=1

Komponenten

9

Edukt 4

HCID 222AmmoniaHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 225730652-(Propan-2-yl)-1,3-thiazole-4-carboxylic acidHCID 57988895(R)-tert-Butyl 2-(6-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)hexylthio)ethyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate

Produkt 1

HCID 67291816(R)-4-Hydroxy-7-(1-hydroxy-2-(2-(6-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)hexylthio)ethylamino)ethyl)benzo[d]thiazol-2(3H)-one formate

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 6228DimethylformamideLösungsmittelHCID 8471TriethylamineLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 57417360Sodium chloride; waterLösungsmittel

Versuchsvorschrift

To a solution (R)-tert-butyl 2-(6-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)hexylthio)ethyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate (example 101, step g) (0.093 g) in DMF (3 mL) was added triethylamine (0.062 mL) and 2-isopropyl-thiazole-4-carboxylic acid (0.025 g) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.079 g). The resultant mixture was stirred at RT for 4 h then 4 drops of ‘880’ aqueous ammonia were added and the mixture was stirred for 15 min. Brine and ethyl acetate were added to the solution and the phases were separated, then the organic phase was extracted with ethyl acetate (×2). The combined organic phase was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in DCM (2 mL) then trifluoroacetic acid (1 mL) was added. The solution was left to stand at RT for 40 min then toluene (20 mL) was added and the mixture was concentrated in vacuo. A further amount of toluene was added and the mixture concentrated again before the material was azeotroped with acetonitrile. Purification was by preparative HPLC (Phenomenex Gemini®, Gradient: 10-40% acetonitrile in 0.1% aqueous formic acid). The fractions containing product were combined and freeze dried to give the titled compound as a colourless solid. Yield 0.016 g.

Aufarbeitung

  1. customthe phases were separated
  2. extractionthe organic phase was extracted with ethyl acetate (×2)
  3. dry with materialThe combined organic phase was dried over sodium sulphate
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. dissolutionThe residue was dissolved in DCM (2 mL)
  7. additiontrifluoroacetic acid (1 mL) was added
  8. waitThe solution was left
  9. waitto stand at RT for 40 min
  10. additiontoluene (20 mL) was added
  11. concentrationthe mixture was concentrated in vacuo
  12. additionA further amount of toluene was added
  13. concentrationthe mixture concentrated again before the material
  14. customwas azeotroped with acetonitrile
  15. customPurification
  16. additionThe fractions containing product
  17. customfreeze dried

Quellen und Nachweise

ORD-Eintrag
ord-38d1730df8f24a59961f7ed066e12eae
Quelldatensatz
uspto-grants-2014_01
Patentnummer
US08629271B2

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