Knowledge Centre
  • Home

Welcome to the CARBOGEN AMCIS Knowledge Centre

We want to share our knowledge with the Life Sciences industry in the hope that this information may help you overcome the challenges you face across all stages of the drug development process.

Search by Topic

You can select the Knowledge Centre area you would like to explore above, or filter by using the tags below.

Publications

Cage-like molecules with triple bonds

Cage-like molecules with triple bonds Tuesday, 31 March 2020

1,8-diazabicyclo[6.6.6]eicosa-4,11,17-triyne and 1,8-diazacyclotetradeca-4,11-diyne.

The syntheses of 1,8-diazacyclotetradeca-4,11-diyne and 1,8-diazabicyclo[6.6.6]eicosa-4,11,17-triyne and 1,8-diazabicyclo[6.6.6]eicosa-4,11,17-triene are reported.

A bridgehead amine with planar nitrogens

A bridgehead amine with planar nitrogens Tuesday, 31 March 2020

1,8-Diazabicyclo[ 6.6.4]octadeca-4,11,16-triyne.

The synthesis of 1,8-diazabicyclo[ 6.6.4]octadeca-4,11,16-triyne (3) has been achieved, X-ray investigations on single crystals reveal an almost planar conformation of the nitrogen atoms.

Syntheses and properties of N,N′-bridged-1,10-diazabicyclooctadeca-5,14-diynes

Syntheses and properties of N,N′-bridged-1,10-diazabicyclooctadeca-5,14-diynes Tuesday, 31 March 2020

The conformations and properties of 1,(k + 2)-diazabicyclo[ k.l.m]alkanes are reviewed briefly.

The conformations and properties of 1,(k + 2)-diazabicyclo[ k.l.m]alkanes are reviewed briefly. In these species the alkane chains allow inside protonation but no metal complexation. Inside metal complexation is made possible if the alkane chains incorporate alkyne units. The preparation and structures of bridged 1,10-diazacyclooctadeca-5,14-diynes are reported.

Reaction of N,N'-bridged 1,10-diazacyclooctadeca-5,14-diynes with [  CpCo(cod)]

Reaction of N,N'-bridged 1,10-diazacyclooctadeca-5,14-diynes with [ CpCo(cod)] Tuesday, 31 March 2020

The reaction of N,N′-bridged 1,10-diazacyclooctadeca-5,14-diynes 1a–d with [ CpCo(cod)] leads to both intra- and inter-molecular (4) CpCo–cyclobutadiene complexes.

The reaction of N,N′-bridged 1,10-diazacyclooctadeca-5,14-diynes 1a–d with [ CpCo(cod)] leads to both intra- and inter-molecular (4) CpCo–cyclobutadiene complexes. The yield of intramolecular complex decreases and the yield of intermolecular complex increases with growing length of the alkane bridge. X-Ray investigations on single crystals of 3a, 3d and 4d reveal that the repulsions between the Cp ring and two CH2-groups in β-position to the cyclobutadiene ring increase from 3a to 3d. Such steric repulsions are not found in 4d.

Synthesis of (S)-1-Boc-2,5-dihydro-1H-pyrrole-2- carboxylic Acid

Synthesis of (S)-1-Boc-2,5-dihydro-1H-pyrrole-2- carboxylic Acid Tuesday, 31 March 2020

A short and efficient synthesis of (S)-1-Boc-2,5-dihydro-1H-pyrrole-2-carboxylic acid is described.

A short and efficient synthesis of (S)-1-Boc-2,5-dihydro-1H-pyrrole-2-carboxylic acid is described. Starting from N-Boc-diallylamine, the synthesis involves ring-closing metathesis (RCM), directed alkoxycarbonylation (using strong lithium bases and alkyl carbonates) and enzymatic kinetic resolution of the racemate.

Example of a Stereoselective Synthesis in Industrial API Manufacture

Example of a Stereoselective Synthesis in Industrial API Manufacture Tuesday, 31 March 2020

Stereoselective transformation performed on multi-kilogram scale at CARBOGEN AMCIS AG.

