2-Hydrazinoethanol → 2-[1,2-Di(methanesulfonyl)hydrazinyl]ethyl methanesulfonate

HRID 913784Notes

Reaction equation

CNC([N:5]([S:14]([CH3:17])(=[O:16])=[O:15])[N:6]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][CH2:8]Cl)=O.[OH:18]CCNN.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH3:13][S:10]([N:6]([CH2:7][CH2:8][O:25][S:24]([CH3:23])(=[O:26])=[O:18])[NH:5][S:14]([CH3:17])(=[O:16])=[O:15])(=[O:12])=[O:11]

Participants

Reactant 3

HCID 80172-Hydrazinoethanol

HCID 31297Methanesulfonyl chloride

HCID 3081349Laromustine

Product 1

HCID 156346932-[1,2-Di(methanesulfonyl)hydrazinyl]ethyl methanesulfonateYield 10%

Procedure

A three-step process with a total yield less than 10% has been previously reported published in the following patents and journal articles: U.S. Pat. No. 5,637,619 (Jun. 10, 1997 for VNP40101M); U.S. Pat. No. 4,684,747 (Aug. 4, 1987 for intermediate VNP4090CE); WO97/02029 (Jan. 23, 1997); Journal of Medicinal Chemistry, 1990, 33(8): 2259-2264; Journal of Medicinal Chemistry, 1996, 39(3): 796-801, as illustrated in FIG. 1. 2-Hydroxyethylhydrazine (HEH) was used a starting material and reacted with methanesulfonyl chloride to obtain 1,2-bis(methylsulfonyl)-1-[2-(methylsulfonyloxy)ethyl]hydrazine (BMH) at −20° C. for 18 hours, using pyridine as base. The crude intermediate BMH was treated with lithium chloride in acetone under reflux for 3 days to afford 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (VNP4090CE). After purification by flash column chromatography, an approximately 20% yield was reached for the two steps. VNP4090CE was condensed with methyl isocyanate at room temperature using triethylamine (TEA) as a base. After crystallization from ethanol, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylcarbamoyl)hydrazine (VNP40101M) with an approximately 42% yield. The total yield of this process was less than 10%. It is noted that the process used methyl isocyanate, which is extremely dangerous for manufacturing in scaleup kilogram amounts. For this reason, the present inventors investigated the synthesis and have developed new methods to prepare VNP40101M.

Sources & evidence

ORD record: ord-58641d4d0fd140a892c9b2c3c92109a7
Source dataset: uspto-grants-2011_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08026395B1

Reaction notes

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