Potassium Carbonate → (2S)-2-(tert-Butoxy)-2-[(22S)-17-fluoro-5-methanesulfonamido-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid

HRID 1482055Notes

Reaction equation

HRID 1482055 reaction equation
[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39](Br)[C:38]2=[N:43][C:35]3=[C:36](Br)[N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[C:26]([CH3:47])[C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].C([O-])([O-])=O.[K+].[K+].O[Li].O>CN(C=O)C.[Cu]I.O>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[C:26]([CH3:47])[C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 72879Methanesulfonamide2×HCID 168937Lithium hydroxide, monohydrateHCID 118316307methyl(2S)-2-(tert-butoxy)-2-[(22S)-5,8-dibromo-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate

Product 1

HCID 118316309(2S)-2-(tert-Butoxy)-2-[(22S)-17-fluoro-5-methanesulfonamido-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acidYield 12.8%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-5,8-dibromo-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (21 mg, 0.025 mmol, 1 equiv), methanesulfonamide (7 mg, 0.076 mmol, 3 equiv), CuI (7 mg, 0.038 mmol, 1.5 equiv), and K2CO3 (14 mg, 0.101 mmol, 4 equiv) in DMF (1.3 mL) was added (1S,2S)-(+)-N,N′-dimethylcyclohexanr-1,2-diamine (0.012 mL, 0.076 mmol, 3 equiv). The now blue reaction was heated to 100° C. for 24 h. More methanesulfonamide (7 mg, 0.076 mmol, 3 equiv), CuI (7 mg, 0.038 mmol, 1.5 equiv), and (1S,2S)-(+)-N,N′-dimethylcyclohexanr-1,2-diamine (0.012 mL, 0.076 mmol, 3 equiv) was added and the temperature was raised to 120° C. After 24 h, the reaction was removed from heat. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with water. The EtOAc was dried (Na2SO4) and concentrated in vacuo. The crude product was taken up in 9:1 MeOH:water (1 mL) and LiOH.H2O (32 mg, 0.759 mmol, 30 equiv) was added. The reaction was heated to 70° C. for 2 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: The crude material was purified via preparative LC/MS with the following conditions: The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (2.4 mg, 12% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.08 (d, J=7.7 Hz, 1H), 8.04 (s, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.15 (d, J=10.3 Hz, 1H), 7.10 (d, J=6.2 Hz, 1H), 6.00-5.82 (m, 1H), 4.63 (br. s., 1H), 3.89-3.80 (m, 1H), 3.70-3.59 (m, 1H), 3.52-3.42 (m, 5H), 3.37-3.19 (m, 1H), 2.72-2.64 (m, 1H), 2.41 (s, 3H), 2.29 (s, 3H), 1.97-1.50 (m, 10H), 1.22 (s, 3H), 1.18 (s, 9H), 1.08 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 750.3.

Workup

  1. customThe now blue reaction
  2. temperaturethe temperature was raised to 120° C
  3. customthe reaction was removed
  4. temperaturefrom heat
  5. temperatureUpon cooling to ambient temperature
  6. additionthe reaction was diluted with EtOAc
  7. washwashed with water
  8. dry with materialThe EtOAc was dried (Na2SO4)
  9. concentrationconcentrated in vacuo
  10. temperatureThe reaction was heated to 70° C. for 2 h
  11. temperatureUpon cooling to ambient temperature
  12. filtrationthe reaction was filtered
  13. custompurified via preparative LC/MS with the following conditions
  14. customThe crude material was purified via preparative LC/MS with the following conditions
  15. customThe crude material was purified via preparative LC/MS with the following conditions
  16. waitGradient: 50-100% B over 25 minutes
  17. customa 5-minute hold

Sources & evidence

ORD record
ord-2b22545e88714199832b2df94b78a108
Source dataset
uspto-grants-2016_08
Patent number
US09409922B2

Reaction notes

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