Synthesis of Permethrin Metabolites and Related Compounds - ACS

18 Synthesis of Permethrin Metabolites and Related

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on February 5, 2016 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0042.ch018

Compounds T A D A A K I U N A I and J O H N E . C A S I D A

Pesticide Chemistry and Toxicology Laboratory, Department of Entomological Sciences, University of California, Berkeley, Calif. 94720

Considerable progress has been made in understanding the metabolism of the trans- and cis-isomers of 3-phenoxybenzyl 3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate (permethrin) in rats (1-3), in cows (3), in insects (4), in bean and cotton plants (3) and in microsomal mixed-function oxidase systems from mammalian l i v e r (5) and insects (4), in part be cause of the a v a i l a b i l i t y of authentic standards from synthesis for use in cochromatographic comparisons with the metabolites. This report outlines synthesis routes used to prepare these monohydroxy- and dihydroxy-derivatives of trans- and c i s permethrin, their hydrolysis products, and certain further o x i dized or conjugated derivatives of the hydrolysis products. 3 - ( 2,2 -D ichlor ovinyl ) - 2 - hydroxyme t hyl-2 - methylcyclopropane carboxylic Acids There are 4 possible isomeric acids with hydroxylation at one of the gem-dimethyl positions (Figure 1; the IR isomers are shown). [lR,/AuV7s]-permethrin metabolites

[lR,c/s]-permethrin metabolites ^—OH HO—y

CK

cK h & 7 : COOH 2-c/s-hydroxy

R

'C00H

2-//w?s-hydroxy

«

j

c

CI' 2-£/'s-hydroxy [H or DCC

[Η Γ or DCC

COOH cr 2-//O/7S-hydroxy

+

+

CK /-lactone

/-lactone

Figure 1

The 2-cis-hydroxymethyl acids undergo p a r t i a l conversion to the

194

In Synthetic Pyrethroids; Elliott, Michael; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

18.

UNAI

A N D

corresponding complete diimide

(DCC).

zene

These

(saturated

with

from

oxidation

6

compounds

in

conditions and

N,N -dicyclohexylcarbof

are easily

by subjecting formic

acidic

with

isolated

the appropriate

using

hydroxy

glacial

acetic

acetates

cis-compound

dichlorodiene

as

mixtures

2 developments

acid)-ether

(10:3)

acids

isomeric

with

(referred

and 2

to

ben

t o as

γ-lactones

l,l-dichloro-U-methyl-l,3-pentadiene

dichlorodiene the

strong

195

system).

k isomeric

The

under

g e l chromatoplates

BFE solvent

prepared

Metabolites

on treatment

materials

on s i l i c a

the


γ-lactones

conversion

crystalline tic

Permethrin

CASIDA

in

(Figure

acid,

which yields

a ratio 2)

plus

o f 83 other

were

b y SeOp

the desired

for the transproducts

a n d 17 f o r

including the

trans-aldehyde.

6 compounds shown in Fig. I Figure 2 The m i x t u r e

o f acetoxy

diazoacetate tion

[CCI»-ether

hydrolysis

(93:7)3

(NaOH

lactonization of

appropriate

in

permethrin

Hydroxy Derivatives

pared,

i f

(6),

Alcohol

of the

and 3-Fhenoxy-

isomeric

The 6 benzoic

with

suitable

[Cu Clp, 2

,

-10°C,

the desired

methoxy

synthesize

U-methoxyphenols

the 2

t

- , 3 -

(7)

(from

l

while

previ

most

a r e new compounds. ether

by the Ullmann demethylation

t h e BFE solvent

steps

are

system

acetate

with

benzene,

or reduction The acids

with benzene-ethyl

was r e a c t e d

prepared

(thiophene-free

oxidation

acetate-methanol

3-bromobenzoate

(DMF)],

pre

likely

of the diphenyl

intermediates

and alcohols. with

were

routes,

derivatives

formation

2 min) or A1C1-

acids

are resolved

benzene-ethyl

derivatives

derivatives

a c i d were

not being

synthesis

alcohol

involved

t i c on 2 developments

alcohols To

acid

2 h r ) , and appropriate

reflux,

compounds

dimethylformamide

p

(CH C l

obtain

procedure

monohydroxy

a n d 3-phenoxybenzoic

usually by different

general

reaction

by

possible

alcohol

not a l l of the 6 benzyl

linkage BBr

Each

as a metabolite

isomer.

the remaining 2-hydroxy

metabolites.

The

Finally,

t i c (BFE) a n d

[1RSJ-compounds.

found

o f 3-Phenoxybenzyl

o f t h e Ik

3-phenoxybenzyl

ously

ethyl

separa

Acid

Twelve of

(HCl),

the 6 desired i s

by t i c

diesters.

acidification

and lactones

directly with

followed

o f the isomeric

MeOH),

acids

was r e a c t e d

a t 120-130°C,

(DCC) y i e l d e d

t h e hydroxy

benzoic

compounds

a n d C u powder

to

separated

andthe

(6:1)

or

(15:5:1). a n d h -hydroxy

with

T

t h e sodium

the phenols

compounds, salts

o f 2-,

a n d N a H in D M F ) .


methyl 3- a n d

196

SYNTHETIC

Dernethylation


hydride

in

and

reduction

benzene

the

carbomethoxy

and

acids,

compounds

respectively

To p r e p a r e

the

an

(Figure

3).

