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Process Development and Pilot Plant Synthesis of Methyl 2-Bromo-6-chlorobenzoate | A scalable process for a pilot plant synthesis of methyl 2-bromo-6-chlorobenzoate ( 1 ) is described. The strategy employed for the synthesis hinged on the esterification of the sterically encumbered parent acid produced through an o -lithiation/carboxylation approach. Vigilant temperature control was paramount for the... | 10.1021/op0501444 | 0 |
Fieser's Reagents for Organic Synthesis By Tse-Lok Ho. 2004. Wiley-Interscience: Hoboken, New Jersey. Volume 22. 608 + xiv pp. £54.50. ISBN 0-471-285515-3. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTFieser's Reagents for Organic Synthesis By Tse-Lok Ho. 2004. Wiley-Interscience: Hoboken, New Jersey. Volume 22. 608 + xiv pp. £54.50. ISBN 0-471-285515-3.Cite this: Org. Process Res. Dev. 2005, 9, 6, 1017Publication Date (Web):August 20, 2005Publication History Published... | 10.1021/op050141r | 0 |
Amines: Synthesis, Properties and Applications By S. A. Lawrence. Cambridge University Press: Cambridge. 2004. 371 + x pp. £100/$180. ISBN 0-521-78284-8. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTAmines: Synthesis, Properties and Applications By S. A. Lawrence. Cambridge University Press: Cambridge. 2004. 371 + x pp. £100/$180. ISBN 0-521-78284-8.Cite this: Org. Process Res. Dev. 2005, 9, 6, 1016Publication Date (Web):August 20, 2005Publication History Published o... | 10.1021/op0501390 | 0 |
Efficient Total Synthesis of Lycophyll (ψ,ψ-Carotene-16,16‘-diol) | A practical procedure is described for the total synthesis of lycophyll (16,16‘-dihydroxy-lycopene; ψ,ψ-carotene-16,16‘-diol), based on a C10 + C20 + C10 synthetic methodology using the commercially available materials geraniol (C10) and crocetindialdehyde (C20). A late-stage double Wittig olefination on crocetindialde... | 10.1021/op050137f | 1 |
Still Going Wrong! Case Histories of Process Plant Distasters and How They Could Have Been Avoided By Trevor Kletz. Gulf Professional Publishing, Butterworth-Heinemann, Elsevier: Amsterdam, Boston. 2003. £29.95. 230 pp. ISBN 0-7506-7709-0. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTStill Going Wrong! Case Histories of Process Plant Distasters and How They Could Have Been Avoided By Trevor Kletz. Gulf Professional Publishing, Butterworth-Heinemann, Elsevier: Amsterdam, Boston. 2003. £29.95. 230 pp. ISBN 0-7506-7709-0.Peter L. SpargoView Author Inform... | 10.1021/op050135v | 0 |
Scalable Reactor Design for Pharmaceuticals and Fine Chemicals Production. 1: Potential Scale-up Obstacles | A comprehensive review of factors that inhibit scalability of fine chemicals and pharmaceuticals, from the chemical engineering point of view, is presented. These potential scale-up obstacles are generated by the fact that chemical rate constants are scale-independent, whereas physical parameters and phenomena are not.... | 10.1021/op050133a | 0 |
Microwave Assisted Organic Synthesis Edited by J. P. Tierney and P. Lidstrom. Blackwell Publishing: Oxford. 2005. 280 pp. £89.50. ISBN 1-4051-1560-2. (Also published by CRC Press in U.S.A. and Canada, ISBN 0-8493-2371-1.) | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTMicrowave Assisted Organic Synthesis Edited by J. P. Tierney and P. Lidstrom. Blackwell Publishing: Oxford. 2005. 280 pp. £89.50. ISBN 1-4051-1560-2. (Also published by CRC Press in U.S.A. and Canada, ISBN 0-8493-2371-1.)Peter L. SpargoView Author Information Scientific U... | 10.1021/op050132i | 0 |
A Practical and Efficient Synthesis of Thalidomide via Na/Liquid NH<sub>3</sub> Methodology<sup>1</sup> | A facile, efficient, concise, cost-effective, and scalable synthesis of thalidomide in high overall yield (55%) is presented. Treatment of Boc-protected l -glutamic acid diester via Na/liquid (liq.) NH 3 (−33 °C) mediated cyclization methodology produces a corresponding glutarimide ring which was subsequently condensed... | 10.1021/op050129z | 1 |
Process Development Challenges to Accommodate A Late-Appearing Stable Polymorph: A Case Study on the Polymorphism and Crystallization of a Fast-Track Drug Development Compound | The case of disappearing/late-appearing stable polymorphs and their impact is well-understood by scientists in the pharmaceutical industry. This paper discusses an instance where a more stable crystal form was discovered during the development of a fast-track drug candidate. Challenges in adapting to the discovery of t... | 10.1021/op0501287 | 1 |
Active Pharmaceutical Ingredients; Development Manufacturing and Regulation Edited by S. H. Nusim. Taylor and Francis: Boca Raton, FL, 2005. £79.99. xiv + 337 pp. ISBN 0-8247-0293-X | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTActive Pharmaceutical Ingredients; Development Manufacturing and Regulation Edited by S. H. Nusim. Taylor and Francis: Boca Raton, FL, 2005. £79.99. xiv + 337 pp. ISBN 0-8247-0293-XCite this: Org. Process Res. Dev. 2005, 9, 5, 698–699Publication Date (Web):August 5, 2005P... | 10.1021/op050125u | 0 |
Utilization of Lithium Amide in the Synthesis of <i>N</i>-Arylanthranilic Acids and <i>N</i>-Arylanthranilamides | A procedure for the preparation of N -arylanthranilic acids and N -arylanthranilamides was developed. Lithium amide promoted coupling of anilines with 2-fluorobenzoic acids or 2-fluorobenzamides lead to the desired compounds in good yield. Both primary and N -substituted anilines were effective partners for the reactio... | 10.1021/op0501242 | 0 |
Concise Synthesis of a Selective α<sub>1</sub>-Adrenoceptor Antagonist | An efficient synthesis of an adrenoceptor antagonist has been developed and demonstrated in a pilot plant. A linear synthesis that relied on a catalytic reduction of a rather insoluble nitroaromatic proved to be a viable route. The active pharmaceutical ingredient (API) that contained an amidine functional group was ge... | 10.1021/op050122h | 1 |
