247068-83-3

Usage

Uses

Used in Pharmaceutical Industry:
CarbaMic acid, N-[(1S)-3-Methyl-1-[[(2S)-2-Methyl-2-oxiranyl]carbonyl]butyl]-, 1,1-dimethylethyl ester is used as a reagent for the synthesis of epoxomicin, a potent proteasome inhibitor with antitumor, anti-inflammatory, and antibiotic properties. Its role in the synthesis process is crucial, as it contributes to the formation of the final product, which has significant therapeutic applications.
In the synthesis of epoxomicin, CarbaMic acid, N-[(1S)-3-Methyl-1-[[(2S)-2-Methyl-2-oxiranyl]carbonyl]butyl]-, 1,1-diMethylethyl ester serves as a building block, providing the necessary structural elements for the formation of the final molecule. The proteasome inhibition activity of epoxomicin makes it a valuable compound in the development of treatments for various types of cancer, as it can help to regulate cellular processes and inhibit tumor growth.
Additionally, the anti-inflammatory and antibiotic properties of epoxomicin suggest that CarbaMic acid, N-[(1S)-3-Methyl-1-[[(2S)-2-Methyl-2-oxiranyl]carbonyl]butyl]-, 1,1-dimethylethyl ester may also have applications in the development of drugs for inflammatory conditions and bacterial infections. Further research and development in these areas could potentially lead to new therapeutic options for patients suffering from these conditions.

Upstream product

• 247068-81-1 tert-butyl [(1S)-3-methyl-1-(2-methylpropyl)-2-oxobut-3-en-1-yl]carbamate 
• 87694-50-6 N-(tert-butoxycarbonyl)-L-leucine-N'-methoxy-N'-methylamide 
• 13139-15-6 N-tert-butoxycarbonyl-L-leucine 
• 1609959-47-8 tert-butyl N-[(2S)-1-(-2-methyloxirane-2-yl)-1-hydroxy-4-methylpentan-2-yl]carbamate 
• 173899-64-4 (S)-tert-butyl (4-methyl-1-morpholino-1-oxopentan-2-yl)carbamate 
• 1609959-45-6 tert-butyl N-[(4S)-3-hydroxy-2,6-dimethylhept-1-en-4-yl]carbamate 
• 75-65-0 tert-butyl alcohol 
• 1186298-17-8 (1-isobutyl-3-methyl-2-oxo-but-3-enyl)carbamic acid tert-butyl ester 
• 24424-99-5 di-tert-butyl dicarbonate 
• 247068-85-5 (S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one trifluoroacetic acid salt 
• 61-90-5 L-leucine 
• 16937-99-8 N-Boc-D-Leu 
• 338972-00-2 Boc-Leu-Cl 
• 54430-65-8 [(R)-1-(Imidazole-1-carbonyl)-3-methyl-butyl]-carbamic acid tert-butyl ester 

Relevant academic research and scientific papers

Asymmetric Epoxidation of Olefins Catalyzed by Substituted Aminobenzimidazole Manganese Complexes Derived from L-Proline

A family of manganese complexes [Mn(Rpeb)(OTf)2] (peb=1-(1-ethyl-1H-benzo[d]imidazol-2-yl)-N-((1-((1-ethyl-1H-benzo[d]imidazol-2-yl)methyl) pyrrolidin-2-yl)methyl)-N-methylmethanamine)) derived from L-proline has been synthesized and characterized, where R refers to the group at the diamine backbone. X-ray crystallographic analyses indicate that all the manganese complexes [Mn(Rpeb)(OTf)2] exhibit cis-α topology. These types of complexes are shown to catalyze the asymmetric epoxidation of olefins employing H2O2 as a terminal oxidant with up to 96% ee. Obviously, the R group of the diamine backbone can influence the catalytic activity and enantioselectivity in the asymmetric epoxidation of olefins. In particular, Mn(i-Prpeb)(OTf)2 bearing an isopropyl arm, cannot catalyze the epoxidation reaction with H2O2 as the oxidant. However, when PhI(OAc)2 is used as the oxidant instead, all the manganese complexes including Mn(i-Prpeb)(OTf)2 can promote the epoxidation reactions efficiently. Taken together, these results indicate that isopropyl substitution on the Rpeb ligand inhibits the formation of active Mn(V)-oxo species in the H2O2/carboxylic acid system via an acid-assisted pathway.

Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer's Disease

Previously, we reported that immunoproteasome (iP)-targeting linear peptide epoxyketones improve cognitive function in mouse models of Alzheimer's disease (AD) in a manner independent of amyloid β. However, these compounds' clinical prospect for AD is limited due to potential issues, such as poor brain penetration and metabolic instability. Here, we report the development of iP-selective macrocyclic peptide epoxyketones prepared by a ring-closing metathesis reaction between two terminal alkenes attached at the P2 and P3/P4 positions of linear counterparts. We show that a lead macrocyclic compound DB-60 (20) effectively inhibits the catalytic activity of iP in ABCB1-overexpressing cells (IC50: 105 nM) and has metabolic stability superior to its linear counterpart. DB-60 (20) also lowered the serum levels of IL-1α and ameliorated cognitive deficits in Tg2576 mice. The results collectively suggest that macrocyclic peptide epoxyketones have improved CNS drug properties than their linear counterparts and offer promising potential as an AD drug candidate.

Preparation method of carfilzomib intermediate

The invention relates to a preparation method of a carfilzomib intermediate F, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps: by taking t-butyloxycarbonyl-L-leucine as a starting material, carrying out condensation, Grignard reaction, reduction, epoxidation, oxidation and salt forming reaction to obtain a carfilzomib key intermediate F. The method has the advantages of mild reaction conditions, high yield, good selectivity and less generated three wastes, and is suitable for industrial amplification production.

Discovery of novel tripeptide propylene oxide proteasome inhibitors for the treatment of multiple myeloma

The ubiquitin proteasome pathway (UPP) plays a critical role in the maintenance of cell homeostasis and the development of diseases, such as cancer and neurodegenerative disease. A series of novel tripeptide propylene oxide compounds as proteasome inhibitors were designed, synthesized and biologically investigated in this manuscript. The enzymatic activities of final compounds against 20S human proteasome were investigated and structure-activity relationship (SAR) was summarized. Some potent compounds were further evaluated to inhibit the proliferation of multiple myeloma (MM) cancer cell lines RPMI8226 and U266B. The results showed that some compounds were active against MM cancer cell lines with IC50 values of less than 50 nM. The microsomal metabolic stabilities in human, rat and mice species were carried out and the results showed that compounds 30 and 31 were stable enough to be in vivo investigated. The in vivo pharmacokinetic results showed that compounds 30 and 31 had acceptable biological parameters for both ig and iv administrations. In vivo antitumor activities of compounds 30 and 31 with the doses of 100 mg/kg and 50 mg/kg BIW were performed by using RPMI8226 xenograft nude mouse model. Toxicities of compounds 30 and 31 were not observed during the experiment and dose dependent effect was obvious and the tumor volume was greatly inhibited.

Continuous Process Improvement in the Manufacture of Carfilzomib, Part 2: An Improved Process for Synthesis of the Epoxyketone Warhead

The development and kilogram-scale demonstration of an improved process for the synthesis of the epoxyketone warhead of carfilzomib is described. Critical to the success of this process was: (1) development of a scalable asymmetric epoxidation protocol; (2) identification of a crystalline intermediate with improved physical properties for isolation; (3) discovery and optimization of epimerization conditions to set the target stereochemistry; and (4) introduction of a seeded-bed coaddition crystallization to facilitate isolation of the final low-melting target. The results of kilogram-scale demonstration runs are shared, including details of a continuous process for the safe execution of an exothermic Barbier-type Grignard process.

Preparation method of carfilzomib

The invention relates to a preparation method of carfilzomib, which comprises the following steps of: by using a compound represented by a formula I as an intermediate, carrying out deprotection, andreacting with a compound represented by a formula IV to prepare carfilzomib. The preparation method of the compound shown in the formula I comprises the following steps of: taking hydrogen peroxide asan oxidizing agent, and preparing a carfilzomib intermediate, namely the compound shown in the formula I, through selective epoxidation of a chiral organic catalyst. The preparation method disclosedby the invention is simple in reaction condition, simple and convenient to operate, good in asymmetric selectivity, good in yield, high in purity and suitable for industrial production.

