synthetic pyrethroids
TRANSCRIPT
SYNTHETIC PYRETHROIDSA seminar by Meet Patel - 13DYE1001
TABLE OF CONTENTS Synthetic Pyrethroids – Discovery, Classification and Structureso Novelty of synthetic pyrethroids Synthesis Process o Application of synthetic pyrethroids Mode of actiono Mechanism of metabolism Recent developmentso Current market
1. SYNTHETIC PYRETHROIDS – DISCOVERY, CLASSIFICATION AND STRUCTURES
DISCOVERY Pyrethroids insecticides are synthetic analogues of the naturally occurring insecticidal
pyrethrins found in extract of Chrysanthemum cinerariaefolium.
J. J. Schleier & R. K. Peterson, Green Trends in Insect Control, Ch. 3, Royal Society of Chemistry, 2011, 94-13
R
OO
OX
TIMELINE AND CLASSIFICATION
• Hermann Staudinger and Leopold Ruzicka in the 1920sPyrethrins
• Schechter in 1949 • First non-natural pyrethroids, Allenthrin1st Generation
• Further classified as Type1- Permethrin, 1973 Type2- Cypermethrin, 1974
2nd Generation
Dr. Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54
STRUCTURES
O
O
O
O
O
O
OO
OClCl
OO
OClCl
C
N
Allenthrin Resmethrin
Permethrin Cypermethrin
1st generation synthetic pyrethroids
2nd generation synthetic pyrethroids
Type I Type II
STRUCTURAL CHANGES
Etofenprox
Kadethrin Protriefenbute
Fenvalerate
Dr. Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54
OO
OCl
C
N
OO
O
O
O
O
S
O
O
F
O
STEREOCHEMISTRY- TYPE I
The 1R conformations about the cyclopropane ring are considerably more toxic than the 1S isomers.
(S)
(S) H
H
RO
OR'
(S)
(R) H
H
RO
OR'
(R)
(R) H
H
RO
OR'
(S)
(S) H
H
RO
OR'
Cis isomers
Trans isomers
STEREOCHEMISTRY- TYPE II
Pyrethroid Product Isomers Stereo-chemistry
Cypermethrin Alpha 2 (1R)-cis, αS(1S)-cis, αR
Beta 4 (1R)-cis, αS(1S)-cis, αR(1R)-trans, αS(1S)-trans, αR
Cyhalothrin Lambda 2 (1R)-cis, αS(1S)-cis, αR
Super 1 (1R)-cis, αS
R1
O
O
R2
CN
Type II
All type II pyrethroids possess an additional chiral center at the α-C with the α S conformation considerably more toxic towards insects when compared to the α R conformation.
**
*
Table: Examples of commercial product based on isomers
i. Pyrethroids, Agrochemicals Analysis Technical Note, Coresta March 2014ii. Dr. Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54
2 . NOVELTY OF SYNTHETIC PYRETHROIDS
TOXICITY PROFILE
Noritada Matsuo & Tatsuya Mori, Pyrethroids:From Chrysanthemumto Modern Industrial Insecticide, 2012, Ch.1
InsecticidesLD50 (mg /kg)
Mammal (rat) Insects
Ratio of selectivity
Carbamate 45(15) 2.8(27) 16
Organophosphorus 67(83) 2.0(50) 33
Organochlorine 230(21) 2.6(26) 91
Pyrethroids 2000(27) 0.45(35) 4500*Number of pesticides tested in parenthesis
TOXICITY DATA
The Pesticides Manual, Twelfth edition
Insecticide Oral LD50 (rats)
(mg/kg)
Dermal LD50 (rats)
(mg/kg)Chlorpyrifos 135-163 2000 (rabbit)
Diazinon 300-400 >2150
Deltamethrin 531-5000 >2000
Cypermethrin 251-4123 >2400 (rabbit)
Bioresmethrin 7070-8000 >10000 (female)
Allenthrin 1100 (male) >2300
TOXICITY TO NON-TARGET INSECTSFish Bee
i. Noritada Matsuo & Tatsuya Mori, Pyrethroids:From Chrysanthemumto Modern Industrial Insecticide, 2012, Ch.1i. F. Antwi, V. P. Reddy, Toxicology effects of pyrethroids on non-target aquatic insects, Environmental Toxicology and Pharmacology, September 2015
PyrethroidsLC50 Value
Carp(ppm/48 h) Daphnid(ppm/3 h)
Silafluofen >100 7.66Etofenprox 5 40
Cycloprothrin 8 >10Fenvalerate 0.00075 0.3Permethrin 0.043 >10Cyfluthrin 0.012 0.94
Tralomethrin 0.008 0.22Fluvalinate 0.00048 0.298
Pyrethroid
Acute Oral LD50 (μg a.i./bee )
Acute Contact LD50 (μg a.i./bee )
Bifenthrin 0.01 0.002
Cypermethrin
0.03 0.02
Deltamethrin 0.08 0.001
Permethrin 0.03 0.1
TOXICITY TO HUMANS
Technical Report, Louise Hénault-Ethier, Canadian Association of Physicians for the Environment, 2016
Acute toxicity Chronic toxicityEye irritation Change in immunity
Mouth Ulcer Potential carcinogenicity
Irritation in nasal cavity Non-specific symptoms
Tremors Thyroid inactivity
Paraesthesia & Cutaneous reactions
Estrogenic & anti-androgenic activities
Coma, convulsions & Death Neurotoxicity
TOXICITY TO HUMANS – CASE STUDIESCase study 1 In a single case report, a 28-
year-old man who applied some 1.5g permethrin in cream from neck to toe and did not wash for about 10 hours developed severe torticollis and inability to tilt his head to the left. This persisted unchanged for 24 hours and no cause other than the pesticide was identified.
