Isobutyric Anhydride Research Articles

From Batch to Continuous Flow Synthesis in Enzymatic Process Towards Molnupiravir.

Molnupiravir (1) is one among the limited therapeutic options for treating COVID-19 infection and exhibits pan-antiviral potency. Because of urgent demands during the COVID-19 pandemic, a number of methods were developed to offer more efficient routes. In this report, we present a facile 2-step and scalable synthesis of molnupiravir for batch processing and show the implementation of continuous flow biocatalysis to improve the efficiency in synthesis. Our key step entails immobilized lipase and isobutyric anhydride to facilitate regioselective esterification. In batch process, transamination of cytidine (2) provides N4-hydroxycytidine (NHC, 3) with 75 % yield followed by esterification of NHC to give molnupiravir with 64 % yield, providing 48 % overall yield and 99.98 % purity (HPLC). Compared to batch approach in the esterification step, the continuous flow process provides similar product yield and purity and highlights the advantages including 2.42-fold better productivity (mol/day), 2.47-fold improved reaction time, and 30-fold higher space-time-yield. The optimized batch and continuous flow biocatalysis enhance synthesis efficiency and reduce environmental impact, offering a sustainable approach for industrial molnupiravir production.

Synthesis and evaluation of oleic acid‐derived hyperbranched polyester as an efficient plasticizer for PVC

AbstractIn response to the health and environmental concerns associated with the plasticizer dioctyl phthalate (DOP), this research explores the utilization of methyl oleate (MO) derived from plant oil, 1,2,4‐Benzeneticarboxylic anhydride (TMA) and isobutyric anhydride (IA) as a precursor for synthesizing a hyperbranched polyester named IA‐MO‐TMA. This polyester serves as an alternative plasticizer for Polyvinyl chloride (PVC). The chemical structure of IA‐MO‐TMA was thoroughly characterized using Fourier Transform Infrared Spectrometer (FTIR) and nuclear magnetic resonance hydrogen spectra, and its molecular weight was assessed. The PVC film, plasticized with IA‐MO‐TMA, underwent comprehensive testing using techniques such as differential scanning calorimetry, scanning electron microscopy, and thermogravimetric analysis. Notably, the glass transition temperature (Tg) of the plasticized PVC film exhibited a significant reduction from 75°C to −6.7°C. The plasticized film demonstrated an elongation at break of 318.1%, a tensile strength of 19.2 MPa, and a plasticizing efficiency of 109.9%. Moreover, the use of IA‐MO‐TMA as a plasticizer increased the initial decomposition temperature of PVC film from 235.6 to 264.1°C. Additionally, the extraction rate of IA‐MO‐TMA in petroleum ether was found to be 35.6% lower than that of DOP.

Kinetic resolution of 1,1'-binaphthyl-2,2'-diamine derivatives by chiral calcium phosphate-catalyzed acylation.

1,1'-Binaphthyl-2,2'-diamine (BINAM) is a useful axially chiral compound. The kinetic resolution of BINAM is one of the most crucial methods for synthesizing chiral BINAM. We have developed a chiral calcium phosphate-catalyzed kinetic resolution of BINAM by utilizing an acylation reaction to produce a mono-amide. The kinetic resolution of BINAM derivatives was achieved by using isobutyric anhydride in the presence of chiral calcium phosphate and 4-morpholinopyridine with up to s = 127. 6,6'-Substituted BINAM derivatives were also applicable for this reaction. The resulting mono-acylated BINAM could be transformed into BINAM by hydrolysis under acidic conditions.

