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EP-4736890-A2 - PROCESS FOR PRODUCTION OF KETOCARBOXYLIC ACID VINYL ESTERS

EP4736890A2EP 4736890 A2EP4736890 A2EP 4736890A2EP-4736890-A2

Abstract

Vinyl esters of carboxylic acids, especially vinyl esters of ketocarboxylic acids, which can be α-ketocarboxylic acids or β-ketocarboxylic acids. The vinyl esters of the carboxylic acids in their vinyl group can have deuterium in their vinyl group. The vinyl esters can be hydrogenated with para-hydrogen and the spin of the para-hydrogen can be transferred to the carbonyl carbon atom of the carboxyl group, which carbonyl-carbon atom is a 13 C, followed by hydrolysis of the ester group, producing carboxylic acids, especially ketocarboxylic acids having a hyperpolarized 13 C in the carbonyl carbon atom of the carboxyl group.

Inventors

  • HERGES, RAINER
  • Brahms, Arne
  • Pravdivtsev, Andrej
  • HÖVENER, JAN-BERND

Assignees

  • QuantView GmbH

Dates

Publication Date
20260506
Application Date
20221012

Claims (15)

  1. Process for para-hydrogenating a ketocarboxylic acid vinyl ester in the presence of a catalyst, in which the vinyl moiety is fully deuterated, characterized in that the carboxyl carbon of the ketocarboxylic acid is 13 C and the para-hydrogenation is carried out in hypercritical carbon dioxide.
  2. Process according to claim 1, characterized in that after the para-hydrogenation the carbon dioxide is released and an alkaline aqueous solution is added for hydrolysis of the ester bond from the hyperpolarized ketocarboxylic acid.
  3. Process according to claim 2, characterized in that after the release of the carbon dioxide the para-hydrogenated ketocarboxylic acid vinyl ester is contacted with a solvent in order to dissolve the catalyst.
  4. Process according to one of the preceding claims, characterized in that the ketocarboxylic acid moiety is fully deuterated.
  5. Process according to one of claims 3 to 4, characterized in that the solvent is an alkane and in that the aqueous phase contains the ketocarboxylic acid or its anion and is separated from the alkane and from the hydrogenation catalyst by removing the aqueous phase from the alkane solvent phase.
  6. Process according to one of the preceding claims, characterized in that the ketocarboxylic acid vinyl ester is produced by reacting a carboxylic acid halogenide of the ketocarboxylic acid with a trialkyl silylenolether.
  7. Process according to claim 6, characterized in that the enolether moiety of the trialkyl silylenolether is fully deuterated.
  8. Process according to one of the preceding claims, characterized in that the ketocarboxylic acid is fully deuterated.
  9. Process according to one of the preceding claims, characterized in that the ketocarboxylic acid is pyruvate in which the terminal methyl group is fully deuterated and the enolether moiety of the trialkyl silylenolether is a vinyl group.
  10. Process according to claim 9, characterized in that the trialkyl silylenolether has a fully deuterated vinyl group and is produced by reacting fully deuterated tetrahydrofuran with butyllithium (BuLi), and reacting the reaction product with a trialkylhalogensilane.
  11. Process according to one of the preceding claims, characterized in that during the para-hydrogenation the ketocarboxylic acid vinyl ester is present in a pressure vessel in a solvent that consists of hypercritical CO 2 , in the presence of a hydrogenation catalyst, and the para -hydrogen is introduced into the hypercritical CO 2 .
  12. Process according to one of the preceding claims, characterized in that the para- hydrogenation catalyst is composed of a Rh + ion bearing a diphosphine ligand or two monophosphine ligands, a diene ligand and an anion or the para -hydrogenation catalyst has formula I
  13. Use of a vinyl ester of a ketocarboxylic acid in a process according to one of the preceding claims, the vinyl ester of a ketocarboxylic acid having one of the structures: wherein R1, R2 and R3 are each deuterium, and R is a straight chain or branched C 1 -to C 12 -alkyl, and wherein the carboxyl carbon of the ketocarboxylic acid is 13 C followed by spin order transfer from the para -hydrogenated vinyl group to the 13 C carbonyl carbon of the ketocarboxylic acid, hydrolysis of the ester bond and separation of the resulting hyperpolarized ketocarboxylic acid from the reaction mixture.
  14. Use according to claim 13, wherein R is a straight chain or branched C 1 - to C 12 -alkyl that is fully deuterated
  15. Use according to one of claims 13 to 14, characterized in that R is a straight or branched C 1 - to C 12 -alkyl with a carboxyl or carbonylester at the end that is fully deuterated for para -hydrogenation of the vinyl group with para -hydrogen.

