Note: Descriptions are shown in the official language in which they were submitted.
~i~7 ~ ~5
This invention relates to novel esters of amino
acids, novel intermediates therefor, synthesis thereof and the
use of said esters and compositions containing said esters
for-the control of pests.
The esters of amino acids of the present invention
are represented by the following generic formula (A):
~t ~ /
~ N - CH - C - O - R5 (A)
Z R
wherein,
R2 is hydrogen, methyl or ethyl;
R5 is the group IH ~ R9 ;
R6 is hydrogen, cyano, ethynyl, -C-NH2, or methyl;
R9 is phenoxy or p-fluorophenoxy;
Y is hydrogen, trifluoromethyl, fluoro, chloro, bromo,
lower alkyl of 1 to 4 carbon atoms, lower alkoxy of 1 to 4 carbon
atoms or lower alkylthio of 1 to 3 carbon atoms;
Z is independently selected from the values of Y,
and cyclopropyl;
t is zero, one or two; and
the salts thereof of strong inorganic acids or organic
acids.
The compounds of the present invention represented
by generic formula (A) are useful agents for the control of
pests such as insects and acarids. Without any intention
of being bound by theory and although the mode of action of
the compounds of formula (A) as applied to the control of
- 2 -
~",
7~5
insects and acarids is not completely understood, the
compounds of formula (A) appear to be effective for the
control of insects and acarids by reason of mechanisms of
the nature of the insect control agents known as pyrethrins
and synthetic pyrethroids.
In the description hereinafter and the appended
claims, each of R2 through R9, Y, Z and t is as defined
hereinabove, unless otherwise specified.
As a generally applicable method of synthesis, the
compounds of formula (A) can be prepared by the reaction of a
primary or secondary amine of formula (I) with a halo ester
of formula (II) (X is bromo, chloro, or iodo).
~ N - H (I)
Z ~=/ R2
/
CIH ~ (II)
X - CH - C - O - R
The reaction of an amine (i) and halo ester (II)
is generally carried out neat or in an organic solvent such
as hexamethylphosphoric triamide, tetrahydrofuran, dimethyl-
formamide, dimethylsulfoxide, or the like at room temperature
or above. The reaction generally proceeds rather slowly.
~0 It may be assisted by a catalyst such as a small amount of
potassium iodide. A good review of the synthesis of amino
acids and esters of amino acids is given in "Methodicum
Chimicum," Academic Press, New York, Vol. 6, pp 599-623 (1975).
.~
1~47'7'~S
The halo esters of formula II can be prepared from
the acid halide thereof (II, wherein oR5 represents bromo or
chloro) by reaction with an alcohol (R5-oH). The ~-halo-
substituted acid halide and ~-halo-substituted acid can be
prepared by halogenation, using molecular halogen, of (1) a
mono-carboxylic acid, or (2) a malonic ester followed by
saponification using, for example, the Hell-Volhard-Zelinsky
reaction and procedures described in Org. ~y~. Coll., Vol. 2,
93 (1943); ibid., Vol~ 3, 495, 523, 623, and 848 (1955);
ibid., Vol. 4, 358 and 608 (1963); Org. Syn. 50, 31 (1970); and
JACS 91, 7090 (1969). Other suitable methods include the
reaction of N-bromosuccinimide or N-chlorosuccinimide with an
acid halide ~II, wherein oR5 represents bromo or chloro)
following the procedures of Harpp et al., J. Org. Chem. 40,
3420 (1975) and references cited therein. A method suitable
wherein olefinic unsaturation is present is alkylation of aceto-
acetates followed by halogenation of the anion, e.g. the
sodium enolate, and deacetylation. Rathke et al., Tetrahedron
Letters, No. 43, 3995 (1971) and Slotter et al., ibid., No. 40,
4067 (1972). The synthesis of ~-chloro acids may be
accomplished also by reacting the acid with molecular chlorine
in the presence of chlorosulfonic acid and chloranil as
described by Ogata et al., J. Org. Chem. 40, 2960 (1975).
They may also be prepared from ~-hydroxy acids by conventional
methods.
The compounds of formula (A) can be synthesized
also by reacting an acid of formula (III), or the acid chloride
or bromide thereof, with an alcohol Ho-R5.