Improvement of methods for analysing sucrose acetate isobutyrate (SAIB) in soft drinks using GC-FID and evaluating antioxidant effects in the SAIB emulsion system

Sucrose acetate isobutyrate SAIB (E444) is a mixture produced by the esterification of sucrose with acetic anhydride and isobutyric anhydride. It is a food additive that is used as an emulsifier in soft drinks. It is difficult to analyse SAIB quantitatively because there are 256 synthesisable structures in the mixture. This study developed an analytical method for SAIB using gas chromatography-flame ionization detection (GC-FID). The pre-treatment of SAIB in soft drinks was performed using a liquid-liquid extraction method, which demonstrated a recovery rate of 107.8 ± 7.2%. In the GC-FID analysis of SAIB, numerous peaks were observed in the chromatogram, and the content of SAIB was calculated as the sum of these peak areas. A series of analytical methods were validated according to International Conference for Harmonization (ICH) guidelines. Accordingly, the applicability of the developed analytical method was confirmed for both domestic and imported soft drinks distributed in Korea. Additionally, in the linoleic acid emulsion, SAIB exhibited better lipid oxidation stability than the natural antioxidant α-tocopherol and had similar efficacy to the synthetic antioxidant butylated hydroxytoluene (BHT). Although SAIB has excellent lipid oxidation stability, it must be used within legal standards according to consumer demand to reduce the use of synthetic materials in processed foods. The validated GC-FID analytical method will enable subsequent monitoring of the distributed products.

Numerical study of gas-phase pyrolysis reaction with turbulent flow in helically coiled tubes

It is challenging to design a reasonable spiral tube reactor for gas-phase pyrolysis reaction because of the coupling effect of secondary flow and volume expansion. In this paper, two mathematical models are conducted. The three-dimensional (3D) detail model is used to study the effects of volume expansion and thermophysical properties changes on the gas-dynamics, heat transfer, and reactor performance; the one-dimensional (1D) simplified model is developed for designing industrial reactors. The pyrolysis process of isobutyric anhydride (IBAN) is selected as the representative model reaction. The 3D model’s results indicate that the decrease in density significantly increased both axial and radial velocities. The increase of axial velocity increases the pressure drop and decreases the IBAN conversion. The temperature distribution is unaffected by the changes in density and thermophysical properties. Moreover, axial distribution calculated by 1D simplified model are quite consistent with that of the 3D model, indicating that the proposed 1D model can be used to design industrial reactor accurately and efficiently.

Chiral isothiourea-catalyzed kinetic resolution of 4-hydroxy[2.2]paracyclophane.

We herein report a method for the kinetic resolution of racemic 4-hydroxy[2.2]paracyclophane by means of a chiral isothiourea-catalyzed acylation with isobutyric anhydride. This protocol allows for a reasonable synthetically useful s-factor of 20 and provides a novel entry to obtain this interesting planar chiral motive in an enantioenriched manner.

Polymer structure and property effects on solid dispersions with haloperidol: Poly(N-vinyl pyrrolidone) and poly(2-oxazolines) studies.

Poly(2-methyl-2-oxazoline) (PMOZ), poly(2-propyl-2-oxazoline) (PnPOZ) and poly(2-isopropyl-2-oxazoline) (PiPOZ) were synthesized by hydrolysis of 50kDa poly(2-ethyl-2-oxazoline) (PEOZ) and subsequent reaction of the resulting poly(ethylene imine) with acetic, butyric and isobutyric anhydrides, respectively. These polymers were characterized by proton nuclear magnetic resonance, FTIR spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The poly(2-oxazolines) as well as poly(N-vinyl pyrrolidone) (PVP) were used to prepare solid dispersions with haloperidol, a model poorly soluble drug. Dispersions were investigated by powder X-ray diffractometry, differential scanning calorimetry and FTIR spectroscopy. Increasing the number of hydrophobic groups (-CH2- and -CH3) in the polymer resulted in greater inhibition of crystallinity of haloperidol in the order: PVP>PnPOZ=PEOZ>PMOZ. Interestingly, drug crystallization inhibition by PiPOZ was lower than with its isomeric PnPOZ because of the semi-crystalline nature of the former polymer. Crystallization inhibition was consistent with drug dissolution studies using these solid dispersions, with exception of PnPOZ, which exhibited lower critical solution temperature that affected the release of haloperidol.

