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Commercial Manufacturing of Propofol: Simplifying the Isolation Process and Control on Related Substances
Abstract
A commercially viable manufacturing process for propofol (1) is described. The process avoids acid–base neutralization events during isolation of intermediate, 2,6-di-isopropylbenzoic acid (3) and crude propofol, and thus simplifies the synthesis on industrial scale to a considerable extent. Syntheses of five impurities/related substances (USP and EP) are also described.
... Although isopropanol has been proposed to replace the gaseous propylene, these harsh conditions all led to the production of several impurities (2,4-diisopropyl and 2,4,6-triisopropyl phenol, along with the product (Scheme 2, path a)). These side products need to be removed from the final API (<0.05%) for medical use [23]. To address the formation of these undesired products in the synthesis of Propofol, another approach was designed using the 4-hydroxybenzoic acid (1) as the starting material to hamper the undesired alkylation at the para position. ...
... However, this procedure suffers from acid-base neutralization at each step, resulting in exothermic quench, a serious drawback for an industrial implementation of the process. This issue was further tackled by Pramanik, who simplifies the isolation and purification steps by getting rid of the acid-base neutralization, using a toluene/water mixture (Scheme 2b) [23]. Importantly, within the context of the COVID-19 pandemic, Propofol is extensively used to avoid cardio-pulmonary injuries for patients, who are mechanically ventilated by minimizing resistance to this mechanical ventilation [2]. ...
... Although isopropanol has been proposed to replace the gaseous propylene, these harsh conditions all led to the production of several impurities (2,4-diisopropyl and 2,4,6-triisopropyl phenol, along with the product (Scheme 2, path a)). These side products need to be removed from the final API (< 0.05%) for medical use [23]. To address the formation of these undesired products in the synthesis of Propofol, another approach was designed using the 4-hydroxybenzoic acid (1) as the starting material to hamper the undesired alkylation at the para position. ...
Herein, we report a continuous flow process for the synthesis of 2,6-diisopropylphenol—also known as Propofol—a short-acting intravenous anesthesia, widely used in intensive care medicine to provide sedation and hypnosis. The synthesis is based on a two-step procedure: a double Friedel–Crafts alkylation followed by a decarboxylation step, both under continuous flow.
... Pramanik and co-workers developed a simple two-step (Friedel−Crafts double alkylation and decarboxylation) batch process from 4-hydroxybenzoic acid. 4 The authors avoided a neutralization step by direct extraction with toluene, obtaining propofol in 62% overall yield (>99.8% purity). Inspired by the latter, a continuous flow chemistry version was reported by three different groups. ...
The biomimetic two-phase strategy employing polyene cyclization and subsequent oxidation/substitution is an effective approach for divergent syntheses of [6-6-6]-tricyclic diterpenes. However, this strategy requires lengthy sequences for syntheses of oxygenated tricyclic aromatic abietane/podocarpane diterpenes owing to the many linear oxidation/substitution steps after cyclization. Here, we present a new synthetic route based on a convergent reverse two-phase strategy employing a reverse radical cyclization approach, which enabled the unified short syntheses of four aromatic abietane/podocarpane diterpenes and the divergent short syntheses of other related diterpenes. Oxygenated and substituted precursors for cyclization were convergently prepared through Friedel-Crafts acylation and rhodium-catalyzed site-selective iodination. Radical redox cyclization using an iridium photoredox catalyst involving neophyl rearrangement furnished the thermodynamically favored 6-membered ring preferentially. (±)-5,6-Dehydrosugiol, salvinolone, crossogumerin A, and Δ⁵-nimbidiol were synthesized in only 8 steps. An oxygenated cyclized intermediate was also useful for divergent derivatization to sugiol, ferruginol, saprorthoquinone, cryptomeriololide, and salvinolone.
Herein we report a machine-assisted and scaled-up synthesis of propofol, a short-acting drug used in procedural sedation, which is extensively in demand during this COVID-19 pandemic. The continuous-flow protocol proved to be efficient, with great potential for industrial translation, reaching a production up to 71.6 g per day with process intensification (24 h-continuous experiments). We have successfully telescoped a continuous flow approach obtaining 5.74 g of propofol with productivity of 23.0 g/day (6 h-continuous experiment), proving the robustness of the method in both separated and telescoped modes. Substantial progress was also achieved for the in-line workup, which provides greater safety and less waste, also relevant for industrial application. Overall, the synthetic strategy is based on the Friedel-Crafts di-isopropylation of low-cost p-hydroxybenzoic acid, followed by a decarboxylation reaction, giving propofol in up to 84% overall yield and very low by-product formation.
