Advances in synthetic organic chemistry and methods reported in US patents

Functional Group ContentsPatent Titles Azinyloxy, and Phenoxy-Diaryl-Carboxylic Acid Derivatives, Their Preparation and Use as Mixed ETA/ETB Endothelin Receptor Antagonists 5 Compounds D

Advances in

Synthetic Organic Chemistry

and Methods Reported in US Patents

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Functional Group Contents

(Patent Titles)

Azinyloxy, and Phenoxy-Diaryl-Carboxylic Acid Derivatives, Their Preparation and Use

as Mixed ETA/ETB Endothelin Receptor Antagonists 5

Compounds Derived from Benzoic Acid Esters, Composition Containing Said Compounds

1,2-Diarylmethylene Derivatives, Their Methods of Preparation, and Their Uses in

Halogenated Cinnamic Acids and Esters Thereof, Processes for the Preparation Thereof

Method for Producing Alkoxy Malonic Acid Dinitriles 24Phosphonosuccinic Acid Derivatives, Processes for Their Preparation and Medicaments

Preparation of Cyclohexane Carboxylate Derivatives 28Water Soluble Fullerenes with Antiviral Activity 33

Oligiocycloalkanoid Compounds and Methods of Use 44Polymers with Controlled Physical State and Bioerodibility 484-Quinolinemethanol Derivatives as Purine Receptor Antagonists 50Synthesis of 5-Decenyl Acetate and Other Pheromone Components 53

viii FUNCTIONAL GROUP CONTENTS

One Pot Process for the Preparation of

1-[2-Methylamino-(4-Methoxyphenyl)-Ethyl]Cyclohexanol 104Organic Electroluminescence Device and Phenylenediamine Derivative 106Process for Preparing N-Substituted Hydroxylamines and Salts Thereof 110

Substituted 2-Aminoalkyl 1,4-Diaminobenzene Compounds and Oxidation Dye Precursor

Carbonic Acid Derivatives by Isocyanide Multicomponent Reactions, as well as these

Secondary Amidoalkyl Carbonic Acid Derivatives 125Spirodiamino Acid Scaffold for Combinatorial Synthesis 128

10-Substituted 1,8-Dihydroxy-9(10H) Anthracenone Pharmaceuticals 132

Aza and Diaza Bi- and Tricyclics 136

Bi- and Tri-Cyclic Aza Compounds and Their Uses 136Certain Tricyclic Substituted Diazabicyclo[3.2.1]octane Derivatives 141

FUNCTIONAL GROUP CONTENTS ix

N-Alkyl and N-Acyl Derivatives of 3,7-Diazabicyclo-[3.3.1] Nonanes and Selected Salts

8-Aza, 6-Aza and 6,8-Diazo-1,4-dihydroquinoxaline-2,3-diones and the Use Thereof as

Method of Synthesizing t-Amido-Substituted 2-(2-Hydroxyphenyl)benzotriazole

Highly Reactive Form of Copper and Reagents Thereof 205

x FUNCTIONAL GROUP CONTENTS

Aromatic Allene Compounds of the Formula CH2==CH-On-R-Amin Which

R is an Aromatic Group and Preparation Thereof 211

(S)-4-Amino-Hepta-5,6-Dienoic Acid and Intermediates Thereof 217

Method for the Stereoselective Production of Substituted Cyclohexylanhydrins 220

Conjugation of Biomolecules Using Diels-Adler Cycloaddition 223

Cyclopentadienyl Derivatives and Process for Their Preparation 230

Aryl Phenylcyclopropyl Sulfide Derivatives and Their Use as Cell Adhesion Inhibiting

Anti-Inflammatory and Immune Suppressive Agents 233

2-Hydroxymethylcyclopropylidene-Methylpurines and -Pyrimidines as Antiviral Agents 240Process of Producing Cyclopropanecarboxylate Compounds 245Process for the Preparation of Methylenecyclopropane 247Synthesis of Cyclopropaneacetylene by a One Pot Process 249

Preparation and Use of Ionic Liquids in Microwave-Assisted Chemical Transformations 268

