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Investigation of Cocatalysis Conditions Using an Automated Microscale Multireactor Workstation: Synthesis of <i>m</i><i>eso</i>-Tetramesitylporphyrin | Prior manual work has shown that the condensation of mesitaldehyde and pyrrole leading to tetramesitylporphyrin depends sensitively on concentration and requires cocatalysis involving BF 3 ·O(Et) 2 and ethanol or other protic species. We have applied an automated microscale chemistry workstation capable of parallel or ... | 10.1021/op9800459 | 0 |
Facile Synthesis of β-Keto Esters from Methyl Acetoacetate and Acid Chloride: The Barium Oxide/Methanol System<sup>1</sup> | The synthesis of β-keto esters has been performed in good yield by reacting excess methyl acetoacetate with barium oxide, acylating the resulting barium complex with acid chloride, and then cleaving the α-acyl β-keto ester with methanol at a mild temperature. Using this new procedure, various β-keto esters were prepare... | 10.1021/op980044g | 0 |
Ecofriendly Fast Batch Synthesis of Dioxolanes, Dithiolanes, and Oxathiolanes without Solvent under Microwave Irradiation | 2,2-Dimethoxypropane and 3,3-dimethoxypentane react with 1,2-ethanediol, thio, and oxathio analogues to give the corresponding protected carbonyls in high yield under mild solvent-free conditions. These environmentally benign conditions under microwave irradiation are applied to a large-scale synthesis. | 10.1021/op980043o | 0 |
Process Development Aspects of Production of Dibenzyl Ether | To develop an economically viable process for the synthesis of dibenzyl ether, the reaction of benzyl chloride with aqueous sodium hydroxide in the presence of phase-transfer catalysts has been investigated. The effects of agitation speed, catalyst type and concentration, reaction temperature, mole ratio of reactants, ... | 10.1021/op980042w | 0 |
A Scalable Process for the Novel Antidepressant ABT-200 | A scalable process for the novel antidepressant ABT-200, starting with 5,6-methylenedioxy-1-tetralone, is described. The new process improves the scale-up and safety concerns associated with the previously employed route to ABT-200. The scalable process eliminates the potential for HCN exposure to employees and produce... | 10.1021/op9800414 | 1 |
Pilot-Scale Synthesis of a Novel Non-Xanthine Adenosine A<sub>1</sub> Receptor Antagonist. 1,3-Dipolar Cycloaddition of Pyridine <i>N</i>-Imine to an Acetylene | Adenosine A 1 receptor antagonist, FK838, has been synthesized in 44% overall yield by a five-step sequence which is operationally straightforward and readily carried out on a large scale. Investigations into the 1,3-dipolar cycloaddition process that afforded a pyrazolo[1,5- a ]pyridine derivative are also described. ... | 10.1021/op980039c | 1 |
Practical Synthesis of the High-Quality Antitumor Agent KW-2189 from Duocarmycin B2 Using a Facile One-Pot Synthesis of an Intermediate | A facile and large-scale preparation process of a potent antitumor agent KW-2189 ( 2 ), derived from the antitumor antibiotic duocarmycin B2 ( 1 ), has been developed. This new synthetic route required three steps: (i) one-pot carbamoylation and subsequent reduction, (ii) Wagner−Meerwein rearrangement of the methoxycar... | 10.1021/op980038k | 1 |
Handbook of Batch Process Design Edited by P. N. Sharratt. Blackie/Chapman and Hall: London, UK. 1997. 320 pp. ISBN 0 7514 0369 5. £75. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTHandbook of Batch Process Design Edited by P. N. Sharratt. Blackie/Chapman and Hall: London, UK. 1997. 320 pp. ISBN 0 7514 0369 5. £75.T. LairdCite this: Org. Proc. Res. Dev. 1998, 2, 4, 280Publication Date (Web):May 20, 1998Publication History Published online20 May 1998... | 10.1021/op980037s | 0 |
A Process Scheme Involving Transalkylation Reactions To Prepare <i>o</i>-Bromophenol from Phenol | The bromination of phenol to o -bromophenol was carried out by protecting the para position with a tert -butyl group. The latter group was subsequently transferred to toluene using aluminum chloride as a catalyst. The resulting mixture of p - and m - tert -butyltoluene could be converted back to p - tert -butylphenol b... | 10.1021/op9800360 | 0 |
Organic Synthesis in Water. Edited by Paul A Grieco. Blackie/Thomson Science: London, UK, 1998. 320 pp. £75. ISBN 0 7514 0410 1. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewOrganic Synthesis in Water. Edited by Paul A Grieco. Blackie/Thomson Science: London, UK, 1998. 320 pp. £75. ISBN 0 7514 0410 1.T. LairdCite this: Org. Proc. Res. Dev. 1998, 2, 5, 338Publication Date (Web):June 9, 1998Publication History Published online9 June 1998Published i... | 10.1021/op9800358 | 0 |
Scale-Up of a Chiral Resolution Using Cross-Linked Enzyme Crystals | The scale-up of a biocatalytic process using a cross-linked enzyme crystal (ChiroCLEC-PC, Altus Biologics Inc., Cambridge, MA) for the resolution of a racemic mixture ( R / S - sec -phenethyl acetate to R - sec -phenethyl alcohol) is reported. Reaction parameters were initially investigated at the 20-mL and 1-L scale t... | 10.1021/op980032v | 0 |
A Synthesis of Atenolol Using a Nitrile Hydration Catalyst | The synthesis of atenolol is described using a platinum containing homogeneous catalyst for the conversion of a nitrile to an amide. The catalytic reaction may be employed as the final step in the synthesis or in the preparation of the intermediate 4-hydroxyphenylacetamide. The structure of the nitrile intermediate, 1-... | 10.1021/op9800313 | 1 |