Case study 2 Of 12 workers who
sprayed lambda Cyhalothrin indoors,11 complained of nasal irritation and six of throat irritation.
Case study 3 A 45-year-old man died 3 hours
after eating beans and cheese prepared using Cypermethrin 10% instead of oil. He developed symptoms within a few minutes, including prolonged vomiting, tenesmus, diarrhea, convulsions, coma. Death followed respiratory arrest.
A. Vale, Poisoning due to Pyrethroids, Toxicological Reviews, February, 2005
TOXICITY TO ENVIRONMENT
Noritada Matsuo & Tatsuya Mori, Pyrethroids:From Chrysanthemumto Modern Industrial Insecticide, 2012, Ch.1
Isomerization
Homolytic cleavage
SYNERGISTS Synergists are typically non toxic compounds at the dosage applied, but which
enhance the toxicity of the active pesticide ingredients. Methylenedioxyphenyl synergists, such as piperonyl butoxide, are thought to suppress
primarily oxidative detoxification by inhibiting enzymatic action of CYP enzyme within the insect.
C. Pasa, L. Arlian, M. Morgan, R. Gunning, L. Rossiter, D. Holt, S. Walton, S. Beckham, J. McCarthy, Synergists in Pyrethroid-Resistant Scabies Mites, PLOS journal of neglected tropical diseases, January 2009, Volume 3, Issue 1
Treatment Sensitive mites Resistant mitesPermethrin 4 15
Permethrin + PBO 4 4Permethrin + DEF 3.5 6Permethrin + DEM 2 3
3 . SYNTHESIS PROCESS
SYNTHESIS OF CHRYSANTHEMIC ACID
Trans-chrysanthemic acid
Cu - catalyst
N2
OEt
O
OEtO
First industrial process and its still used with better catalysts giving specifically 1R isomer which has more insecticidal activity.
Professor Dr. Bernd Schaefer, Natural Products in the Chemical Industry, Springer-Verlag Berlin Heidelberg 2014, 704-723
ISOMERIZATION OF CHRYSANTHEMIC ACID
O
OH
Thionyl chlorideLewis acid,150° to 170° C
Cis : Trans = 45:55
Cis : Trans = 18.8:81.2
Cis : Trans ratio in the product depends on Lewis acid we use.
Process for isomerization of a cyclopropane carboxylic acid, US 4008268 A, Sumitomo Chemical Company, 15 Feb 1977
MECHANISM OF ISOMERIZATION
Dr. Klaus Naumann, Chemistry of Plant Protection, Ch. - Synthetic Pyrethroid Insecticides: Chemistry and Patents, 1990
GETTING 1R ISOMER
(S)
NH2
(S) (R)HH
OH
O (Z)
Cl
CF3
H
(R) (S)HH
OH
O (Z)
Cl
CF3
H
i. MeOH, H2Oii. Acid hydrolysis
A process for the production of 1r pyrethroid esters, WO 2003053905 A1, Syngenta Limited, Jul 3, 2003
H
F
F
FCl
OH
O Major product
SYNTHESIS OF GAMMA CYHALOTHRIN
Three step synthesis:-
Chlorinating acid derivative Esterification Epimerizing the diastereoisomeric mixture
PRODUCTION PROCESS OF GAMMA-CYHALOTHRIN, Indian Patents: 219118, SYNGENTA LIMITED, Publication Date 06-Jun-2008 http://www.allindianpatents.com/patents/219118-production-process-of-gamma-cyhalothrin
(R)
(R)
(Z)
F3C Cl
O
O
(S)O
CN
(S)- α -cyano-3-phenoxybenzyl (Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate
CHLORINATION
Chlorinating agentSolvent, Tb of solvent(R)
(R)
(Z)
F3C Cl
OH
O
(R)
(R)
(Z)
F3C Cl
Cl
O
ESTERIFICATION
OHC
O Cyanide source SolventOrganic base 0°C and 20°C.