Kinetic Investigation of the Pyrolysis of Isobutyric Anhydride and Isobutyric Acid

Low-carbon ketenes are produced by pyrolysis of corresponding anhydrides or acids. In this work, the pyrolysis experiments of isobutyric anhydride (IBAN) and isobutyric acid (IBA) were carried out ...

Continuous Flow Preparation of Enantiomerically Pure BINOL(s) by Acylative Kinetic Resolution

AbstractA polystyrene‐immobilized isothiourea has been applied to the enantioselective acylative kinetic resolution (KR) of monoacylated BINOL(s) with inexpensive isobutyric anhydride in batch and flow. High selectivity values (s=29 at 0 °C) and a remarkable stability of the catalytic system in the operation conditions have been recorded for unsubstituted BINOL. No significant loss of activity/selectivity is recorded after 10 consecutive KR cycles in batch. A continuous flow process has been implemented and operated with a 100 mmol (32.8 g) sample of racemic monoacetylated BINOL in dichloromethane solution in an 84 hours experiment with a packed bed reactor containing 1 g (f=0.37 mmol.g−1) of the functional resin (s=17–21). Residence time can be decreased to 10 min with the same reactor to achieve a conversion of 58% with a selectivity factor s=17 when a more highly functionalized catalyst (f=0.88 mmol.g−1) is used. This translates into a remarkable combined productivity of 5.5 mmolprod ⋅ mmolcat−1 ⋅ h−1.magnified image

Adsorption and desorption behaviors of HPEI and thermoresponsive HPEI based gels on anionic and cationic dyes

In this work, two hyperbranched polyethyleneimine (HPEI) based gels were prepared and employed as adsorbents for the removal of dyes. HPEI-MBA gel was obtained by a cross-linking reaction between HPEI and N, N′-methylene-bis-acrylamide (MBA). And HPEI-MBA gel was further treated with isobutyric anhydride to form thermoresponsive HPEI-MBA-IBAm gel having important application in aspect of desorption of dyes. The structure and morphology of gels were characterized by FTIR, XPS, SEM and BET. Many different affecting factors for adsorption capacity of gel, such as contact time, pH, concentration of dyes and adsorptive selectivity, were investigated. The HPEI-MBA gel demonstrated a satisfactory adsorption capacity for methyl orange (MO) and xylenol orange (XO) as high as 1552.76 mg/g and 3312.06 mg/g, respectively. Interestingly, the HPEI-MBA gels had a considerable adsorption capacity for mixed system of anionic and cationic dyes by regulating the value of pH. In the MO/methylene blue (MB) mixture system, the adsorption capacities of gels for MO and MB were all higher than that of single-dye system, and in the MO/basic fuchsin (BF) mixture, the adsorption capacity for MO and BF can be improved under neutral condition. In the MO adsorption process, the adsorption/desorption kinetic of HPEI-MBA and HPEI-MBA-IBAm gels exhibited a good fit to the pseudo-second-order model. Meaningfully, the adsorption efficiency of HPEI-MBA gel for MO was still as high as 93.52% after 11 cycles of adsorption/desorption. More importantly, we developed a general and facile method to achieve dye desorption by adjusting temperature which relies on the temperature-sensitive properties of HPEI-MBA-IBAm. Therefore, the HPEI-MBA gels and HPEI-MBA-IBAm gels, as a new recycle adsorbent, could have comprehensive application in the removal of dyes from wastewater.

A C=O⋅⋅⋅Isothiouronium Interaction Dictates Enantiodiscrimination in Acylative Kinetic Resolutions of Tertiary Heterocyclic Alcohols

AbstractA combination of experimental and computational studies have identified a C=O⋅⋅⋅isothiouronium interaction as key to efficient enantiodiscrimination in the kinetic resolution of tertiary heterocyclic alcohols bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. This discrimination was exploited in the isothiourea‐catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols (38 examples, s factors up to >200). The reaction proceeds at low catalyst loadings (generally 1 mol %) with either isobutyric or acetic anhydride as the acylating agent under mild conditions.

