US-12623988-B2 - Scaleable preparation of polyketides

Abstract

Disclosed herein, inter alia, are methods of making polyketide compounds.

Inventors

• Michael D. Burkart
• Warren C. Chan
• Brian Leon
• James J. La Clair
• Kelsey A. Trieger

Assignees

• THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Dates

Publication Date

20260512

Application Date

20200805

Claims (20)

1. 1 . A composition comprising a compound having the formula: wherein, the composition comprises an enantiomeric purity of the compound of at least 95%.
2. 2 . The composition of claim 1 , comprising at least 5 grams of the compound with or without a pharmaceutically acceptable excipient.
3. 3 . The composition of claim 1 , further comprising a pharmaceutically acceptable excipient, wherein the composition comprises an enantiomeric purity of the compound of at least 98%.
4. 4 . The composition of claim 1 , prepared by a method of making the composition, comprising a method of making a compound having the formula: comprising reacting a compound having the formula: with 1-(dimethoxymethyl)-4-methoxybenzene in the presence of CBr 4 , an alcohol, a base, and one or more organic solvents.
5. 5 . The composition of claim 1 , prepared by a method of making the composition, comprising a method of making a compound having the formula: comprising reacting a compound having the formula: with a transition metal catalyst for olefin metathesis in the presence of one or more organic solvents.
6. 6 . The composition of claim 1 , prepared by a method of making the composition, comprising a method of making a compound having the formula: comprising reacting a compound having the formula: with a strong acid, in the presence of an alcohol and one or more organic solvents.
7. 7 . The composition of claim 1 , prepared by a method of making the composition, comprising a method of making a compound having the formula: comprising reacting a compound having the formula: with an acetylating agent in the presence of a strong acid and one or more organic solvents.
8. 8 . The composition of claim 1 , prepared by a method of making the composition, comprising a synthetic step comprising a reaction mixture, the reaction mixture comprising a reactant compound having the formula: wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 95%.
9. 9 . The composition of claim 8 , wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 98%.
10. 10 . The composition of claim 1 , prepared by a method of making the composition, comprising a synthetic step comprising a reaction mixture, the reaction mixture comprising a reactant compound having the formula: wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 95%.
11. 11 . The composition of claim 10 , wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 98%.
12. 12 . The composition of claim 1 , prepared by a method of making the composition, comprising a synthetic step comprising a reaction mixture, the reaction mixture comprising a reactant compound having the formula: wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 95%.
13. 13 . The composition of claim 12 , wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 98%.
14. 14 . The composition of claim 1 , prepared by a method of making the composition, comprising a synthetic step comprising a reaction mixture, the reaction mixture comprising a reactant compound having the formula: wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 95%.
15. 15 . The composition of claim 14 , wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 98%.
16. 16 . The composition of claim 1 , prepared by a method of making the composition, comprising a synthetic step comprising a reaction mixture, the reaction mixture comprising a reactant compound having the formula: wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 95%.
17. 17 . The composition of claim 16 , wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 98%.
18. 18 . The composition of claim 1 , prepared by a method of making the composition, comprising a synthetic step comprising a reaction mixture, the reaction mixture comprising a reactant compound having the formula: wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 95%.
19. 19 . The composition of claim 1 , prepared by a method of making the composition, comprising a synthetic step comprising a reaction mixture, the reaction mixture comprising a reactant compound having the formula: wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 95%.