U-hydroxy

v a n i l l i n

and bromobenzene

ester

Ullmann

and

the

(CH Ν

,

was

of

3-nydroxy-5-methoxytoluene

For

synthesis

of

5-hydroxy

with

5

gave

5-methoxy-3-phenoxytoluene

further

[KMhO^,

ILO-pyridine

reactions

The

reaction

(Figure

6-hydroxy

5)

of

(6),

derivatives

were

of

with

sodium

before

bromide

acetone) (Figure

of

the

the

prepared

dimethyl

methoxy

of

ether iso-

converted

to k).

(Figure

the

the

[LiAlH^

sodium

salt

me t h y l a t i o n

of

then

treatment

with

bromobenzene

subjected

methoxy

to

acid

and

above.

with

the

was

by

of

acetone),

w h i c h was

5-bromosalicylaldehyde (KMaO^,

salt

alcohol

salt to

MeOH) alcohols

reduction

sulfate, this

in

diphenyl

compounds,

(1:2)]

as

for

prepared

dimethyl

NaH.

the

sodium acid

desired

was

with

oxidation

Ullmann

the

(NaOH hydroxy

(KMnO^,

min)

to

3 5-olihydroxytoluene An

5

(THF)]

the

the

hydroxy

0°C,

tetrahydrofuran

of

oxidized

resulting

in

desired

derivatives,

reaction

ether,

bis(2-methoxyethoxy)aluminum

hydrolysis

the

from

demethylated,

or

gave

aldehyde

methyl

[sodium

(Vitride®)]

PYRETHROIDS

aldehyde

sulfate

phenolate

and

further

by

methylation

then and

reaction oxidation

treatments

as

6).


of


18.

UNAI

A N D

The

2 -, f

corresponding

V -

and

and 6-hydroxy benzyl

conjugated

form in

appear

2-3 with

as

metabolites

biological

alcohols of

trans-

acids in

and

free

and/or

the

or cis-

systems.

and Dihydroxypermet h r i n

in

meric EtJtf

197

6-hydroxy-3-phenoxybenzoic

various

The t r a n s - and tion

Metabolites

V -

permethrin Mono-

Permethrin

CASIDA

the

hydroxy in

cis-isomers

a c i d moiety acids

(Figure

DMF s o l u t i o n

hr

(Figure

7).

of

lactonization

of

l)

with

product

was

(6:1)

or

by

N

2

gas

the

at

p u r i f i e d by

was

not

h

isoand

for

preparative

tic

acetate-

observed a

the

bromide

80-90°C

and benzene-ethyl

p u r i f i c a t i o n but

occurred with

monohydroxyla-

heating

3-phenoxybenzyl

with

Isomerization

reaction

permethrin with

synthesized

ampoules

acetate

(15:5:1).

conditions

in Each

benzene-ethyl

methanol

were

under

small

amount

2-cis-hydroxymethyl

these of

compounds.

Figure 7 For 2'-

and

synthesis

trans-ester methoxy

of

V-positions with

esters

a

the of

cis-esters

the

phenoxy

V-hydroxy

prepared by

the

with monohydroxylation at ring

and

substituent, acid

the

the

chloride

the

corresponding appropriate

method

were


treated

198

SYNTHETIC

with

BBr-

esters

(CH C1 , 2

as

corresponding major

products, ester)

hydroxy

esters)

isomeric

either


desired

or

for

in

to

the

yield

preparative

tic

desired

acetate

isolations. of

w i t h benzene (6:1)

case

the

trans-ester

(Figure

with

a

as

(for

the

2 -

(for

the

k -

Reesterification

3-phenoxybenzyl

the

bromide

of

1

1

the

bromide

cis-dichlorovinyl acid yielded

(including

monohydroxy

and

3-phenoxybenzyl

benzene-ethyl

derivatives

the

dichlorovinyl acid of

the

or

each

min)

and

derivatives

with

trans-

ester

stituent)

using

hydroxy

the

2

products

hydroxy

hydroxy 2

-10°C,

2

minor

PYRETHROIDS

with

the

2 -hydroxy

sub

1

b ). 1

BBr, ,0H

CK

11

^ COOH

V

ΓΊ

Br—^

Figure 8

acid 9)

Esters

hydroxylated

moiety

and

were

prepared by

hydroxylation k

with

the

at

h

at

both

-position

1

esterifying

the

2-trans-methyl

the

the

trans-methyl

-hydroxy-3-phenoxybenzyl

1

the of

2

to

alcohol isomeric

the

bromide

of

the

moiety acids

carboxyl (Figure

(Figure with

(Figure

l)

9).