Assessment of a Reductive Amination Route to Methyl(3-nitrobenzyl)amine Hydrochloride | During the development of a sodium borohydride mediated reductive amination of 3-nitrobenzaldehyde with methylamine, studies revealed that partial reduction of the nitro group occurred, and potentially dangerous azo- and azoxy-containing products were generated. Borane- tert -butylamine activated with methanesulfonic a... | 10.1021/op050120x | 0 |
Developing Processes for Crystallization-Induced Asymmetric Transformation | Crystallization-induced dynamic resolution (CIDR) is an adaptation of dynamic resolution, a process that can afford in principle a quantitative yield of chiral product from a racemic starting material through in situ resolution. Crystallization-induced asymmetric transformation (CIAT) includes CIDR and the preparation ... | 10.1021/op050119y | 0 |
Chemoenzymatic Synthesis of <i>N</i>-Trifluoroacetyl Doxorubicin-14-Valerate (Valrubicin) | An efficient two-step, chemoenzymatic synthesis of N -trifluoroacetyl doxorubicin-14-valerate (Valrubicin) from doxorubicin hydrochloride salt is reported. The key step is a lipase-catalyzed regioselective esterification of N -trifluoroacetyl doxorubicin using commercially available valeric acid as the acyl donor. The ... | 10.1021/op0501186 | 0 |
Process Development and Large-Scale Synthesis of a PDE4 Inhibitor | An efficient, scalable synthesis of the PDE4 inhibitor, 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{( E )-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-(methylsulfonyl)phenyl]vinyl}phenyl)quinoline benzenesulfonate ( 10 ) is described. The synthesis is highly convergent, generating the penultimate 9 by coupling aldehyde 7 and ... | 10.1021/op050116l | 1 |
Design and Optimization in Organic Synthesis, 2nd revised and enlarged edition Rolf Carlson and Johan E. Carlson. Elsevier: Dordrecht, The Netherlands. 2005. 574 pp (+ CD). Price: £180, $290, 265 Euro. ISBN 0-444-51527-5. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTDesign and Optimization in Organic Synthesis, 2nd revised and enlarged edition Rolf Carlson and Johan E. Carlson. Elsevier: Dordrecht, The Netherlands. 2005. 574 pp (+ CD). Price: £180, $290, 265 Euro. ISBN 0-444-51527-5.Derek RobinsonView Author Information 38 Millbrook ... | 10.1021/op050112g | 0 |
Development of a Scalable Process for 1-β-Methyl Azetidinone: A Carbapenem Key Intermediate | An optimized process for the stereoselective synthesis of 1-β-methyl carbapenem key intermediate (3 S,4 S )-[( R )-1‘-(( tert -butyldimethylsilyl)oxy)ethyl]-4-[( R )-1-carboxyethyl]-2-azetidinone ( 1 ) and (3 R,4 R )-4-acetoxy-3-[( R )-1‘-(( tert -butyldimethylsilyl)oxy)ethyl]-2-azetidinone has been developed employing... | 10.1021/op0501085 | 1 |
A Preparative Route to Methyl 3-(Heteroaryl)acrylates Using Heck Methodology | Methyl 3-(heteroaryl)acrylates were prepared using Heck coupling of heteroarene halides with methyl acrylate mediated by Pd(OAc) 2 /P(OCH 3 ) 3 . Reactions were highly efficient (reaction times between 60 and 120 min) and scalable to 100 g of heteroarene halide. The isolated yields are from 76 to 99%. | 10.1021/op050106k | 1 |
Catalytic Mesylation of Alcohols: A Highly Productive Process for Trifluoroethyl Mesylate | “Intermediate” Lewis acids are efficient catalysts for mesylation of trifluoroethanol (TFE) by mesyl chloride at 80 °C. In the absence of solvent, trifluoroethyl mesylate (TFEMes) is obtained in a chemical yield of 98% with total conversion of TFE. The only coproduct of the reaction, hydrochloric acid, simply distills ... | 10.1021/op050105s | 0 |
An Efficient and Scalable Synthesis of the Endothelin Antagonists UK-350,926 and UK-349,862 Using a Dynamic Resolution Process | The development and scale-up of a potential manufacturing route to the endothelin antagonists UK-350,926 1 and UK-349,862 2 are described. A key synthetic challenge in designing an efficient route to these molecules was the optical lability of the stereogenic centre during the construction of the acylsulfonamide functi... | 10.1021/op050102f | 1 |
Process Design and Scale-Up Elements for Solvent Mediated Polymorphic Controlled Tecastemizole Crystallization | Tecastemizole, an active metabolite of the histamine H 1 -receptor antagonist Astemizole (Hismanal), crystallizes out in two polymorphic forms (form A and form B). Thermodynamic stability screening results show that form A is more stable and form B is kinetically favorable (metastable) in the temperature range of proce... | 10.1021/op050101n | 0 |
A New Process for Synthesis of the Astrocyte Activation Suppressor, ONO-2506 | Development of a new process for the synthesis of ONO-2506, an agent that suppresses astrocyte activation, is described. Previous processes that involved asymmetric synthesis with a chiral auxiliary were unsatisfactory from a cost perspective because the relatively expensive chiral auxiliaries were not recyclable. To d... | 10.1021/op0500988 | 1 |
Improved and High Yield Synthesis of the Potent Arginase Inhibitor: 2(<i>S</i>)-Amino-6-boronohexanoic Acid | A simple three-step synthesis of the potent arginase inhibitor 2( S )-amino-6-boronohexanoic acid (ABH) has been developed. The key step was alkylation of the Ni II complex of the Schiff base derived from glycine and ( S )-2-[ N ‘-( N -benzylprolyl)amino]benzophenone (BPB) with pinacol 4-bromobutylboronate. Acidic hydr... | 10.1021/op050096n | 1 |
