Potassium Carbonate → 4-{2-[methyl(2-methyl-2-(methyldisulphanyl)propyl)amino]ethoxy}-2,6-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-5-one-8-yloxymethyl]pyridine

HRID 446640Notes

Reaction equation

HRID 446640 reaction equation
CS(Cl)(=O)=O.[CH3:6][N:7]([CH2:21][C:22]([CH3:27])([S:24][S:25][CH3:26])[CH3:23])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[C:13]([CH2:19][OH:20])[CH:12]=1.[CH3:28]/[CH:29]=[C:30]1\[CH2:31][C@H:32]2[N:43]([CH2:44]\1)[C:41](=[O:42])[C:40]1[C:35](=[CH:36][C:37](O)=[C:38]([O:45][CH3:46])[CH:39]=1)[NH:34][CH:33]2OC.[C:50]([O-:53])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C.O>[CH3:6][N:7]([CH2:21][C:22]([CH3:27])([S:24][S:25][CH3:26])[CH3:23])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][C:37]2[C:38]([O:53][CH3:50])=[CH:39][C:40]3[C:41](=[O:42])[N:43]4[CH2:44][C:30](=[CH:29][CH3:28])[CH2:31][C@H:32]4[CH:33]=[N:34][C:35]=3[CH:36]=2)[N:14]=[C:13]([CH2:19][O:20][C:37]2[C:38]([O:45][CH3:46])=[CH:39][C:40]3[C:41](=[O:42])[N:43]4[CH2:44][C:30](=[CH:29][CH3:28])[CH2:31][C@H:32]4[CH:33]=[N:34][C:35]=3[CH:36]=2)[CH:12]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 5383620(6aR,8E)-8-ethylidene-3-hydroxy-2,6-dimethoxy-6,6a,7,9-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-oneHCID 575709534-{2-[Methyl(2-methyl-2-(methyldisulphanyl)propyl)amino]ethoxy)-2,6-bis(hydroxymethyl)pyridine

Product 1

HCID 1232406724-{2-[methyl(2-methyl-2-(methyldisulphanyl)propyl)amino]ethoxy}-2,6-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-5-one-8-yloxymethyl]pyridineYield 28.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

19.6 μl of methanesulphonyl chloride are added to a solution, cooled to −25° C., of 22 mg of 4-{2-[methyl(2-methyl-2-(methyldisulphanyl)propyl)amino]ethoxy}-2,6-bis(hydroxymethyl)pyridine and of 53 μl of TEA in 0.5 ml of DCM. After stirring for 30 min, the mixture is hydrolysed and the organic phase is washed with water, then dried over MgSO4 and concentrated under RP. The residue thus obtained (22 mg) is added to a solution of 20 mg of tomaymycin in 0.7 ml of DMF, and also 30 mg of K2CO3 and 12 mg of KI. The mixture is stirred at 30° C. for 2 h and then hydrolysed with 4 ml of water. The resulting precipitate is washed with water, dried under vacuum, then dissolved in DCM, concentrated under RP and purified by flash chromatography on silica (Merck SuperVarioFlash 15 g column, Si60 15-40 μm), using a gradient from 0 to 5% of MeOH in DCM. The fractions comprising the desired product are combined and concentrated under RP. 8 mg of 4-{2-[methyl(2-methyl-2-(methyldisulphanyl)propyl)amino]ethoxy}-2,6-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-5-one-8-yloxymethyl]pyridine are thus obtained. 1H NMR (500 MHz, d-chloroform): 1.28 (s, 6H); 1.76 (d, J=6.4 Hz, 6H); 2.39 (s, 3H); 2.43 (s, 3H); 2.60 (s, 2H); 2.91 (s, 2H); 2.97 (s, 4H); 3.91 (d, J=4.2 Hz, 2H); 4.00 (s, 6H); 4.09 (s, 2H); 4.27 (s, 4H); 5.27 (s, 4H); 5.61 (q, J=6.4 Hz, 2H); 6.85 (s, 2H); 7.00 (s, 2H); 7.56 (s, 2H); 7.65 (d, J=4.2 Hz, 2H). LC/MS (A): rt=0.74 min; [M+H]+: m/z 855; [M−H]−: m/z 853.

Workup

  1. washthe organic phase is washed with water
  2. dry with materialdried over MgSO4
  3. concentrationconcentrated under RP
  4. customThe residue thus obtained (22 mg)
  5. stirringThe mixture is stirred at 30° C. for 2 h
  6. washThe resulting precipitate is washed with water
  7. customdried under vacuum
  8. dissolutiondissolved in DCM
  9. concentrationconcentrated under RP
  10. custompurified by flash chromatography on silica (Merck SuperVarioFlash 15 g column, Si60 15-40 μm)
  11. concentrationconcentrated under RP

Sources & evidence

ORD record
ord-28bc43f378774d28a7d2d6440994b491
Source dataset
uspto-grants-2013_07
Patent number
US08481042B2

Reaction notes

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