Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
2002-08-07
2004-11-09
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C544S338000
Reexamination Certificate
active
06815544
ABSTRACT:
BACKGROUND OF THE INVENTION
Ecteinascidin 743 (1, Et 743) is an exceedingly potent marine-derived antitumor agent
1
which is now being studied in various clinics with human patients.
2
Because this compound is not sufficiently available from the natural source, the tunicate
Ecteinascidia turbinata
, it is being produced industrially by the totally synthetic route described in 1996.
3
More recently a structural analog of Et 743, compound 2 (phthalascidin, Pt 650) has been found to exhibit antitumor activity essentially indistinguishable from 1.
4
Both 1 and 2 are synthesized from building blocks 3 and 4
3
via a common pentacyclic intermediate 5.
The synthesis of 5 was accomplished originally
3
from building blocks 3a and 4 in six steps with an overall yield of 35% (average yield per step of ca. 84%). Because the industrial syntheses of 1 and/or 2 would eventually have to be produced economically on a multi-kilogram scale, we sought to find a more efficient and reproducible alternative route from 2 and 3 to 5.
SUMMARY OF THE INVENTION
One embodiment of the present invention is thus directed to a new synthetic process for the preparation of the intermediate compound 5 which is simpler to carry out than the original and which proceeds from 3b
3
+4 to 5 in six steps with an overall yield of 57% (average yield per step of nearly 92%). The preferred process for the synthesis of pentacycle 5 is summarized below in Scheme 1.
5
The second preferred embodiment of the present invention entails a new synthetic process for converting the pentacycle compound 5 to phthalascidin 2, which proceeds smoothly and in excellent yield (average yield per step 90.8%). This process is outlined below in Scheme 2.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As illustrated above in Scheme 1, a solution of azeotropically dried (C
7
H
8
B
THF) amino lactone 4 in THF at 0 EC was treated dropwise with an acylating reagent prepared from the acid 3b
3
(1.03 equiv), 1-hydroxy-7-azabenzo-triazole (HOAT, 1.08 equiv), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP, 1.03 equiv) and triethylamine (2.06 equiv) in CH
2
Cl
2
solution at 0 EC.
6
The coupling product 6, which was obtained by extractive workup, was allylated without further purification by treatment in DMF solution at 23 EC with excess allyl bromide and 1.09 equiv of Cs
2
CO
3
to give amide 7 in 81% overall yield from 3a and 4 after flash chromatography on silica gel.
Selective reduction of the lactone function of 7 to the corresponding lactol (8) was effected by reaction with 1.1 equiv of lithium diethoxyaluminum hydride (LiAlH
2
(OEt)
2
) in ether at −78E for 15 min in 95% yield.
7,8
Desilylation of 8 to 9 and cyclization of 9 (without purification) using 0.6 M triflic acid in 3:2H
2
O
B
CF
3
CH
2
OH at 45 EC for 7 h produced the pentacyclic product 10 in 89% overall yield from 8.
Finally, the lactam function of 10 could be reduced cleanly by treatment with 4 equiv of LiAlH
2
(OEt)
2
in THF at 0 EC for 35 min to the corresponding cyclic aminal which upon exposure to HCN provided the pentacyclic amino nitrile 5 in 87% overall yield from 10 after flash chromatography on silica gel.
9
The synthesis of 5 which is outlined in Scheme 1 and described above is advantageous relative to the originally used synthetic pathway
3
not only because of the substantially greater overall yield (57 vs 35%), but also because of the simplicity and reproducibility of the individual steps, especially the amide coupling (2a+3→6) and the internal Pictet-Spengler cyclization (9→10). In addition no difficulties have been encountered either in product purification or scale up.
A critical element to the success of the sequence shown in Scheme 1 was the high efficiency and selectivity of LiAlH
2
(OEt)
2
for the two reduction steps: 8→9 and 10→5, which suggest that this reagent can be used to advantage in synthesis much more frequently than it has been previously.
In Scheme 2, the pentacyclic triol 5 was first converted to the phenolic monotriflate 11 (step not shown) by treatment with 1.1 equiv of PhNTf
2
(McMurry reagent), 2 equiv of Et
3
N and 0.2 equiv of 4-dimethyl-aminopyridine in CH
2
Cl
2
at −30 EC for 38 h (74%). Conversion of 11 to the mono t-butyldimethylsilyl (TBS) ether 12 and etherification with methoxymethyl chloride (MOMCl) produced 23 in high yield.
Cleavage of the N-allyloxycarbonyl and O-allyl groups in 13 gave the secondary amine 14 (94%) which was N-methylated to 15 and C-methylated to 16. Acetylation of phenol 16 produced the corresponding acetate 17 which upon desilylation formed the primary alcohol 18. Mitsunobu displacement of the primary hydroxyl of 18 produced the phthalimide 19 which upon acid-catalyzed cleavage of the methoxymethyl ether provided pure phthalascidin 2.
Since the original synthetic route to Et 743 (1) has proved to be acceptable for large scale synthesis, it is our expectation that the improved process described herein will be even more useful, as will the new route to phthalascidin (2).
4
Because phthalascidin is more stable than ecteinascidin 743 and considerably easier to make, it may prove to be a more practical therapeutic agent.
The present invention will be further illustrated with reference to the following examples which aid in the understanding of the present invention, but which are not to be construed as limitations thereof. All percentages reported herein, unless otherwise specified, are percent by weight. All temperatures are expressed in degrees Celsius.
REFERENCES:
patent: 5721362 (1998-02-01), Corey et al.
patent: 6124292 (2000-09-01), Corey
Cuevas, et al. Synthesis of Ecteinascidin ET-743 and Phthalascidin Pt-650 from Cyanosafracin B. Organic Letters. (Jul. 19, 2000), vol. 2, No. 16, pp. 2545-2548.
Martinez, et al. A New, More Efficient, and Effective Process For the Synthesis of a Key Pentacyclic Intermediate for Production of Ecteinascidin and Phthalascidin Antitumor Agents. Organic Letters. (Mar. 15, 2000), vol. 2, No. 7, pp. 993-996.
Corey, et al. Enantioselective Total Synthesis of Ecteinascidin 743. J. Am. Chem. Soc. 1996, 118, 9202-3.
Greene, et al. Protective Groups in Organic Synthesis. New York: John Wiley & Sons, Inc. 1991, second edition, pp. 77 and 83.
Kifle Bruck
President and Fellows of Harvard College
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