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Building IP: CELG Patent Application re "PREPARATION OF MAYTANSINOL"
PREPARATION OF MAYTANSINOL A scaled process of preparing maytansinol, FORMULA II, is provided by reacting a compound of Formula I, wherein R is selected from the group consisting essentially of alkyl, branched alkyl, aryl, alkenyl, alkynyl, as well as substituted variations thereof, with at least one organometallic reagent to produce the compound of Formula II; and, isolating the compound of Formula II.
1. A method of preparing a compound of Formula II ##STR00006## comprising reacting, in a polar aprotic ethereal solvent, a compound of Formula I, wherein R is selected from the group consisting of alkyl, branched alkyl, aryl, alkenyl, alkynyl, as well as substituted carbon or heteroatom containing alkyl, branched alkyl, aryl, alkenyl or alkynyl, with at least one organometallic reagent to produce the compound of Formula II; and, isolating the compound of Formula II. 2. The method according to claim 1 wherein the compound of Formula I is provided from ansamitocins. 3. The method according to claim 2 wherein the compound of Formula I is provided as Ansamitocin P-3 (AP-3). 4. The method according to claim 1 wherein the organometallic reagent is an organomagnesium reagent. 5. The method according to claim 4 wherein the organometallic reagent is selected from the group consisting of methyl magnesium halide, ethyl magnesium halide, propyl magnesium halide, butyl magnesium halide, and hexyl magnesium halide, where the halide is chloride, bromide, or iodide. 6. The method according to claim 5 wherein the organometallic reagent comprises magnesium bromide. 7. The method according to claim 6 wherein the organometallic reagent is methyl magnesium bromide. 8. The method according claim 1 wherein the organometallic reagent is a nucleophilic organometallic reagent. 9. The method according to claim 8 wherein the nucleophilic organometallic reagent is selected from the group consisting essentially of methyl-lithium, ethyl-lithium, n-butyl-lithium, hexyl-lithium and alkylaluminum reagents. 10. (canceled) 11. The method according to claim 1, wherein the polar aprotic ethereal solvent is selected from the group consisting of 1,4-dioxane, diethyl ether, cyclopropylmethyl ether, cyclopentylmethyl ether, dimethoxyethane, methyl tert-butyl ether, diglyme, tetrahydropyran and 2-methyltetrahydrofuran. 12. The method according to claim 9, wherein the nucleophilic organometallic reagent is selected from the group consisting of trimethylaluminum, and organocuprates. CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is entitled to priority under 35 U.S.C. .sctn. 119(e) to U.S. Provisional Application No. 62/812,379, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] A scaled process for the preparation of maytansinol from maytansinoids is provided which employs an organometallic reagent. BACKGROUND OF THE INVENTION [0003] Maytansine derivatives are highly toxic chemotherapeutic agents employed as payloads integral to Antibody Drug Conjugates (ADCs). 30% of ADCs in development employ maytansine derivatives. Chemical and Engineering News, 93:3,13 (2014). Maytansine derivatives are generally attached to a linker via an alcohol to yield a linker-payload entity which is then attached to an antibody. Maytansinol is a necessary intermediate for the formation of maytansine derivatives and hence the construction of maytansine-derivative-ADCs. Maytansinoids, Ansamitocins, e.g., Ansamitocin P-3 (AP-3), are natural source of a mixture of esters of maytansinol. AP-3, for example, is a polyketide antibiotic isolated from the microorganism Actinosynnema pretiosum. Each maytansinoid ester moiety can be removed to yield the alcohol, maytansinol. [0004] The discovery of maytansine was originally reported by Kupchan, S M, J Am Chem Soc, 1354 (1972). Maytansinol was similarly reported several years later. Kupchan, S M, J Am Chem Soc, 5294 (1975); Kupchan, S M, J Med Chem, 31 (1978). Isolation of maytansinoids and the conversion of maytansinoids to maytansinol using lithium aluminum hydride is well known in the art. U.S. Pat. Nos. 4,308,269 and 4,362,663; Asai, M, Tetrahedron, 1079 (1979). Conversion of maytansinoids to maytansinol using lithium/sodium aluminum alkoxide hydrides and workup. See, e.g., U.S. Pat. Nos. 6,333,410 and 7,411,063; J Med Chem 4392 (2006). [0005] Previous descriptions of removing various ester moieties to expose maytansinol employ aluminum hydride. Maytansinol 1 has previously been prepared by the reduction of AP-3 generally using 4-9 equivalents of lithium aluminum hydride (LAH; LiAlH.sub.4), or a variant thereof such as lithium trimethoxyaluminum hydride (LiAlH(OMe).sub.3), which itself is prepared from LAH. J. Med. Chem. 49, 4392 (2006). Major drawbacks of this methodology however include (a) formation of overreduced by-product, and (b) formation of des-chloro-maytansinol. The current state of the art higher yielding procedures utilize LiAlH(OMe).sub.3 formed prior to the reaction by the addition of Methanol to LiAlH.sub.4. The current high yield reaction generates multiple equivalents of hydrogen gas, which in turn requires specific safety equipment to minimize fire hazard. The current state of the art procedure requires the direct addition of methanol to LiAlH.sub.4 to form LiAlH(OMe).sub.3. U.S. Pat. No. 6,333,410. The reagents cause difficulty in increasing scale of the exothermic reaction due to dangerous release of hydrogen. Current state of the art reactions also call for direct quench with a protic solvent, such as water or water/formic acid directly to the reaction mixture. This direct quench results in release of hydrogen gas which becomes more difficult to control as the reaction increases in scale. SUMMARY OF THE INVENTION [0006] The invention is directed to a scalable process of preparing maytansinol, FORMULA II, ##STR00001## and related analogs, comprising reacting a compound of FORMULA I and related analogs, wherein R is selected from the group consisting essentially of alkyl, branched alkyl, aryl, alkenyl, alkynyl, as well as substituted variations thereof, with at least one organometallic reagent to produce the compound of Formula II, for example; and, isolating the compound of Formula II, for example. [0007] In some embodiments, the compound of Formula I is provided from ansamitocins. In further embodiments, the compound of Formula I is provided as Ansamitocin P-3 (AP-3). [0008] In some embodiments, the organometallic reagent is an organomagnesium reagent. [0009] In some embodiments, the organometallic reagent is selected from the group consisting essentially of methyl magnesium halide, ethyl magnesium halide, propyl magnesium halide, butyl magnesium halide, and hexyl magnesium halide, where the halide is chloride, bromide, or iodide. In further embodiments, the organometallic reagent comprises magnesium bromide. In yet further embodiments, the organometallic reagent is methyl magnesium bromide. [0010] In some embodiments, the organometallic reagent is a nucleophilic organometallic reagent. In further embodiments, the nucleophilic organometallic reagent is selected from the group consisting essentially of methyl-lithium, ethyl-lithium, n-butyl-lithium, hexyl-lithium and alkylaluminum reagents including but not limited to trimethylaluminum, and organocuprates. [0011] Provided is a compound of Formula II prepared by reacting a compound of Formula I, wherein R is selected from the group consisting essentially of alkyl, branched alkyl, aryl, alkenyl, alkynyl, as well as carbon and heteroatom substituted variations thereof, with at least one organometallic reagent to produce the compound of Formula II; and, isolating the compound of Formula II. |
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