Continuous Process Improvement in the Manufacture of Carfilzomib, Part 1: Process Understanding and Improvements in the Commercial Route to Prepare the Epoxyketone Warhead

Epoxyketone 4 is an isolated intermediate in the manufacturing route to the commercial proteasome inhibitor carfilzomib (Kyprolis). Commercial process development and optimization efforts toward the preparation of epoxyketone 4 highlighted several opportunities for process improvement. In this article, three case studies are presented that demonstrate how a detailed understanding of the reaction mechanism led to improvements that increased the overall robustness of the process. In the first case study, the mechanism of racemization of an α-chiral enone was investigated, resulting in the development of an improved aqueous workup procedure. Next, the stability of a bleach/pyridine mixture used for the step 3 epoxidation reaction was studied, leading to the identification of pyridine as a key raw material and improved reaction conditions and control strategy to meet the conversion target. Finally, oxidized butylated hydroxytoluene (oBHT) was identified as an impurity arising from the use of BHT-stabilized tetrahydrofuran in steps preceding the oxidation. The process understanding obtained from these investigations led to the implementation of process improvements that improved the robustness of the process. The development of a second-generation route to 4 is the subject of part 2 in this series (DOI: 10.1021/acs.oprd.0c00052).

LMP2 Inhibitors as a Potential Treatment for Alzheimer's Disease

The immunoproteasome (iP), an inducible proteasome variant harboring three immunosubunits, low molecular mass polypeptide-2 (LMP2), multicatalytic endopeptidase complex subunit-1, and low molecular mass polypeptide-7 (LMP7), is involved in multiple facets of inflammatory responses. We recently reported that YU102, a dual inhibitor of the iP subunit LMP2 and the constitutive proteasome catalytic subunit β1, ameliorates cognitive impairments in mouse models of Alzheimer's disease (AD) independently of amyloid deposits. To investigate whether inhibition of LMP2 is sufficient to improve the cognitive functions of AD mice, here we prepared 37 YU102 analogues and identified a potent LMP2 inhibitor DB-310 (28) (IC50: 80.6 nM) with improved selectivity and permeability in cells overexpressing ABCB1 transporters. We show that DB-310 induces suppression of IL-1α production in microglia cells and improves cognitive functions in the Tg2576 transgenic mouse model of AD. This study supports that inhibition of LMP2 is a promising therapeutic strategy for treatment of AD.

Bioinspired manganese complexes catalyzed epoxidation for the synthesis of the epoxyketone fragment of carfilzomib

We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone (tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermediate of carfilzomib. A series of bioinspired manganese complexes bearing N4 ligands are carefully investigated in the epoxidation of enone precursor with H2O2 as oxidant in the presence of carboxylic acid (e.g., acetic acid).

Exploration of the carmaphycins as payloads in antibody drug conjugate anticancer agents

Antibody–drug conjugates (ADCs) represent a new dimension of anticancer chemotherapeutics, with warheads to date generally involving either antitubulin or DNA-directed agents to achieve low-to sub-nanomolar potency. However, other potent cytotoxins working by different pharmacological mechanisms are under investigation, such as α,β-epoxyketone based proteasome inhibitors. These proteasome active agents are an emerging class of anticancer drug that possesses ultra-potent cytotoxicity to some cancer cell lines. The carmaphycins are representatives of this latter class that we isolated and characterized from a marine cyanobacterium, and these as well as several synthetic analogues exhibit this level of potency. In the current work, we investigated the use of these highly potent cytotoxic compounds as warheads in the design of novel ADCs. We designed and synthesized a library of carmaphycin B analogues that contain amine handles, enabling their attachment to an antibody linker. The basicity of these incorporated amine handles was shown to strongly affect their cytotoxic properties. Linear amines resulted in the greatest reduction in cytotoxicity whereas less basic aromatic amines retained potent activity as demonstrated by a 4-sulfonylaniline derivative. These investigations resulted in identifying the P2 residue in the carmaphycins as the most suitable site for linker attachment point, and hence, we synthesized a highly potent analogue of carmaphycin B that contained a 4-sulfonylaniline handle as an attachment point for the linker antibody.