The continuous flow synthesis of propofol 3 is presented as a two-step protocol. The isopropylated intermediate 2 was obtained from 4-hydroxybenzoic acid (1) in up 43.8 g, 85% yield and 30 min residence time. Propofol 3 was then obtained in 71.6 g, 87% yield, and 16 min residence time. A safe and cost-competitive machine-assisted protocol is described with a process intensification demonstration (24 h experiments) and a telescoped process intensification (6 h).
Imidazole hydrochloride, a hydrochloric acid carrier, was used to mediate the decarboxylation of ortho-para position amino-substituted aromatic acids and nitrogen-containing heterocyclic acids, which gave excellent yields within a short time. In addition, the method can be well adapted to a gram scale, and the imidazole hydrochloride additives can be appropriately recovered for secondary utilization.
The 1,2-rearrangement of o-quinols has been a long-standing unsolved problem since 1958. Although the rearrangement is expected to be useful for syntheses of catechol derivatives, it is hampered by many competing reactions and has not been developed as a useful methodology. Here, we succeeded in settling this problem by a first systematic thorough investigation, establishing the 1,2-rearrangement as a cascade reaction with a retro Diels-Alder reaction from o-quinol dimers. This is a useful strategy for syntheses of substituted catechols used as synthetic building blocks for bioactive compounds and material molecules. o-Quinol dimers were synthesized by improved oxidative hydroxylation of substituted phenols followed by spontaneous Diels-Alder reaction. The dimers then underwent the retro Diels-Alder reaction to regenerate the o-quinols followed by 1,2-rearrangement under neutral heating conditions at an appropriate temperature depending on the migratory substituent, furnishing substituted catechols in good yields. The competing reactions such as an elimination of a substituent or α-ketol rearrangement were minimized by controlling the reaction temperature.
Two transition-metal-free methods to access substituted phenols via the arylation of silanols or hydrogen peroxide with diaryliodonium salts are presented. The complementary reactivity of the two nucleophiles allows synthesis of a broad range of phenols without competing aryne formation, as illustrated by the synthesis of the anesthetic Propofol. Furthermore, silyl-protected phenols can easily be obtained, which are suitable for further transformations.
Sterically encumbered 4-hydroxy-3,5-diisopropylbenzoic acid (H(2)diphba), bearing a carboxylic acid, a phenol and two isopropyl substituents, has been investigated for the first time as a ligand and supramolecular synthon to isolate eight Zn(II) complexes, [Zn-2(Hdiphba)(3)(OAc)(L)] (L = DMF(1) or pyz (2)), [Zn (Hdiphba)(2)(2,2'-bpy)] (3), [Zn(Hdiphba)(2)(1,10-phen)] (4), [Zn (Hdiphba)(2)(pz)(2)] (5) and [Zn-2(Hdiphba)(2)(mu(2)-dmpz)(2)(Hdmpz)(2)] (6), [Zn(Hdiphba)(2)(4,4'-bpy)](n).4nCH(3)OH (7.4nCH(3)OH), [Zn-2(Hdiphba)(4) (4,4'-azobpy)(H2O)(2)] (8.H(2)diphba), which have been structurally characterized. Compounds 1 and 2 are rare examples of symmetrically bridged triple-blade molecular tricarboxylate paddle-wheels which self-assemble into hexameric units. Compounds 3, 4 and 5 are mononuclear complexes, bearing two exposed phenolic -OH groups self-assembled into 2-D arrays via both hydrogen bonding and p-p stacking interactions. Compound 6 is a rare example of bis-pyrazolate bridged dinuclear Zn(II) complex with two pyrazole N-H and two phenolic -OH groups on the molecular periphery to form hydrogen bonds. The use of 4,4'-bpy leading to a zig-zag 1-D polymer 7 composed of [Zn(Hdiphba) 2(4,4'-bpy)] n chains, positioned 10.77 angstrom apart. The 1-D channels of 7 are occupied by hydrogen bonded methanol with a rare (CH3OH)(4) cluster as the repeating unit. Compound 8 is a discrete bimetallic complex, isolated with a free H(2)diphba ligand. The photoluminescence spectra of 1-8 exhibit ligand centered emission at around 325 nm.