Refined Synthesis of 2,3,4,5-Tetrahydro-1,3,3-trimethyldipyrrin, a Deceptively Simple Precursor to Hydroporphyrins | 2,3,4,5-Tetrahydro-1,3,3-trimethyldipyrrin (1) is a crucial building block in the rational synthesis of chlorins and oxochlorins. The prior 5-step synthesis of 1 from pyrrole-2-carboxaldehyde (2) employed relatively simple and well-known reactions yet suffered from several drawbacks, including limited scale (>/= 0.5 g ... | 10.1021/op050087e | 1 |
Process Development of an Inherently Safer Oxidation: Synthesis of 2-Chloro-6-methylbenzoic Acid in the R411 Manufacturing Process | Many oxidation reactions can be hazardous when run on large scale. The manufacturing process for the production of R411, a developmental compound indicated for the treatment of asthma, includes the oxidation of 2-chloro-6-methylbenzaldehyde to the corresponding carboxylic acid. The use of sodium chlorite in this transf... | 10.1021/op050083+ | 0 |
Development and Semicommercial Implementation of an Environmentally Benign, Hydrogen Peroxide Mediated Oxidation of Aliphatic Alcohols | A process for the oxidation of an aliphatic alcohol (primary alcohol in C12−C15 region, substrate selected on the basis of a customer requirement) was developed and scaled up from laboratory (100 mL and 1 L scale) to bench (CR26 reactor) and to semicommercial scale (1000 litre) for toll manufacturing purposes. This oxi... | 10.1021/op050082h | 0 |
A Practical and Efficient Process for the Preparation of Tazarotene | We describe an efficient process for the preparation of tazarotene starting from 4,4-dimethyl-6-bromothiochromane S -oxide ( 9 ), 2-methyl-3-butyn-2-ol ( 10 ), and 6-chloronicotinic acid ethyl ester ( 8 ). Our synthetic pathway compares favorably over the previously reported procedures since tazarotene was prepared str... | 10.1021/op050080x | 1 |
An Efficient Process for Synthesis of 3-(<i>R</i>)-3-(2,3-Dihydrobenzofuran-5-yl)- 1,2,3,4-tetrahydropyrrolo[3,4-<i>b</i>]quinolin-9-one | 3-( R )-3-(2,3-Dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4- b ]quinolin-9-one ( 1 ) is a key intermediate in the synthesis of pyrroloquinolone analogues, a series of highly potent and selective phosphodiesterase 5 (PDE5) inhibitors. Racemic 1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H -β-carboline ( ... | 10.1021/op050079y | 1 |
First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin | A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the... | 10.1021/op0500786 | 1 |
Nucleosidic Phosphoramidite Synthesis via Phosphitylation: Activator Selection and Process Development | Nucleosidic phosphoramidites are key building blocks for the automated, solid supported syntheses of oligonucleotide-based drugs. A safe, industrially viable process for preparing nucleosidic phosphoramidites 5-Me-MOE-U and MOE-A has been developed and utilized on multikilogram scales. The optimization of this process ... | 10.1021/op050077d | 0 |
Practical, Scalable, Enantioselective Synthesis of (2<i>R</i>,3<i>R</i>)-<i>N</i>-Boc-2-amino-3- cyclohexyl-3-hydroxypropanoic Acid | An enantioselective synthesis of (2 R,3 R )-2-( tert -butoxycarbonyl)amino-3-cyclohexyl-3-hydroxypropanoic acid has been described starting from enantiomerically enriched ethyl 3-cyclohexyl-2,3-dihydroxypropanoate, easily available by Sharpless asymmetric dihydroxylation. The key reaction is the direct preparation of a... | 10.1021/op050076l | 1 |
Diastereomeric Salt Resolution Based Synthesis of LY503430, an AMPA (α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid) Potentiator | This article describes the development and optimization of chemical reactions and subsequent preparation of the API LY503430 under cGMPs to fund first human dose (FHD) clinical evaluation as a potential therapeutic agent for Parkinson's disease. Reasons and rationale are presented for changes in solvents and reagents. ... | 10.1021/op0500741 | 1 |
Regioselective Synthesis of 2,6-Dimethyltetralin: Key Precursor to 2,6-Dimethylnaphthalene | A novel regioselective synthesis for 2,6-dimethyltetralin (2,6-DMT), a key precursor to 2,6-dimethylnaphthalene (2,6-DMN), is described. The synthesis comprises the following three steps; the Heck reaction between commercially available 4-bromotoluene and 3-methyl-3-buten-1-ol, the catalytic reduction of the coupling p... | 10.1021/op050072g | 1 |
A Practical Synthesis of the Dual Matrix Metalloprotease/Tumor Necrosis Factor Inhibitor MMP090 | A practical 9-step synthesis of the dual matrix metalloprotease/tumor necrosis factor inhibitor MMP090, trans -( R )-[[ N -(4-ethoxyphenylsulfonyl)- N -(4-pyridinylmethyl)]amino]- N -hydroxy-4-propoxy cyclohexaneacetamide 10, was accomplished in 12% overall yield from d -4-hydroxyphenylglycine. Highlights include: (1) ... | 10.1021/op050066k | 1 |
Efficient Synthesis of a 5-HT<sub>2C</sub> Receptor Agonist Precursor | A short, scaleable, synthetic approach toward the tricyclic indole derivative 2, an intermediate in the synthesis of the 5-HT 2C agonist 1, is described. The synthesis started with Williamson etherification of inexpensive 4-nitro-3-methylphenol ( 11 ) followed by reduction to the corresponding aniline 13 and subsequent... | 10.1021/op050065s | 1 |
A Continuous Reactive Separation Process for Ethyl Lactate Formation | The continuous formation of ethyl lactate (L 1 E) from aqueous lactic acid solution and ethanol is carried out in a reactive separation column. Nearly complete conversion of lactic acid can be achieved with L 1 E yield exceeding 85%; byproduct lactate oligomer esters and acids formed can be further converted to additio... | 10.1021/op0500640 | 0 |
Development of a Scalable Synthesis of Gastrazole (JB95008): A Potent CC<i>K</i><sub>2</sub> Receptor Antagonist | A practical and scalable synthesis was developed that was used to prepare multikilogram batches of gastrazole, a selective cholecystokinin-2 receptor antagonist. In addition, evidence was found to indicate an amide bond-forming reaction proceeded via the isoimide of a benzimidazoleamide acid derivative. | 10.1021/op0500638 | 1 |