745
Yl t ~ ~
fi~ CH O ( I I I )
~, ~ N - CH - C - OH
Z R2
The acid of formula (II~) can be made from the
halo acid or lower alkyl ester of formula (IV) (R21 is hydrogen
or lower alkyl) using the conditions described hereinabove
by reaction with the amine of formula (I).
C\3 /CH 3
CH O ( IV)
X - 1H - C - OR
Following reaction of a halo ester of formula (IV)
wherein R21 is lower alkyl with an amine of formula (I), the
resulting amino ester of formula (V)
~ /
~ N - 8H - C - OR21 (V)
Z R2
is saponified by conventional methods to the amino acid of
formula (III) or a reactive derivative thereof such as the acid
chloride, acid bromide or an inorganic salt thereof such as
the sodium or potassium salt.
The following terms, wherever used in the description
herein and the appended claims, have the meaning defined below,
unless otherwise specified hereinafter.
~;~
f 45
The term "lower alkyl" refers to an alkyl group,
straight or branched, having a chain length of one to eight
carbon atoms. The term "lower alkoxy" refers to an alkoxy
group, straight or branched, having a chain length of one to
eight carbon atoms. The term "lower alkylthio" refers to an
alkylthio group, straight or branched, having a chain length
of one to eight carbon atoms.
The compounds of the present invention of formula
( A) have one or more asymmetric carbon atoms. The present
- 6, 7, 8 -
11477'~5
invention includes each of the optical isomers and racemic
mixtures thereof. In the examples hereinafter, unless other-
wise specified, the compound prepared is a racemic mixture.
Included within the present invention are salts of
the compounds of formula A. The salts are formed from strong
inorganic acids or organic acids such as hydrochloric acid,
sulfuric acid, phosphoric acid, p-toluenesulfonic acid,
p-benzenesulfonic acid, methanesulfonic acid, Lewis acid and
the like. Many of the compounds of formula A are oils which
advantageously are converted into the salt for convenience
of handling and formulating and superior stability. The salts
are useful for the control of pests in the same way as the
compounds of formula A.
The compounds of the present invention of formula A
are useful pest control agents, particularly for the control
of insects and acarids. In the use of the compounds of formula
A for combating insects and acarids for the protection of
agricultural crops, for example soybeans, cotton, alfalfa,
etc., a compound of formula A, or mixtures thereof, together
with a carrier i9 applied to the locus in a pesticidally
effective amount. The carrier can be liquid or solid and
include adjuvants such as wetting agents, dispersing agents
and other surface active agents. The compounds of formula A
can be used in formulations such as wettable powders, solutions,
dusts, granules, emulsifiable concentrates, and the like.
Suitable solid carriers include natural and synthetic silicates
and clays, carbon or charcoal granules, natural and synthetic
resins, waxes, and the like. Suitable liquid carriers include
water, aromatic hydrocarbons, alcohols, vegetable and minera
oils, ketones, and the like. The amount of a compound of
1~4~7~5
formula A in the formulation can vary widely, generally within
the range of about 0.01 percent to about 90.0 percent, by
weight.
As shown hereinafter, the compounds of the present
invention are effective on many different insects and on acarids.
The compounds are effective control agents for insects such as
mosquitoes, flies, aphids, weevils and acarids such as the
spider mite and ticks. Depending upon the particular combination
of the substituents of formula A herein, the compounds have a
broad or relatively narrow spectrum of unusually high pesticidal
activity on insects and acarids. Among the pests against which
the compounds of the present invention are pesticidally
effective are insects of the order Lepidoptera, Orthoptera,
Heteroptera, Homoptera, Diptera, Coleoptera or Hymenoptera, and
acarids of the order Acarina including mites of the family
Tetranychidae or Tarsonemidae and ticks such as Ornithodoros.
The compounds of the present invention can be used
in combination with other pesticides such as the carbamates,
phosphates and insect growth regulators, e.g. propoxur, carbaryl,
naled, dichlorvos, methoprene, kinoprene, hydroprene, cyhexatin
and resmethrin.
