PROCESS ECONOMICS PROGRAM

SRI INTERNATIONAL Menlo Park, California 94025

Abstract

Process Economics Program Report No. 143

PYRETHROID INSECTICIDES

(June 1981)

The technology, economics, and marketing strategies of synthetic pyrethroids are reviewed. Four relatively new compounds--permethrin, cypermethrin, decamethrin, and fenvalerate--are being commercially used in controlling many agricultural insect pests at practical doses up to one-tenth that required by conventional synthetic insecticides, with significantly lower polluting persistence, lower mammalian toxicity, and lower insect resistance.

The technology consists of a series of complex stepwise organic syntheses, most of which are covered by recent patents issued to many companies which are already active in or planning to enter this field.

An in-depth technical and economic analysis is made for a perme- thrin design at 2 million lb per year with educated cost approximations for the other compounds. The processes are based upon the use of rela- tively inexpensive raw materials to produce all the required intermedi- ates rather than purchase these intermediates at expensive prices.

PEP'79 LAW

For detailed marketing data and information, the reader is referred to one of the SRI programs specializing in marketing research. The CHEMICAL ECONOMICS HANDBOOK Program covers most major chemicals and chemical products produced in the United States and the WORLD PETROCHEMICALS Program covers major hydrocarbons and their derivatives on a worldwide basis. In addition, the SRI DIRECTORY OF CHEMICAL PRODUCERS services provide detailed lists of chemical producers by company, prod- uct, and plant for the United States and Western Europe.

ii CONTENTS

1 INTRODUCTION...... 1

2 SUMMARY ...... 3 General ...... 3 Marketers ...... 6 Applications...... ,...... 7 Agricultural...... 7 Animal Health...... 8 Industrial, Warehouse, and Household Insect Control .... 9 Market ...... 9 Economic Aspects...... 11 Technical Aspects ...... 14 Permethrin (NRDC 143) ...... 14 Cypermethrin (NRDC 149) ...... 16 Fenvalerate (S-5602)...... 18 Decamethrin (NRDC 161)...... 18

3 INDUSTRY STATUS ...... 21 Relative Activities and Toxicities...... 21 Marketers ...... 28 Applications...... 30 Agricultural...... 30 Animal Health...... 32 Industrial, Warehouse, and Household Insect Control .... 32 Insect Resistance ...... 33 Market ...... 34 Supplier Manufacturing and Marketing Strategies ...... 40 FMC Corporation (U.S.)...... 40 ICI Ltd. (U.K.) ...... 42 Shell International Chemical Company (Netherlands); Shell Chemical Company (U.S.) ...... 44 Sumitomo...... 45 Roussel-UCLAF ...... 46 Mitchell Cotts Chemicals (U.K.) ...... 47 Alcoholic Pyrethroid Intermediate ...... 47 Review ...... 49

iii CONTENTS

4 CHEMISTRY OF NATURAL PYRETHRINS AND SYNTHETIC PYRETHROIDS. . . 51 Natural Pyrethrins ...... 52 Synthetic Pyrethroids:...... 56 Photostability ...... 61

5 PERMETHRIN ...... 65 Chemistry ...... 65 Synthesis of the Acid Moiety (DV-Acid Ester) ...... 65 Farkas and FMC Methods ...... 67 Sagami Method ...... 69 Kuraray Method ...... 71 NRDC Method ...... 71 Synthesis of the Alcohol Moiety ...... 74 meta-Phenoxybenzyl Alcohol ...... 74 alpha-Cyano-meta-PhenoxybenzylAlcohol ...... 76 Permethrin Synthesis ...... 78 Cypermethrin Preparation ...... 78 Isomerism ...... 81 Process Description...... 98 General ...... 98 Acid Moiety (DV-Acid Ester)--Sagami Method (Figure 5.12) . . 99 Acid Moiety DV-Acid Ester--Kuraray Method (Figure 5.13). .. 109 Alcohol Moiety--Synthesis of m-Phenoxybenzyl Alcohol (XI) (Figure 5.14) ...... 111 Permethrin (XII) Synthesis (Figure 5.15) ...... 114 Triethyl Orthoacetate (II) Synthesis (Figure 5.16) ..... 115 Synthesis of Isoprenol, 3-methyl-2-buten-l-01 (I), for Sagami Method (Figure 5.17)...... 116 Equipment for Design ...... 117 Process Discussion ...... 118 Acid Moiety--Sagami Method ...... 118 Acid Moiety--Kuraray Method...... 120 m-Phenoxybenzyl Alcohol (XI) ...... 121 Permethrin (XII) Synthesis ...... 123 Triethyl Orthoacetate (II) Synthesis ...... 124 Isoprenol (I) Synthesis...... 124