Development of a Seeding Technique for the Crystallization of the Metastable A Modification of Abecarnil | Abecarnil, a partial agonist of the benzodiazepine receptor, crystallizes in three modifications, A, B, and C. Depending on the solvent, the form crystallized in an unseeded process is one of the two metastable forms A or B. Isopropyl acetate was chosen as solvent for the crystallization of the drug substance Abecarnil... | 10.1021/op980029b | 0 |
Catalytic Processes of Oxidation by Hydrogen Peroxide in the Presence of Br<sub>2</sub> or HBr. Mechanism and Synthetic Applications | The mechanism and the synthetic applications for the oxidation of alcohols, ethers, and aldehydes by H 2 O 2 catalyzed by Br 2 or Br - in a liquid two-phase system (aqueous and organic) are reported. Aliphatic and benzylic primary alcohols and ethers show an opposite behavior, which has been rationalized on the ground ... | 10.1021/op980028j | 0 |
Synthesis of Phenethyl Alcohol by Catalytic Hydrogenation of Styrene Oxide | In the current work, phenethyl alcohol was synthesized by the hydrogenation of styrene oxide, which may be obtained by the oxidation of styrene. Conventional method of synthesis of phenethyl alcohol is by the Friedel−Crafts alkylation of benzene by using ethylene oxide and molar quantities of aluminum chloride. This me... | 10.1021/op980027r | 0 |
Production of (<i>R</i>)-2-Bromo-5-phthalimidopentanoic Acid via a Diazotisation Process from (<i>R</i>)-Ornithine | A scaleable “one-pot” preparation of ( R )-2-bromo-5-phthalimidopentanoic acid from ( R )-ornithine is described. The use of this chirality pool method allowed for rapid development of the process. Acetic acid was found to be an efficient antifoaming agent during the diazotisation reaction. The use of an extractive wor... | 10.1021/op980026z | 0 |
Large-Scale Preparation of Iodobenzene Dichloride and Efficient Monochlorination of 4-Aminoacetophenone | Large-scale monochlorination of 4-aminoacetophenone using iodobenzene dichloride is described. Special emphasis was given to the characterization of the iodobenzene dichloride and to the development of a practical procedure for handling this agent from the viewpoint of hazards. This process was successfully scaled up i... | 10.1021/op980024e | 0 |
A Liquid−Liquid Process for Production of 2,4-Diphenyl-4-methyl-1-pentene by Dimerization of α-Methylstyrene | A liquid−liquid process for the dimerization of α-methylstyrene (AMS) in order to produce selectively the commercially useful 2,4-diphenyl-4-methyl-1-pentene has been developed. The aqueous phase contained sulfuric acid as a catalyst and methanol as an additive, and the organic phase was 97% α-methylstyrene (AMS). An A... | 10.1021/op980023m | 0 |
Synthesis of Alkyl Glyoxylates | Glyoxylic acid esters are prepared using commercially available 50% w/w aqueous solution of glyoxylic acid. The method involves neutralization of aqueous solution of glyoxylic acid with sodium hydroxide followed by isolation of glyoxylic acid as a calcium salt by double decomposition technique. Suspending this calcium ... | 10.1021/op9800212 | 0 |
Technical-Scale Homologation of a Cholanic Acid Derivative through the Barton Ester. A Practical Approach to 25-Hydroxy Vitamin D<sub>3</sub> and Congeners | A novel method was developed of the homologation of a cholanic acid derivative using the Barton ester, as a practical approach to 25-hydroxy vitamin D and congeners. The method involves transformation of a cholanic acid derivative into a nor-bromide by using 2-mercaptopyridine N -oxide sodium salt and bromotrichloromet... | 10.1021/op980018i | 1 |
Enhanced Selectivity in the Preparation of Linear Alkylbenzenes Using Hexagonal Mesoporous Silica Supported Aluminium Chloride<sup>1</sup> | For decades sulphonated linear alkylbenzenes have been one of the worlds most important detergents. Industrially, their preparation involves the use of either aluminium chloride or hydrogen fluoride as catalysts in the alkylation stage of the reaction. The use of these catalysts presents severe problems in terms of bot... | 10.1021/op980017q | 0 |
Process Safety AnalysisAn Introduction By R. Skelton. Institute of Chemical Engineers: Rugby, UK. 1997. 213 pp. ISBN 0-85295-378X. £26.00. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTProcess Safety AnalysisAn Introduction By R. Skelton. Institute of Chemical Engineers: Rugby, UK. 1997. 213 pp. ISBN 0-85295-378X. £26.00.Cite this: Org. Proc. Res. Dev. 1998, 2, 5, 337Publication Date (Web):February 19, 1998Publication History Published online19 February... | 10.1021/op980013l | 0 |
Research & Development Management By P. Bamfield. VCH: Weinheim. 1997. 178 pp. ISBN 3-527-28778-7. £50.00. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTResearch & Development Management By P. Bamfield. VCH: Weinheim. 1997. 178 pp. ISBN 3-527-28778-7. £50.00.Cite this: Org. Proc. Res. Dev. 1998, 2, 5, 338Publication Date (Web):February 19, 1998Publication History Published online19 February 1998Published inissue 1 Septemb... | 10.1021/op980012t | 0 |
Is Your Process R & D Department Under-Resourced? | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTIs Your Process R & D Department Under-Resourced?Cite this: Org. Proc. Res. Dev. 1998, 2, 2, 63Publication Date (Web):February 19, 1998Publication History Published online19 February 1998Published inissue 1 March 1998https://doi.org/10.1021/op980009+Copyright © 1998 American Ch... | 10.1021/op980009+ | 0 |
