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1.
Org Process Res Dev ; 28(4): 891-923, 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38660379

ABSTRACT

Separation and purification in organic solvents are indispensable procedures in pharmaceutical manufacturing. However, they still heavily rely on the conventional separation technologies of distillation and chromatography, resulting in high energy and massive solvent consumption. As an alternative, organic solvent nanofiltration (OSN) offers the benefits of low energy consumption, low solid waste generation, and easy scale-up and incorporation into continuous processes. Thus, there is a growing interest in employing membrane technology in the pharmaceutical area to improve process sustainability and energy efficiency. This Review comprehensively summarizes the recent progress (especially the last 10 years) of organic solvent nanofiltration and its applications in the pharmaceutical industry, including the concentration and purification of active pharmaceutical ingredients, homogeneous catalyst recovery, solvent exchange and recovery, and OSN-assisted peptide/oligonucleotide synthesis. Furthermore, the challenges and future perspectives of membrane technology in pharmaceutical applications are discussed in detail.

2.
Int J Pharm ; 628: 122238, 2022 Nov 25.
Article in English | MEDLINE | ID: mdl-36174850

ABSTRACT

This paper reviews many of the properties of a peptide that need to be considered prior to development as an oral dosage form when co-formulated with a permeation enhancer to improve oral bioavailability, including the importance and implications of peptide half-life on variability in pharmacokinetic profiles. Clinical considerations in terms of food and drug-drug interactions are also discussed. The paper further gives a brief overview how permeation enhancers overcome barriers that limit oral absorption of peptides and thereby improve their oral bioavailability, albeit bioavailabilities are still low single digit and variability is high.


Subject(s)
Drug Delivery Systems , Peptides , Administration, Oral , Peptides/chemistry , Biological Availability , Half-Life
3.
Org Lett ; 24(38): 7015-7020, 2022 Sep 30.
Article in English | MEDLINE | ID: mdl-36130142

ABSTRACT

Thiols easily react with [1.1.1]propellane to give sulfur-substituted bicyclo[1.1.1]pentanes in radical reactions, but this reactivity is not replicated in the case of heterocyclic thiols. Herein, we address this issue by electrophilically activating [1.1.1]propellane to promote its iodo-sulfenylation with 10 classes of heterocyclic thiols in two protocols that can be conducted on a multigram scale without exclusion of air or moisture.

4.
Chem Commun (Camb) ; 58(32): 4966-4968, 2022 Apr 19.
Article in English | MEDLINE | ID: mdl-35348143

ABSTRACT

The total synthesis of (-)-γ-lycorane (10 steps) and synthesis of (±)-γ-lycorane (8 steps) was completed from cyclohexenone. A new two step hydrogen borrowing alkylation of an aziridinyl alcohol, coupled with a Ph* (Me5C6) deprotection/cyclisation procedure was developed for de novo formation of the fused 6,5 heterocyclic ring. This work is one of the first examples of hydrogen borrowing C-C bond formation being used as a key step in a total synthesis project.


Subject(s)
Amaryllidaceae Alkaloids , Hydrogen , Alkylation , Amaryllidaceae Alkaloids/chemistry , Cyclization , Hydrogen/chemistry
5.
Angew Chem Int Ed Engl ; 61(2): e202111291, 2022 Jan 10.
Article in English | MEDLINE | ID: mdl-34705316

ABSTRACT

Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron-neutral nucleophiles such as anilines and azoles to give nitrogen-substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs.

6.
ChemSusChem ; 15(9): e202102592, 2022 May 06.
Article in English | MEDLINE | ID: mdl-34931761

ABSTRACT

The potential of antibody conjugates with high drug loading in anticancer therapy has recently been highlighted by the approval of Trastuzumab deruxtecan and Sacituzumab govitecan. These biopharmaceutical approaches have spurred interest in bioconjugation strategies with high and defined degrees of drug-to-antibody ratio (DAR), in particular on native antibodies. Here, a glycoengineering methodology was developed to generate antibody drug conjugates with DAR of up to eight, by combining highly selective enzymatic galactosylation and oxidation with biorthogonal tandem Knoevenagel-Michael addition chemistry. This four-step approach offers a selective route to conjugates from native antibodies with high drug loading, and thus illustrates how biocatalysis can be used for the generation of biopharmaceuticals using mild reaction conditions.


Subject(s)
Galactose Oxidase
7.
Angew Chem Int Ed Engl ; 60(13): 6981-6985, 2021 03 22.
Article in English | MEDLINE | ID: mdl-33561302

ABSTRACT

For the first time we have been able to employ enantiopure 1,2-amino alcohols derived from abundant amino acids in C-C bond-forming hydrogen-borrowing alkylation reactions. These reactions are facilitated by the use of the aryl ketone Ph*COMe. Racemisation of the amine stereocentre during alkylation can be prevented by the use of sub-stoichiometric base and protection of the nitrogen with a sterically hindered triphenylmethane (trityl) or benzyl group. The Ph* and trityl groups are readily cleaved in one pot to give γ-aminobutyric acid (GABA) products as their HCl salts without further purification. Both steps may be performed in sequence without isolation of the hydrogen-borrowing intermediate, removing the need for column chromatography.

8.
J Org Chem ; 84(8): 4830-4836, 2019 04 19.
Article in English | MEDLINE | ID: mdl-30602115

ABSTRACT

An analysis of Antibody-Drug Conjugate Payload manufacturing has revealed that the majority of the cost is associated with the use of high-containment facilities for the latter stages of the synthesis. To make a significant reduction in the Cost of Goods (CoGs), a new approach to route design has been introduced which focuses on minimizing the number of steps that require high containment. This approach has been exemplified in a new synthesis of tesirine, including the first application of a ring-closing copper(I)/TEMPO aerobic oxidation to the pyrrolobenzodiazepine ring system, affording a 60% reduction in CoGs.


Subject(s)
Benzodiazepines/chemical synthesis , Drug Design , Immunoconjugates/chemistry , Pyrroles/chemical synthesis , Benzodiazepines/chemistry , Cyclization , Molecular Structure , Pyrroles/chemistry
9.
Org Lett ; 14(18): 4934-7, 2012 Sep 21.
Article in English | MEDLINE | ID: mdl-22954424

ABSTRACT

In the presence of a diene-ligated rhodium complex, ynamides and nitroalkenes undergo catalytic [2 + 2] cycloadditions to provide cyclobutenamides. The presence of sodium tetraphenylborate was found to be crucial for the reactions to proceed efficiently.


Subject(s)
Alkenes/chemistry , Alkynes/chemistry , Amides/chemistry , Nitro Compounds/chemistry , Nitro Compounds/chemical synthesis , Rhodium/chemistry , Tetraphenylborate/chemistry , Catalysis , Cycloaddition Reaction , Molecular Structure
10.
Chem Commun (Camb) ; 48(10): 1505-7, 2012 Feb 01.
Article in English | MEDLINE | ID: mdl-21858353

ABSTRACT

In the presence of substoichiometric Pd(OAc)(2), carboxylic acids undergo highly regio- and stereoselective additions to ynamides to provide α-acyloxyenamides.


Subject(s)
Acetates/chemistry , Amides/chemistry , Amides/chemical synthesis , Organometallic Compounds/chemistry , Palladium/chemistry , Catalysis , Molecular Structure
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