Stereochemistry is an important topic not only in academic research, but also in industrial manufacture. Herein, we present an example of a stereoselective transformation performed on multi-kilogram scale at CARBOGEN AMCIS AG for VenatoRx Pharmaceuticals.

Process Development and Multikilogram Syntheses of XL228

Process Development and Multikilogram Syntheses of XL228 Tuesday, 31 March 2020

Route scouting, process development, and multikilogram syntheses of an IGF-1R/Src/Bcr-Abl inihibitor are reported.

Route scouting, process development, and multikilogram syntheses of an IGF-1R/Src/Bcr-Abl inihibitor are reported. Key aspects of the developed route are a regioselective [ 3 + 2] isoxazole formation on a pyrimidine core and a selective SNAr addition of an aryl amine to a symmetrical dichloro substituted pyrimidine. The route contains six synthetic steps and was demonstrated twice on scale, delivering 4.6 and 11.2 kg (25% and 16% overall yield), for Phase I clinical studies.

Safety Assessment for the Scale-up of an Oxime Reduction

Safety Assessment for the Scale-up of an Oxime Reduction Tuesday, 31 March 2020

A pilot-plant process is described for the reduction of 2-allyl cyclohexanone oxime with melted sodium in xylenes, toluene, and 4-methyl-2-pentanol.

A pilot-plant process is described for the reduction of 2-allyl cyclohexanone oxime with melted sodium in xylenes, toluene, and 4-methyl-2-pentanol. The trans/cis ratio was 3–4:1. Safety data are presented from a range of thermokinetic experiments (heat flow calorimetry, differential scanning calorimetry, and accelerating rate calorimetry). The process has been designed and developed to enable an expedient and safe scale-up in a standard enameled 100-L steel reactor and has been reproduced six times on 209 mol scale (each 4.8 kg sodium). Crystallization of the product 2-allyl cyclohexylamine with oxalic acid from the reaction mixture in tert-butyl methyl ether successfully avoided the yield losses associated with the isolation of the volatile free 2-allyl cyclohexylamine.

Identification of a 1,2,4,5-Tetraoxane Antimalarial Drug-Development Candidate

Identification of a 1,2,4,5-Tetraoxane Antimalarial Drug-Development Candidate Tuesday, 31 March 2020

From a library of over 150 1,2,4,5‐tetraoxanes, the candidate RKA 182 was selected for preclinical development as an antimalarial agent.

From a library of over 150 1,2,4,5‐tetraoxanes, the candidate RKA 182 was selected for preclinical development as an antimalarial agent. RKA 182 has outstanding in vitro activity against resistant strains of P. falciparum and retains this level of activity against southeast asian isolates that failed artemisinin‐based combination therapy.

Scale-up of a high temperature Claisen synthesis

Scale-up of a high temperature Claisen synthesis Tuesday, 31 March 2020

Control of trace inorganics and an understanding of reaction kinetics and impurity generation proved critical in allowing safe and reliable scale-up of a high-temperature Claisen reaction.

Control of trace inorganics and an understanding of reaction kinetics and impurity generation proved critical in allowing safe and reliable scale-up of a high-temperature Claisen reaction in support of multikilogram manufacture of a key chromene intermediate 4. Implementation of a Medicinal Chemistry route allowed for rapid early phase delivery of 1 to support early clinical studies.

Process Optimization for GSK369796 (N-tert-Butyl Isoquine)

Process Optimization for GSK369796 (N-tert-Butyl Isoquine) Tuesday, 31 March 2020

An improved process to the novel 4-aminoquinoline antimalarial GSK369796 is described.

An improved process to the novel 4-aminoquinoline antimalarial GSK369796 is described. Although the initial synthetic route consisted of only two steps from readily available starting materials, the product isolated via the key Mannich reaction was hampered by both low yields and low purity. In addition to instability under the reaction conditions used for the Mannich reaction, the drug substance was found to decompose during attempts to purify by recrystallisation. Reaction conditions were developed that resolved these issues, culminating in the successful production of multi-kg quantities of GSK369796 in >98% a/a purity and in 57% overall yield.

