Hydrochloric Acid → (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 253681

Reaction equation

HRID 253681 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.C(N(C(C)C)C(C)C)C.O([CH2:83][CH2:84][O:85][CH2:86][CH3:87])S(C(F)(F)F)(=O)=O.Cl>C(OCC)(=O)C.C(Cl)Cl>[CH3:83][CH2:84][O:85][CH2:86][CH2:87][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

7

Reactant 4

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 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 44.5%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

In a reaction flask, sirolimus (1 g, 1.1 mmol), ethyl di-isopropyl amine (7.8 g, 60.3 mmol), methylene chloride (3.5 ml) and 2-ethoxyethyl triflate (2.0 g, 8.8 mmol) as previously made in Example 3A were added into the flask, which is filled with nitrogen gas. The reaction mixture is heated to 60° C. and is agitated for one hour and twenty minutes. Then, it is cooled, added with ethyl acetate (100 ml) and aqueous solution of hydrochloric acid (1N, 100 ml) and is further agitated. After agitation, it is settled for separating the layers. The organic layer is collected and respectively washed with pure water (100 ml), saturated saline (80 ml). The washed organic layer is dried and concentrated. The residue is then separated and purified by silica gel column chromatography to obtain white product of Biolimus A9 (0.48 g, 0.49 mmol), with a yield of 44.5%.

Workup

  1. additionwere added into the flask, which
  2. additionis filled with nitrogen gas
  3. temperatureThen, it is cooled
  4. customfor separating the layers
  5. customThe organic layer is collected
  6. washrespectively washed with pure water (100 ml), saturated saline (80 ml)
  7. customThe washed organic layer is dried
  8. concentrationconcentrated
  9. customThe residue is then separated
  10. custompurified by silica gel column chromatography

Sources & evidence

ORD record
ord-f4d2611bff2b4848ac6f0ad20929f5f1
Source dataset
uspto-grants-2011_01
Patent number
US07872122B2

Linked notes

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