The following examples are provided to illustrate
the practice o~ the present invention. Temperature is given
in degrees Centigrade. ~T means room temperature.
--10--
11~7745
EXAMPIE 1
A. To a-bromoisovaleric acid ~10 g, O.O5S mole) in
60 ml ether, cooled to 10, is added dimethylformamide ~DMF)
~2.8 ml, 0.0332 mole), followed by slow addition of thionyl-
chloride (5.9 ml, 0.0828 mole). After about one hour at
24, the acid chloride intermedia~e is isolated by decanting
off the top ether layer from the oily residue and removing the
ether under vacuum. To the acid chloride (O.OS~ mole) in
100 ml of ether, cooled to 10, is added m-phenoxy~enzyl
alcohol (11.49 g, 0.0495 mole) followed by addition of pyridine
(9 ml, 0.11 mole) over about 15 minutes. ~he resulting
white slu~ry is stirred at 24 for about 16 hours and then a
trace of water is added to decompose exc~ss acid chloride.
The ester is isolated by pouring reaction slurry into ice
water (100 ml), acidifying with 2N sulfuric acid (60 ml) and
extracting with ether ~3X 100 ml). The combined ether
extracts are washed with 10% sodium bicarbonata (10 ml),
followed by water (2X lOO ml) and brine (25 ml) and dried o~er
calcium sulfate to give m-phenoxybenzyl a-bromoisovalerate in
~uant~tative yield.
nmr (CC14) ~ 1.03 lm, 6, (CH3)2CH3, 2.18 ~m, 6,
(C~3)2CX), 3.94 (d, 1, J - 8 Hz, Br-CX-~- ), and 5.11 ppm
(g 21 ArC~20- ). T~ (film) 1744 cm 1 (~,O)~
B. To m-phenoxybenzyl a-~romoisovalerate (3 g,
0.0083 mole) in 6 ml of hexamethylphosphorictriamide (HMPT),
24, is added aniline (0.0248 mole) followed by a catalytic
amoun~ of potassium iodide (28 mg). The reaction mixture is
114~74S
heated, at 65, for about 90 hours and then poured into
ice-water (35 ml) and extracted with ether (3X 50 ml). The
combined ether extracts are washed with 2N sulfuric acid, water
(2X 50 ml) until neutral, and with brine fo~lowed by drying
over calcium sulfate. The product is concentrated under vacuum
and isolated by preparative thin layer chromatography (T~C).
m-Phenoxybenzyl ester of N-phenylvaline.
nmr (CDC13) ~ l 00 ~m, 6~ CH312CX]~ ?-07 tm~ l, ( 3 2
C~, 3.95 ~m, 1, k-CH-CO2-~, 4.00 (m, 1, NH), and 5.13 ppm
o ts, 2, ArCH20). IR (film) 3400 cm 1 (s) (NHj and 1738 cm 1
(C30) ~
EXANPLE 2
To the m-phenoxybenzyl ester of N-phenylvaline (0.25 g)
in EMPT (1 ml) and tetrahydrofuran (l ml), at 24~, is added
methyl iodide ~0.12 ml) followed by potassium car~onate
~0.092 g~. The reaction mixture is heated at 60 for 4 days.
The reaction is wor~ed up by pouring into ics-water (~ ml) and
extracting with ether t3X 10 ml). The combined ether extracts
are washed with water (2X 10 ml) and brine (lX 5 ml~ and dried
over calcium sulfate. The product is isolated and purified by
preparative TLC to give the m-phenoxybenzyl ester of N-phenyl-
N-methylvaline.
nmr (CDC13) ~ 0.92 [m, 6, (C~3)2C~], 2.3 [m, 1, (C~3)2-
2S C~, 2.88 (s, 3, C~3N), 3.96 ~d, 1, N-CH-C02), and 5.08 ppm
(s, 2, ArC~2O). IR (film) 1740 ~C=O).
- EXAMP~E 3
A. To valine (11.7 g, 0.10 mole) in 88~ formic acid
(40 ml) is added acetic for~lyl~hydride ~26.3 g, 0.30 mole~
-12-
745
over O.S hr at 5~ The reaction mixture is warmed to 24 and
stirred for 17 hours. The reaction is wor~ed up by distilling
off (~ath temp. 45-50) the solvent, excess anhydride and
acetic acid, to give, as a white solid, N-formylvaline,
recrystallized from hot ethanol, m.p. 143-145.