Description

The present invention relates to a process for producing vinyl esters of carboxylic acids, especially vinyl esters of ketocarboxylic acids, which can be α- ketocarboxylic acids or β-ketocarboxylic acids. The vinyl esters of the carboxylic acids in their vinyl group can have hydrogen and have preferably deuterium in their vinyl group. The vinyl esters can be hydrogenated with para-hydrogen and the spin of the para-hydrogen can be transferred to the carbonyl carbon atom of the carboxyl group, which carbonyl-carbon atom is a 13C, followed by hydrolysis of the ester group, producing carboxylic acids, especially ketocarboxylic acids having a hyperpolarized 13C in the carbonyl carbon atom of the carboxyl group. Transfer of the spin order created by hydrogenation of the vinyl group with para hydrogen to achieve hyperpolarization of the 13C carbonyl atom of the carboxyl group can be accelerated by magnetic field cycling or by suitable NMR pulse sequences. The process for producing vinyl esters of carboxylic acids, especially vinyl esters of ketocarboxylic acids, has the advantage of a high yield, of allowing the production of deuterated vinyl esters of 13C-carbonyl-labelled ketocarboxylic acids, and of ketocarboxylic acids having a hyperpolarized 13C as the carbonyl atom. Products of the process are 1-13C-hyperpolarized carboxylic acids, preferably 1-13C-hyperpolarized ketocarboxylic acids that are e.g. suitable for use as magnetically labelled molecules in magnetic resonance imaging (MRI) diagnostics. A preferred ketocarboxylic acid ester is pyruvic acid vinyl ester, also called vinyl pyruvate, having a hyperpolarized 13C in the carbonyl carbon atom of the carboxyl group for use in diagnostic 13C-MRI. State of the art EP 3 063 119 B1 describes producing 1-13C-hyperpolarized carboxylate containing compounds by providing an unsaturated ester of a carboxylate, hydrogenating the unsaturated ester with para-hydrogen to produce the para-hydrogenated ester, followed by spin order transfer to the 1-13C carbonyl carbon atom, e.g. by magnetic field cycling, which ester is converted by removal of the hydrogenated group to yield the 1-13C-hyperpolarized carboxylic acid. Particularly the allyl ester and the propargyl ester are suggested as substrates for para-hydrogenation because their synthesis from the corresponding alcohols and carboxylic acids is straightforward. Vinyl esters that are more efficient substrates for 1-13C-hyperpolarization (the spin ordered H atoms are closer to the 13C-carbonyl) are more difficult to prepare. A route for synthesis of vinyl pyruvate that could give acceptable yields is not described. The unsaturated ester is kept in an organic solvent and reacted therein with para-hydrogen, then the magnetic field cycling is applied and the organic phase is mixed with an aqueous phase, which promotes hydrolysis of the ester and enrichment of the water-soluble 1-13C-hyperpolarized carboxylic acid in the aqueous phase. Chukanov et al., ACS Omega 2018, 3, 6673-6682 describes a yield of 6% of synthesizing vinyl pyruvate from vinyl acetate and pyruvic acid with PdII acetate and KOH at 25°C for 3d, which was considered nonefficient and too low for spin transfer from para-hydrogen. Salnikov et al., ChemPhysChem 2021, 22, 1389-1396, describes a synthetic procedure, related to Chukanov 2018, with slightly improved yields (8%), which also was not sufficient to perform hyperpolarization experiments. Salnikov et al., J. Phys. Chem C 2019, 12827-12840 describes the para-hydrogenation of the pyruvate vinyl ester having a natural 13C content. Korchak et al., ChemistryOpen 2018 672-676 describes the para-hydrogenation of per-deuterated vinyl acetate with natural abundance of 13C to produce hyperpolarized acetate. As the precursor contained only the natural abundance of 13C, also the resulting hyperpolarized acetate can only contain the natural abundance of 13C of approx. 1.1%. Kaltschnee et al., Chem. Eur. J. 2019, 11031-11035 relates to synthesis of deuterated vinyl esters of glycine and alanine, both of them amino acids with the carbonyl being 13C, using Boc-protection of the amino group in KOH with vinyl acetate-d6, followed by deprotection in TFA. Hyperpolarization by para-hydrogenation with ESOTHERIC pulsed spin order transfer yielded polarizations of 0.8% for the 13C carbonyl of glycine and 0.65% for the 13C carbonyl of alanine. J. van den Broeke, E. de Wolf, B.-J. Deelman, G. van Koten, Adv. Synth. Catal. 2003, 345, 625-635 describe a Rhodium-diphosphine catalyst with alkanes or cycloalkanes or alkane bridges as substituents at the phosphine ligands. W.-X. Lv., Q. Li, J.-L. Li, Z. Li, E Lin, D.-H. Tan, Y.-H. Cai, W.-X. Fan, .H. Wang, Angew. Chem. Int. Ed. 2018, 57, 16544-16548, describe the production of vinyl boronic MIDA ester (MIDA=methyliminodiacetic acid). Steemers et al. (Adv. Synth. Catal. 2018, 360, 4241-4245) describes a method to react deuterated vinyl boronic MIDA ester with arylcarboxylic acids. Object o