Water → (2S)-2-(tert-Butoxy)-2-[(22S)-8,17,18-trifluoro-4,22,28-trimethyl-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 1482051Notes

Reaction equation

HRID 1482051 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[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F: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].[F:50][B-](F)(F)F.ClC1C=CC=C(Cl)[N+]=1F.O.O[Li].O>CC#N>[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]([F:50])[N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F: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])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 962WaterHCID 168937Lithium hydroxide, monohydrateHCID 27373072,6-Dichloro-1-fluoropyridiniumtetrafluoroborateHCID 118316281Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17,18-difluoro-4,22,28-trimethyl-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 118316303(2S)-2-(tert-Butoxy)-2-[(22S)-8,17,18-trifluoro-4,22,28-trimethyl-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 5.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-17,18-difluoro-4,22,28-trimethyl-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 (22 mg, 0.033 mmol, 1 equiv) in MeCN (0.33 mL) was added 2,6-dichloro-1-fluoropyridin-1-ium, tetrafluoroborate salt (8 mg, 0.031 mmol, 1 equiv). The reaction turned dark orange. After 3 h, the reaction was concentrated in vacuo. The crude fluoride product was taken up in 9:1 MeOH:water (1.8 mL) and LiOH.H2O (27 mg, 0.651 mmol, 20 equiv) was added. The reaction was heated to 60° C. for 4 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: 40-90% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (1.1 mg, 5%) 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=1.5 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.37-7.33 (m, 1H), 7.32-7.27 (m, 1H), 7.19 (s, 1H), 7.11 (dd, J=12.8, 7.0 Hz, 1H), 6.04 (br. s., 1H), 4.56 (d, J=5.9 Hz, 1H), 3.76-3.48 (m, 4H), 3.28 (d, J=11.0 Hz, 1H), 2.71 (d, J=6.8 Hz, 1H), 2.53 (s, 3H), 2.09-1.64 (m, 10H), 1.28 (s, 9H), 1.27 (s, 3H), 1.19 (d, J=6.1 Hz, 3H); LCMS (ESI, M): 679.3.

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: 40-90% B over 20 minutes
  6. customa 5-minute hold

Sources & evidence

ORD record
ord-d9469f8a825b450ab71d7f80e0f9cdbb
Source dataset
uspto-grants-2016_08
Patent number
US09409922B2

Reaction notes

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