B. To 8 g (0.055 mole) of the product of part A in
55 ml o~ HMPT is added m-phenoxybenzyl bromide (14.4 g, O.055
mole) ~ollowed by anhydrous potassium carbonate (7.6 g, 0.055
mole). The reaction mixture is stirred, at 24, for 48 hours
and then worked up by pouring into ice-water (250 ml) and
extracting with ether (3X 100 ml). The combined ether
extracts are washed with water (2X 100 ml) and brine (25 ml~
and dried over calciu~ sulfate and e~aporated under vacuum
to gi~e the m-phenoxybenzyl ester of N-formylvaline.
1~ C. To the ester (26 g, 0.0835 mole) of part B, in
84 ml of anhydrous methanol, is added lN methanolic HCl
(92 ml, 0.092 mole). The reaction mixture is stirred at 24
for 18 hours and then the methanol removed under vacuum. The
residue is poured into ice-water (200 ml) followed by removal
of neutral impurities with ether. The a~ueous layer is made
basic by addition of 10~ sodium bicarbonate and then éxtracted
with ether (3X 200 ml). The c~mbined ether phases are washed
with water t2X 200 ml) until neutral and brine ~lOQ ml) and
then dried over calcium sulfate, filtered and rotoevaporated
to give the m-phenoxy~enzyl ester of ~aline
nmr (CDC13) ~ 0.91 [m, 6, (CX3~2C~, 1.37 (bs, 2,
NH23, 2.00 ~m, 1, (C~3)2CX], 3.31 (d, 1, N-CX-C~-), and 5.17 ppm
(s, 2, ArCH20~ (film) ~3400 cm 1 (NH2), 1?40 cm 1 (C=o).
-13-
1147745
EXAM~LE 4
To m-phenoxybenzyl -~romoisovalerate ~5 g, 0.0138
mole) in 9 ml of BMPT, at 24, is added p-chloroaniline
(5. 27 g, 0 . 0413 mole) and a catalytic amount of potassium
iodide (60 mg). The reaction mixture is stirred at 70 for
four,days. The reaction is then poured into ice-water (30
ml) and 10 ml of 2N sulfuric acid which is extracted with
ether (3X 30 ml). The combined ether extracts are washed
with water ~X 30 ml) and brine tlO ml), dried`over calcium
sulfate, filtered and evaporated. The crude product is
purified by preparative TLC to yield the m-phenoxy~enzyl
ester of N-~p-chlorophenyl)valine.
nmr (CDC13) ~ 0.99 ~m, 6, (CX3)2C~,
(C~3~2C~, 3.93 (m, 2, N~ and N-C~-C02), and 5.10 ppm (s, 2,
ArCH20-). IR ~film) 3410 cm 1 (s) ~N~), and 1740 cm 1 ~C-O).
EXAMPLE ~
To m-phenoxybenzyl a-bromoisovaler~te (2 g, O.OOSS
mole) in 4 ml of HMPT, at 24, i9 added toluidine (1.77 g,
0.0165 mole) and potassium iodide (25 mg). The reaction
mixture i~ stlrred at 60 for five days, cooled, and poured
~nto ice-water (20 ml) plus 10 ml of 2N sulfuric acid. The
reaction is worked up as in Example 4 yielding the m-phe~oxy-
benzyl ester of N-(p-methylphenyl)valine.
rmr (CDC13~ ~ 0 . 99 ~m, 6 , (CR3) 2C~, 2 - 20 ~s , 3 , C~3-
Ar), 3.90 (m, 2, NH and ~-C~-C02), and 5.11 ppm (s, 2, ArCR20).
IR (film) 3400 cm 1 (s~ (NH), and 1740 cm 1 ~C-O).
The a~ove procedure is repeated using anisdine in
place of toluidine to yield the m-phenoxy~enzyl ester of
N-(p-methoxyphenyl)valine.
