Synthetic process for preparing 2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl 5-tetradecyloxy)furan-2-carboxylate
Inventors
SHAW, Anthony Adrian • Khumtaveeporn, Kanjai • Krasik, Pavel
Assignees
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Publication Number
US-9745277-B2
Publication Date
2017-08-29
Expiration Date
Abstract
Disclosed herein are processes for forming 2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl 5-tetradecyloxy)furan-2-carboxylate:
Core Innovation
The invention relates to a process for preparing a compound of Formula (I), including a TOFA prodrug described as 2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl 5-tetradecyloxy)furan-2-carboxylate. The process includes providing a mixture of a compound of Formula (II) in an ether solvent and combining a compound of Formula (III) with the mixture and a base. The substituent variables are defined with R1 as C10-20 alkyl, R2 as C1-4 alkyl, and X as a leaving group.
A key aspect is carrying out the preparation in an ether solvent, with variants specifying a solvent having a boiling point below 100°C. In the described route, the mixture of Formula (II) in the ether is combined with Formula (III) under base to form the coupling product, using X as a leaving group. The document emphasizes that the ether solvent can be used across steps to improve process throughput.
In the illustrated example, the route uses an MTBE-mediated two-step sequence in which the same ether (MTBE) is used across steps, including preparation involving chloroacetyl chloride and subsequent coupling using a base. The document states improved scalability and yield, including scalability to about 13 kg and yields of about 60–80% for the first step and about 83% for the coupling product, with increased throughput attributed to reuse of MTBE across steps.
Claims Coverage
Two independent claims define the claimed process for preparing a compound of Formula (I), with a shared set of inventive features: preparation using a Formula (II) mixture in an ether/low-boiling solvent and coupling with a Formula (III) compound in the presence of a base, where R1 is C10-20 alkyl, R2 is C1-4 alkyl, and X is a leaving group/halogen.
Providing Formula (II) Mixture in Ether Solvent
Providing a mixture of a compound of Formula (II) in an ether solvent.
Coupling Formula (III) with Mixture and Base
Combining a compound of Formula (III) with the mixture and a base.
R1 and R2 Substituent Ranges
R1 is C10-20 alkyl and R2 is C1-4 alkyl.
Leaving Group X
X is a leaving group.
Providing Formula (II) Mixture in Below-100°C Boiling Solvent
Providing a mixture of a compound of Formula (II) in a solvent having a boiling point of below 100°C.
Organic Base Coupling with Halogen Leaving Group
Combining a compound of Formula (III) with the mixture and an organic base, wherein X is halogen.
Across both independent claims, the inventive process centers on preparing a mixture of Formula (II) in an ether (or below-100°C boiling solvent) and combining Formula (III) with the mixture and a base to form a compound of Formula (I), while defining R1 as C10-20 alkyl, R2 as C1-4 alkyl, and X as the leaving group/halogen.
Stated Advantages
Improved scalability.
Improved yield (as stated for the example).
Improved throughput due to reuse of MTBE across steps.
Documented Applications
Not explicitly described in patent.
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