20. 20 . The composition of claim 1 , prepared by a method of making the composition, comprising a synthetic step comprising a reaction mixture, the reaction mixture comprising a reactant compound having the formula: wherein the reaction mixture comprises an enantiomeric purity of the reactant compound of at least 95%.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62/883,491, filed Aug. 6, 2019, which is incorporated herein by reference in its entirety and for all purposes. BACKGROUND While initial efforts suggested the rapid translation of small molecule splice modulators to the clinic for patients suffering from cancers, the inability to practically access gram scale lead molecules with viable pharmacological properties continues to stall their clinical application. Here, we report a gram-scalable approach to prepare 17S-FD-895, a highly potent and pharmacologically stable splice modulator, an observation that is supported by parallel, synthetically enabled structure activity relationship (SAR) validation efforts. BRIEF SUMMARY In an aspect is provided a compound having the formula: wherein, the compound is at least 95% enantiomerically pure. In an aspect is provided a compound having the formula: wherein, R1 is a silyl protecting group and wherein the compound is at least 95% enantiomerically pure. In an aspect is provided a compound having the formula: wherein, the compound is at least 95% enantiomerically pure. In an aspect is provided a compound having the formula: wherein, the compound is at least 95% enantiomerically pure. In an aspect is provided a compound having the formula: wherein, R1 is a silyl protecting group and wherein the compound is at least 95% enantiomerically pure. In an aspect is provided a compound having the formula: wherein, R1 is a silyl protecting group and wherein the compound is at least 95% enantiomerically pure. In an aspect is provided a compound having the formula: wherein, the compound is at least 95% enantiomerically pure. In an aspect is provided a compound having the formula: wherein, the compound is at least 95% enantiomerically pure. In an aspect is provided a compound having the formula: wherein, the compound is at least 95% enantiomerically pure. In an aspect is provided a pharmaceutical composition including a compound having the formula: and a pharmaceutically acceptable excipient, wherein the compound is at least 95% enantiomerically pure. In an aspect is provided a method of making a compound having the formula: comprising reacting a compound having the formula: with 1-(dimethoxymethyl)-4-methoxybenzene in the presence of CBr4, an alcohol, a base, and one or more organic solvents. In an aspect is provided a method of making a compound having the formula: comprising reacting a compound having the formula: with a transition metal catalyst for olefin metathesis in the presence of one or more organic solvents. In an aspect is provided a method of making a compound having the formula: comprising reacting a compound having the formula: with Hoveyda-Grubbs 2nd generation catalyst in the presence of toluene. In an aspect is provided a method of making a compound having the formula: comprising reacting a compound having the formula: with a strong acid, in the presence of an alcohol and one or more organic solvents. In an aspect is provided a method of making a compound having the formula: comprising reacting a compound having the formula: with an acetylating agent in the presence of a strong acid and one or more organic solvents. In embodiments, is provided a method of making a compound having the formula: comprising reacting a compound having the formula: with acetic anhydride, in the presence of 4-dimethylaminopyridine and pyridine. In an aspect is provided a method of making a linear polyketide compound. In an aspect is provided a method of treating cancer, the method including administering to a subject in need thereof an effective amount of the polyketide compound made using the method as described herein. In an aspect is provided a method of making a 17S-FD-895, the method including the use of compounds 6a, 6b, 6c, 6d and 6e, as described herein. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. Synthetic design. The synthesis of 17S-FD-895 arises through the coupling of two fragments as given by side chain 3 and its associated components 6e and 6d, and core 2 and its three associated components 6a-6c. The 11 sp3 stereocenters and stereochemistry of the 3 olefins of 1 are distributed between components 6a (contains the C6 and C7 stereodiad), 6b (induces the C3 stereocenter and influences the C8-C9 olefin), 6c (C10, C11 stereocenters, contains the C12-C13 olefin and induces the C13-C14 stereochemistry and C8-C9 olefin), 6d (contains the C20-C21 stereodiad, contains functionality to install the C18-C19 epoxide) and 6e (induces the C16-C17 stereodiad). A tabulation of the number of steps to prepare (st), number chromatographic purifications (ch), % yield (% y) and amount of material (in g) prepared to date. Color-coded shading is used to highlight the assembly process. FIGS. 2A-2F. Synthetic issues. A tabulation of the top issues identified and remediated in the development of a gram-scaled synthesis of 1. (FIG. 2A) The con