Furazancarboxylic Acid Derivatives 275

Hydroxymethylfurazancarboxylic acid derivatives 275

FUNCTIONAL GROUP CONTENTS xi

Spiroimidazolidine Derivatives, Their Preparation, Their use and Pharmaceutical

Iminocarboxylic Acid Methyl Amides 322

Preparation of -Methoxyiminocarboxylic Acid Methylamides and Intermediates Therefore 322

Acetoacetic Acid Derivatives, Process for Their Preparation and Their Use 349

xii FUNCTIONAL GROUP CONTENTS

Process for Preparing 3-Hydroxymethyl-4-(Aryl or Heterocyclic)-Cyclopentanones 355

Process for the Preparation of High Purity Alkyladamanantyl Esters 362

Anticonvulsant and Anxiolytic Lactam and Thiolactam Derivatives 364

-Diketone Compounds, -Diketone Compounds Coordinated to Metal, Method

1,4-Dioxacylcycloalkane-2-one and 1,4-Dioxacylcycloalkene-2-one 392

Vicarious Nucleophilic Substitution Using 4-Amino-1,2,4-Triazole, Hydroxylamine

or O-Alkylhydroxylamine to Prepare 1,3-Diamino-2,4,6-Trinitrobenzene or

Method for Producing Monoaryloxy-ansa-Metallocenes 429Process for Preparing Bisallylboranes and Non-Aromatic Boronic Acids 432Synthetic Molecules That Specifically React with Target Sequences 434

FUNCTIONAL GROUP CONTENTS xiii

Orthocarbonates, Esters, and Derivatives 437

Substituted Sprioalkylamino and Alkoxy Heterocyclics, Processes for Their Preparation,

Synthesis of Spiro Orthoesters, Spiro Orthocarbonates, and Intermediates 444

Opiate Compounds, Methods of Making and Methods of Use 505Process for Production of Piperidine Derivatives (Note 1) 509

xiv FUNCTIONAL GROUP CONTENTS

Pyridone and Tetrahydropyridone 537

Pyridone Derivatives, Their Preparation and Their Use as Synthesis Intermediates 537

7-Azabicyclo[2.2.1]Heptane and Heptene Derivatives as Cholinergic Receptor Ligands 548

Compositions and Methods for Treating Viral Infections 555Quinone Compound, Liquid Crystal Composition, and Guest-Host-Type Liquid Crystal

Polycyclic Aryl and Heteroaryl Substituted 1,4-Quinones Useful for Selective Inhibition of

Radioligands and Their Use for Identifying Potassium Channel Modulators 570Synthesis of2H- and13C-Substituted Dithanes 574Tritioacetylating Reagents and Processes for Preparation Thereof 576

2-Saccharinylmethyl Heterocyclic Carboxylates Useful as Proteolytic Enzyme Inhibitors

Preparation of Thioarabinofuranosyl Compounds and Use Thereof 587Process for the Alkaline Oxidative Degradation of Reducing Sugars 591Sugar Derivatives of Hydromorphorine, Dihydromorphorine and Dihydroisomorphorine

Compositions Thereof and Uses for Treating or Preventing Pain 594

Nitromethylthiobenzene Derivatives as Inhibitors of Aldose Reductase 605

FUNCTIONAL GROUP CONTENTS xv

Process for the Preparation of Ethanesulfonyl-piperidine Derivatives 608

 -Unsaturated Sulfones for Treating Proliferative Disorders 612

Oxazolo, Thiazolo and Selenazolo [4,5-c]-Quinolin-4-Amines and Analogues Thereof 643

3,4-Diaryl Thiopenes and Analogs Thereof Having Use as Anti-inflammatory Agents 651

Aryloxy- and Arylthio-substituted Pyrimidines and Triazines and Derivatives Thereof 661

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The first US Patent was issued to inventor John Ruggles on July 13, 1836 for improvedTraction Wheels for locomotive-engines The Traction Wheels addressed the need for loco-motives to efficiently climb ‘inclined plains and hills with heavy loads drawn up to thesame with more facility and economy than heretofore.’ US Patent 130 was the first chemicalinvention patent issued on February 16, 1837 to English chemist Webster Flockton Flocktonhad developed a method of preserving wood by treating lumber with ‘the essential oil ofvegetable tar saturated with the oxide of iron.’