iV CONTENTS

6 FENVALERATE...... 127 Chemistry ...... 129 Industrial Process Procedure ...... 134

7 DECAMETHRIN...... 141 Chemistry ...... 144 NRDC Synthesis of Decamethrin (NRDC 161) ...... 144 Chrysanthemic Acid from 2,5-Dimethylhexa-2,4-diene . . . . 144 Roussel-UCLAF Developments ...... 146 Epimerization and Resolution of NRDC 156 Mother Liquors ...... 146 (lR)-cis-ChrysanthemicAcid by Interconversion from the trans Acids ...... 149 Resolution of Racemic (RS)-alpha-Cyano-3-Phenoxybenzyl Alcohol ...... 149 Commercial Preparation of Decamethrin...... 153 Recent Developments in Decamethrin Synthesis ...... 155 Conversion of 2,2-Dichlorovinyl Cyclopropane Derivatives to Dibromovinyl Analogs...... 155 Stereoselective Synthesis of cis-3-(2,2-Dihalovinyl)- 2,2-DimethylcyclopropaneCarboxylic Acids...... 156 Stereospecific Synthesis of (lR)-cis-3(2,2-Dichlorovinyl)- 2,2-DimethylcyclopropanecarboxylicAcid (cis-"Acid") . . . 156

8 COSTESTIMATES ...... 163 Permethrin ...... 163 Capital Costs--Sagami Process ...... 163 Capital Costs--Kuraray Process ...... 164 Production Costs--Sagami Process ...... 167 Production Costs--Kuraray Process...... 171 Cypermethrin ...... 174 Fenvalerate ...... 174 Decamethrin ...... 175

9 DEVELOPMENT OF OTHER SYNTHETIC PYRETHROIDS ...... 177

CITED REFERENCES ...... 199

PATENT REFERENCES BY COMPANY ...... 215

V ILLUSTRATIONS 0 2.1 Chemical Structures of Selected Pyrethroids and Their Relative Toxicities...... 5 2.2 Permethrin Synthesis Flow Chart...... 15 2.3 Cypermethrin and Fenvalerate ...... 17 2.4 Decamethrin (S)-Stereoisomer ...... 20 3.1 Summary of U.S. Insecticide Consumption...... 38 3.2 U.S. Demand by Type of Insecticide ...... 39 4.1 Chemical Structures of Natural Pyrethrins...... 53 4.2 Structure of Synthetic Pyrethroids ...... 59 4.3 Recent Synthetic Pyrethroids for Commercial Development. .. 62 4.4 Comparison of Unstable and Stable Pyrethroids...... 63 5.1 Methods of Synthesis of DV-Acid Ester for NRDC-143 and NRDC-149 ...... 66 5.2 Farkas and FMC Routes to DV-Acid Ester Using l,l.-Dichloro-4-Methyl-1.3-Pentadiene...... 68 5.3 Sagami Synthesis of DV-Acid Ester...... 70 5.4 Kuraray Synthesis of DV-Acid Ester ...... 72 5.5 NRDC Synthesis of DV-Acid Ester ...... 73 5.6 Synthesis of the Alcohol Moiety ...... 75 5.7 Synthesis Routes for 3-Phenoxybenzaldehyde ...... 77 5.8 Permethrin Preparation ...... 79 5.9 Cypermethrin Preparation ...... 80 5.10 Active Permethrin Isomers (D-Configuration)...... 82 5.11 Permethrin Schematic Material Flow Diagram ...... 221 5.12 DV-Acid Ester Synthesis--Sagami Method Flow Diagram ...... 223 5.13 DV-Acid Ester Synthesis--KurarayMethod Flow Diagram ...... 225 5.14 Alcohol Moiety Synthesis Flow Diagram ...... 227