-14-
1147745
nmr (CDCi3) ~ 0.98 [m, 6, (CH3)2CH], 2.03 tm, 1,
(CH3)2CH], 3.73 (s, 3, OCH3), 3.77 (m, 2, NH and N-CH-CO2),
and 5.10 ppm (s, 2, ArCH2O-). IR (film) 3400 cm 1 (s) (NH),
and 1740 cm 1 (C=O).
EXAMP~E 6
A. To a-~romoisovaleric acid (5.18 g, 0.0286 mole)
~n 30 ml of ether, cooled to 10~, is added 1.3 ml of DMF
followed by 910w addition of 3 ~1 of thionyl chloride (0.0429
mole). After one hour at 24, the acid chloride is isola~ed
in quanti~ative yield by decanting off top the ether layer
and removing the sol~ent and excess thionyl chloride under
vacuum.
To the acid chloride (5.7 g, 0.0286 mole) in 30 ml
of ether at 10 is added S.38 g of m-phenoxybenzaldehyde
cyanohydrin (0.0257 moie) ~ollowed by slow addition of 4.6
ml of pyridine over 10 minutes. The reaction mixture is
stirred at 24 for 17 hourQ and then a trace of water is added
to destroy excess acid chloride. The reaction product is
worked up by pouring into lcs-water 150 ml) plus 2N sulfuric
ac~d (30 ml) and extracting with ether (3X 30 ml~. The
c~mbined ether extracts are washed with 10% sodium bicar~onate
~10 ml), water (2X 50 ml) and br~ne ~10 ml), dried o~er calcium
sulfate and e~aporated to yield m-phenoxy-a-cyanoben2yl
-bromoisovalerate.
nmr (CDC13~ ~ 1.05 tm, 6, (CH3~2CH], 2.23 tm, 1,
(CH3) 2CX3 , 4.0~ (d, l, J = 8 Hz, Br-CH-C-), and 6.41 ppm ts, 1,
ArCH tCN) 0~ . IR (film) 1762 cm ~ tC=o) .
1147745
B. To m-phenoxy-a-cyanobenzyl a-bromoisovalerate
(2.0 g, 0.0052 mole) in 4 ml of EMPT, at 24, is added
aniline (1.5 g, 0.016 mole) and potassium iodide (21 mg).
The reaction is stirred at 65 for 90 hours and then cooled
and poured into ice-water (20 ml) plus 2N sul~uric acid (10 ml).
The reaction is wor~ed up as in Example 4 and purified by
preparative TLC to give the m-phenoxy-a-cyanobenzyl ester of
N-phenylvaline.
nmr (CDC13) ~ 1.02 ~m, 6, (CH3)2CH], 2.10 [m, 1,
(CH3)2CH], 4.0 (m, 2, -NH and N-CH-CO2), and 6.33 ppm ~s, 1,
ArC~(CN)O]. IR (film) 3400 cm~l (s)(NH), 2260 cm~l (w)(C-N),
1758 cm 1 (C-O).
EXAMPLE 7
Following the procedure of Example 5, each of the
compounds under column I is reacted with m-phenoxybenzyl
a-bromoisovalerate to yield the repsective ester under column
II.
I
3,4,5-trimethoxyaniline
4-phenetidine
2,4-dimethoxyaniline
3,5-dimethoxyaniline
2-anisidine
4-ethylaniline
2,4,6-trimethylaniline
4-nitroaniline
2,4,6-trichloroaniline
4-fluoroaniline
4-bromoaniline
-16-
1147745
3-chloro-2-methoxyaniline
2-chloro-4-methylaniline
2,6-dichloroaniline
4-chloro-2-nitroaniline
2,6-dichloro-4-nitroaniline
4-aminoacetophenone
3-aminobenzonitrile
2-aminobenzonitrile
2,6-dimethylaniline
2,5-dimethylaniline
The m-phenoxybenzyl ester of
N-(3,4,5-trimethoxyphenyl~valine
N-(4-ethoxyphenyl)valine
N-(2,4-dimethoxyphenyl)valine
N-(3,5-dimethoxyphenyl)valine
N-(2-methoxyphenyl)valine
N-(4-ethylphenyl)valine
N-(2,4,6-trimethylphenyl)valine
N-(4-nitrophenyl)valine
N-(2,4,6-trichlorophenyl)valine
N-(4-fluorophenyl)valine
N-(4-bromophenyl)valine
N-(3-chloro-2-methoxyphenyl)valine
N-(2-chloro-4-methylphenyl)valine
N-(2,6-dichlorophenyl)valine
N-(4-chloro-2-nitrophenyl)valine
N-(2,6-dichloro-4-nitrophenyl)valine
N-(4-methylcarbonylphenyl)valine
-17-
1~47745
N-(3-cyanophenyl)valine
N-(2-cyanophenyl)valine
N-(2,6-dimethylphenyl)valine
N-(2,5-dimethylphenyl)valine
E~MPLE 8
Following the procedure of Example 1, ~-bromoisovaleric
acid via the acid halide is reacted with the alcohols listed
in column III to yield the respective ester under column IV.