This initially small stream of issued patents has become a deluge In February, 2005,12,915 US patents were granted; on March 1, 2005, US Patent 6,862,742 issued Assigneesare not limited to individuals and small and large corporations, but also include academicinstitutions and national and international government agencies

The purpose of this book is to provide academic and industrial chemists with significantadvances in current chemical research in 46 subject areas as reported in the US Patentliterature This objective is best achieved using four inter-connected components First,chemical reactions necessary to achieve the inventor’s stated goal are depicted foreach patent All structural transformations, reagents, chemical intermediates, as well asexperimental conditions have been supplied Second, chemical agents have been classified

by both their Functional Group Type and Product Utility For example, water solublefullerenes derivatives are classified as ‘Acids and Derivatives’ under Functional Group Typeand as ‘Pharmaceuticals, Virucides’ under the Product Utility designation Third, explicitlaboratory procedures for synthesizing targeted compounds, intermediates, and derivativeshave been provided to assist in the preparation, isolation, characterization, and assaying ofchemical agents of interests Where available, relevant prior art US Patent references areincorporated throughout the text which are assessable from the US Patent and TrademarkOffice database (www.uspto.gov) Finally, individual Reagent, Product, and Name Reactionindices are incorporated to more efficiently access required information

Thomas F DeRosa,

May, 2005

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Acids and Derivatives

Patent: Aromatic Carboxylic Acid Derivatives

M Klaus et al, US Patent 6,610,877 (August 26, 2003)

Assignee: Hoffman-La Roche Inc.

Utility: Treatment of Photodamaged Skin

Reaction

i- Aluminium trichloride, carbon disulfide

ii- Carbon tetrachloride, iron, bromine

iii- t-Butyl lithium,

N,N-dimethylformamide, THF

iv- Diethyl(4-carboethoxybenzyl)phosphonate, sodium hydride,dimethylsulphoxide, THFv- Ethyl alcohol, potassium hydroxide

2 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

Experimental

1 1,1,4,4-Tetramethyl-6-hexyl-1,2,3,4-tetrahydro-naphthalene

6-Hexylbenzene (83 ml) and AlCl3(1.8 g) were mixed while cooling and dimethyl-hexane (40 g) dissolved in 300 ml CS2added dropwise Thereafter, the mixturewas stirred 2 hours, poured into 6 M HCl in ice, extracted with EtOAc, and the crudeproduct isolated as a colorless oil, bp= 141–152C at 0.8 mm Hg.

2,5-dichloro-2,5-2 7-Bromo-1,1,4,4-tetramethyl-6-hexyl-1,2,3,4-tetrahydro-naphthalene

The product from Step 1 (10 g) was dissolved in 100 ml CCl4followed by the addition of aspatula full of iron and bromine (6.4 g) and the mixture stirred at 0C for 3 hours The mixturewas poured into ice water, extracted with diethyl ether, and purified by column chromato-graphy on silica gel with hexane/EtOAc, 9:1, the product isolated as a pale yellow oil

The product from Step 4 (8 g) was dissolved in 50 ml ethyl alcohol and treated with

10 g KOH dissolved in 10 ml apiece ethyl alcohol and water Thereafter 50 ml THF wasadded and the mixture heated to 40C 4 hours, poured into ice water containing 6 MHCl, extracted with EtOAc, and the crude product re-crystallized using hexane/EtOAc,

mp= 134–136C.

