Acetate → HCID 87686369, compound

HRID 1787410Notes

Reaction equation

HRID 1787410 reaction equation
C([O-])(=O)C.[CH3:5][CH2:6][C@@H:7]1[NH:50][C:48](=[O:49])[C@H:47]([C@H:51]([OH:58])[C@@H:52]([CH2:54]/[CH:55]=[CH:56]/[CH3:57])[CH3:53])[N:46]([CH3:59])[C:44](=[O:45])[C@H:43]([CH:60]([CH3:62])[CH3:61])[N:42]([CH3:63])[C:40](=[O:41])[C@H:39]([CH2:64][CH:65]([CH3:67])[CH3:66])[N:38]([CH3:68])[C:36](=[O:37])[C@H:35]([CH2:69][CH:70]([CH3:72])[CH3:71])[N:34]([CH3:73])[C:32](=[O:33])[C@@H:31]([CH3:74])[NH:30][C:28](=[O:29])[C@H:27]([CH3:75])[NH:26][C:24](=[O:25])[C@H:23]([CH2:76][CH:77]([CH3:79])[CH3:78])[N:22]([CH3:80])[C:20](=[O:21])[C@H:19]([CH:81]([CH3:83])[CH3:82])[NH:18][C:16](=[O:17])[C@H:15]([CH2:84][CH:85]([CH3:87])[CH3:86])[N:14]([CH3:88])[C:12](=[O:13])[CH2:11][N:10]([CH3:89])[C:8]1=[O:9].[NH:90]1[CH2:95][CH2:94][S:93][CH2:92][CH2:91]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CO.C(OCC)(=O)C>[CH3:5][CH2:6][C@@H:7]1[NH:50][C:48](=[O:49])[C@H:47]([C@H:51]([OH:58])[C@@H:52]([CH2:54]/[CH:55]=[CH:56]/[CH3:57])[CH3:53])[N:46]([CH3:59])[C:44](=[O:45])[C@H:43]([CH:60]([CH3:61])[CH3:62])[N:42]([CH3:63])[C:40](=[O:41])[C@H:39]([CH2:64][CH:65]([CH3:66])[CH3:67])[N:38]([CH3:68])[C:36](=[O:37])[C@H:35]([CH2:69][CH:70]([CH3:72])[CH3:71])[N:34]([CH3:73])[C:32](=[O:33])[C@@H:31]([CH3:74])[NH:30][C:28](=[O:29])[C@H:27]([CH3:75])[NH:26][C:24](=[O:25])[C@H:23]([CH2:76][CH:77]([CH3:79])[CH3:78])[N:22]([CH3:80])[C:20](=[O:21])[C@H:19]([CH:81]([CH3:83])[CH3:82])[NH:18][C:16](=[O:17])[C@H:15]([CH2:84][CH:85]([CH3:87])[CH3:86])[N:14]([CH3:88])[C:12](=[O:13])[CH2:11][N:10]([CH3:89])[C:8]1=[O:9].[NH:90]1[CH2:95][CH2:94][S:93][CH2:92][CH2:91]1

Participants

8

Reactant 4

HCID 175AcetateHCID 11430Potassium CarbonateHCID 67164ThiomorpholineHCID 5284373Cyclosporin A

Product 1

HCID 87686369HCID 87686369, compoundYield 46.9%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of the acetate of cyclosporin allylic chloride from Example 35 (60 mg, 0.047 mmol) and thiomorpholine (48 mg, 0.47 mmol) in methylene chloride (3 mL) was stirred overnight at room temperature under N2 atmosphere. The mixture was concentrated in vacuo. The residue and potassium carbonate (102 mg, 0.740 mmol) were dissolved in methanol (3 mL) and allowed to stir overnight at room temperature under N2 atmosphere. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by semi-preparative HPLC to afford cyclosporine thiomorpholine (28.8 mg, 33%) as a white solid: 1H NMR (300 MHz, CD2Cl2) δ 7.96 (d, J=9.7 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.44 (d, J=7.4 Hz, 1H), 7.15 (d, J=7.7 Hz, 1H), 5.67 (dd, J=10.9, 4.1 Hz, 1H), 5.05-5.48 (m, 9H), 5.43 (d, J=6.6 Hz, 2H), 5.28 (d, J=3.8 Hz, 1H), 5.24 (d, J=3.8 Hz, 1H), 5.15-4.89 (m, 5H), 4.79 (t, J=14.5 Hz, 2H), 4.72 (s, 1H), 4.64 (dd, J=14.8, 5.8 Hz, 2H), 4.23 (t, J=14.5 Hz, 2H), 3.44 (s, 3H), 3.35 (s, 3H), 3.21(s, 3H), 3.09 (s, 3H), 3.08 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H), 2.50-1.40 (m, 15H), 1.27-0.70 (m, 54H): ESI MS m/z 1304 [C66H118N12O12S+H]+; HPLC>99% (AUC), tR=13.00 min.

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. washwashed with saturated sodium bicarbonate solution and brine
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated in vacuo
  5. customThe crude product was purified by semi-preparative HPLC

Sources & evidence

ORD record
ord-91e3c3347aaa46518e183d5c7f5d63ac
Source dataset
uspto-grants-2009_03
Patent number
US07511013B2

Reaction notes

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