Development of a Continuous Homogeneous Metal Complex Catalyzed, Asymmetric Hydrogenation under High Pressure (270 bar) | A kinetic model and simulation as well as a continuous stirred tank reactor (CSTR) system for the synthesis of ( S )-2-(4-fluorophenyl)-3-methylbutanoic acid, an important optically active intermediate in the synthesis of mibefradil (POSICOR, a new type of calcium antagonist), by asymmetric hydrogenation of 2-(4-fluoro... | 10.1021/op980007p | 0 |
Process Development of 5-Methoxy-1<i>H</i>-indole-2-carboxylic Acid from Ethyl 2-Methylmalonate | Development is described of a new process for the preparation from malonates of 5-methoxy-1 H -indole-2-carboxylic acid esters, useful intermediates in the synthesis of pharmaceutical compounds. The process uses readily available starting materials, produces little waste, can be operated safely on at least 1 molar scal... | 10.1021/op980006x | 1 |
Pilot Scale Synthesis of a Novel Nonpeptide Angiotensin II Receptor Antagonist | FR143187 is a novel nonpeptide angiotensin II receptor antagonist under development at Fujisawa Pharmaceutical Co. for the treatment of hypertension. Development of a process for preparation on a large scale is described. The optimized process is 10 steps in length and uses only commercially available materials for eac... | 10.1021/op9800055 | 1 |
Scale-Up of an Intermolecular Barbier Reaction | Addition of n -BuLi to a mixture of ketone (2) and 1,4-diiodobenzene provides access to alcohol (1) in high yield. This procedure has successfully been used on molar scale. | 10.1021/op980003k | 0 |
Process Improvements in the Synthesis of 2,4,5-Trifluorobenzoic Acid. Selective Hydrodefluorination of Tetrafluorophthalimides | An improved preparation of the fluoroquinolone antibacterial intermediate 2,4,5-trifluorobenzoic acid is described. A combination of a selective hydrodefluorination and hydrolysis reaction of 3,4,5,6-tetrafluoro- N -methylphthalimide leading to 3,5,6-trifluorophthalic acid was key to the success of the process. In addi... | 10.1021/op970244c | 1 |
Reaction Kinetics of a Condensation Polymer between 1,10-Dibromodecane and Hexamethylenediamine: Scale-Up Considerations | The end point, rates of reaction, and heat of reaction have been determined for the reaction of 1,10-dibromodecane and 1,6-hexamethylenediamine, which forms a moderately cross-linked polymer useful as a bile acid sequestrant in the treatment of elevated cholesterol. The parameters have been used to predict scale-up of ... | 10.1021/op970243k | 0 |
Efficient Large Scale Preparation of Neutral Endopeptidase/Angiotensin-Converting Enzyme Dual Inhibitor CGS30440 | The development and piloting of a potential manufacturing process for ACE/NEP dual inhibitor CGS30440 is described. The synthesis proceeds sequentially from 1-aminocyclopentanecarboxylic acid via N-protection, peptide coupling with l -tyrosine ethyl ester, O-methylation of N-protected [(1-amino-1-cyclopentyl)carbonyl]-... | 10.1021/op970242s | 1 |
Process Research and Large-Scale Synthesis of 4‘‘,6‘‘-Bis((2-fluorophenyl)carbamoyl)hecogenyl β-<i>O</i>-Cellobioside: A Potent Cholesterol Absorption Inhibitor | This paper describes process research leading to the successful scale-up of a potent cholesterol absorption inhibitor 4‘‘,6‘‘-bis((2-fluorophenyl)carbamoyl)hecogenyl β- O -cellobioside 3 . The synthesis of 3 from hecogenyl β- O -cellobioside 4 required five synthetic steps: (1) the selective protection of the 4‘‘,6‘‘-d... | 10.1021/op9702206 | 0 |
Isoquinoline Alkaloids. 3. Synthesis of the 6-Ethyl and 6-Butyl Analogs of <i>d,l</i>-6-Methyl-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-4<i>H</i>-dibenzo[<i>de,g</i>]- quinoline 1.5 Phosphate (<i>d,l</i>-Glaucine 1.5 Phosphate) | The syntheses of the 6-ethyl ( 12b ) and 6-butyl ( 12c ) analogs of d,l -glaucine 1.5 phosphate ( 12a ) in 10 steps from papaverine hydrochloride ( 1 ) are described. Mechanistic rationale for the formation of Hofmann degradation products observed during the methylation of the 6-ethyl ( 7b ) and 6-butyl ( 7c ) analogs ... | 10.1021/op970217m | 1 |
Isoquinoline Alkaloids. 2. Preparation of <i>d,l</i>-Glaucine 1.5 Phosphate from <i>d,l</i>-Laudanosoline Hydrobromide | A high-yield, commercially viable synthesis of d,l -glaucine 1.5 phosphate ( 1 ) from d,l -laudanosoline hydrobromide ( 2 ) is described. Oxidation of 2 with ferric chloride in ethanol/ water buffered with sodium acetate gave d,l -1,2,9,10-tetrahydroxyaporphine hydrochloride ( 3 ) in 76−83% yield. This was converted to... | 10.1021/op970216u | 0 |
Development of a Commercially Viable Clonazepam Process | A commercial process to clonazepam ( 1 ) is described. An advanced chloro intermediate, 2-(2-chloroacetamido)-5-nitro-2‘-chlorobenzophenone ( 6 ), is activated to the corresponding iodide 2-(2-iodoacetamido)-5-nitro-2‘-chlorobenzophenone ( 7 ) via substitution with potassium iodide. Subsequent alkylation of ammonia wit... | 10.1021/op9702152 | 1 |
A Practical Asymmetric Synthesis of the Antiviral Agent Lobucavir, BMS-180194 | A practical synthesis of the antiviral agent lobucavir, [1 R -(1α,2β,3α)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6 H -purin-6-one (BMS-180194), is described. The key chiral intermediate, [1 S -(1α,2β,3α)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzoate ester, was made by an asymmetric [2 + 2] cycloaddition of dim... | 10.1021/op970214+ | 0 |
Process Development of 5-Fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1- piperazinyl]propyl]-1<i>H</i>-indole Dihydrochloride | 5-Fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1 H -indole dihydrochloride ( 1 ) facilitates 5-HT neurotransmission and was an antidepressant drug candidate. The development of a safe, rugged process for the large-scale, chromatography-free preparation of this compound is described. The main areas of ... | 10.1021/op970213h | 0 |
