Phosgenation Reactions - Phosgenations - page 51

Highly water-soluble taxol derivatives were prepared by attachment of polyethylene
glycol (molecular weight 2-5 kD) at the 7-position of taxol via a urethane or car-
bonate linkage [20]. The most direct route to accomplish this conversion involves
condensation of substituted isocyanates with 2 0 -O-acetyl-taxol. Limitations of this
procedure due to a lack of commercial availability of key isocyanates and occasional
unexplained variations in yield prompted a search for routes of greater utility, and
which would not threaten the integrity of the taxane ring system. The first of these
was conversion of 2 0 -O-acetyl-taxol 13 to the 7-chloroformate derivative using tri-
phosgene and either N,N-diisopropylethylamine (DIEA) or pyridine.
In practice, it was found that approximately 6 equivalents of triphosgene and 9
equivalents of base were required to give yields of just 60-70% of chloroformate
15. Chloroformates are generally water-sensitive; therefore, no attempts were made
to isolate the chloroformate, which was reacted directly with excess amine to afford
the 7-carbamate derivative 16. As an alternative to employing triphosgene, it was
found that the alcohol reacted smoothly with an excess of N,N-carbonyldiimidazole
(CDI) to give high yields of the easily isolated and relatively stable carbon-
ylimidazole derivative. This compound did not react readily with amines in chlo-
roform solution, but in 2-propanol the 2 0 -O-acetyl carbamates 16 were produced in
high yield.

Typical procedure. 2 0 -O-(Methoxyacetyl)-7-O-(imidazolylcarbonyl)taxol [20]: In a 25
mL round-bottomed flask were placed 2 0 -O-(methoxyacetyl)taxol (102 mg, 0.11
mmol), CDI (53 mg, 0.33 mmol), and dichloromethane (5 mL). The resulting clear
solution was stirred at room temperature under nitrogen atmosphere for 5 h. The
reaction mixture was then diluted with dichloromethane (5 mL), washed with
water (2 5 mL), dried over anhydrous magnesium sulfate, and concentrated to

dryness. The crude product thus obtained (105 mg, 94%) was used without further
purification for the preparation of 7-substituted taxol derivatives.

Typical procedure. 2 0 -O-Acetyltaxol 7-PEG carbamates [20]: In a 25 mL three-necked,
round-bottomed flask equipped with a reflux condenser, a magnetic stirrer, and a
guard tube containing NaOH pellets, were placed 2-O-acetyltaxol (25 mg, 0.028
mmol) and anhydrous dichloromethane (5 mL). To this solution were added tri-
phosgene (17 mg, 0.057 mmol) and pyridine (20 mg, 0.22 mmol), and stirring was
continued for 30 min. Dry nitrogen was bubbled through the reaction mixture
until all volatiles had evaporated. A solution of PEG-NH 2 (mw 5000, 280 mg, 0.056
mmol) in dichloromethane was added to the residue and the resulting mixture was
stirred for 15 min. After standard work-up, the product was purified by preparative
HPLC.
A complex transformation of lactam 17 occurs in the presence of triphosgene
and 4-dimethylaminopyridine (DMAP) in dichloromethane, as reported in [21].
The reaction was first reported using phosgene [22], but triphosgene gave identical
results and was experimentally preferable. The reaction was not straightforward in
that three compounds were formed in differing amounts depending on the con-
ditions. All three materials were unstable but could be separated under argon for