Derivatives

R 1 R 2 Melting Point (C)

Pentyl (2E, 4E, 6E)-3-Methyl-hepta-trienoic acid 170–174

Octyl E-[(5H-Benzocyclohepten-2-yl)vinyl]benzoic acid 183–183

ACIDS AND DERIVATIVES 3

Notes

1 This is an example of the Horner-Wadsworth-Emmons reaction and is discussed (1)

2 (2E, 4E, methyl-hepta-2,4,6-trienoic acid (II) was also prepared by reacting 2-formyl-3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene with ethyl (E,E)-6-(diethoxy-phosphinyl)-3-methyl-2,4-hexdienolate followed by basic hydrolysis illustrated in Eq 1

6E)-7-(3-Hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthanen-2-yl)-3-as described below by the author

i- Dimethyl sulfoxideii- Potassium hydroxide, ethyl alcohol, THF

70 ml DMSO and 35 ml THF added The mixture was stirred 2 hours and the productprecipitated in ice water acidified with 6M HCl The mixture was extracted with EtOAcand purified by flash chromatography on silica gel with hexane/methyl t-butyl ether, 98:2,and the product isolated as a pale yellow oil

4 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

ethynyl-trimethylsilane, tetrabutylammonium fluorideii- THF, n-butyl lithium, DMF

iii- Sodium hydride, dimethylsulfoxide, ethyl4-ethoxyphosphinyl-3-methyl-cronateiv- Potassium hydroxide, ethyl alcohol, THF

4 The preparation of other 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthanen-2-yl-benzoicacid derivatives is provided (3)

References

1 J Boutagy, Chem Rev 79, 87 (1974)

2 M Klaus et al, US Patent 5,700,836 (December 23, 1997)

3 H.-H.Wuest et al, US Patent 4,801,733 (January 31,1989)

ACIDS AND DERIVATIVES 5

Patent: Azinyloxy, and Phenoxy-Diaryl-Carboxylic Acid Derivatives, Their

Preparation and Use as Mixed ETA/ETB Endothelin Receptor

Antagonists

W Amberg et al, US Patent 6,670,367 (December 30, 2003)

Assignee: Abbott GmbH & Co., KG

Utility: Treatment of Vasoconstrictive Disorders

Reaction

i- 2-(3,4-Dimethoxyphenyl)ethanol, CH2Cl2, boron trifluoride

etherateii- Dioxane, sodium hydroxide

iii- N,N-dimethylformamide, sodium hydride,

2 2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl-propionic acid

The product from Step 1 (27.5 mmol) was dissolved in 110 ml dioxane, 55 ml 1 M NaOHadded, and the mixture stirred at 80C for 2 hours Water was added to the mixture andthe aqueous phase extracted twice with diethyl ether The aqueous phase was acidifiedwith 1 M HCl, extracted with ether, and the combined organics, dried, and concentrated

6 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

The residue was recrystallized from diethyl ether/n-hexane and the product isolated in87% yield, mp= 133–135C.

3

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)-ethoxy)-3,3-diphenylpropionic acid

The product from Step 2 (2.3 mmol) was dissolved in 10 ml N,N-dimethylformamide,NaH (340 mg, 50% suspension) added, stirred 15 minutes, and 4-methoxy-6-methyl-2-methylsulfonylpyrimidine (526 mg) added The reaction stirred 3 hours at ambienttemperature, water was then added, and the mixture extracted with diethyl ether Theaqueous phase was acidified with 1 M HCl, extracted with diethyl ether, dried, andconcentrated The residue was purified by liquid chromatography, and the product isolated

in 52% yield.1H-NMR and MS data supplied

Derivatives

R 1 R 2 n Melting Point (C)

Methoxy 4-Ethoxy-3-methoxy-phenyl 2 166–169 (dec)

Methoxy 3,4-Methylenedioxyphenyl 2 146–148 (dec)

ACIDS AND DERIVATIVES 7

3 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3,3-diphenylvaleronitrile has previously been pared and converted to 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3,3-diphenylvaleric acid byhydrolysis (2) as illustrated in Eq 2:

pre-i- Hydrochloric acid, ethyl alcohol

4 In an earlier investigation by the author (3), the thio analogue of the current invention,methyl 3,3-di(4-methoxyphenyl)-2-(4,6-dimethylpyrimidine-2-sulfanyl)-pentanoate, (I),was prepared

References

1 H Riechers et al, US Patent 5,969,134 (October 19, 1999) and US Patent 5,932,730 (August 3,

1999)