A C=O⋅⋅⋅Isothiouronium Interaction Dictates Enantiodiscrimination in Acylative Kinetic Resolutions of Tertiary Heterocyclic Alcohols.

A combination of experimental and computational studies have identified a C=O⋅⋅⋅isothiouronium interaction as key to efficient enantiodiscrimination in the kinetic resolution of tertiary heterocyclic alcohols bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. This discrimination was exploited in the isothiourea-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols (38 examples, s factors up to >200). The reaction proceeds at low catalyst loadings (generally 1 mol %) with either isobutyric or acetic anhydride as the acylating agent under mild conditions.

Acylative Kinetic Resolution of Alcohols Using a Recyclable Polymer-Supported Isothiourea Catalyst in Batch and Flow

A polystyrene-supported isothiourea catalyst, based on the homogeneous catalyst HyperBTM, has been prepared and used for the acylative kinetic resolution of secondary alcohols. A wide range of alcohols, including benzylic, allylic, and propargylic alcohols, cycloalkanol derivatives, and a 1,2-diol, has been resolved using either propionic or isobutyric anhydride with good to excellent selectivity factors obtained (28 examples, s values up to 600). The catalyst can be recovered and reused by a simple filtration and washing sequence, with no special precautions needed. The recyclability of the catalyst was demonstrated (15 cycles) with no significant loss in either activity or selectivity. The recyclable catalyst was also used for the sequential resolution of 10 different alcohols using different anhydrides with no cross-contamination between cycles. Finally, successful application in a continuous flow process demonstrated the first example of an immobilized Lewis base catalyst used for the kinetic resoluti...

A Scalable Route for the Regio- and Enantioselective Preparation of a Tetrazole Prodrug: Application to the Multi-Gram-Scale Synthesis of a PCSK9 Inhibitor

The synthesis of multigram quantities of small molecule PCSK9 inhibitor (R,S)-3 is described. The route features a safe, multikilogram method to prepare 5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazole (10). A three-component dynamic kinetic resolution between tetrazole 10, acetaldehyde, and isobutyric anhydride was catalyzed by a chiral DMAP catalyst to afford enantiomerically enriched hemiaminal ester (S)-12 on multikilogram scale. Magnesiation, transmetalation, and Negishi coupling provided access to Boc-intermediate (R,S)-13, which was deprotected to provide (R,S)-3 in multigram quantities.

Isothiourea-Catalysed Acylative Kinetic Resolution of Aryl-Alkenyl (sp2 vs. sp2 ) Substituted Secondary Alcohols.

The non‐enzymatic acylative kinetic resolution of challenging aryl–alkenyl (sp2 vs. sp2) substituted secondary alcohols is described, with effective enantiodiscrimination achieved using the isothiourea organocatalyst HyperBTM (1 mol %) and isobutyric anhydride. The kinetic resolution of a wide range of aryl–alkenyl substituted alcohols has been evaluated, with either electron‐rich or naphthyl aryl substituents in combination with an unsubstituted vinyl substituent providing the highest selectivity (S=2–1980). The use of this protocol for the gram‐scale (2.5 g) kinetic resolution of a model aryl–vinyl (sp2 vs. sp2) substituted secondary alcohol is demonstrated, giving access to >1 g of each of the product enantiomers both in 99:1 e.r.

Oxidative and inert pyrolysis on-line coupled to gas chromatography with mass spectrometric detection: On the pyrolysis products of tobacco additives.