HMG-CoA Reductase Inhibitor

HMG-CoA Reductase Inhibitor Tuesday, 31 March 2020

Preparation of a HMG-CoA Reductase Inhibitor via an Optimized Imidazole-Forming Condensation Reaction.

Development work toward an enabling synthesis of preparative scale batches of an imidazole-based HMG-CoA reductase inhibitor is described. The desired target was synthesized in 16% yield over 7 steps, highlighted by an imidazole-forming condensation reaction in which the yield was improved from 20% to >70% via modification of the solvent, acid, and amine equivalents. The step 2 acylation was improved, and a problematic benzyl ester in step 4 was converted into the corresponding benzyl amide to decrease trans-amidation during the step 5 imidazole formation. A highly effective salt formation and crystallization protocol was also developed.

2-(Diethylamino)ethanethiol

2-(Diethylamino)ethanethiol Tuesday, 31 March 2020

A new reagent for the Odorless Deprotection of Aromatic Methyl Ethers.

A new reagent for the deprotection of aromatic methyl ethers, 2-(diethylamino)ethanethiol, is reported. This compound, commercially available as its HCl salt, affords the corresponding phenols in good to excellent yields on a wide variety of substrates. A clear advantage of this method over the use of more common thiols, such as ethanethiol, is the easy extraction of both the deprotecting reagent and the byproduct 2-(diethylamino)ethyl methyl sulfide into the aqueous phase by quenching with dilute acid, which allows an essentially odorless workup.

Chiroptical Properties of some Monoazapentahelicenes

Chiroptical Properties of some Monoazapentahelicenes Tuesday, 31 March 2020

Synthesized monoaza[ 5]helicenes have been resolved into their enantiomers via enantioselective HPLC.

Three closely related previously synthesized monoaza[ 5]helicenes have been resolved into their enantiomers via enantioselective HPLC using a cellulose-derivative Chiralcel OD column.

Synthesis of 2-Amino-8-hydroxyquinoline

Synthesis of 2-Amino-8-hydroxyquinoline Tuesday, 31 March 2020

The first safe and efficient synthesis of the important building block 2-amino-8-hydroxyquinoline is described.

The first safe and efficient synthesis of the important building block 2-amino-8-hydroxyquinoline is described. Starting from the readily available N-oxide 3 of the cheap bulk chemical 8-hydroxyquinoline, the target compound is obtained in a two-step one pot procedure in good overall yield (53−66%) and purity (>98%) on a kilogram scale without chromatography.

Process scale-up of cis-N-Benzyl-3-methylamino-4-methylpiperidine

Process scale-up of cis-N-Benzyl-3-methylamino-4-methylpiperidine Monday, 30 March 2020

The synthesis was optimized and scaled-up to produce 10kg quantities of final product.

The synthesis of cis-N-benzyl-3-methylamino-4-methylpiperidine via hydroboration of tetrahydropyridine followed by oxidation and reductive amination was optimized and scaled up to produce 10kg quantities of product. Three routes to were identified, and the reduction of pyridinium salt was selected as the most preferable to run on-scale. The hydroboration and oxidative workup were carefully studied to optimize throughput on that transformation, as was the reductive amination.

Large scale preparation of 3-Methyl-4H-[  1,  2,  4]oxadiazol-5-one

Large scale preparation of 3-Methyl-4H-[ 1, 2, 4]oxadiazol-5-one Monday, 30 March 2020

Process Development for the potassium and sodium salts of 3-Methyl-4H-[ 1, 2, 4]oxadiazol-5-one 1A and 1B.

The development of a safe and practical process for the potassium and sodium salts of 3-Methyl-4H-[ 1, 2, 4]oxadiazol-5-one 1A and 1B is described. The focus of the report is how the scale-up issues of the original procedure are overcome, in particular, the thermal hazards of the starting material, hydroxylamine, and the intermediate, acetamidoxime. The final process was demonstrated multiple times on a 600-L scale with consistent yields (70%) and purities (95%).

If you can’t find the information you are looking for then please contact us and we will be glad to help with your request.