2 D Klinge et al, US Patent 6,686,369 (February 3, 2004)

3 W Amberg et al, US Patent 6,235,903 (May 22, 2001)

8 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

Patent: Cinnamic Acid Derivatives

S.C Archibald et al, US Patent 6,329,362 (December 11, 2001)

Assignee: Celltech Therapeutics Limited

Utility: Treatment of Immune or Inflammatory Disorders

Reaction

ACIDS AND DERIVATIVES 9

i- Potassium carbonate, N,N-dimethylformamide

ii- 10% Palladium on carbon, methyl alcohol,

N-acetyl-thioproline, 1-hydroxylbenzotriazole,N-methylmorpholine,

CH2Cl2,1-(3-dimethylaminopropyl)-3ethylcarbodiimideiii- THF, sodium hydride

iv- Lithium diisopropylamide, THF

v- THF, lithium hydroxide monohydrate

Experimental

1 4-(2,6-Dichlorobenzoxy)benzaldehyde

A suspension of 4-hydroxybezaldehyde (157.5 mmol), 2,6-dichlorobenzylbromide(150 mmol) and K2CO3 in 150 ml DMF was stirred overnight at ambient temperature.The mixture was filtered, evaporated, and the residue dissolved in 500 ml diether ether

It was washed with 100 ml apiece water and brine, dried, and evaporated under reducedpressure The solid was re-crystallized in diisopropylether to give the product in 85%yield, mp= 70–71C.1H-NMR and elemental analysis data supplied

2 N-Acetyl-D-thioproline--phosphonoglycine trimethyl ester

A mixture of N-(benzyloxycarbonyl)--phosphonoglycine trimethyl ester (15 mmol) and10% palladium on carbon (500 mg) in 50 ml methyl alcohol was stirred under a hydro-gen atmosphere (balloon) at ambient temperature for 4 hours The mixture was filteredand the solvent evaporated N-acetyl thioproline (15 mmol), 1-hydroxylbenzotriazole(15 mmol), N-methylmorpholine (16.5 mmol) dissolved in 75 ml CH2Cl2, and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (16.5 mmol) were added to the residue andthe mixture stirred overnight at ambient temperature Thereafter it was diluted with

CH2Cl2, washed with 50 ml apiece 1 M HCl, NaHCO3 and water It was purified bycolumn chromatography on silica gel using CH2Cl2/methyl alcohol, 93:7, and the productisolated in 53% yield.1H-NMR data supplied

10 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

3 N-Acetyl-D-thioproline-O-(2,6-dichlorobenzyl)-(Z)-didehydotyrosine methyl ester

The product from Step 2 (2.06 mmol) was dissolved in 10 ml THF and added dropwise

to a stirred suspension of NaH (2.27 mmol) in 5 ml THF at ambient temperature After

15 minutes, the product from Step 1 (2.1 mmol) dissolved in 5 ml THF was added, themixture stirred for several hours and was then quenched with 1 ml water The organicphase was evaporated and the residue purified by column chromatography on silica with

CH2Cl2/methyl alcohol, 95:5, yielding a Z/E geometric isomer ratio of 76:24, respectively.The desired Z-isomer was isolated by re-crystallization, mp= 189–190C.1H-NMR andmass spectrum data supplied

4 N-Acetyl-D-thioproline-O-(2,6-dichlorobenzyl)-(E)-didehydotyrosine methyl ester

The product from Step 2 (1.45 mmol) was dissolved in 10 ml THF and added to a solution

of 2 M LDA (1.45 mmol) in 5 THF at−78C The mixture warm to 0C and the product

from Step 1 (1.45 mmol) dissolved in 3 ml THF added followed by 2 ml DMF Thesolution was stirred overnight at ambient temperature and then the solution evaporated.The residue yielded Z/E geometric isomer ratio of 56:44, respectively The mixture waspurified by column chromatography on silica gel using CH2Cl2/methyl alcohol, 97:3,providing 105 mg of the desired E-isomer.1H-NMR data supplied