A Scalable Process for the Synthesis of 2-Methyl-1,4,5,6-tetrahydroimidazo[4,5-<i>d</i>][1]benzazepine Monohydrate and 4-[(Biphenyl-2-ylcarbonyl)amino]benzoic Acid: Two New Key Intermediates for the Synthesis of the AVP Antagonist Conivaptan Hydrochloride | A process for the multikilogram synthesis of the dual vasopressin-receptor antagonist, conivaptan hydrochloride, has been developed. This method relies on the introduction of operationally simple chemistry during the final stages of the process when two key intermediates, isolated by crystallization, are reacted to ass... | 10.1021/op050061n | 1 |
Process Development of CP-481715, a Novel CCR1 Antagonist | Process development for the synthesis of 2-quinoxalinecarboxamide, N -[(1 S,2 S,4 R )-4-(aminocarbonyl)-1-[(3-fluorophenyl)methyl]-2,7-dihydroxy-7-methyloctyl] is described. An optimized and streamlined process starting from lactone 2 was developed: Lactone 2 was alkylated diastereoselectively with prenyl bromide, foll... | 10.1021/op050059w | 1 |
Process Development: From the Initial Idea to the Chemical Production Plant By G. Herbert Vogel. Wiley VCH: Weinheim. 2005. 478 pp. $195. ISBN 3-527-31089-4. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewProcess Development: From the Initial Idea to the Chemical Production Plant By G. Herbert Vogel. Wiley VCH: Weinheim. 2005. 478 pp. $195. ISBN 3-527-31089-4.Francis McConvilleView Author Information FXM Engineering & Design Worcester, Massachusetts 01602Cite this: Org. Proces... | 10.1021/op0500537 | 0 |
Synthesis of Methyl 1-(2,3,5-Tri-<i>O</i>-acetyl-β-<scp>l</scp>-ribofuranosyl)-1,2,4- triazole-3-carboxylate from <scp>l</scp>-Ribose: From a Laboratory Procedure to a Manufacturing Process | A two-step manufacturing process for methyl 1-(2,3,5-tri- O -acetyl-β- l -ribofuranosyl)-1,2,4-triazole-3-carboxylate ( 1 ) was developed. In step 1, l -ribose was converted to a β/α mixture of 1,2,3,5-tetra- O -acetyl- l -ribofuranoses ( 2 and 4 ). The step contained four chemical transformations and was completed in ... | 10.1021/op050051m | 0 |
Control of Product Quality in Batch Crystallization of Pharmaceuticals and Fine Chemicals. Part 1: Design of the Crystallization Process and the Effect of Solvent | The product quality in a crystallization process refers to the crystal size distribution (CSD), crystal morphology, polymorphic outcome and the degree of crystallinity, and purity. In addition, the product yield is also important. Properties such as the filterability and solid bulk density are directly related to the C... | 10.1021/op050049v | 0 |
Process Enabling and the Scale-Up of 6β-Hydroxymethylsulbactam and Its Esters | The optimization of the synthesis of 6β-hydroxymethylsulbactam is described. The primary challenge in this synthesis is the installation of the 6β-hydroxymethyl group with the proper stereochemistry. Engineering challenges associated with the addition of gaseous formaldehyde to a Grignard reagent at low temperature and... | 10.1021/op050047a | 0 |
Aqueous Kolbe−Schmitt Synthesis Using Resorcinol in a Microreactor Laboratory Rig under High-p,T Conditions | The aqueous Kolbe−Schmitt synthesis using resorcinol to yield 2,4-dihydroxy benzoic acid was performed in a microreactor rig. This small-scale plant was equipped initially with one capillary reactor and one microstructured cooler only. Later, two upgraded versions were constructed, having in addition a microstructured ... | 10.1021/op050045q | 0 |
Development of a Novel Synthetic Process for 2-Deoxy-3,5-di-<i>O</i>-<i>p</i>-toluoyl-α-<scp>l</scp>-ribofuranosyl Chloride: A Versatile Intermediate in the Synthesis of 2‘-Deoxy-<scp>l</scp>-ribonucleosides | A novel synthetic route to 2-deoxy-3,5-di- O - p -toluoyl-α- l -ribofuranosyl chloride ( 1 ) from inexpensive d -xylose ( 3 ) is described. 1 is a key intermediate in the synthesis of the antiviral agent 1-(2-deoxy-β- l -ribofuranosyl)thymine (β- l -thymidine) (2) and other 2 ‘-deoxy- l -ribonucleosides. This seven-ste... | 10.1021/op0500436 | 1 |
Evaluation of Kilogram-Scale Sonagashira, Suzuki, and Heck Coupling Routes to Oncology Candidate CP-724,714 | The synthesis of the anti-cancer compound 2-methoxy- N -(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)phenylamino]quinazolin-6-yl}- E -allyl)acetamide (CP-724,714) ( 1 ) on multikilogram scale using several different synthetic routes is described. Application of the Sonogashira, Suzuki, and Heck couplings to this synthes... | 10.1021/op050039u | 1 |
BP Process Safety Series. IChemE: Rugby, 2004 (A) Hazards of Water. £15. ISBN 0-85295-466-2. (B) Hazards of Steam. £15. ISBN 0-85295-468-9. (C) Hazards of Air and Oxygen. £15. ISBN 0-85295-467-0. (D) Hazards of Nitrogen and Catalyst Handling. £15. ISBN 0-85295-469-7. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBP Process Safety Series. IChemE: Rugby, 2004 (A) Hazards of Water. £15. ISBN 0-85295-466-2. (B) Hazards of Steam. £15. ISBN 0-85295-468-9. (C) Hazards of Air and Oxygen. £15. ISBN 0-85295-467-0. (D) Hazards of Nitrogen and Catalyst Handling. £15. ISBN 0-85295-469-7.Cite ... | 10.1021/op0500382 | 0 |
Chemical Process Equipment: Selection and Design, 2nd edition By J. R. Couper, W. R. Penney, J. R. Fair, S. M. Walas. Elsevier/Gulf Professional Publishing: Oxford. 2005. 814 + xvii pp. £125. ISBN 0-7506-7510-1. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTChemical Process Equipment: Selection and Design, 2nd edition By J. R. Couper, W. R. Penney, J. R. Fair, S. M. Walas. Elsevier/Gulf Professional Publishing: Oxford. 2005. 814 + xvii pp. £125. ISBN 0-7506-7510-1.Cite this: Org. Process Res. Dev. 2005, 9, 3, 373–374Publicat... | 10.1021/op050036h | 0 |