The manufacturing of pharmaceutical intermediates and drug molecules is mainly dominated by chemists. There are number of chemical reactions that use stoichiometric reagents and hence, produce large quantities of waste per kg of the finished product. With the introduction of a new catalyst system and the various inventions in catalysis, the API industry is transforming itself into a clean chemical industry. Advances in catalysis have made a tremendous impact on the pharmaceutical as well as fine chemical process development. Catalysis enables the synthesis of new, highly complex small-molecule in a fewer steps, especially enantiomerically pure chiral molecules, with increased atom economy, and often high selectivity and yield. This chapter discusses various reactions such as hydrogenation, carbonylation, carboxylation, hydroformylation, various coupling reactions, protection, de-protection reactions, etc., and their usefulness in API manufacture. A number of case studies illustrating the utility of new catalyst systems and their role in making the manufacturing processes efficient and economical has been discussed. The examples quoted are very important in understanding the phases in technology development and may be useful as a guideline for the development of various catalytic chemistries. The regulatory requirement of catalyst contamination in the drug molecule has also been discussed briefly.
In the last few decades there has been probably more interest in drugs obtained from plant sources than at any time in history because of success with antibiotics, and other plant drugs showing encouraging results in controlling serious diseases such as cancerous tumours and acting as stimulants and contraceptives, controlling cardiac arrests, and in the treatment of rheumatoid arthritis and several other ailments. With an increase in population and decrease in per capita available arable land (particularly in developing countries), it has become very difficult to find fertile land for cultivation of medicinal and aromatic plants (MAPs). The results reported in this review clearly indicate that cultivation of MAPs on degraded lands through biosaline agriculture is feasible and profitable. Experiments have been conducted in arid regions of the Indian subcontinent growing various MAPs on salt-affected lands and irrigating them judiciously with saline water. Several medicinal species (such as Plantago ovata , Aloe vera , Catharanthus roseus , Cassia angustifolia , Withania somnifera , Asparagus racemosus , Emblica officinalis , Terminalia arjuna , Azadirachta indica , Lepidium latifolium , etc.) and aromatic species (such as Cymbopogon flexuosus , Cymbopogon martinii , Vetiveria zizanioides , Matricaria chamomilla , Mentha arvensis , Pandanus odoratissimus , etc.) can successfully be cultivated on moderate alkaline/saline soils using saline irrigation, showing their potential. There are plenty of salt-tolerant species found in nature that can easily be domesticated to improve economic gains. Attempts should be made to educate the farming community about the practicalities of growing these plants and to create market avenues for procurement of these products. Scientists must develop more salt-tolerant and productive cultivars. These will not only provide better economic returns but also help in ameliorating the saline environment.
The death of a female anaesthesiologist is reported. Although the situation at the scene indicated propofol overdose-related death, self-administration of such high doses of propofol was unlikely, given the pharmacological properties of this drug. The analysis of the situation at the scene and the toxicological analysis in which the blood and liver propofol concentrations were 2.40microg/ml and 0.56microg/g, respectively, supported the conclusion that the death was a consequence of propofol self-administration at therapeutic doses from a person who used the drug on chronic basis seeking to its euphoric effects. However, because the toxic concentrations of propofol in non-intubated patients may be different from those intubated and fully supported in the operating room or in the intensive care unit, a mere interpretation of the blood and tissue concentrations of propofol in the toxicological analysis can confirm the drug intake but it may be of limited diagnostic significance without taking into account this difference.
A highly efficient synthesis of various 3-substituted salicylic acids is described starting from inexpensive starting materials and requiring no special apparatus.Key words: salicylic acids, ortho-metalation, halogen–metal exchange, methoxymethyl group.On décrit une synthèse très efficace d'acides salicyliques substitués en position 3, à partir de produits peu dispendieux et ne requérant pas d'appareils spéciaux.Mots clés : acides salicyliques, ortho-métallation, échange halogène–métal, groupe méthoxyméthyle.[Traduit par la Rédaction]
The reaction of phenols with dhenols in the presence of aluminum phenoxide-type catalysts has been investigated and under proper reaction conditions found capable of yielding predominantly 2-alkyl and 2,6-dialkylphenole. The mechanism of the reaction is discussed.
Ethyl-substituted bicyclooctenones have been obtained by the thermal addition of ethylene to monohydric phenols at high pressure. This ketone synthesis apparently involves ortho alkylation followed by the 1,4-addition of ethylene. Dihydric phenols react similarly to give cyclohexendiones and bicyclic ketones.