5 N-Acetyl-D-thioproline-O-(2,6-dichlorobenzyl)-(Z)-didehydotyrosine (Note 2)

The product from Step 3 (0.75 mmol) was dissolved in 7.5 ml THF and 7.5 ml water to whichwas added lithium hydroxide monohydrate (0.83 mmol) and the mixture stirred overnight

at ambient temperature The organic solvent was removed, the aqueous phase acidified with

1 M HCl, and the product extracted twice with 50 ml CH2Cl2 The organic phase was driedand evaporated under reduced pressure The Z-isomer was isolated by lyophilisation from amixture of methyl alcohol and water in 95% yield.1H-NMR data supplied

Derivatives

N-Acetyl-(L)-thioproline Hydrogen o-Benzoyl 449N-Acetyl-(L)-thioproline Phenyl Acetamide 378(2-Chloro-3-pyridinyl)carbonyl Hydrogen o-2,6-Dichlorobenzyl 477Trimethylacetal Phenyl 2,6-Dichlorobenzylamino 435

ACIDS AND DERIVATIVES 11

R 1 R 2 R 3 MS (M +1)

Trimethylacetal Phenyl 2,6-Dichlorobenzylamino 435

N-Acetyl-(L)-thioproline Phenyl 2,6-Dichlorobenzylamino 508

N-Acetyl-(L)-thioproline Hydrogen o-Benzoyl 427

N-Acetyl-(L)-thioproline Hydrogen o-2,6-Dichlorobenzyl 495

3 N-Acetyl-D-thioproline-O-(2,6-dichlorobenzyl)-(E)-didehydotyrosine was also prepared

by the author in the current invention and is described

4 1H-NMR data for all derivatives supplied by author

12 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

Patent: Compounds Derived from Benzoic Acid Esters, Composition

Containing Said Compounds and Use Thereof

J.-B Galey et al, US Patent 6,602,869 (August 5, 2003)

Assignee: L’Oreal S.A.

Utility: Treatment of Alopecia

100 ml ice water The mixture was extracted 3 times with 50 ml CH2Cl2washed withwater, dried and concentrated

The oil was dissolved in 20 ml toluene/heptane, 1:1, and the product isolated by matographyon silica gel with CH2Cl2in 50% yield Elemental analysis data supplied

chro-ACIDS AND DERIVATIVES 13

Notes

1 Although structural conformation of compounds of this invention were confirmed by

500 MHz 1H-NMR in d6-DMSO, spectra were not supplied by author Derivatives,however, were used in skin lotion formulations and results provided

2 Phenyl 2-hydroxy-4-(3,3,3-trifluoromethyl-2-hydroxy-2-methylpropionylamino)benzoicacid is the latest chemical agent designed to treat alopecia supplanting 6-amino-1,2dihydro-1-hydroxy-2-aminopyrimidine (Minoxidil) (I) (1) and pyrimidine oxide deriva-tives (II) (2), (III) (3), and (IV) (4)

References

1 W.C Anthony et al, US Patent 3,461,461 (August 12, 1969)

2 E Terranova et al, US Patent 5,466,694 (November 14, 1995)

3 M Hocquaux et al, US Patent 5,772,990 (June 30, 1998)

4 D Dufetel et al, US Patent 5,760,043 (June 2, 1998)

14 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

Patent: 1,2-Diarylmethylene Derivatives, Their Methods of Preparation, and

Their Uses in Therapeutics

E Nicolai et al, US Patent 5,972,950 (October 26, 1999)

Assignee: Laboratories UPSA

Utility: Anti-Inflammatory and Analgesic Agents

Reaction

i- CH2Cl2, aluminum chloride

ii- CH2Cl2, 3-chloroperbenzoic acid

iii- Ethyl succinate, potassium t-butoxide, t-butyl alcohol

iv- THF, borane/dimethyl sulfide

v- Sodium hydroxide, ethyl alcohol

Experimental

1 4-Chloro-4-methylthiobenzophenone

Thioanisole (0.852 mol) and 4-chlorobenzoyl chloride (0.894 mol) were dissolved in

600 ml CH2Cl2, AlCl3 (0.98 mol) added, and the mixture stirred while maintaining thetemperature between 0C and−5C for 2 hours Thereafter it stood overnight and was

then refluxed for 6 hours The mixture was poured into ice water containing dilute HCl,the aqueous phase extracted with CH2Cl2 and combined with the organic phase, dried,and the product is isolated, mp= 134C.