Diastereoisomeric mixture of Cyhalothrin isomers
(R)
(R)
(Z)
F3C Cl
Cl
O
(R)
(R)
(Z)
F3C Cl
O
O
(S)O
CN
(R)
(R)
(Z)
F3C Cl
O
O
(R)O
CN
EPIMERIZING THE DIASTEREOISOMERIC MIXTUREDiastereoisomeric mixture of Cyhalothrin isomers
Solvent, -10°C to 10°C
Source of cyanide / tertiary amine / a seed of gamma-Cyhalothrin
gamma-Cyhalothrin and a diastereomer ratio of 95:5.
Second and third step can be done in a single reactor without any isolation but we need to compromise with yield.
PRODUCTION PROCESS OF GAMMA-CYHALOTHRIN, Indian Patents: 219118, SYNGENTA LIMITED, Publication Date 06-Jun-2008 http://www.allindianpatents.com/patents/219118-production-process-of-gamma-cyhalothrin
FORMULATIONSPyrethroid Formulation
PermethrinEmulsifiable concentrate (100-500 g a.i/l)
Wettable powders (100-500 g/kg)Aerosol conc. & Fumigants ( household use)
Cypermethrin Emulsifiable concentrate (25-200 g/l)ULV concentrates (10-50 g/l)
DeltamethrinEmulsifiable concentrate (25 g a.i/l)
Granules (0.5 g/kg)Wettable powders (25 g/l)
Bioresmethrin Aerosol concentrates (1 g/l)Ready to use liquid (for oil/water based sprays, 2.5 g/l)
The Pesticides Manual, Twelfth edition
4 . APPLICATIONS OF SYNTHETIC PYRETHROIDS
AGRICULTURAL APPLICATIONS
Pyrethroids Insects Crops
Bifenthrin Beetles, aphids, moths, locust, lice, houseflies
Beans, cereals, corn, cotton, melons
Cypermethrin Cockroaches, flies, moths, mosquitoes
Cotton, onions, pears, peaches
Deltamethrin Aphids, bollworms, caterpillars, cicadas
Alfalfa, beet, maize, cotton potatoes, soyabean
Fluvalinate Leafhoppers, thrips spider mites, moths
Cereals, cotton, tobacco, apples
Permethrin Ants, termites, lice, weevils, Cotton, lettuce, wheat, tomatoes
OTHER APPLICATIONS
Pyrethroids
Households
Medical uses
Veterinary uses
OrnamentalsPlants
i. A.J. Thatheyus, A.Deborah Gnana Selvam, Synthetic Pyrethroids: Toxicity and Biodegradation, App. Eco. & Env. Sci., 2013, Vol. 1, 33-36 ii http://www.anapsid.org/pyrethroids.html
5 . MODE OF ACTION
MODE OF ACTION
SYMPTOMS Mammalian intoxication by type I pyrethroids causes symptoms characterized by tremor
i.e. T-class, exaggerated startle response, and hyperexcitability. Intoxication by type II pyrethroids results in burrowing and pawing behavior, followed by
salivation and coarse tremor, which evolves into choreoathetosis (involuntary movement and writhing). This second type of poisoning is referred to as CS-class.
Some pyrethroids, such as fenpropathrin and cyphenothrin can result in symptoms from both T and CS-class, thus are called TS-class.
i. E. Wakeling, A. Neal & W. Atchison, Pesticides-Advances in Chemical and Botanical Pesticides, Ch. 3 ii. Technical Report, Louise Hénault-Ethier, Canadian Association of Physicians for the Environment, 2016
RESISTANCE TO PYRETHROIDS A major contributory factor is that pyrethroids exhibit cross-resistance to DDT,
which is thought to act at the same binding site on the voltage-gated sodium channel.
Resistance
Increased detoxification Target site Insensitivity
Dr. Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54
6 . MECHANISM OF METABOLISM
METABOLIC PATHWAYS
Phase 1 reaction
• Ester hydrolysis• Oxidation
Phase 2 reaction
• Hydrophilic conjugate• Lipophilic conjugate
Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791
ESTER HYDROLYSIS
Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791
H
COOR2
H
R1
R1
COOR2
H
HR1
R1
H
R
R
H COOCH2
O
H
R
R
H COOCH
O
C
N
Trans isomer Cis isomer
OXIDATION
i. Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791 ii. Junshi Miyamoto, Degradation, Metabolism and Toxicity of Synthetic Pyrethroids, EHP, 1976, vol. 14,15-28
N
O
O
O
O
O
C
O
N
OBrBr
O
O
O
OO
O
(1RS, trans)- tetramethrin
Deltamethrin
(1R, trans)- resmethrin
(1R, tans)- phenothrin
HYDROPHILIC CONJUGATION
Thiocynates conjugates
Sulfonic acid conjugates
Kaneko, H. Pyrethroid chemistry and metabolism, Hayes’ Handbook of Pesticide Toxicology, 3rd ed., 2010; Ch.76.