Side Reactions in Organic Synthesis: A Guide to Successful Synthesis Design By F. Zaragoza Dörwald. Wiley VCH: Weinheim. 2005. 374 pp. £65.00 (Paperback). ISBN 3-527-310215. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTSide Reactions in Organic Synthesis: A Guide to Successful Synthesis Design By F. Zaragoza Dörwald. Wiley VCH: Weinheim. 2005. 374 pp. £65.00 (Paperback). ISBN 3-527-310215.Cite this: Org. Process Res. Dev. 2005, 9, 3, 372–373Publication Date (Web):March 12, 2005Publicati... | 10.1021/op0500281 | 0 |
Organometallics in Process Chemistry Edited by R. D. Larsen. Springer-Verlag: Heidelberg, Germany. 2004. 299 pp. $229.00. ISBN 3-540-01603-1 (also available in electronic version via springerlink.com) | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTOrganometallics in Process Chemistry Edited by R. D. Larsen. Springer-Verlag: Heidelberg, Germany. 2004. 299 pp. $229.00. ISBN 3-540-01603-1 (also available in electronic version via springerlink.com)Cite this: Org. Process Res. Dev. 2005, 9, 3, 372Publication Date (Web):... | 10.1021/op0500279 | 0 |
The Preparation of Single Enantiomer 2-Naphthylalanine Derivatives Using Rhodium−Methyl <i>BoPhoz</i>-catalyzed Asymmetric Hydrogenation | The single enantiomers of 2-naphthylalanine and N - tert -butoxycarbonyl 2-naphthylalanine were prepared from 2-naphthaldehyde. The sequence has been optimized and run on multikilogram scale, with the key step the asymmetric hydrogenation of methyl 2-acetamido-3-(2-naphthyl)propenoate using the rhodium complex of the m... | 10.1021/op050026g | 1 |
An Improved, Scalable, and Impurity-Free Process for Tolterodine Tartrate | Tolterodine tartrate is an anticholinergic muscle relaxant used to treat urinary frequency, urinary urgency, and incontinence in people with unstable bladders. An improved, cost-effective, and impurity-free process for tolterodine tartrate suitable for large-scale commercial production is described here by addressing v... | 10.1021/op050024w | 1 |
Two-Step Catalytic Oxidative Dehydrogenation of Propane: An Alternative Route to Propene | The use of solid oxygen carriers (SOCs) in catalytic dehydrogenation may provide a more efficient production process for small alkenes by shifting the equilibrium to the product side. In this paper we use dynamic simulations to investigate the feasibility of two-step oxidative dehydrogenation of propane to propene usin... | 10.1021/op050020r | 0 |
Synthesis of a Substance P Antagonist: An Efficient Synthesis of 5-Substituted-4-<i>N,N</i>-dimethylamino-1,2,3-triazoles | A highly efficient synthesis of the substance P antagonist 1 is reported starting from the optically pure morpholine acetal derivative 2 . The 5-dimethylaminomethyl-1,2,3-triazole moiety is elaborated via a 1,3-dipolar cycloaddition between an activated acetylenic intermediate and sodium azide. Two approaches to the co... | 10.1021/op050019s | 1 |
Ion-Exchange Resin Catalysis in Benign Synthesis of Perfumery Grade <i>p</i>-Cresylphenyl Acetate from <i>p</i>-Cresol and Phenylacetic Acid | p-Cresyl phenyl acetate is a very important perfume that finds wide applications and possesses an organoleptic character similar to those of honey, nuts, and butter. It is produced by mineral acid-catalyzed esterification of p -cresol with phenylacetic acid. Use of homogeneous acid catalysts leads to posttreatment poll... | 10.1021/op0500133 | 0 |
Efficient and Scalable Synthesis of Ethyl 2,6-Dichloro-5-Fluoronicotinoyl Acetate Using the Blaise Reaction as a Key Step<sup>1</sup> | An efficient synthesis of 2,6-dichloro-5-fluoronicotinoyl acetate ( 1 ) has been accomplished in a single step using the Blaise reaction of ethyl bromoacetate with 3-cyano-2,6-dichloro-5-fluoropyridine ( 4 ). Use of methanesulfonic acid as an in situ activator of zinc removed the induction period of the Blaise reaction... | 10.1021/op050012a | 1 |
Selective Crystallization of an Allylic 7α-Bromide: A Facile Synthesis of (1α,3β)-3-Hydroxycholeste-5,7-diene-1,25-diol Diacetate | An efficient synthesis of (3β)-7-dehydro-1α,25-diacetoxycholesterol ( 1 ) is described. When acetonitrile was used as the crystallizing solvent, only the 7α-bromide 6a was isolated and bromide 6a was prepared in a 69% yield starting from 3β-TBDMS-1α,25-diacetoxycholesterol ( 5 ). Dehydrobromination with sym -collidine ... | 10.1021/op050009r | 1 |
Towards a PAT-Based Strategy for Crystallization Development | A strategy for the rapid, material-efficient development of crystallization processes centred around the use of process analytical technology (PAT) is presented and demonstrated on an active pharmaceutical ingredient (API) currently in development at Pfizer's Sandwich laboratories. PAT is implemented at scales as small... | 10.1021/op0500077 | 0 |
Synthesis of Alkyl Aryl Ethers by Catalytic Williamson Ether Synthesis with Weak Alkylation Agents | For almost 70 years, there have been attempts to advance the Williamson ether synthesis process to allow the use of low-cost, noncarcinogenic, weak alkylating agents and avoid salt production. These attempts to produce a “green” version of Williamson ether synthesis have been based on the use of weak alkylating agents ... | 10.1021/op050001h | 0 |
Alternate Synthesis of a β-3 Adrenergic Receptor Agonist | Previously our group reported synthetic efforts used to synthesize kilogram quantities of the β-3 receptor agonist ( R )-(4-(2-(2-(6-aminopyridin-3-yl)-2-hydroxyethylamino)ethoxy)phenyl)acetic acid, 1 . Additional research was conducted to explore an alternate chiral route with a streamlined protecting group scheme. Th... | 10.1021/op0499775 | 1 |