ACIDS AND DERIVATIVES 15

3

(Z)-3-Ethoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulfonyl-1-phenyl)but-3-enoic acid.

The product from Step 2 (1.16 mol), ethyl succinate (1.85 mol), potassium t-butoxide(1.74 mol) and 2.5 L t-butyl alcohol were mixed and a temperature rise to 45C observed.Thereafter, the mixture was stirred for 7 hours at ambient temperature and then pouredinto ice water acidified with HCl to pH 3 The product was extracted with diethylether and dried Overnight the Z isomer precipated from solution, was filtered from themixture, re-crystallized in isopropanol, and had a mp= 184–186C The corresponding

(E) isomer was obtained upon evaporation of the solvent

4 Ethyl (Z)-3-(4-chlorophenyl)3-(4-methanesulphonylphenyl)-2-(hydroxyethyl)

prop-2-enolate

The product from Step 3 (0.0775 mol) was dissolved in 90 ml THF and borane/dimethylsulfide added dropwise The mixture was stirred at ambient temperature for 8 hoursand 23.5 ml ethyl alcohol added The mixture was evaporated to dryness, the residuere-dissolved in EtOAc, washed, dried, and the product isolated after re-crystallization inisopropanol, mp= 128C.

5 Sodium (Z)-3-(4-chlorophenyl)3-(4-methanesulphonylphenyl)-2-(hydroxyethyl)

prop-2-enolate

The product from Step 4 (0.0122 mol) was dissolved in 10 ml ethyl alcohol and 11 ml

1 M NaOH added The mixture was refluxed for 2 hours then evaporated to dryness Thecrystals were washed with EtOAc and diethyl ether and isolated, mp= 257–259C.

Derivatives

R 1 R 2 R 3 MPC

Ethyl 4-Fluorophenyl Carboxylic acid 155–156

Methyl 3,5-Dichlorophenyl Carboxylic Acid 207–209

Ethyl 4-Fluorophenyl Ethoxycarbonyl 130

Ethyl 4-Fluorophenyl Carboxylic acid 207–209

Amine 3-Methylphenyl Carboxylic acid 161

16 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

Notes

1 (E)- and (Z)-isomers were separated and purified by re-crystallization in isopropanol

In a typical separation procedure 82% of the (E)-isomer remained dissolved while the(Z)-isomer precipitated from solution and was isolated by filtration

2 Diarylmethylenefuran derivatives of the current invention have also been prepared (1)using a modified Reformatsky reaction illustrated in Eq 1:

i- N,N-Diethylamine, bromoethane, magnesium, diethyl etherii- Trifluoroacetic acid/trifluoroacetic anhydride

3 4- or 5-Sulfonylmethyl-3(2H)-furanone derivatives have also been prepared (2) as trated in Eq 2:

illus-i- Sodium hydride, THFii- m-Chloroperbenzoic acid

ACIDS AND DERIVATIVES 17

4 2,3,4,5-Tetrahydrofuran-2-one derivatives were previously prepared by the author bycyclization of (E)-3-(4-fluorophenyl)-3-(4-sulfamoyl-phenyl)-2-(2-hydroxylethyl)propen-2-enoic acid, (I), and are discussed (3)

References

1 E Nicolai et al, US Patent 5,807,873 (September 15, 1998)

2 S.W Felman et al, US Patent 5,389,673 (February 14, 1995)

3 E Nicolai et al, US Patent 5,840,753 (November 24, 1998)

18 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

Patent: Geranic Acid Derivatives

P Frankhauser et al, US Patent 6,384,242 (May 7, 2002)