Hydrophilic conjugates are often found as glucuronides, sulfates, or amino acid conjugates. But in few pyrethroids other conjugates are also formed like
LIPOPHILIC CONJUGATES
Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791
METABOLISM OF CYHALOTHRIN
OHC
O
C
N
OCF3Cl
COOHCl
F3C
O
CN
HO
OHOOC
OHOOC
OH
COOHCl
F3C
HO
Glucuronide
Glucuronide Glycerides
Sulfate
Kaneko, H. Pyrethroid chemistry and metabolism, Hayes’ Handbook of Pesticide Toxicology, 3rd ed., 2010; Ch.76.
7 . RECENT DEVELOPMENTS
DISCOVERY OF SILAFLUOFEN High insecticidal activity and low mammalian toxicity, this compound features low fish
toxicity, chemical stability under sunlight, in the soil and under alkaline environments.
F
OSi
O
Acute oral toxicity for rat (LD50): >5,000 mg/kg Acute dermal toxicity for rat (LD50): >5,000 mg/kg Fish toxicity for carp (LC50 after 48 hours): >100
ppm
Y. Katsuda, Y. Minamite, and C. Vongkaluang, Development of Silafluofen-Based Termiticides in Japan and Thailand, December 2011
DISCOVERY OF METOFLUTHRIN
N. MATSUO, K. UJIHARA, Y. SHONO, T. IWASAKI, M. SUGANO, Discovery and Development of a Novel Pyrethroid Insecticide Metofluthrin (SumiOne®, Eminence®), SUMITOMO KAGAKU, vol. 2005-II.
F
F
F
F
O
O
O
Compound Recovery rate(%)Metofluthrin 98.2Empenthrin 82.7d - Allenthrin 6.9Prallenthrin 11.2
Photo stability Compound Culex pipiens Adese albopictus
Metofluthrin 0.0015 0.00047d - Allenthrin 0.038 0.023Prallenthrin 0.0056 0.0050
D-tetramethrin 0.0096 0.0036permethrin 0.0028 0.0012
LD50 (μg/ female adult)
PROPERTIES OF METOFLUTHRIN
N. MATSUO, K. UJIHARA, Y. SHONO, T. IWASAKI, M. SUGANO, Discovery and Development of a Novel Pyrethroid Insecticide Metofluthrin (SumiOne®, Eminence®), SUMITOMO KAGAKU, vol. 2005-II.
Efficacy
Acute toxicity to mammals
Species Route Lethal doseRat Oral >2000 mg/kgRat Dermal >2000 mg/kg
Rat Inhalation Male: 1960 mg/m3
Female: 1080 mg/m3
Dog Oral >2000 mg/kg
Compound
Conc. (%w/w)
No. of mosquitoesPretreatment After
treatment
Reduction%
Metofluthrin 0.005 210 18 93Transfluthrin 0.03 187 26 88d - Allenthrin 0.3 188 27 88
7 . CURRENT MARKET & FUTURE SCOPE
CURRENT MARKET Pyrethroids account for up to 17% of global insecticide sales – a market worth more than
$7Bn each year.
Extermination
Vegetal Farming
Domestic
Animal Farming
Technical Report, Louise Hénault-Ethier, Canadian Association of Physicians for the Environment, 2016 http://www.foodsecurity.ac.uk/research/impact/pyrethroids.html
PROBLEMS FACED BY PYRETHROIDS
• Cancellation of Fenvalerate and EsfenvalerateProblem 1
• Increase in resistanceProblem 2
• Least commercial researchProblem 3
J. J. Schleier & R. K. Peterson, Green Trends in Insect Control, Ch. 3, Royal Society of Chemistry, 2011, 94-13
ALTERNATIVES TO PYRETHROIDS
Silicon dioxide provides an effective and safer control against household and pet animal pests.
Bollcure – a biopesticides can be used on cotton. Biopesticides derived from vegetable oil can be used in
grain protection.
Alternative to Pyrethroids are Biopesticides
A. Singh, A. Khare, A. P. Singh, Use of Vegetable Oils as Biopesticide in Grain Protection, J. of Fertilizers & Pesticides, January 25, 2012
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