Λ)Η

TOOH

C -4 - ^ ^ c o O H

B r - — ^0 —

ci—f^

CI Each

of

the

mono-

described

above

ester)

a metabolite

more

is

of

the

Amino A c i d

from acids

the

L-amino

10).

The

amino the or

of

are

in

as

glutamate

Figure 9

acid

2

cis-permethrin

T

permethrin

-hydroxy-trans in

one

conjugates

were

of

the

prepared trans-

acid

THF-benzene

pyridine

in

and

as

and

3-phenoxybenzoic

the

their

methyl

cis-dichloromethyl

esters

solution

the

glycine

with

glycine,

trans-

but

with

cows.

in

and

rats,

not

cows

serine the

and

cis-acid insects

from

glutamic

Phenoxybenzoic and

of

(Figure

cis -dichlorovinyl acid metabolites

cows

or

examined.

chlorides

and

of

trans-

or

the

with

and

in

derivatives of

Conjugates

conjugate

with

dihydroxy exception

systems

conjugated

insects

glutamic

of

acid

acid

acids

acid

conjugated

and the

Sulfate

trans-

permethrin a

(with

biological and

Twelve esters vinyl

^cœ—-^^Nx^

CI

is

detected

acid

and

is

with

insects.


18.

U N A I A N D CASIDA

Permethrin Metabolites Structures

199

RinEach Structure -H = glycine -CH = alanine 3

CHOH = serine Downloaded by UNIV OF CALIFORNIA SAN DIEGO on February 5, 2016 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0042.ch018

2

f\ f\ ? ^^C^^CONH-CH-COOMe

-CHCHCOOMe = glutamic acid 2

2

Figure 10

The sulfate conjugate of V-hydroxy-3-phenoxybenzoic acid, found as a major permethrin metabolite in rats, was prepared by sulfation of the acid with C1S0 H in pyridine solution (Figure l l ) . The product obtained in poor y i e l d was purified by preparative t i c with n-butanol-acetic acid-H 0 (6:1:1). The starting material was obtained on hydrolysis of this sulfate with sulfatase or 3N HC1. CIS0H in , . f^i fY° *" sulfatase HO-C^^XT^ I ] I Figure 11 3

ίΓϋ fY° ι-ς^^^Τ^ I

H

p y r i d i n e

or

S0

H+

Abstract Mono- and dihydroxy derivatives of [1RS]-trans- and [1RS]cis-permethrin, their ester hydrolysis products, and conjugates of the acid moieties and of 3-phenoxybenzoic acid and 4'hydroxy-3-phenoxybenzoic acid were prepared for v e r i f i c a t i o n and stereochemical assignments of the free and conjugated [ C]metabolites of the [ C] permethrin isomers. At least 2 d i f f e r ent solvent systems were used in each case for cochromatographic identification, with and without derivatization of the compounds. Twenty-nine of the products synthesized are identified as per methrin metabolites in free or conjugated form. These com pounds were important in assigning structures for the permethrin metabolites formed in various organisms and enzymatic systems. They should also be useful standards in studies on metabolism of related pyrethroids. 14

14

Acknowledgments The authors thank Loretta Gaughan, Roy Holmstead, Toshio Shono, David Soderlund and Kenzo Ueda for valuable suggestions and assistance. This study was supported in part by grants from: National Institutes of Health (2 P01 ES00CA-9); Agricultu r a l Chemical D i v . , FMC Corp., Middleport, N.Y.; Agricultural


200

SYNTHETIC

PYRETHROIDS

Chemicals D i v . , ICI United States I n c . , Goldsboro, N. C.; Sumitomo Chemical Co., Osaka, Japan; Roussel-Uclaf-Procida, Paris, France; Mitchell Cotts & Co. L t d . , London, England; Wellcome Foundation L t d . , London, England; National Research Development Corp., London, England. Literature Cited


1. 2. 3. 4. 5. 6. 7.

Elliott, M . , Janes, N. F., Pulman, D. Α . , Gaughan, L. C., Unai, T . , Casida, J. E., J. Agr. Food Chem. (1976) 24, 270. Gaugnan, L. C., Unai, T . , Casida, J. E., J. Agr. Food Chem. (1977) in press. Gaughan, L. C., Unai, T . , Casida, J. E., ACS Symp. Ser. (1977) this volume. Shono, T . , Unai, T . , Casida, J. E., unpublished results. Soderlund, D. Μ., Casida, J. E., ACS Symp. Ser. (1977) this volume. Ungnade, H. E., Rubin, L., J. Org. Chem. (1951) 16, 1 3 H Miyamoto, J., Suzuki, T . , Nakae, C., Pestic. Biochem. Physiol. ( 1 9 7 4 ) ,4,438.


Synthesis of Permethrin Metabolites and Related Compounds - ACS

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