Tacrolimus-13C,D2 → HCID 72524391, compound

HRID 1991023Notes

Reaction equation

HRID 1991023 reaction equation
[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3].C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:63][C:64](=[O:74])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71](O)=[O:72])(C)(C)C.Cl.CN(C)CCCN=C=NCC.F>ClCCl.CN(C)C1C=CN=CC=1.C(#N)C.C1C=CC=CC=1>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:71](=[O:72])[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][C:64]([OH:74])=[O:63])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3]

Participants

9

Reactant 4

HCID 5372Tacrolimus-13C,D2HCID 14917Hydrofluoric AcidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 23084396HCID 23084396, compound

Product 1

HCID 72524391HCID 72524391, compound

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 241BenzeneSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent3×

Procedure

17-allyl-1,14-di-hydroxy-12-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone (FK-506, 1, 3.3 mg, 4.10 μmol) was twice boiled together with benzene, and dissolved in dichloromethane (39 μl), and 16.2 μl (4.09 μmol) of a solution of O-mono(tert-butyl-diphenyl-silanyl)octanedioic acid in dichloromethane (100 mg/ml) was added. After this was dissolved by the addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (WSC/HCl, 0.94 mg, 4.90 μmol) and 23 μl (1.88 μmol) of a solution of 4-dimethylaminopyridine in dichloromethane (10 mg/ml) at room temperature, the solution was allowed to stand for 1.5 hours. This solution was extracted by the addition of dichloromethane (150 μl) and saturated aqueous sodium carbonate (150 μl). The organic phase collected was concentrated by blowing a nitrogen stream. After the syrup obtained was dissolved by the addition of acetonitrile (28 μl), 46-48% aqueous hydrogen fluoride (6.5 μl) was added at room temperature, and the solution was allowed to stand for 1.5 hours. This solution was extracted by the addition of ethyl acetate (100 μl) and saturated aqueous sodium carbonate (100 μl), and the organic phase was concentrated by blowing a nitrogen stream, to yield a syrup of mixture A. The mixture A was used as is without purification and the like in the next step. The mixture A was used while no structural information was available about whether or not the mixture A contains a compound having the spacer introduced thereto only at a position where the binding to FKBP12 is not affected, for example, 17-allyl-1,14-di-hydroxy-12-{2-[4-(7-carboxy-heptanoyl-oxy)-3-methoxy-cyclohexyl]-1-methyl-vinyl}-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone shown in Reference Production Example 2, or contains FK506 having the spacer introduced therein at a position where there is a contribution to the binding to FKBP12, or contains FK506 having a plurality of spacers introduced thereto, and the like.

Workup

  1. extractionThis solution was extracted by the addition of dichloromethane (150 μl) and saturated aqueous sodium carbonate (150 μl)
  2. customThe organic phase collected
  3. concentrationwas concentrated
  4. customAfter the syrup obtained
  5. additionwas added at room temperature
  6. waitto stand for 1.5 hours
  7. extractionThis solution was extracted by the addition of ethyl acetate (100 μl) and saturated aqueous sodium carbonate (100 μl)
  8. concentrationthe organic phase was concentrated
  9. customto yield a syrup of mixture A
  10. customas is without purification
  11. additionintroduced
  12. additionintroduced
  13. additionintroduced

Sources & evidence

ORD record
ord-0a990ec682894841a59cc096cd217636
Source dataset
uspto-grants-2010_01
Patent number
US07645614B2

Reaction notes

Loading…