Preparation of 9,9-Disubstituted 4,5-Diazafluorenes Useful as Cognitive Enhancers | A novel synthesis of symmetric and nonsymmetric 9,9-disubstituted 4,5-diazafluorenes has been developed. These compounds have activity in both an in vitro acetylcholine release assay and in vivo rodent models of learning and memory. Preparation of these compounds involves a unique aldol condensation between 4,5-diazafl... | 10.1021/op970212p | 1 |
Scale-Up of the Nitration of 1-Acetyl-3,4-dichloro-1,2-(ethylenedioxy)benzene Using Nitric Acid/Trifluoroacetic Acid | The process development of the nitration of 3-acetyl-4,5-dichloro-1,2-(ethylenedioxy)benzene ( 1 ) to 3-acetyl-4,5-dichloro-1,2-(ethylenedioxy)-6-nitrobenzene ( 2 ) led to two potential scale-up processes. The two nitration processes were a solids addition to nitric acid and nitric acid addition to a trifluoroacetic ac... | 10.1021/op970211x | 0 |
Generation and Fate of Regioisomeric Side-Chain Impurities in the Preparation of Fosinopril Sodium | A regioisomeric impurity is routinely formed during preparation of the first intermediate of the fosinopril sodium side chain. This first step, the radical-initiated condensation of 4-phenyl-1-butene ( 1 ) and aqueous hypophosphorous acid, provides low levels of the phosphinic acid ( 8 ) resulting from carbon−phosphoru... | 10.1021/op9702105 | 1 |
Preparation of 3‘-Bromodiphenyl Ethers from 3‘-Carboxydiphenyl Ethers Using Free Radical Methodology | The ability to convert commercial 3‘-carboxydiphenyl ether herbicides to 3‘-alkoxydiphenyl ether herbicides could allow more cost efficient preparation of the 3‘-alkoxydiphenyl ethers. The free radical brominative decarboxylation of 3‘-carboxydiphenyl ethers was explored and optimized. Yields of 50% were obtained, whic... | 10.1021/op9702051 | 0 |
Efficient Synthesis of <i>N-tert</i>-Butyl-2-{3(<i>R</i>)-[3-(3-chlorophenyl)ureido]- 8-methyl-2-oxo-5(<i>R</i>)-phenyl-1,3,4,5-tetrahydrobenz[<i>b</i>]azepin-1-yl}acetamide and Related CCK<sub>B</sub> Antagonists | An efficient synthesis of the CCK B antagonist N - tert -butyl-2-{3( R )-[3-(3-chlorophenyl)ureido]-8-methyl-2-oxo-5( R )-phenyl-1,3,4,5-tetrahydrobenz[ b ]azepin-1-yl}acetamide [( R )- 1a ] in optically active form is presented. The synthesis of the core 3-amino-5-phenylbenzazepin-2-one moiety started with the couplin... | 10.1021/op9702049 | 1 |
Process Development for the Preparation of a Monopril Intermediate by a Trimethylsilyl-Modified Arbuzov Reaction | A safe, rugged process for the manufacture of a Monopril intermediate using a trimethylsilyl-mediated Arbuzov reaction was developed. The problems encountered and overcome in iterations from pilot plant to manufacturing are described. The final process gives high-quality product (99.9% purity) in 82% yield. One key was... | 10.1021/op970202o | 1 |
Biphasic Synthesis of 2-Phenylpropionic Acid and Ester by Interfacial Carbonylation of α-Methylbenzyl Bromide | An interfacial synthesis technique has been successfully extended to the carbonylation of α-methylbenzyl bromide in an organic−aqueous sodium hydroxide mixture at 35−60 °C and 1 atm using surface-active palladium−(4-dimethylaminophenyl)diphenylphosphine complex as the catalyst and dodecyl sodium sulfate as the emulsifi... | 10.1021/op9701292 | 0 |
A Practical Synthesis of (<i>R</i>)-(−)-Phenylephrine Hydrochloride | ( R )-(−)-Phenylephrine hydrochloride is a clinically potent adrenergic agent and β-receptor sympathomimetic drug, exclusively marketed in the optically active form. An asymmetric synthesis has been developed with high enantiomeric excess based on hydrolytic kinetic resolution of a styrene oxide derivative using ( R,R ... | 10.1021/op970128+ | 0 |
Independent Synthesis and Fate Studies of Impurities in Process Intermediates of the Anti-AIDS Drug d4T | Impurities in isolated intermediates in a process to prepare d4T were identified, independently synthesized, and then taken through the process to determine their ultimate fate. Some of the products from these fate studies were also independently synthesized and used in the validation of impurity assay methods. | 10.1021/op970126p | 1 |
Process Development in the Synthesis of the ACE Intermediate MDL 28,726 | MDL 28,726 is a key intermediate in the synthesis of the ACE inhibitors MDL 27,210A and MDL 100,240. An efficient nine-step synthesis of this tricyclic acid, which has three chiral centers, was developed beginning with 3,4-dihydro-2 H -pyran. A key step in the synthesis features an enzyme-catalyzed resolution of the li... | 10.1021/op970125x | 0 |
Development of the Carbocyclic Nucleoside MDL 201449A: A Tumor Necrosis Factor-α Inhibitor | An efficient synthesis of (1 S,4 R )-(−)-4- tert -butyldimethylsilyloxy-2-cyclopentenyl acetate and (1 R,4 S )-(−)-4- tert -butyldimethylsilyloxy-2-cyclopentenol is described utilizing a furfuryl alcohol rearrangement, followed by a lithium aluminum hydride reduction with high facial selectivity and an efficient enzyma... | 10.1021/op9701245 | 1 |
An Efficient and Scalable Synthesis of Perfluorinated Phosphatidylcholines | Perfluorinated glycerophosphocholine ( 1 ), which is useful as an emulsifier in fluorocarbon suspensions, was prepared in multikilogram scale in 38% overall yield. The desired phosphocholine was prepared from diacylglycerol ( 6 ) by sequential phosporylation by POCl 3, reaction with choline p -toluenesulfonate, and aqu... | 10.1021/op970123c | 0 |
