Dicyclohexylcarbodiimide → Maytansine

HRID 734163Notes

Reaction equation

HRID 734163 reaction equation
[CH3:1][N:2]([C:8](=[O:14])[CH2:9]CSSC)[C@H:3]([C:5]([OH:7])=[O:6])[CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:30][CH:31]1[CH:56]2[O:57][C:55]2([CH3:58])[CH:54](O)[CH2:53][C:51](=[O:52])[N:50]([CH3:60])[C:43]2=[C:44]([Cl:49])[C:45]([O:47][CH3:48])=[CH:46][C:41](=[CH:42]2)[CH2:40][C:39]([CH3:61])=[CH:38][CH:37]=[CH:36][CH:35]([O:62][CH3:63])[C:34]2([OH:68])[NH:64][C:65]([O:67][CH:32]1[CH2:33]2)=[O:66]>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:30][C@H:31]1[C@@H:56]2[O:57][C@@:55]2([CH3:58])[C@@H:54]([O:7][C:5]([C@@H:3]([N:2]([C:8]([CH3:9])=[O:14])[CH3:1])[CH3:4])=[O:6])[CH2:53][C:51](=[O:52])[N:50]([CH3:60])[C:43]2=[C:44]([Cl:49])[C:45]([O:47][CH3:48])=[CH:46][C:41](=[CH:42]2)[CH2:40][C:39]([CH3:61])=[CH:38][CH:37]=[CH:36][C@@H:35]([O:62][CH3:63])[C@:34]2([OH:68])[NH:64][C:65]([O:67][C@H:32]1[CH2:33]2)=[O:66]

Participants

6

Reactant 3

HCID 10868DicyclohexylcarbodiimideHCID 5358230HCID 5358230, compoundHCID 9942784HCID 9942784, compound

Product 1

HCID 5281828MaytansineYield 17.3%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalyst2×HCID 6344DichloromethaneSolvent2×

Procedure

N-methyl-N-(methyl dithiopropanoyl)-L-alanine (26 mg) prepared by a different process in accordance with a reference was dissolved in 3 ml of CH2Cl2, 30 mg of dicyclohexylcarbodiimide (2 equivalent amounts) and 20 μl of 1M zinc chloride (1 equivalent amount) were added thereto, and the mixture was stirred at room temperature for 30 minutes. Since the reaction did not proceed under this condition, the amount of 1M zinc chloride added was changed to 100 μl (5 equivalent amounts), and the mixture was stirred at room temperature for 30 minutes. A solution of 11.8 mg of maytansinol in 1 ml of CH2Cl2 was added thereto for esterification. The reaction solution was concentrated to dryness 3 hours later, the main product was purified by preparative TLC (CH2Cl2:MeOH=10:1) and then by preparative HPLC (ODS column, eluent: 60% CH3CN). As a result, 2.5 mg of maytansine derivative (May-SS-Me) was obtained. FIG. 6 shows the resulting May-SS-Me by 500 MHz 1H NMR. In the test for assaying the cellular cytotoxicity of the human myeloma cell strain IM9 as described in Example 19, IC50 of the obtained May-SS-Me was 10 nM, which was 1/1000 or less than that of ansamitocin P-3.

Workup

  1. stirringthe mixture was stirred at room temperature for 30 minutes
  2. concentrationThe reaction solution was concentrated to dryness 3 hours later
  3. customthe main product was purified by preparative TLC (CH2Cl2:MeOH=10:1)

Sources & evidence

ORD record
ord-889ecb9d882f4de29e5b93f890a21948
Source dataset
uspto-grants-2009_09
Patent number
US07592005B2

Reaction notes

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