III
p-phenoxybenzyl alcohol
m-benzylbenzyl alcohol
p-propargylbenzyl alcohol
4-allyl-2,6-dimethylbenzyl alcohol
p-allylbenzyl alcohol
2,6-dimethyl-4-propargylbenzyl alcohol
a-ethynyl-3-t~ifluoromethylbenzyl alcohol
5-benzyl-3-furylmethyl alcohol
a-cyano-5-benzyl-3-furylmethyl alcohol
5-propargylfurfuryl alcohol
2-methyl-5-propargyl-3-furylmethyl alcohol
5-propargyl-a-ethynylfurfuryl alcohol
5-benzyl-2-methyl-3-furylmethyl alcohol
3-methyl-2-propargyl-2-cyclopentene-1-one-~-ol
2-allyl-3-methyl-2-cyclopentene-l-one-4-ol
2-benzyl-2-cyclopentene-1-one-4-ol
3,4,5,6-tetrahydrophthalimidomethyl alcohol
phthalimidomethyl alcohol
4-phenyl-3-chloro-2-butene-1-ol
5-propargyl-2-thiophenemethanol
-18-
il477~
5-benzyl-2-thiophenemethanol
5-benzyl-3-thiophenemethanol
IV
p-phenoxybenzyl a-bromoisovalerate
m-benzylbenzyl a-bromoisovalerate
p-propargyl-benzyl Y-bromoisovalerate
4-allyl-2,6-dimethylbenzyl a-bromoisovalerate
p-allylbenzyl a-bromoisovalerate
2,6-dimethyl-4-propargyl-benzyl ~-bromoisovalerate
-ethynyl-3-trifluoromethylbenzyl a-bromoisovalerate
5-benzyl-3-furylmethyl a-bromoisovalerate
a-cyano-5-benzyl-3-furylmethyl a-bromoisovalerate
S-propargylfurfuryl a-bromoisovalerate
2-methyl-5-propargyl-3-furylmethyl a-bromoisovalerate
5-propargyl--ethynylfurfuryl a-bromoisovalerate
5-benzyl-2-methyl-3-furylmethyl a-bromoisovalerate
2-methyl-3-propargyl-4-oxo-2-cyclopentene-1-yl
a-bromoisovalerate
3-allyl-2-methyl-4-oxo-2-cyclopentene-1-yl
a-bromoisovalerate
3-benzyl-4-oxo-2-cyclopentene-l-yl a-bromoisovalerate
3,4,5,6-tetrahydrophthalimidomethyl a-bromoisovalerate
phthalimidomethyl a-bromoisovalerate
4-phenyl-3-chloro-2-butene-1-yl a-bromoisovalerate
5-propargyl-2-thiophenemethyl a-bromoisovalerate
5-benzyl-2-thiophenemethyl a-bromoisovalerate
5-benzyl-3-thiophenemethyl a-bromoisovalerate
--19--
~47745
EX~MPT.F. 9
Each of the ~-bromo ester intermediates listed under
column IV is reacted with 4-chloroaniline using the procedure
hereinabove, e.g. Example 1, 4 or 5, to yield the respective
ester of N-(4-chlorophenyl)valine listed under column V.