Development and Pilot-Scale Demonstration of a Process for Inhibitors of the HIV Nucleocapsid Protein, NCp7 | A manufacturing process to prepare two antiretroviral agents that denature the HIV-1 nucleocapsid protein (NCp7) has been developed and demonstrated on a pilot scale. 2,2‘-Dithiobis(benzoyl chloride) (4), prepared from commercially available 2,2‘-dithiobis(benzoic acid) (3), was coupled directly with l -isoleucine to g... | 10.1021/op9701191 | 1 |
Large-Scale Synthesis of Enantio- and Diastereomerically Pure (<i>R</i>,<i>R</i>)-Formoterol | ( R, R )-Formoterol ( 1 ) is a long-acting, very potent β 2 -agonist, which is used as a bronchodilator in the therapy of asthma and chronic bronchitis. Highly convergent synthesis of enantio- and diastereomerically pure ( R, R )-formoterol fumarate is achieved by a chromatography-free process with an overall yield of ... | 10.1021/op970116o | 1 |
A Calorimetric Investigation To Safely Scale-Up a Curtius Rearrangement of Acryloyl Azide | N -Vinyl- O -benzyl urethane was prepared for use as a starting material in a multistep synthesis of a drug candidate. After unsuccessful attempts to employ non-Curtius options to prepare this intermediate, we decided to assess the thermodynamic and kinetic parameters of the acyl azide Curtius rearrangement and trappin... | 10.1021/op970115w | 0 |
Utilization of a Benzoyl Migration To Effect an Expeditious Synthesis of the Paclitaxel C-13 Side Chain | A benzoyl migration has been used to remove two steps during the asymmetric dihydroxylation literature route to (2 R,3 S )- N -benzoyl-3-phenylisoserine, the C-13 position side chain of paclitaxel. The modification provides the product as its more desirable methyl ester in similar overall yields with no loss of enantio... | 10.1021/op970113b | 1 |
Facile Synthesis of 5,6-Dimethoxy-1-tetralone | A facile synthesis of 5,6-dimethoxy-1-tetralone, a key intermediate in the synthesis of an antidepressant compound, ABT-200, was developed from the inexpensive starting material guaiacol. | 10.1021/op970111r | 1 |
Practical Synthesis of 4-Chloro-2-(2-naphthyl)quinoline, a Precursor to Triple-Helix DNA Intercalators | Several synthetic approaches to the title compound and analogs have been evaluated. This compound is a practical precursor to N -substituted 2-(2-naphthyl)quinolin-4-amines, the triple-helix DNA specific intercalators. | 10.1021/op970110z | 1 |
Optimization and Scale-Up of an Asymmetric Route to the LTB<sub>4</sub> Inhibitor Ontazolast | An efficient asymmetric synthesis of the LTB 4 inhibitor Ontazolast is described. Commercially available ( S )-α-pinene, which contains a 93.5% enantiomeric excess (ee) of the desired isomer, can be oxidized using phase-transfer conditions to the corresponding ( R )-hydroxy ketone. Condensation of this keto alcohol wit... | 10.1021/op9701090 | 1 |
In Pursuit of Higher Purity: Use of <sup>13</sup>C NMR and <sup>13</sup>C-Enriched Substrates To Trace Impurity Generation and Removal in the Synthesis of Atorvastatin | The use of 13 C-labeled starting materials and intermediates in the synthesis of the lipid regulator atorvastatin is described. 13 C NMR of the 13 C-enriched intermediates allowed monitoring of problematic nonchromophoric low-level impurities which were unobservable using standard analytical techniques. | 10.1021/op9701088 | 0 |
Fenleuton: Development of a Manufacturing Process | The evolution and development of a commercially viable synthesis of fenleuton, a second-generation 5-lipoxygenase inhibitor, is discussed. Special emphasis is given to the challenges and operational issues encountered on scale-up in the pilot plant. Three separate processes were developed and scaled up, providing valua... | 10.1021/op970106n | 1 |
An Efficient Large-Scale Synthesis of Methyl 5-[2-(2,5-Dimethoxyphenyl)ethyl]-2-hydroxybenzoate | Methyl 5-[2-(2,5-dimethoxyphenyl)ethyl]-2-hydroxybenzoate ( 1 ) is a new chemical entity designed by Novartis Pharmaceuticals Corporation for the treatment of hyperproliferative and inflammatory disorders and cancer. Development of a prototype adequate process for its preparation is described. The finalized process was... | 10.1021/op9701043 | 1 |
One-Pot Process for the Preparation of a β-Alkynyl β-Amino Acid Ester | The large-scale preparation of the β-alkynyl β-amino acid ester (±)-1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate ( A ) is discussed. It was discovered that addition of a catalytic amount of lithium bis(trimethylsilyl)amide (LHMDS) to a mixture of tert -butyl acetate and N,3-bis(trimethylsilyl)-2-propyn-1-i... | 10.1021/op970102i | 0 |
Development of a Manufacturing Process for Zatosetron Maleate | Zatosetron maleate is a potent, selective 5-hydroxytryptamine receptor antagonist. In anticipation of commercialization, a manufacturing synthesis of zatosetron from tropinone and 5-chlorosalicylic acid was developed. Development efforts focused on addressing several key issues including the supply and quality of the c... | 10.1021/op970101q | 1 |
Risk Analysis and Reduction in the Chemical Process Industries By J. M. Santamaría Ramiro and P. A. Braña Aísa. Translated by J. Hutchinson. Blackie Academic & Professional: London. English language edition 1998. 370 pp. Hardcover. ISBN 7514-0374-1. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTRisk Analysis and Reduction in the Chemical Process Industries By J. M. Santamaría Ramiro and P. A. Braña Aísa. Translated by J. Hutchinson. Blackie Academic & Professional: London. English language edition 1998. 370 pp. Hardcover. ISBN 7514-0374-1.Paul LambertCite this: ... | 10.1021/op970061q | 0 |
