Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Patent
1998-02-25
2000-02-01
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
549529, 556428, 558 51, C07C30972, C07F 708
Patent
active
060205121
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the fields of pharmaceutical and organic chemistry and provides novel intermediates and processes useful for the preparation of cryptophycin compounds.
Antimetabolites have been used for a number of years as chemotherapeutic agents in the treatment of cancer. A new class of antimetabolites, cryptophycin compounds are useful for disrupting the microtubule system and, thus, can be useful for the treatment of cancer. In order to produce sufficient quantities of these compounds, there is a need for efficient totally synthetic processes for their preparation.
The novel processes and intermediates of this invention are important elements in providing an efficient route for preparing other cryptophycin intermediates. A special advantage provided is that the intermediates thus prepared have only minimal residual impurities. Ultimately, these intermediates can be linked to provide a total synthesis of cryptophycin compounds.
In one aspect this invention provides an intermediate of formula VIII ##STR1## wherein Ar is an aromatic, substituted aromatic, heteroaromatic or substituted heteroaromatic group;
This invention also relates to the compound (2R, 3R)-2-hydroxy-3-methyl-5-phenylpent-1-yl tosylate in crystalline form. Previously this compound was only available as an oil. The crystalline compound (18 infra) is a distinct advantage in obtaining purified product.
In another aspect this invention provides a process for preparing an intermediate of formula IX ##STR2##
comprising
contacting 1) L-(+)-diethyl tartrate with 2) a catalytic amount of Ti(O-i-propyl) .sub.4, 3) t-butylhydroperoxide, and 4) a substrate of the formula X ##STR3##
Additionally, this invention provides a process for preparing a compound of the formula XI ##STR4## wherein Ar and R.sup.P are as defined supra; TBS is tert-butyldimethylsilyl; and R.sup.H is Br, Cl or I;
comprising contacting a compound of formula XII ##STR5##
with N-(R.sup.H)succinimide and a catalytic quantity of 2,2'-azobisisobutyronitrile in a hydrocarbon or halohydrocarbon solvent.
Preferred hydrocarbon solvents are hexane and heptane. A preferred halohydrocarbon solvent is 1,2-dichloroethane. The advantages of this process are that it permits the use of an environmentally preferred solvent and it gives a cost savings. Yields are not sacrificed, and product purity is enhanced.
Further, in the process for preparing a compound of formula III ##STR6## by reacting a compound of formula II ##STR7## with NaCN or KCN, this invention provides the improvement comprising adding from 0.5 to 2 equivalents of sodium bicarbonate to the reaction mixture. The bicarbonate acts as a buffer to lower the basicity of the reaction. The reaction temperature should be in the range of 60 to 90.degree.C. This improvement results in more consistent reaction results and increased product recovery.
In yet another aspect, this invention provides a new process for epoxidizing an allylic alcohol of formula X to produce an epoxide of formula IX. This procedure replaces dichloromethane with toluene as the reaction medium for the Sharpless asymmetric epoxidation (SAE).
For example, the allylic alcohol 15 (infra) undergoes the Sharpless asymmetric epoxidation in toluene to afford 16 (infra) in high yield and enantiomeric excess. Using toluene as solvent represents a novel development where tradition calls for methylene chloride as the preferred reaction medium.
According to the known synthetic method, the Sharpless asymmetric epoxidation (SAE) is used in the preparation of cryptophycin 52 and other representative cryptophycins. The SAE involves the conversion of allylic alcohols (i.e. 15) to epoxides in high enantiopurity and yield using a novel tartrate-derived catalyst system where the oxygen transfer agent is tert-butyl hydroperoxide and the preferred reaction medium is methylene chloride. An attempt to use toluene instead of methylene chloride in the SAE has been reported for stoichiometric amounts, but useful rates were not obtained, and methylene chloride remained the solvent of choic
REFERENCES:
Barrow, et al. J.Am.Chem. Soc. 1995, 117, 2479-2490.
Hoard David W
Khau Vien V
Martinelli Michael J.
Moher Eric D
Nayyar Naresh K
Boudreaux William R.
Eli Lilly and Company
Engelmann John H.
Raymond Richard L.
University of Hawai'i
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