Practical One-Pot Synthesis of <i>N</i>-(<i>tert</i>-Butoxycarbonyl)sulfamide from Chlorosulfonyl Isocyanate via <i>N</i>-(<i>tert</i>-Butoxycarbonyl)aminosulfonylpyridinium Salt | An efficient and practical process for the one-pot synthesis of N -( tert -butoxycarbonyl)sulfamide ( 4 ), a raw material for the aminosulfamoyl-containing side chain 3 of a novel carbapenem antibiotic doripenem hydrate (S-4661: 1 ), is described. In the previous process, chlorosulfonyl isocyanate was converted to N -(... | 10.1021/op0499728 | 1 |
Online Spectroscopy and Multivariate Data Analysis as a Combined Tool for Process Monitoring and Reaction Optimization | Multivariate modeling and spectroscopy taken together constitute a powerful tool applicable to both process monitoring and to process and reaction optimizing. The present article establishes how near-IR spectroscopy utilizing a fiber-optical transmission probe can be combined with principal component analysis to extrac... | 10.1021/op049971f | 0 |
Novel Innovation Systems for a Cellular Approach to Continuous Process Chemistry from Discovery to Market | Continuous processing of liquid/liquid synthesis and microreaction technology are shown to reduce the cost of process development and manufacturing of active pharmaceutical ingredients and other functional molecules on a commercial scale. Combinatorial synthesis systems for continuous chemistry are introduced, and thei... | 10.1021/op049970n | 0 |
Process Research and Scale-Up for a β-3 Adrenergic Receptor Agonist | A scaleable synthesis of the β-3 adrenergic receptor agonist, (4-{2-[2-(6-aminopyridin-3-yl)-(2 R )-hydroxy-ethylamino]ethoxy}phenyl)acetic acid is presented. The key coupling step utilizes a silyl-protected β-hydroxy tosylate to alkylate a primary amine, thus avoiding water-soluble intermediates and reducing unwanted ... | 10.1021/op049969o | 1 |
Pilot-Plant Preparation of an α<sub>v</sub>β<sub>3</sub> Integrin Antagonist. Part 2. Synthesis of <i>N</i>-[2-(5-Hydroxy-4,6-tetrahydropyrimidine)]-3-amino-5-hydroxybenzoic Acid | Studies directed toward the process research and development of a scalable method for preparing tetrahydropyrimidine 2, a key intermediate to the α v β 3 integrin antagonist 1, are described. A linear approach employing 3-amino-5-hydroxybenzoic acid, methyl isothiocyanate, and 1,3-diaminopropan-2-ol as key reagents is ... | 10.1021/op049968w | 1 |
An Improved Synthesis of the Selective Matrix Metalloproteinase Inhibitor, Ro 28-2653 | An efficient synthesis of Ro 28-2653, a selective matrix metalloproteinase inhibitor, has been developed. The title compound was prepared in four steps and 76% overall yield from 4-biphenylacetic acid. The key, barbituric acid formation step was significantly improved by using 2-propanol and potassium tert -butoxide as... | 10.1021/op049965j | 1 |
Efficient Fast Screening Methodology for Optical Resolution Agents: Solvent Effects Are Used To Affect the Efficiency of the Resolution Process | An efficient and fast screening methodology for optical resolution agents through the classical crystallization of the corresponding diastereomeric salts is described. In this contribution, we demonstrate that the determination of the eutectic composition by chiral analysis of the corresponding mother liquor (ML) obtai... | 10.1021/op0499627 | 0 |
The Highly Selective Equatorial Hydride Delivery by Biocatalysis: Chemoenzymatic Synthesis of <i>trans</i>-2-(4-Propylcyclohexyl)-1,3-propanediol via <i>cis</i>-4-Propylcyclohexanol | 4-Propylcyclohexanone 10a (69 g/L) is reduced by the catalysis of Galactomyces geotrichum JCM 6359 using i -PrOH (4.0 equiv) as an auxiliary substrate for recycling externally supplemented NAD + (0.001 equiv) in 40 mM potassium phosphate buffer (pH 7.5) for 20 h to provide a mixture of cis -4-propylcyclohexanol 3a [ ci... | 10.1021/op049961e | 1 |
Drying an Organic Monohydrate: Crystal Form Instabilities and a Factory-Scale Drying Scheme to Ensure Monohydrate Preservation | This contribution discusses the laboratory results and factory-scale drying of an organic monohydrate with therapeutic qualities. The crystal form instabilities of this monohydrate are discussed with respect to undesired dehydrated crystalline species and an IPA solvate. To reproducibly determine the end-of-drying whil... | 10.1021/op049956a | 0 |
Approaches to a Scaleable Synthesis of CH8757: A Potent Inhibitor of Matrix Metalloproteinases | The synthesis of the matrix metalloproteinase (MMP) inhibitor CH8757 is described. The discovery route has been modified to incorporate a three-stage one-pot sequence using α,α,α-trifluorotoluene as solvent. The formation of the hydroxamic acid using oxalyl chloride is catalysed by DBU, thus avoiding the use of DMF, wh... | 10.1021/op049954q | 1 |
Development of a Manufacturing Process for Sibenadet Hydrochloride, the Active Ingredient of Viozan | A process for commercial manufacture of the dual D 2 -β 2 receptor agonist sibenadet hydrochloride has been developed. The process relies upon introduction of operationally simple chemistry at the final stages where two key intermediates are reacted to assemble the final molecule, isolated by crystallization. A nine-st... | 10.1021/op049953y | 1 |
Demethylation of 4-Methoxyphenylbutyric Acid Using Molten Pyridinium Hydrochloride on Multikilogram Scale | 4-Methoxyphenylbutyric acid ( 2 ) is smoothly demethylated in 3 h at 180 °C when melted with pyridinium hydrochloride (Pyr·HCl), affording 4-hydroxyphenylbutyric acid ( 3 ), a key starting material for the preclinical candidate LY518674 ( 1 ). The adaptation of this chemistry to 22-L and pilot-plant scale is described,... | 10.1021/op0499526 | 0 |
An Efficient Synthesis of 2-Quinoxalinecarboxylic Acid | Development of a cost efficient and scaleable process for 2-quinoxalinecarboxylic acid is described. The primarily goals of the development work were to improve the overall yield of the process, to minimize the use of environmentally unacceptable materials, and to obtain a material with a high level of purity. A variet... | 10.1021/op049951d | 1 |