A Scalable Synthesis of the Thromboxane Receptor Antagonist 3-{3-[2-(4-Chlorobenzenesulfonamido)ethyl]-5-(4-fluorobenzyl)phenyl}propionic Acid via a Regioselective Heck Cross-Coupling Strategy | A regioselective Heck cross-coupling strategy is presented for the large-scale preparation of the thromboxane receptor antagonist 3-{3-[2-(4-chlorobenzenesulfonamido)ethyl]-5-(4-fluorobenzyl)phenyl}propionic acid ( 1 ). Commercially available 3-bromo-5-iodobenzoic acid was first converted to the corresponding acid chlo... | 10.1021/op970060y | 1 |
Selective Catalytic Hydrogenation of Organic Compounds in Supercritical Fluids as a Continuous Process | We report a new method for continuous hydrogenation in supercritical fluids (CO 2 or propane) using heterogeneous noble metal catalysts on Deloxan aminopolysiloxane supports. The method has considerable promise both for laboratory-scale hydrogenation and for the industrial production of fine chemicals. It can be applie... | 10.1021/op970056m | 0 |
Process Improvement in the Production of a Pharmaceutical Intermediate Using a Reaction Calorimeter for Studies on the Reaction Kinetics of Amination of a Bromopropyl Compound | A synthetic process to produce a pharmaceutical intermediate, [3-(dimethylamino)propyl]triphenylphosphonium bromide ( 1 ), was established in the laboratory. Process safety evaluations did not show any severe problems. In order to scale up to plant scale, we simulated the reaction for both heat production and byproduct... | 10.1021/op970055u | 0 |
Efficient Large-Scale Synthesis of 4-Phenyl-3-butyn-2-one, a Key Intermediate for a Novel Potent Adenosine Antagonist | Phenylacetylenic Grignard reagent reacts with acetic anhydride under mild conditions to give 4-phenyl-3-butyn-2-one in high yield. This method was applicable to a large-scale synthesis, and optimized reaction conditions have been investigated. | 10.1021/op9700486 | 0 |
An Ecofriendly Catalytic Route for the Preparation of Perfumery Grade Methyl Anthranilate from Anthranilic Acid and Methanol | Methyl anthranilate is a very important perfumery ester and also a precursor to a number of Schiff bases which are used in several fragrance formulations. The current practice is to use homogeneous acids as catalysts in the manufacture of methyl anthranilate either starting with isatoic anhydride and methanol or by the... | 10.1021/op970047d | 0 |
Synthesis of 4-Sulfur-Substituted (2<i>S</i>,3<i>R</i>)-3-Phenylserines by Enzymatic Resolution. Enantiopure Precursors for Thiamphenicol and Florfenicol | Enantiomerically pure 4-methylthio- and 4-methylsulfonyl-substituted (2 S, 3 R )-3-phenylserines are prepared by enzymatic resolution of the corresponding racemic threo amides using the amidase from Ochrobactrum anthropi NCIMB 40321. The unwanted (2 R, 3 S ) enantiomers of the amides are separated from the enantiopure ... | 10.1021/op970045t | 0 |
Process Development of a Novel Anti-Inflammatory Agent. The Regiospecific Bromination of 4‘-Acetylmethanesulfonanilide | An efficient, practical synthesis of a novel antiinflammatory agent (FK3311, 1 ) which is acceptable environmentally and could be used for pilot plant manufacture is described. Regiospecific bromination of 4‘-acetylmethanesulfonanilide, allowing selective side chain or nuclear halogenation, also has been investigated. ... | 10.1021/op970039x | 1 |
Process Development of the PDE IV Inhibitor 3-(Cyclopentyloxy)-<i>N</i>-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide | Development of an industrial process for 3-(cyclopentyloxy)- N -(3,5-dichloropyrid-4-yl)-4-methoxybenzamide, a potent PDE IV type inhibitor, is described. The rapid identification of scalable reaction conditions allowed pilot-scale synthesis of kilogramme quantities for early clinical evaluation. However, as more compo... | 10.1021/op9700385 | 1 |
Development of Large-Scale Syntheses of Ropinirole in the Pursuit of a Manufacturing Process<sup>1</sup> | Two plant syntheses of ropinirole {4-[2-(di- n -propylamino)ethyl]-1,3-dihydro-2 H -indolin-2-one hydrochloride, SK&F-101468-A} using the ferric chloride mediated cyclisation of β-nitrostyrenes to form 3-chlorooxindoles as the key step are described. The first synthesis suffered the severe limitation of the final-step ... | 10.1021/op970037c | 1 |
Synthesis and Use of<i>N</i>-(Trimethylsilyl)imines | The introduction of aminic nitrogen in organic molecules has been achieved in many different ways, one of the most popular being the use of imines. The main disadvantage of these starting materials lies in the difficulty of synthesising and using imines of ammonia, due to their instability, which results in their tende... | 10.1021/op970036k | 0 |
Runaway Reaction Hazards in Processing Organic Nitro Compounds | Pure organic nitro compounds, i.e., aromatic or aliphatic nitro compounds, decompose at high temperatures, exhibiting large decomposition exotherms. In most cases, the decomposition is violent or explosive. In practical process situations, nitro compounds are mixed with other chemicals or contaminated by impurities whi... | 10.1021/op970035s | 0 |
The Use of Ultrasound in Industrial Chemical Synthesis and Crystallization. 1. Applications to Synthetic Chemistry | Sonochemistry, or the application of power ultrasound to chemical processes, is a technology that has undergone very intensive research and development in the last 15−20 years, with respect to both its range of application and the methods employed for its implementation at industrial manufacturing scales. In a series o... | 10.1021/op9700340 | 0 |