vii ILLUSTRATIONS

5.15 Permethrin Synthesis by Transesterification Flow Diagram...... 229 5.16 Triethyl Orthoacetate Synthesis Flow Diagram...... 231 5.17 3-Methyl-2 Buten-l-01 Synthesis (Iroprenol) for Sagami Method Flow Diagram...... 233 6.1 Comparison of Structural Formulas ...... 128 6.2 Synthesis of Fenvalerate via 2-(4-Chlorophenyl)- Isovaleric Acid ...... 130 6.3 Synthesis of Fenvalerate A/alpha Via (S)-2-(Chlorophenyl)- Isovaleric Acid ...... 133 6.4 Fenvalerate Synthesis Schematic Material Flow Diagram . . . 135 6.5 Fenvalerate Synthesis Process Block Flow Diagram...... 136 7.1 Chemical Formula for Active Decamethrin ...... 142 7.2 Synthesis of Decamethrin...... 145 7.3 Chrysanthemic Acid from 2,5-Dimethylhexa-2,4-Diene.. . . . 147 7.4 Inversion of Inactive (R) Isomer to Active (S) Isomer . . . 148 7.5 (+)-cis-ChrysanthemicAcid From (+)-trans and (-)-trans-ChrysanthemicAcids ...... 150 7.6 Resolution of (RS)-alpha-Cyano-3-PhenoxybenzylAlcohol Using (lR,4R,5S)-4-Hydroxy-6,6-Dimethyl-3-Oxabicyclo (3.1.0) Hexan-2-One ...... 152 7.7 Decamethrin Industrial Process Schematic BlockFlowDiagram ...... 154 7.8 Scheme for the Synthesis of (lR)-cis-3-(2,2-Dichlorovinyl) 2,2-DimethylcyclopropanecarboxylicAcid ...... 157 7.9 Synthesis of Optically Active (lR)-cis-"Acid" ...... 159 7.10 Bicyclic Lactone Synthesis Route for (lR)-cis-"Acid". . . . 160 8.1 Permethrin Effect of Plant Capacity on Total Fixed Capital ...... 168 8.2 Permethrin--Sagami Process Effect of Operating Level and Plant Capacity on Production Cost ...... 170

viii ILLUSTRATIONS

8.3 Permethrin--Kuraray Process Effect of Operating Level and Plant Capacity on Production Cost...... 173 9.1 Chemical Structures of Other Pyrethroids...... 178

iX TABLES

2.1 Permethrin Synthesis Summary of Capital and Production Costs...... 12 3.1 Relative Toxicities of Some Commercial Pyrethroids Versus Other Organic Chemical Insecticides to 12 Species of Insects by Topical Application...... 22 3.2 Median Lethal Doses (NG/FLY) of Insecticides to Teneral Glossina Austeni (Tsetse Fly) ...... 25 3.3 Relative Toxicities of Insecticides to Schistocerca Gregaria (Mature Male Locusts) and Rats ...... 25 3.4 Median Effective Doses of Various Poisons and Insecticides to Mammals and Insects (mg kg-l)...... 26 3.5 Field Rates of Different Classes of Insecticides ...... 27 3.6 Synthetic Pyrethroid Licensees and Producers ...... 29 3.7 World Pesticide Sales...... 37 3.8 Selected Grower Prices ...... 41 4.1 Typical Components of Pyrethrum Oleoresin and Refined Extract ...... , ...... 52 4.2 Summary of Synthetic Pyrethroids ...... 58 5.1 DV-Acid Ester--Isomer Content ...... 83 5.2 Permethrin and Cypermethrin; Modified Cyclopropane Carboxylates Patent Summary...... 86 5.3 Isoprenol (3-Methyl-2-Buten-l-01) Patent summary...... 92 5.4 Alcohol Moiety Synthesis Patent summary...... 95 5.5 Permethrin Design Bases and Assumptions ...... 100 6.1 Stereoisomers, Stereoisomer Mixtures of Fenvalerate and Their Biocidal Activities ...... 131

xi TABLES

8.1 Permethrin--Sagami Process Estimated Capital Investment...... 165 8.2 Permethrin--Kuraray Process Estimated Capital Investment...... 166 8.3 Permethrin--Sagami Process Production Costs ...... 169 8.4 Permethrin--Kuraray Process Production Costs ...... 172 9.1 General Patent References ...... 181

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