A Practical Building Block for the Synthesis of Discodermolide | A new highly diastereoselective and practical route to the lactone 6a which is used as a key building block for the total synthesis of the microtubule-stabilizing anticancer agent discodermolide is reported. This exploits the chiral auxiliary (4 R )-4-isopropyl-5,5-diphenyloxazolidin-2-one ( 7 ) which conveys crystalli... | 10.1021/op049950l | 1 |
First Safe and Practical Synthesis of 2-Amino-8-hydroxyquinoline | The first safe and efficient synthesis of the important building block 2-amino-8-hydroxyquinoline ( 1 ) is described. Starting from the readily available N -oxide 3 of the cheap bulk chemical 8-hydroxyquinoline ( 2 ), the target compound is obtained in a two-step one pot procedure in good overall yield (53−66%) and pur... | 10.1021/op049944p | 0 |
Development of an Efficient Synthesis for a Nipecotate-Containing Immunopotentiator | The preparation of Elanco Animal Health immunopotentiator ( S )-ethyl-1-(2-thiopheneacetyl)-3-piperidinecarboxylate ( 1 ) is described. The synthesis includes a new resolution of racemic ethyl nipecotate with dibenzoyl- l -tartaric acid. The resolved salt is found to couple directly with commercially available 2-thioph... | 10.1021/op049941c | 0 |
Lawesson's Reagent: A New Entry in the Preparation of 2-Azetidinones | Lawesson's reagent is found to be a unique reagent that provides a convenient route for the synthesis of β-lactams from Schiff's bases and alkoxy/aryloxy acetic acids. The process involves the formation of a titanium enolate of a mixed anhydride followed by condensation with imine to afford β-lactam. | 10.1021/op049939l | 0 |
A Practical Synthesis of 3,4-Dimethoxy-<i>o</i>-toluic Acid | A streamlined, telescoped process has been developed for the preparation of 3,4-dimethoxy- o -toluic acid, starting with economical and readily available 2,3-dimethoxybenzaldehyde. Catalytic reduction of the aldehyde functional group generated dimethoxytoluene, which was brominated in situ. The resultant aryl bromide w... | 10.1021/op049938t | 0 |
An Efficient Amination Method for Manufacturing Cytidines | A novel method for amination of uridine derivatives was developed and applied to the syntheses of cytidines. The method consists of an activation step with 1-methylpiperidine at the C 4 -position of a uracil base. Large-scale preparation of 2‘-deoxycytidine was performed using this method. | 10.1021/op0499371 | 1 |
Successful Development and Scale-up of a Palladium-Catalysed Amination Process in the Manufacture of ZM549865 | Key steps in the synthesis of ZM549865 (a 5-HT receptor antagonist) are the palladium-catalysed amination of ethyl 8-bromo-6-fluoro-4-oxo-4 H -2-chromenecarboxylate and subsequent hydrolysis of the ester group. The development of a simple, robust process capable of making multikilogram amounts of the required intermedi... | 10.1021/op0499369 | 1 |
Streamlined Processes for the Synthesis of a Farnesyl Transferase Inhibitor Drug Candidate | As part of a fast-paced oncology program, quinolinone 1 was discovered and developed as a potent inhibitor of farnesyl transferase for the treatment of cancer. The initial synthesis, which suffered from a lengthy linear sequence and a late-stage chromatographic resolution, was deemed not amenable to large-scale product... | 10.1021/op049935g | 1 |
ChemProject: A Valuable, Easy-To-Use Tool for COGS Calculations in Chemical Process Research and Development | In this paper, we describe the software “ChemProject” which is used to perform cost of goods (COGS) calculations. Then, we exemplify its use by comparing the COGS of a synthesis before and after process development. | 10.1021/op049933w | 1 |
Reinvestigation of Phase-Transfer-Catalyzed Chlorpyrifos Synthesis | Production of chlorpyrifos via the phase-transfer-catalyzed reaction of O, O -diethylphosphorochloridothioate and the sodium salt of 3,5,6-trichloropyridin-2-ol was reinvestigated. The formation of sulfotep (the major byproduct) and the yield are influenced by the nature and concentration of the catalysts, temperature,... | 10.1021/op049929k | 0 |
<i>SPECIAL FEATURE SECTION: <u>NEW TECHNOLOGIES IN PROCESS RESEARCH</u></i> | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSPECIAL FEATURE SECTION: NEW TECHNOLOGIES IN PROCESS RESEARCHUlf TilstamView Author Information Lilly Development Centre S.A.,B-1348 Mont-Saint-Guibert, Belgium Cite this: Org. Proc. Res. Dev. 2004, 8, 3, 421Publication Date (Web):April 21, 2004Publication History Published... | 10.1021/op049928s | 0 |
Practical Large-Scale Synthesis of Cefmatilen, A New Cephalosporin Antibiotic | A practical large-scale process for the synthesis of cefmatilen hydrochloride hydrate ( 1 ), a new oral cephalosporin antibiotic, is described. Several impurities are isolated from a bulk drug and identified. Side reactions are discussed in order to prevent them. The conditions were optimized to control the formation o... | 10.1021/op049920i | 1 |
Development of a Safe and Scalable Oxidation Process for the Preparation of 6-Hydroxybuspirone: Application of In-Line Monitoring for Process Ruggedness and Product Quality | The development of a safe and scalable oxidation process for the hydroxylation of the azapirone psychotropic agent buspirone ( 1 ) to furnish 6-hydroxybuspirone ( 2 ) is described. A mechanistic understanding of how key process factors affected product quality led to the successful application of FTIR as a process anal... | 10.1021/op049918r | 0 |
“One-Pot” Preparation of<i>N</i>-Carbamate Protected Amino Acids via the Azide | A convenient and efficient method for the preparation of fluorenylmethyloxycarbonyl (Fmoc) and allyloxycarbonyl (Alloc) amino acids is proposed. This method is particularly attractive due to the fact that the reaction sequence Fmoc/Alloc-chloride to Fmoc/Alloc-azide to Fmoc/Alloc-amino acid can readily be carried out i... | 10.1021/op049917z | 0 |