Assignee: Firmenich SA and Lonza AG

Utility: Fragrance and Perfume Component

Reaction

i- CH2Cl2, boron trifluoride etherate, ketene, urotropine

ii- Sodium hydroxide, tributylbenzylammonium chloride

Experimental

1 4-Methyl-4-(4-methylpent-3-en-1-yl)-oxetane-2-one

A vessel was charged with 6-methyl-5-hepten-2-one (1.0 mol) and 516 g CH2Cl2, cooled

to −19C, and boron trifluoride etherate (0.5 mol) and ketene gas metered in over the

course of 4 hours Throughout this period the temperature was maintained between

−12C and−14C Thereafter urotropine (2.5 mmol) was added and the solution stirred

for 30 minutes at 0C The solvent was evaporated at 15 mbarr at 20C and the productisolated in 80.9% yield by vacuum distillation.1H-NMR and mass spectrum data supplied

2 (+/−)-3-Hydroxy-3,7-dimethyl-oct-6-enoic acid [3-hydroxycitronellic acid]

The product from Step 1 (0.259 mol) was dissolved in 180 ml 2 M NaOH containingtributylbenzylammonium chloride (0.49 g) whereupon the temperature rose to 51C andstirred for 2.5 hours The mixture was cooled to 20C and stirred overnight The productwas extracted twice with 100 ml diethyl ether, acidified with 390 ml 1 M HCl, dried, andthe product isolated in 83.4% yield as a yellow oil

Notes

1 The oligomeric ester, (I), of the product of Step 1 was also by the author and is described:

ACIDS AND DERIVATIVES 19

Procedure

To the product from Step 1 (0.118 mol) at 10C was added 98% H2SO4(0.2 g) dropwise

so that the temperature remained below 28C After the exotherm had subsided, themixture was stirred 7 hours at 25C resulting in a slightly viscous solution Titrationwith Bu4NOH in methyl alcohol determined the oligomer had a molecular weight of

450 AMU

Thermal decomposition of the oligomeric ester produced - and -cyclogeranic acids

in 47% and 30% yields, respectively Other preparative methods for these acids isdescribed (1)

2 When the product of Step 1 was heated to between 180C and 250C, decarboxylationoccurred forming 2,6-dimethyl-hepta-1,5-diene as illustrated in Eq 1:

Decomposition conversions at considerably lower temperatures have been observed whenthe reaction was performed in protonated DMF (2)

3 The preparation of  -dicarboxylic acid diesters is described (3)

References

1 K-H Schulte-Eite, US Patent 3,887,625 (June 3, 1975)

2 M Fujisawa et al, Bull Soc Chem Jpn., 55, 3555 (1982)

3 R Fischer, US Patent 5,453,535 (September 26, 1995)

20 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

Patent: Halogenated Cinnamic Acids and Esters Thereof, Processes for the

Preparation Thereof and Halogenated Aryldiazonium Salts

M Beller et al, US Patent 5,516,932 (May 14, 1996)

Assignee: Hoechst Aktiengesellschaft

Utility: Sun Screen Additive

Reaction

i- THF, tetrafluoroboric acid, sodium nitrite

ii- 2-Ethylhexyl acrylate, dimethylsulfoxide, 5% palladium on

in 84% yield, bp= 363C (extrapolated from GC).1H- and19F-NMR and mass spectrumdata supplied

ACIDS AND DERIVATIVES 21

Derivatives

R 1 R 2 R 3 Yield (%)

Ethyl Chloro Chloro 93n-Butyl Chloro Chloro 862-Ethylhexyl Fluoro Fluoro 87

3 The preparation of other polyhalobenzoic acid cinnimates is described (1)

4 The preparation of 2,4,5-trihaloaniline analogues of the current invention is described (2)

5 In a subsequent investigation by the author, cis- and cinnamonitrile derivatives were prepared (3)

trans-4-(2,2,3,3-tetrafluoropropoxy)-References

1 S Kuami et al, US Patent 5,093,515 (May 3, 1992)

2 D.S Davenport et al, US Patent 4,346,248 (August 24, 1984)

3 M Beller et al, US Patent 5,663,410 (September 2, 1997)