According to European legislation, tobacco additives may not increase the toxicity or the addictive potency of the product, but there is an ongoing debate on how to reliably characterize and measure such properties. Further, too little is known on pyrolysis patterns of tobacco additives to assume that no additional toxicological risks need to be suspected. An on-line pyrolysis technique was used and coupled to gas chromatography-mass spectrometry (GC/MS) to identify the pattern of chemical species formed upon thermal decomposition of 19 different tobacco additives like raw cane sugar, licorice or cocoa. To simulate the combustion of a cigarette it was necessary to perform pyrolysis at inert conditions as well as under oxygen supply. All individual additives were pyrolyzed under inert or oxidative conditions at 350, 700 and 1000°C, respectively, and the formation of different toxicants was monitored. We observed the generation of vinyl acrylate, fumaronitrile, methacrylic anhydride, isobutyric anhydride and 3-buten-2-ol exclusively during pyrolysis of tobacco additives. According to the literature, these toxicants so far remained undetectable in tobacco or tobacco smoke. Further, the formation of 20 selected polycyclic aromatic hydrocarbons (PAHs) with molecular weights of up to 278Da was monitored during pyrolysis of cocoa in a semi-quantitative approach. It was shown that the adding of cocoa to tobacco had no influence on the relative amounts of the PAHs formed.

Manufacture, Characterization, and Properties of Poly-(lactic acid) and its Blends with Esterified Pine Lignin

Pinus pinaster wood was pulped in ethanol/water medium catalyzed with sulfuric acid, and lignin was recovered from the liquid phase by precipitation upon water addition. Lignin samples were characterized for composition and thermal properties. Lignin samples were reacted with selected esterification agents (butyric, isobutyric, or crotonic anhydrides) under experimental conditions leading to extensive conversion of the available hydroxyl groups, and the esterified lignins were assessed for composition and thermal properties. Samples made up of crude polylactic acid or its blends with lignins (raw or esterified) were assayed for mechanical properties. The blends of polylactic acid with lignin modified with butyric anhydride presented higher Young’s modulus and elongation at break than neat polylactic acid.

Study on the phase transition behaviors of thermoresponsive hyperbranched polyampholytes in water

The amino groups of hyperbranched polyethylenimine (HPEI) were partially modified with isobutyric anhydride to introduce isobutyramide (IBAm) groups to HPEI, resulting in an LCST-type thermoresponsive HPEI-IBAm that is positively-charged or neutral depending on the media pH. Succinic acid (SA) units were further introduced to HPEI-IBAm through acylation with succinic anhydride, resulting in the hyperbranched polyampholyte, HPEI-IBAm-SA, with both amino and carboxylic acid groups. 1H NMR characterization proved the successful preparation of HPEI-IBAm-SA. Turbidimetry measurements showed that HPEI-IBAm-SA was also an LCST-type thermoresponsive polymer. The cloud point temperature (Tcp) of HPEI-IBAm-SA was pH-dependent. Compared with the HPEI-IBAm precursor, HPEI-IBAm-SA showed the thermoresponsive property in a wider pH range. At isoelectric point, HPEI-IBAm-SA had the lowest Tcp. The isoelectric point of HPEI-IBAm-SA could be tuned by controlling the amount of SA units, and the one with more SA units had a lower isoelectric point. Four halide anions with sodium as the counterion and four cations (Na+, K+, Mg2+ and Ca2+) with chloride as the counterion were used to measure the salt effects on the Tcp of HPEI-IBAm-SA. The specific ranking orderings of these ions in reducing the Tcp of HPEI-IBAm-SA were opposite at pH below and above isoelectric point. At pH above isoelectric point, the anion ranking is I−<Br−<Cl−<F−, and the cation ranking is Ca2+ > Mg2+ > Na+ ≈ K+. At pH below isoelectric point, and, the anion ranking is F−∼Cl−<Br−<I− in the low-salt-concentration region (≤10−2 M), while the cation ranking is Na+ ≈ K+ > Mg2+ ≈ Ca2+. All the specific salt ordering found in HPEI-IBAm-SA system could be also found in the system of the protein representative, ovalbumin, implying that HPEI-IBAm-SA was a better protein model to mimic the interactions among ions and proteins with a different isoelectric point.

