US-12617754-B2 - Process for synthesizing lipids

Abstract

The present application provides processes for synthesizing lipids of Formula I useful in the synthesis of fat-soluble compounds for targeting and enhancing activity of therapeutic molecules, including siRNA.

Inventors

• Gregory Louis BEUTNER
• Federico Lora Gonzalez
• Patricia Y. Cho
• Michael J. Smith

Assignees

• BRISTOL-MYERS SQUIBB COMPANY

Dates

Publication Date

20260505

Application Date

20210622

Claims (16)

1. 1 . A process for synthesizing a compound of Formula I: wherein n is an integer from 8-16, the process comprising, a) reacting in a first solvent a compound of Formula II: wherein R is a protecting group; with a compound of Formula III wherein n is an integer from 8-16, and X is a halogen; followed by treatment with methane sulfonic acid, to form a compound of Formula IV: b) reacting in a second solvent a compound of Formula IV with a first base and a compound of Formula V: wherein each Y is independently a halogen; to form a compound of Formula VI: c) reacting in a third solvent a compound of Formula VI under coupling conditions with a second base and 2-(dimethylamino) ethanethiol HCl, followed by treatment with oxalic acid, to form a compound of Formula VII: and d) reacting a compound of Formula VII with a third base to produce a compound of Formula I.
2. 2 . The process of claim 1 , wherein the first base is triethylamine.
3. 3 . The process of claim 1 , wherein the second base is triethylamine.
4. 4 . The process of claim 1 , wherein n is 12.
5. 5 . The process of claim 1 , wherein R is selected from the group consisting of carboxybenzyl, p-methoxybenzyl carbonyl, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, trifluoroacetyl, benzoyl, benzyl, carbamate, 3,4-dimethoxybenzyl, p-methoxybenzyl, tosyl, trichloroethyl chloroformate, (4-nitrophenyl) sulfonyl, methyl, ethyl, propyl, n-butyl, t-butyl, succinimide, 2,6-dimethylphenol, 2,6-diisopropylphenol, 2,6-di-tert-butylphenol, trimethylsilyl, allyl, 1,1-dimethylallyl, 2,2,2-trifluoro ethyl, phenyl, and 4-methoxybenzyl.
6. 6 . The process of claim 5 wherein R is t-butyloxycarbonyl.
7. 7 . The process of claim 1 wherein each Y is independently selected from Cl, Br, and I.
8. 8 . The process of claim 4 wherein each Y is Cl.
9. 9 . The process of claim 1 wherein X is selected from Cl, Br, and I.
10. 10 . The process of claim 9 wherein X is Cl.
11. 11 . The process of claim 1 wherein the compound of Formula VI is the compound
12. 12 . The process of claim 1 , wherein the compound of Formula I is the compound
13. 13 . The process of claim 1 wherein, the yield of a) is at least about 80%.
14. 14 . The process of claim 1 , wherein the compound of Formula I is produced in at least about 60% yield from the compound of Formula II.
15. 15 . The process of claim 1 wherein a compound of Formula VIII: is present in the product from step d) in a concentration of less than 100 ppm.
16. 16 . The process of claim 1 wherein the compound of Formula VII is isolated as a crystalline solid.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. National Phase Application under 35 U.S.C. § 371 of International Patent Application Number PCT/US2021/038525, filed Jun. 22, 2021, which claims the benefit of U.S. Provisional Application 63/043,521 filed Jun. 24, 2020, each of which is incorporated herein by reference in its entirety for all purposes. FIELD OF THE INVENTION The present application provides processes for synthesizing lipids useful in the synthesis of fat-soluble compounds for targeting and enhancing activity of therapeutic molecules, including siRNA. BACKGROUND OF THE INVENTION A number of techniques are available for delivering a therapeutic agent such as siRNA into a cell, including the use of viral transfection systems and non-viral transfection systems. Non-viral transfection systems can include, for example, polymers, lipids, liposomes, micelles, dendrimers, and nano materials. Examples of polymers that have previously been studied for cell transfection include cationic polymers such as poly(L-lysine) (PLL), polyethyleneimine (PEI), chitosan, and poly(2-dimethylamino)ethyl methacrylate (pD MAEMA). Each type of system has its respective advantages and drawbacks. For example, viral systems can yield high transfection efficiency, but may not be as safe as some non-viral systems. In addition, viral systems can be complicated and/or expensive to prepare. Non-viral transfection systems, such as cationic polymers and/or lipids, have been reported to transfer plasmid DNA into cells. Cationic lipids possess a number of advantages. One such example of a cationic lipid is ((2-((2-(dimethylamino)ethyl)thio)acetyl)azanediyl)bis(ethane-2,1-diyl)ditetradecanoate (S104), as disclosed in U.S. Pat. No. 8,308,267. Previous synthetic strategies for producing S104 and similar compounds were plagued with low yield, inconvenient work-up procedures, and a high number of side products. There remains a need for a synthetic process to produce these cationic lipids that facilitates increased product yield, low by-product yield, and uses more accessible synthetic techniques. SUMMARY OF THE INVENTION In one aspect, the present application provides a process for producing S104. In one embodiment the present application provides a process for synthesizing a compound of Formula I wherein n is an integer from 8-16the process comprising, a) reacting a compound of Formula II wherein R is a protecting group;with a compound of Formula III wherein X is a halogen;followed by treatment with methane sulfonic acid, to form a compound of Formula IV; b) reacting a compound of Formula IV under coupling conditions with a compound of Formula V wherein each Y is independently a halogen;to form a compound of Formula VI; c) reacting a compound of Formula VI under coupling conditions with 2-(dimethylamino)ethanethiol HCl, followed by treatment with oxalic acid, to form a compound of Formula VII; andd) reacting the compound of Formula VII with a base to produce a compound of Formula I. In an embodiment the coupling conditions of step b) comprise reacting a compound of Formula IV with a base. In an embodiment the base is trimethylamine. In an embodiment the coupling conditions of step c) comprise reacting a compound of Formula VI with a base. In an embodiment the base is trimethylamine. In another further embodiment n is 12. In another embodiment R is independently selected from the group consisting of carboxybenzyl, p-methoxybenzyl carbonyl, t-butyloxycarbonyl, 9-fluorenylmetholoxycarbonyl, acetyl, trifluoroacetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxybenzyl, tosyl, trichloroethyl chloroformate, (4-nitrophenyl)sulfonyl, methyl, ethyl, propyl, n-butyl, t-butyl, succinimide, 2,6-dimethylphenol, 2,6-diisopropylphenol, 2,6-di-tert-butylphenol, trimethylsilyl, allyl, 1,1-dimethylallyl, 2,2,2-trifluoro ethyl, phenyl, and 4-methoxybenzyl. In a further embodiment R is t-butyloxycarbonyl. In another embodiment each Y is independently selected from Cl, Br, and I. In another embodiment each Y is the same. In a further embodiment each Y is Cl. In another embodiment X is independently selected from Cl, Br, and I. In a further embodiment X is Cl. In a further embodiment the compound of Formula VI is In a further embodiment the yield of step a) is at least about 75%. In a further embodiment the compound of Formula I is In a further embodiment the compound of Formula I is produced in at least about 70% yield from the compound of Formula II. In a further embodiment a compound VIII is present in the product from step d) in a concentration of less than 500 ppm. In a further embodiment compound VIII is present in the product from step d) in a concentration of less than 100 ppm. In a further embodiment the compound of Formula VII is isolated as a solid. In a further embodiment the compound of Formula VII is isolated as a crystalline solid. In an embodiment the purity of the produced compound of F