2,6-Lutidine → (1R,9S,15R,16E,18R,19R,21R,24E,26E,28E,30S,32S,35R)-12-[(2R)-1-[(3R,4R)-4-(2-ethoxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone

HRID 1352240Notes

Reaction equation

HRID 1352240 reaction equation
[CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.S(O[CH2:82][CH2:83][O:84][CH2:85][CH3:86])(C(F)(F)F)(=O)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:82][CH2:83][O:84][CH2:85][CH2:86][O:55][C@H:50]1[C@H:51]([O:53][CH3:54])[CH2:52][CH:47]([CH2:46][C@H:44]([CH:27]2[O:28][C:29](=[O:30])[C@H:31]3[N:36]([CH2:35][CH2:34][CH2:33][CH2:32]3)[C:37](=[O:38])[C:39](=[O:40])[C@:41]3([OH:43])[O:42][C@@H:5]([CH2:4][CH2:3][C@H:2]3[CH3:1])[CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17](=[O:18])[C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24](=[O:25])[CH2:26]2)[CH3:45])[CH2:48][CH2:49]1

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 8857Ethyl AcetateHCID 5284616SirolimusHCID 160501642-Ethoxyethyl triflate

Product 1

HCID 56841932(1R,9S,15R,16E,18R,19R,21R,24E,26E,28E,30S,32S,35R)-12-[(2R)-1-[(3R,4R)-4-(2-ethoxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentoneYield 19.5%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a stirred solution of 1 g rapamycin, and 7.66 g 2,6-lutidine in 14.65 mL toluene held at 60° C. was added 5.81 g 2-ethoxyethanol triflate. Stirring was continued for 90 minutes after which 50 mL ethyl acetate was added to the reaction and the solution was washed with 50 mL 1M HCl. The organic material was washed with D.I. water until pH of wash solution was neutral and the organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, 200–400 mesh (40:60 hexane-ethyl acetate (v/v) to give 210 mg 42-O-(2-ethoxyethyl) rapamycin. TLC Rf=0.41 using 40:60 hexane-ethyl acetate (v/v). MS (ESI) m/z 1008.5 C55H87NNaO14. A mass spectrum of the title compound is shown in FIG. 1.

Workup

  1. customheld at 60° C.
  2. washthe solution was washed with 50 mL 1M HCl
  3. washThe organic material was washed with D.I
  4. dry with materialthe organic solution was dried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by flash chromatography on silica gel, 200–400 mesh (40:60 hexane-ethyl acetate (v/v)

Sources & evidence

ORD record
ord-b967a51f6f804238b5fdf16832923977
Source dataset
uspto-grants-2007_05
Patent number
US07220755B2

Reaction notes

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