Propofol is an intravenous anaesthetic which is chemically unrelated to other anaesthetics. Induction of anaesthesia with propofol is rapid, and maintenance can be achieved by either continuous infusion or intermittent bolus injections, with either nitrous oxide or opioids used to provide analgesia. Comparative studies have shown propofol to be at least as effective as thiopentone, methohexitone or etomidate for anaesthesia during general surgery. The incidence of excitatory effects is lower with propofol than with methohexitone, but apnoea on induction occurs more frequently with propofol than with other anaesthetics. Additionally, a small number of studies of induction and maintenance of anaesthesia have found propofol to be a suitable alternative to induction with thiopentone and maintenance with halothane, isoflurane or enflurane. Propofol is particularly suitable for outpatient surgery since it provides superior operating conditions to methohexitone (particularly less movement), and rapid recovery in the postoperative period associated with a low incidence of nausea and vomiting. When used in combination with fentanyl or alfentanil, propofol is suitable for the provision of total intravenous anaesthesia, and comparative studies found it to be superior to methohexitone or etomidate in this setting. Infusions of subanaesthetic doses of propofol have been used to sedate patients for surgery under regional anaesthesia, and also to provide sedation of patients in intensive care. In the latter situation it is particularly encouraging that propofol did not suppress adrenal responsiveness during short term studies. If this is confirmed during longer term administration this would offer an important advantage over etomidate. Thus, propofol is clearly an effective addition to the limited range of intravenous anaesthetics. While certain areas of its use need further study, as would be expected at this stage of its development, propofol should find a useful role in anaesthetic practice.
When the pharmacokinetic evaluation of propofol in its emulsion formulation began, there existed a considerable amount of pharmacokinetic and metabolic data on the Cremophor formulation which it is now replacing. The existence of these data did not reduce the detail of the evaluation of the emulsion formulation but aided the optimum design of studies. The pharmacokinetic evaluation of the emulsion formulation commenced with studies in rats, dogs and rabbits in support of the preclinical safety evaluation. A comparison between the Cremophor and emulsion formulations in a rat pharmacokinetic study at 5 mg/kg indicated, on the basis of anaesthetic activity, that the emulsion formulation was somewhat less potent than the Cremophor formulation; this correlated well with the lower propofol blood concentrations during the first 60 min after induction with the emulsion formulation compared to the Cremophor formulation. Although the rate constants defining distribution and elimination of propofol are similar for both formulations, the emulsion formulation displays in rats a higher apparent volume of distribution for propofol than the Cremophor formulation. Studies in all toxicology species confirmed the safety of the emulsion formulation and the clinical trials commenced with a dose range-finding trial. It was reassuring to note that the ED95 induction dose for unpremedicated patients of 2.5 mg/kg reported by Cummings et al. (1984) was slightly higher than the induction dose in general usage for the Cremophor formulation (2.0 mg/kg) in similar patients.
Propofol is a phenolic derivative that is structurally unrelated to other sedative hypnotic agents. It has been used extensively as an anaesthetic agent, particularly in procedures of short duration. More recently it has been investigated as a sedative in the intensive care unit (ICU) where it produces sedation and hypnosis in a dose-dependent manner. Propofol also provides control of stress responses and has anticonvulsant and amnesic properties. Importantly, its pharmacokinetic properties are characterised by a rapid onset and short duration of action. Noncomparative and comparative trials have evaluated the use of propofol for the sedation of mechanically ventilated patients in the ICU (postsurgical, general medical, trauma). Overall, propofol provides satisfactory sedation and is associated with good haemodynamic stability. It produces results similar to or better than those seen with midazolam or other comparator agents when the quality of sedation and/or the amount of time that patients were at adequate levels of sedation are measured. Patients sedated with propofol also tend to have a faster recovery (time to spontaneous ventilation or extubation) than patients sedated with midazolam. Although most studies did not measure time to discharge from the ICU, propofol tended to be superior to midazolam in this respect. In a few small trials in patients with head trauma or following neurosurgery, propofol was associated with adequate sedation and control of cerebral haemodynamics. The rapid recovery of patients after stopping propofol makes it an attractive option in the ICU, particularly for patients requiring only short term sedation. In short term sedation, propofol, despite its generally higher acquisition costs, has the potential to reduce overall medical costs if patients are able to be extubated and discharged from the ICU sooner. Because of the potential for hyperlipidaemia and the development of tolerance to its sedative effects, and because of the reduced need for rapid reversal of drug effects in long term sedation, the usefulness of propofol in long term situations is less well established. While experience with propofol for the sedation of patients in the ICU is extensive, there are still areas requiring further investigation. These include studies in children, trials examining cerebral and haemodynamic outcomes following long term administration and in patients with head trauma and, importantly, pharmacoeconomic investigations to determine those situations where propofol is cost effective. In the meantime, propofol is a well established treatment native to benzodiazepines and/or other hypnotics or analgesics when sedation of patients in the ICU is required. In particular, propofol possesses unique advantages over these agents in patients requiring only short term sedation.
