Water → (2S)-2-(tert-Butoxy)-2-[(22S)-8-chloro-4,17,22,28-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 1482046Notes

Reaction equation

HRID 1482046 reaction equation
[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[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].C1C(=O)N([Cl:56])C(=O)C1.O.O[Li].O>CC#N.C1COCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([Cl:56])[N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 962WaterHCID 31398ChlorosuccinimideHCID 168937Lithium hydroxide, monohydrateHCID 131736665methyl(2S)-2-(tert-butoxy)-2-[(22S)-4,17,22,28-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 118332041(2S)-2-(tert-Butoxy)-2-[(22S)-8-chloro-4,17,22,28-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 48%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-4,17,22,28-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 (20 mg, 0.031 mmol, 1 equiv) in MeCN (1 mL) was added NCS (4 mg, 0.031 mmol, 1 equiv). After 1 h, the reaction was concentrated in vacuo. The crude chloride was taken up in 9:1 MeOH:water (1.1 mL) and LiOH.H2O (39 mg, 0.918 mmol, 30 equiv) was added. A few drops of THF were added to aid solubility. The reaction was heated to 70° C. for 1.5 h. Upon cooling to ambient temperature, the reaction was filtered and 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: 60-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (10 mg, 48%). 1H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.36 (s, 1H), 7.16-7.08 (m, 3H), 6.02-5.67 (m, 1H), 4.60 (d, J=3.3 Hz, 1H), 3.96 (d, J=10.6 Hz, 2H), 3.52 (d, J=8.4 Hz, 1H), 3.42-3.30 (m, 1H), 2.44 (s, 3H), 2.40-2.31 (m, 2H), 2.29 (s, 3H), 2.05-1.51 (m, 10H), 1.20 (br. s., 3H), 1.19 (s, 9H), 1.03 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 673.3.

Workup

  1. concentrationthe reaction was concentrated in vacuo
  2. temperatureUpon cooling to ambient temperature
  3. filtrationthe reaction was filtered
  4. custompurified via preparative LC/MS with the following conditions
  5. waitGradient: 60-100% B over 15 minutes
  6. customa 5-minute hold

Sources & evidence

ORD record
ord-62b7f11cebfe4536a2e4c60965e0dcb1
Source dataset
uspto-grants-2016_08
Patent number
US09409922B2

Reaction notes

Loading…