Processes for preparing tubulysins

Inactive Publication Date: 2014-09-04
ENDOCTYE INC
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Benefits of technology

[0017]A total synthesis of tubulysin D possessing C-terminal tubuphenylalanine (RA=H) (H. Peltier, et al., J. Am. Chem. Soc. 2006, 128, 16018-16019) has been reported. Recently, a modified synthetic protocol toward the synthesis of tubulysin B (RA=OH) (O. Pando, et at., Org. Lett. 2009, 11, 5567-5569) has been reported. However, attempts to follow the published procedures to provide larger quantities of tubulysins were unsuccessful, being hampered in part by low yields, difficult to remove impurities, the need for expensive chromatographic steps, and/or the lack of reproducibility of several steps. The interest in using tubulysins for anticancer therapeutics accents the need for reliable and efficient processes for preparing tubulysins, and analogs and derivatives thereof. Described herein are imp

Problems solved by technology

However, attempts to follow the published procedures to provide larger quantities of tubulysins were unsuccessful, being hampered in part by

Method used

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  • Processes for preparing tubulysins
  • Processes for preparing tubulysins
  • Processes for preparing tubulysins

Examples

Experimental program
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examples

[0213]

Example

Synthesis of Dipeptide 3

[0214]4.9 g of dipeptide 1 (11.6 mmol) was dissolved in 60 mL dichloromethane, imidazole (0.87 g, 12.7 mmol) was added to the resulting solution at 0° C. The reaction mixture was warmed slightly to dissolve all solids and re-cooled to 0° C. TESCl (2.02 mL, 12.1 mmol) was added drop-wise at 0° C., the reaction mixture was stirred under argon and warmed to room temperature over 2 h. TLC (3:1 hexanes / EtOAc) showed complete conversion. The reaction was filtered to remove the imidazole HCl salt, extracted with de-ionized water, and the aqueous phase was back-washed with dichloromethane, the combined organic phase was washed with brine, dried over Na2SO4, filtered to remove the Na2SO4, concentrated under reduced pressure, co-evaporated with toluene and dried under high-vacuum overnight to give 6.4 g of crude product 2 (vs 5.9 g of theoretical yield).

[0215]The crude product 2 was co-evaporated with toluene again and used without further purification. TE...

example

Synthesis of EC1662 (Scheme 3)

[0246]Step 1: Anhydrous DCM (5.0 mL) was added to a mixture of EC1623 (II: R=n-pentyl. 114 mg), pentafluorophenol (PFP, 67.3 mg), and DCC-resin (2.3 mmol / g, 396 mg) and the suspension was stirred at ambient temperature under argon for 23 hours. The resin was filtered off and washed with anhydrous DCM (3.0 mL) and the combined filtrates were concentrated under reduced pressure to give a residue, which was vacuumed at ambient temperature for 1 hour prior to use in Step 3.

[0247]Step 2: EC1426 (114 mg) was dissolved in anhydrous DCM (1.5 mL) and to which was added TFA (0.50 mL). The resulting solution was stirred at ambient temperature under argon for 70 minutes and concentrated under reduced pressure to give a residue, which was co-evaporated with anhydrous DCM (2.0 mL×3) and vacuumed at ambient temperature for 9 hours prior to use in Step 3.

[0248]Step 3: The residue from Step 1 was dissolved in anhydrous DCM (1.5 mL) and to this solution was added DIPEA (...

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Abstract

Processes for preparing tubulysins and derivatives thereof are described. In addition, processes for preparing unnatural tubulysins are described.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims the benefit, under 35 U.S.C. §119(e), of U.S. Provisional Application No. 61 / 771,429, filed Mar. 1, 2013, and U.S. Provisional Application 61 / 793,082, filed Mar. 15, 2013, the entirety of each of the disclosures of which are hereby incorporated herein by reference.TECHNICAL FIELD[0002]The invention described herein pertains to processes for preparing tubulysins and derivatives thereof. In particular, the processes pertain to the preparation of unnatural tubulysins.BACKGROUND AND SUMMARY OF THE INVENTION[0003]The tubulysins are members of a new class of natural products isolated from myxobacterial species (F. Sasse, et al., J. Antibiot. 2000, 53, 879-885). As cytoskeleton interacting agents, the tubulysins are mitotic poisons that inhibit tubulin polymerization and lead to cell cycle arrest and apoptosis (H. Steinmetz, et al., Chem. Int. Ed. 2004, 43, 4888-4892; M. Khalil, et al., ChemBioChem. 2006, 7, 678-68...

Claims

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Application Information

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IPC IPC(8): C07D417/14C07D417/12
CPCC07D417/12C07D417/14C07K5/0606C07K5/0821
Inventor VLAHOV, IONTCHO R.LEAMON, CHRISTOPHER P.
Owner ENDOCTYE INC
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