Preparation and characterization of thermoresponsive hyperbranched polyethylenimine with plenty of reactive primary amine groups

Certain amount of primary amine (NH2) groups of hyperbranched polyethylenimine (HPEI) was first protected by Boc groups. Subsequently, the residual reactive amine groups were reacted with isobutyric anhydride to introduce isobutyramide (IBAm) groups to HPEI. Finally, Boc groups were deprotected to result in HPEI-IBAm-NH2 with 18% of primary amine terminals on the periphery and 80% of IBAm terminal groups (abbreviated as HPEI-IBAm0.80-NH2). 1H-NMR characterization proved the successful preparation of the product in each step. Compared with its spatial isomer HPEIIBAm0.80 without primary amine groups, 1H-NMR spectra verified that more IBAm groups were located in the interior of HPEI-IBAm0.80-NH2. The further modification of HPEI-IBAm0.80-NH2 and HPEI-IBAm0.80 with p-nitrobenzaldehyde demonstrated that HPEI-IBAm0.80-NH2 was more reactive than HPEI-IBAm0.80 due to its possession of primary amines. Turbidimetry measurements showed that HPEI-IBAm0.80-NH2 was thermoresponsive in water. In the pH range of 9.5–10 its cloud point temperature (T cp) was constant, and it increased obviously upon decreasing the pH below 9.5. The thermoresponsive HPEI-IBAm0.8 exhibited the similar trend, but the pH threshold to achieve the constant T cp was around 8.5. Moreover, HPEI-IBAm0.8-NH2 showed higher T cp and broader phase transition than HPEI-IBAm0.8. The mechanism leading to the different thermoresponsive properties between HPEI-IBAm0.8-NH2 and its spatial isomer HPEI-IBAm0.8 was discussed.

Preparation and characterization of multi stimuli-responsive photoluminescent nanocomposites of graphene quantum dots with hyperbranched polyethylenimine derivatives.

Oxidized graphene sheets (OGS) were treated with a hyperbranched polyethylenimine (PEI) under hydrothermal conditions to generate nanocomposites of graphene quantum dots (GQDs) functionalized with PEI (GQD-PEIs). The influence of the reaction temperature and the PEI/OGS feed ratio on the photoluminescence properties of the GQD-PEIs was studied. The obtained GQD-PEIs were characterized by TEM, dynamic light scattering, elemental analysis, FTIR, zeta potential measurements and (1)H NMR spectroscopy, from which their structural information was inferred. Subsequently, isobutyric amide (IBAm) groups were attached to the GQD-PEIs through the amidation reaction of isobutyric anhydride with the PEI moieties, which resulted in GQD-PEI-IBAm nanocomposites. GQD-PEI-IBAm was not only thermoresponsive, but also responded to other stimuli, including inorganic salts, pH, and loaded organic guests. The cloud point temperature (Tcp) of aqueous solutions of GQD-PEI-IBAm could be modulated through changing the number of IBAm units in GQD-PEI-IBAm, by varying the type and concentration of the inorganic salts and loaded organic guests, or by varying the pH. All the obtained GQD-PEI-IBAm nanocomposites were photoluminescent, and their maximum emission wavelengths were not influenced by outside stimuli. Their emission intensities were influenced a little or negligibly by pH, traditional salting-out anions (Cl(-) and SO4(2-)), and the relatively polar aspirin guest. However, the traditional salting-in I(-) anion and the more hydrophobic 1-pyrenebutyric acid (PBA) guest could effectively quench their fluorescence. 2D NOESY (1)H NMR spectra verified that GQD-PEI-IBAm accommodated the relatively polar aspirin guest using the PEI-IBAm shell, but adsorbed the relatively hydrophobic PBA guest through the nanographene core. The release rate of the guest encapsulated by the thermoresponsive GQD is different below and above Tcp.