Process for preparing alpha-carboxamide pyrrolidine derivatives
Inventors
Chen, Weirong • Couming, Vinny • Irdam, Erwin • Kiesman, William F. • Kwok, Daw-long A. • Mack, Tamera L. • OPALKA, Suzanne M. • Patience, Daniel B. • Walker, Donald G. • Liang, Wenli
Assignees
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Publication Number
US-11192856-B2
Publication Date
2021-12-07
Expiration Date
Abstract
The invention relates to a novel process for preparing a-carboxamide pyrrolidine derivatives, in particular (2S, 5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide, and to novel intermediates for use in said process along with processes for preparing said intermediates.
Core Innovation
The patent discloses a process for preparing a compound of formula (I) by reacting a compound of formula (II) with formamide. The compound of formula (II) contains a protecting group P1 selected from tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), carbamates, p-methoxyphenyl (PMP), tosyl (Ts), sulfonamides selected from Nosyl and Nps, and trifluoroacetyl.
The process is structured as a sequence in which compounds of formulas (VI), (VII), and (VIII) are prepared sequentially, using defined protecting-group choices including P2 and defined leaving groups including L1 and L2, with the final intermediate (VIII) converted to (II) by reaction with (IX). The disclosed route also includes variations involving leaving-group selections such as L2 being bromine or chlorine, together with selected bases and solvents for step (d).
The document further describes that step (b) can be carried out using methanesulfonic acid or sulfuric acid under specified solvent conditions, and that step (b) may be executed in a flow process. It also emphasizes flow or continuous chemistry implementations, including plug flow, static mixer, and Y-mixer arrangements, and refers to compound (I) as a valuable intermediate for preparing compound (III) and α-carboxamide pyrrolidine derivatives of formula (III)/(IIIa).
Claims Coverage
The independent claim coverage centers on producing a compound of formula (I) by reacting a compound of formula (II) with formamide, with one independent claim explicitly identified and dependent claims refining the sequence and process conditions. The inventive features include the protected intermediate, the stepwise build-up to formula (II), and narrowed reagent, solvent, catalyst, and flow-process selections.
Preparing formula (I) from formula (II) using formamide
A process for preparing a compound of formula (I) by reacting a compound of formula (II) with formamide.
Protecting group P1 selection
P1 in the compound of formula (II) is selected from tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), carbamates, p-methoxyphenyl (PMP), tosyl (Ts), a sulfonamide selected from Nosyl and Nps, and trifluoroacetyl.
Sequential intermediate preparation to reach formula (II)
The process includes sequentially preparing compounds of formulas (VI), (VII), (VIII), and (II) by reacting starting compounds of formulas (IV) and (V) with P2 as a protecting group and L1 as a leaving group, then preparing (VII) from (VI), then preparing (VIII) from (VII), and finally preparing (II) by reacting (VIII) with (IX) with L2 as a leaving group.
Leaving group L2 selection and step (d) reagent/solvent choices
L2 is bromine or chlorine, and step (d) uses a selected base of potassium carbonate, NaOMe, or t-BuOK and a selected solvent of acetonitrile, DMF, DMSO, or a mixture of acetonitrile and formamide.
Catalyst selection for the process
The process is carried out using a Pd(OH)2/C or Pd/Al2O3 catalyst.
Flow execution for step (b)
Step (b) is carried out using a flow process.
The claim set focuses on producing formula (I) by reacting formula (II) with formamide, with P1 restricted to a defined set of protecting groups. The scope is further defined by a multi-step sequence assembling intermediates (VI→VII→VIII→II) with specified protecting groups and leaving groups, and it is narrowed through selections such as L2 being bromine or chlorine, selected bases and solvents for step (d), catalyst selections, and flow execution of step (b).
Stated Advantages
Avoids isolation of intermediate (II).
Improved volume efficiency and safety.
Reduces waste.
Lowers cost and cycle time.
Reduces need for chromatography.
Improves purity/yield.
Amenable to scale-up to hundreds of kilograms.
Can combine deprotection with HCl salt formation (HCl-IPA).
One-step deprotection and hydrochloride salt formation via HCl-IPA treatment of compound (I).
Good impurity rejection.
Documented Applications
Use of compound (I) as a valuable intermediate to prepare compound (III).
Preparation of α-carboxamide pyrrolidine derivatives of formula (III)/(IIIa) using compound of formula (I) as a valuable intermediate.
Linkage enabling formula (IIIa) examples and their intermediate preparation context.
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