To report an adult trauma patient fatality related to propofol administration.
Retrospective case review.
Trauma intensive care unit (ICU) in a level one trauma center.
An 18-yr-old man involved in a motor vehicle crash.
Treatment for multiple trauma injuries and propofol sedation.
Posttrauma ICU monitoring was performed. The patient developed cardiac arrhythmia, metabolic acidosis, and cardiac failure, which resulted in death.
Death related to propofol infusion can occur in adults as well as in pediatric patients.
Propofol (2, 6-diisopropylphenol) is a potent intravenous hypnotic agent which is widely used for the induction and maintenance of anesthesia and for sedation in the intensive care unit. Propofol is an oil at room temperature and insoluble in aqueous solution. Present formulations consists of 1% or 2% (w/v) propofol, 10% soybean oil, 2.25% glycerol, and 1.2% egg phosphatide. Disodium edetate (EDTA) or metabisulfite is added to retard bacterial and fungal growth. Propofol is a global central nervous system depressant. It directly activates GABA(A) receptors. In addition, propofol inhibits the NMDA receptor and modulates calcium influx through slow calcium ion channels. Propofol has a rapid onset of action with a dose-related hypnotic effect. Recovery is rapid even after prolonged use. Propofol decreases cerebral oxygen consumption, reduces intracranial pressure and has potent anti-convulsant properties. It is a potent antioxidant, has anti-inflammatory properties and is a bronchodilator. As a consequence of these properties propofol is being increasingly used in the management of traumatic head injury, status epilepticus, delirium tremens, status asthmaticus and in critically ill septic patients. Propofol has a remarkable safety profile. Dose dependent hypotension is the commonest complication; particularly in volume depleted patients. Hypertriglyceridemia and pancreatitis are uncommon complications. Allergic complications, which may include bronchospasm, have been reported with the formulation containing metabisulfite. In addition, this formulation has been demonstrated to result in the generation of oxygen free radicals. High dose propofol infusions have been associated with the "propofol syndrome"; this is a potentially fatal complication characterized by severe metabolic acidosis and circulatory collapse. This is a rare complication first reported in pediatric patients and believed to be due to decreased transmembrane electrical potential and alteration of electron transport across the inner mitochondrial membrane.
Propofol (2,6-diisopropylphenol) is a potent intravenous hypnotic agent widely administered for induction and maintenance of anesthesia and for sedation in the intensive care unit. Propofol is insoluble in water and therefore is formulated in a lipid emulsion. In addition, a preservative (ethylenediaminetetraacetic acid [EDTA] or sodium metabisulfite) is added to retard bacterial growth. Propofol has antiinflammatory properties, decreasing production of proinflammatory cytokines, altering expression of nitric oxide, and inhibiting neutrophil function. Propofol also is a potent antioxidant. The added preservatives have biologic activity; EDTA has antiinflammatory properties, whereas metabisulfite may cause lipid peroxidation. The antiinflammatory and antioxidant properties of propofol may have beneficial effects in patients with sepsis and systemic inflammatory response syndrome.
A convergent total synthesis of ecteinascidin 743 is realized from five building blocks of almost equal size. It takes 23 steps from L-3-hydroxy-4-methoxy-5-Me phenylalanol (I) with an overall yield of 3%. The most notable features include (a) rapid construction of the D-E segment by highly diastereoselective Pictet-Spengler condensation of Garner's aldehyde with I, (b) diastereoselective N-alkylation of racemic benzyl bromide II by enantiomerically pure amino alc. III, and (c) one-pot deprotection/cyclization of the S-protected precursor IV leading to a 1,4-bridged 10-membered ring. [on SciFinder (R)]
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