Improved Synthetic Route to Dexamethasone Acetate from Tigogenin | In the synthesis of dexamethasone acetate from tigogenin, the introduction of the 17α-hydroxy-16α-methyl and the 1,4-diene moieties was improved. For the introduction of the 17α-hydroxy-16α-methyl moiety, the key step, epoxidation, was accomplished in high yield with peracetic acid in a buffer solution of sodium acetat... | 10.1021/op9700338 | 1 |
Sharpless Asymmetric Dihydroxylation on an Industrial Scale | It is shown in this study that the inexpensive N -methylmorpholine N -oxide can be successfully employed as a reoxidant in the Sharpless asymmetric dihydroxylation reaction on a large scale. The reaction of o -isopropoxy- m -methoxystyrene on a 2 kg scale gave the corresponding diol in high yield and high enantiomeric ... | 10.1021/op970030v | 0 |
Practical Synthesis of 8α-Amino-2,6-dimethylergoline: An Industrial Perspective | 8 α-Amino-2,6-dimethylergoline is the key intermediate for the synthesis of a number of ergot derivatives under clinical development. They are structurally related to the better known lysergic acid and its derivative, the diethylamide (LSD). The use of lysergic acid or its isomer, paspalic acid, both of which are readi... | 10.1021/op9700284 | 0 |
Process Research and Development for the Production of Intermediates for the Synthesis of Carbocyclic Nucleosides | The synthesis of [3a R,4 S,6 R,6a S ]-6-amino- N -ethyltetrahydro-2,2-dimethyl-4 H -cyclopenta-1,3-dioxole-4-carboxamide, a key single enantiomer intermediate to carbocyclic nucleosides such as adenosine agonists, is reported involving a scalable catalytic osmium tetraoxide dihydroxylation of (−)-2-azabicyclo[2.2.1]hep... | 10.1021/op970026j | 1 |
6-(Trifluoromethyl)pyrid-2-one: Development and Scale-Up of a Ring Synthesis Route Based on Trifluoroacetic Anhydride | Three routes to 6-(trifluoromethyl)pyrid-2-one involving de novo synthesis of the pyridine ring have been investigated which would potentially allow rapid semi-technical scale manufacture. A route starting from ethyl 4,4,4-trifluoroacetoacetate (β-keto ester route) has been demonstrated. Development of the route was at... | 10.1021/op970024z | 1 |
Pilot Plants and Scale-up of Chemical Processes Edited by W. Hoyle. Royal Society of Chemistry: London, UK. 1997. 98 pp. ISBN 0-85404-796-4. £42.50. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTPilot Plants and Scale-up of Chemical Processes Edited by W. Hoyle. Royal Society of Chemistry: London, UK. 1997. 98 pp. ISBN 0-85404-796-4. £42.50.Trevor LairdCite this: Org. Process Res. Dev. 1997, 1, 5, 391Publication Date (Web):September 15, 1997Publication History Pu... | 10.1021/op970019v | 1 |
Catalytic Oxidation of Ethylbenzene to Acetophenone Using Alumina-Supported Dichromate: Process Optimisation and Development of a Continuous Process | Potassium dichromate supported on neutral alumina is a heterogeneous catalyst for the liquid phase oxidation of hydrocarbons. The material has been used to catalyse the oxidation of ethylbenzene to acetophenone using air as the consumable oxidant with high selectivity and is truly catalytic in the metal, unlike homogen... | 10.1021/op9700183 | 0 |
Recent Developments in the Assessment of Thermal Risks of Chemical Processes | In the past two decades, the assessment of thermal risks linked to the practice of chemical reactions on an industrial scale has made great progress. Nowadays chemists understand these risks and are able to assess them. Nevertheless, incidents still occur which indicate that some weaknesses still exist, especially in r... | 10.1021/op970016i | 0 |
Kinetic and Calorimetric Considerations in the Scale-Up of the Catalytic Reduction of a Substituted Nitrobenzene | A reaction calorimetric investigation was conducted to assess proposed scale-up conditions (30 psig, 10 °C, initial reactant concentration = 0.69 M, catalyst concentration of 6.66 × 10 -3 g/g of reactant) for the batchwise reduction of a substituted nitrobenzene to give the corresponding aniline in the presence of H 2,... | 10.1021/op970015q | 0 |
A New Era Begins for Process Chemistry | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTA New Era Begins for Process ChemistryView Author InformationEditor%Cite this: Org. Process Res. Dev. 1997, 1, 1, 1Publication Date (Web):January 15, 1997Publication History Published online15 January 1997Published inissue 1 January 1997https://doi.org/10.1021/op970006hCopyrigh... | 10.1021/op970006h | 0 |
Synthetic Routes to Quinoline Derivatives: Novel Syntheses of 3-Butyryl-8-methoxy-4-[(2-methylphenyl)amino]quinoline and 3-Butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quinoline | The 3,4,8-trisubstituted quinoline derivatives 2-butyryl-8-methoxy-4-[(2-methylphenyl)amino]quinoline and 3-butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quinoline were prepared using five novel synthetic strategies, each involving a different disconnection as a basis for the key step. One such strategy led to t... | 10.1021/op9700035 | 1 |
Industrial Scale Synthesis of Thiophosgene and Its Derivatives | Thiophosgene is manufactured on a mulittonne scale, using the continuous chlorination of carbon disulfide under aqueous conditions to prepare the key intermediate perchloromethyl mercaptan. The development of this process is described, and the uses of thiophosgene in the manufacture of chlorothioformates and isothiocya... | 10.1021/op970002c | 0 |
Synthesis of a Serinamide by Aminolysis of an N-Unsubstituted α-Amino Ester | l -2-Amino-3-hydroxy- N -pentylpropanamide ( 1 ) was readily prepared and isolated as its oxalate salt in 81% yield and >99% ee through a “one-pot” process from l -serine methyl ester ( 4 ). | 10.1021/op960044l | 0 |