Process Development and Pilot-Scale Synthesis of Cefotetan | Strategies that were adopted during the process development of Cefotetan in order to achieve a cost-effective commercial-scale synthesis are described herein. These included replacement of the trifluoroacetic acid used for cleavage of the benzhydryl ester and the development of an alternative synthetic route. This work... | 10.1021/op049914m | 1 |
Synthesis of the Intermediate of Gemifloxacin by the Chemoselective Hydrogenation of 4-Cyano-3-methoxyimino-1-(<i>N</i>-<i>tert</i>-butoxycarbonyl)pyrrolidine. Part 1. Screening of Metal Catalysts | A novel synthetic route was devised for 4-aminomethyl-3- Z -methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate of gemifloxacin, based on chemoselective hydrogenation of the cyano group in 4-cyano-3-methoxyimino-1-( N - tert -butoxycarbonyl)pyrrolidine (CMBP) with minimum reduction of the methyloxime ... | 10.1021/op049913u | 1 |
Synthesis of the Intermediate of Gemifloxacin by the Chemoselective Hydrogenation of 4-Cyano-3-methoxyimino-1-(<i>N</i><i>-tert</i>-butoxycarbonyl)pyrrolidine. Part 2. The Palladium Catalysts in Acidic Media | Chemoselective hydrogenation of 4-cyano-3-methoxyimino-1-( N - tert -butoxycarbonyl)pyrrolidine (CMBP) to 4-aminomethyl-3- Z -methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate for gemifloxacin, was investigated over Pd catalysts with in situ acid protection. Addition of more than 1.6 equiv of acidic... | 10.1021/op0499122 | 0 |
Investigation into the Acidification Process of Zafirluskast Nitroacid Leads to a Surprising Improvement in Product Quality | An investigation into the acidification step of the zafirlukast nitroacid process was conducted by varying a range of parameters, including acid molarity, addition time, final pH, and temperature. A significant and unexpected improvement in product quality was achieved by using dilute rather than concentrated acid, ind... | 10.1021/op049911+ | 0 |
Integrated Approach to the Development and Understanding of the Borane Reduction of a Carboxylic Acid | A delayed exotherm was recorded during the reduction of a carboxylic acid with BH 3 ·THF. This article will describe our efforts to explain and control the observed exotherm using a reactor integrated with a mass-flow meter, a reaction calorimeter, and an in situ FT-IR probe. In the end, a kinetic model is proposed tha... | 10.1021/op049910h | 0 |
The Efficient Synthesis of Disodium Disuccinate Astaxanthin (Cardax) | A practical procedure is described for the multigram preparation of disodium disuccinate derivatives of synthetic astaxanthin (Cardax) [from all- trans -(all- E )-3 S,3‘ S-, meso -(3 R,3‘ S )-, and 3 R,3‘ R -dihydroxy-β,β-carotene-4,4‘-dione) in a 1:2:1 statistical mixture of stereoisomers, as well as from the individu... | 10.1021/op049909i | 1 |
Process Control Limits from a Laboratory Study on the Ni(0)-Mediated Coupling of Ethyl Acrylate with a C-22 Steroidal Iodide: A Case Study on the Role of Experimental Design in Highly Developed Processes | An experimental design was used to assess the process robustness in the Ni(0)-mediated coupling of the C-22 steroidal iodide 15 with ethyl acrylate to yield the coupled product 16 . Although the reaction conditions were optimized by empirical means, an experimental design was employed to assess the process sensitivity ... | 10.1021/op049908q | 1 |
Molar-Scale Synthesis of 1,2:5,6-Di-<i>O</i>-isopropylidene-α-<scp>d</scp>-allofuranose: DMSO Oxidation of 1,2:5,6-Di-<i>O</i>-isopropylidene-α-<scp>d</scp>-glucofuranose and Subsequent Sodium Borohydride Reduction | Two variants of oxidation with DMSO followed by sodium borohydride reduction have been investigated to make the synthesis of 1,2:5,6-di- O -isopropylidene-α- d -allofuranose ( 4 ) suitable for large-scale manufacturing. | 10.1021/op049903t | 0 |
Multi-Kiloscale Enantioselective Synthesis of a Vitronectin Receptor Antagonist | The development of a novel, cost-effective synthesis of the vitronectin receptor antagonist SB-273005 became necessary as the compound proceeded to Phase 1. A practical synthesis of the compound presented challenges to the process chemist. Chief among the challenges was developing an enantioselective route to the compo... | 10.1021/op0499021 | 1 |
A Pressure-Resistant Small-Scale Reaction Calorimeter That Combines the Principles of Power Compensation and Heat Balance (CRC.v4) | An improved version of a small-scale reaction calorimeter fitted with an integrated infrared-attenuated total reflection (IR-ATR) probe has been developed. The new device has a sample volume of 20−50 mL, a metal block as an intermediate thermostat and is applicable to higher pressure up to 30 bar. Isothermal conditions... | 10.1021/op049900g | 0 |
Development of an Efficient and Scalable Process of a Respiratory Syncytial Virus Inhibitor | An improved process has been developed for compound 1, a respiratory syncytial virus (RSV) inhibitor. This improved process is convergent, safe, efficient, and useful to prepare compound 1 in kilogram quantities. | 10.1021/op049899l | 1 |
Ortho Lithiation of <i>N</i>-Pivaloylfluoroanilines as a Useful Tool for Either Selective Methylation or Benzoxazole Synthesis | Lithiation of N- pivaloyl-3,4-difluoroaniline ( 1a ) with a slight excess of 2 mole equiv of n -butyllithium followed by methylation was studied. The reaction was found to be useful for either the selective methylation of 3,4-difluoroaniline or the synthesis of benzoxazole derivatives, depending on the reaction tempera... | 10.1021/op0498969 | 0 |
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