Asymmetric Synthesis of the Antiarrhythmia Agent <i>d</i>-Sotalol | A chiral synthesis of d -Sotalol was developed starting from commercially available 4‘-(chloroacetyl)methanesulfonanilide ( 2 ). | 10.1021/op960043t | 1 |
Chemical Development of a Pilot Scale Process for the ACAT Inhibitor 2,6-Diisopropylphenyl [(2,4,6-Triisopropylphenyl)acetyl]sulfamate | A manufacturing process to prepare the ACAT inhibitor 2,6-diisopropylphenyl [(2,4,6-triisopropylphenyl)acetyl]sulfamate ( 1; CI-1011) has been developed and successfully demonstrated on a pilot scale. Commercially available 1,3,5-triisopropylbenzene ( 9 ) was chloromethylated to give 2,4,6-triisopropylbenzyl chloride (... | 10.1021/op9600419 | 1 |
Development of a Large-Scale Process for an HIV Protease Inhibitor | An efficient large-scale process to prepare the HIV protease inhibitor urea intermediate, N -[3( S )-[bis(phenylmethyl)amino-2( R )-hydroxy-4-phenylbutyl]- N ‘-(1,1-dimethylethyl)- N -(2methylpropyl)urea was developed. The protected alcohol, β( S )-[bis(phenylmethyl)amino]benzenepropanol, was obtained in 95% yield in o... | 10.1021/op960040g | 1 |
Evaluation and Rapid Scale-Up of the Synthesis of the Pyrrolopyrimidines U-101033E and U-104067F | Large quantities of pure bulk drug were required to initiate development for possible indications as antiasthma and neuroprotective agents. Safety concerns and reproducibility problems encountered with the laboratory procedures (Bundy, G. L.; et al. J . Med . Chem . 1995, 38, 4161) forced the development of a reliable ... | 10.1021/op960038p | 1 |
A Commercially Viable Synthesis of Cyanotrimethylsilane | The important synthetic reagent cyanotrimethylsilane is readily formed by the direct trimethylsilylation of 3 equiv of hydrogen cyanide with 1 equiv each of trimethylchlorosilane and hexamethyldisilazane in a solvent-free reaction. This results in the formation of cyanotrimethylsilane in 98% yield. The product, which c... | 10.1021/op9600365 | 0 |
One-Step Synthesis of Biphenylacetic Acids via Pd/C-Catalyzed Arylation | An efficient, convenient, one-step synthesis of biphenylacetic acids using Pd/C as a catalyst is described. This has been successfully used for the preparation of mole amounts of acids. | 10.1021/op960035c | 0 |
Diastereoselective Reaction of a Grignard Reagent with Chiral Imides: A Practical Preparation of a Key Intermediate in the Synthesis of Ifetroban Sodium | A novel and highly efficient synthesis of [1 S -(1α,2α,3α,4α)]-2-[[2-(3-methoxy-3-oxopropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid ( A ), a key intermediate in the synthesis of ifetroban sodium, BMS-180291, is described. Reaction of chiral imides such as [2( S ),3aα,4β,7β,7aα]-hexahydro-2-(1-phenyl... | 10.1021/op960034k | 1 |
Chemical Development of CI-1008, an Enantiomerically Pure Anticonvulsant | Development of a manufacturing process for ( S )-3-(aminomethyl)-5-methylhexanoic acid, an anticonvulsant, is described. Initial preparation employed an Evans chiral alkylation on (4 R,5 S )-4-methyl-3-(1-oxo-4-methylpentyl)-5-phenyl-2-oxazolidinone, using benzyl bromoacetate. Use of tert -butyl bromoacetate proved adv... | 10.1021/op9600320 | 1 |
Production Scale Synthesis of the Non-Nucleoside Reverse Transcriptase Inhibitor Atevirdine Mesylate (U-87,201E) | A practical synthesis of atevirdine mesylate, Pharmacia & Upjohn's first-generation non-nucleoside reverse transcriptase (RT) inhibitor for treatment of AIDS, is described. The route consists of three steps. In the first step, the starting material, 3-amino-2-chloropyridine, is N -ethylated by conversion into the aceti... | 10.1021/op9600318 | 1 |
A Cationic Surfactant as a Phase-Transfer Catalyst for Reactions in Liquid/Liquid and Solid/Liquid Systems. Its Use in the Manufacturing of Trichlorobenzene from Lindane Wastes and Vitamin A Production | The results of pilot plant experiments on phase-transfer-catalysed dehydrochlorination of hexachlorocyclohexane and vitamin A manufacturing using phase-transfer catalysis are discussed. A long-chain cationic surfactant (Katamine AB) was a suitable catalyst in these cases. Phase-transfer catalysis is shown to provide ad... | 10.1021/op960030f | 0 |
Use of a Titanium Thienyl Anion and a Simple Procedure for Introducing a Thiol Group into Thiophene in the Development of a Manufacturing Route to the 5-Lipoxygenase Inhibitor ZD4407 | Process development has been conducted to identify a synthetic route to the 5-lipoxygenase inhibitor ZD4407 that could be used for pilot plant manufacture. Efficient and environmentally acceptable carbon-functionalisation of the 3-position of thiophene using readily available 3-bromothiophene has been achieved using a ... | 10.1021/op960029g | 1 |
Unnatural Amino Acids. 1. A Facile Synthesis of the Methyl Ester of Aziridine-2-carboxylic Acid | The methodology of aziridine-2-carboxylic acid methyl ester ( 4 ) synthesis by aziridine ring formation from methyl 3-(2,2,2-trimethylhydrazinio)propionate bromide ( 1a ) has been developed by N−N bond cleavage. The process gives the title compound in 75% theoretical yield (>99% purity). We found important factors for ... | 10.1021/op960027w | 0 |
Efficient Preparation of (<i>R</i>)- and (<i>S</i>)-2-Amino-1-phenylethanol | The preparation of optically pure 2-amino-1-phenylethanol was investigated using three methods. The opening of styrene oxide with ammonia, the reduction of mandelamide, and the resolution of (±)-2-amino-1-phenylethanol were compared from a process R&D viewpoint. The resolution using di- O - p -toluoyltartaric acid was ... | 10.1021/op9600264 | 1 |
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