4-phenoxybenzyl ester of N-(4-chlorophenyl)valine
3-benzylbenzyl ester of N-(4-chlorophenyl)valine
4-propargylbenzyl ester of N-(4-chlorophenyl3valine
4-allyl-2,6-dimethylbenzyl ester of N-(4-chloro-
phenyl)valine
p-allyl~enzyl ester of N-(4-chlorophenyl)valine
2,6-dimethyl-4-propargylbenzyl ester of N-(4-chloro
phenyl)valine
~-ethynyl-3-trilfuoromethylbenzyl ester of N-(4-
chlorophenyl?valine
5-benzyl-3-furylmethyl ester of N-(4-chlorophenyl)
valine
a-cyano-5-benzyl-3-furylmethyl ester of N-(4-chloro-
phenyl)valine
5-propargylfurfuryl ester of N-(4-chlorophenyl)valine
2-methyl-5-propargyl-3-furylmethyl ester of N-(4-
chlorophenyl)valine
5-propargyl-a-ethynylfurfuryl ester of N-(4-chloro-
phenyl)valine
5-benzyl-2-methyl-3-furylmethyl ester of N-(4-chloro-
phenyl)valine
2-methyl-3-propargyl-4-oxo-2-cyclopentene-1-yl ester
of N-t4-chlorophenyl)valine
_20-
1147745
3-allyl-2-methyl-4-oxo-2-cyclopentene-1-yl ester of
N-(4-chlorophenyl)valine
3-benzyl-4-oxo-2-cyclopentene-1-yl ester of N-(4-
chlorophenyl)valine
3,4,5,6-tetrahydrophthalimidomethyl ester of N-(4-
chlorophenyl)valine
phthalimidomethyl ester of N-(4-chlorophenyl)valine
4-phenyl-3-chloro-2-butene-1-yl ester of N-(4-chloro-
phenyl)valine
5-propargyl-2-thiophenemethyl ester of N-(4-chloro-
phenyl)valine
S-benzyl-2-thiophenemethyl ester of N-(4-chloro-
phenyl)valine
5-benzyl-3-thiophenemethyl ester of N-(4-chloro-
phenyl)valine
EXAMPLE 10
Following the procedure of Example 5, each of the
amino compounds listed under column VI is reacted with
m-phenoxybenzyl a-bromoisovalerate to yield the respective
N-substituted ester listed under column VII.
VI
2-chloro-6-methylaniline
4-chloro-2-methylaniline
4-chloro-3-trifluoromethylaniline
2-chloro-5-trifluoromethylaniline
2-~rifluoromethylaniline
3-trifluoromethylaniline
3r5-dichloro-4-hydroxyaniline
4-chloro-3-nitroaniline
-21-
1147745
2,3-dichloroaniline
2-fluoroaniline
2,6-diiodo-4-nitroaniline
3,4,5-trichloroaniline
4-ethoxycarbonylaniline
2-nitroaniline
3-nitroaniline
4-(n-butyl)aniline
4-cyclopropylaniline
2,3-dimethylaniline
4-isopropylaniline
3,5-dimethylaniline
2,4-dimethylaniline
4-hydroxyaniline
2-methylthioaniline
2,5-dichloraniline
3,4-methylenedioxyaniline
3,4-dimethoxyaniline
2,6-difluoroaniline
3,4-dichloroaniline
VII
The m-phenoxybenzyl ester of
N-(2-chloro-6-methylphenyl)valine
N-(4-chloro-2-methylphenyl)valine
N-t4-chloro-3-trifluoromethylphenyl)valine
N-(2-chloro-5-trifluoromethylphenyl)valine
N-(2-trifluoromethylphenyl)valine
N-(3-trifluoromethylphenyl)valine
N-(3,5-dichloro-4-hydroxyphenyl)valine
N-(4-chloro-3-nitrophenyl)valine
-22-
1~47745
N-(2,3-dichlorophenyl)valine
N-(2-fluorophenyl)valine
N-(2,6-diiodo-4-nitrophenyl)valine
N-(3,4,5-trichlorophenyl)valine
N-(4-ethoxycarbonylphenyl)valine
N-(2-nitrophenyl)valine
N-~3-nitrophenyl)valine
N-(4-n-butylphenyl)valine
N-(4-cyclopropylphenyl)valine
N-t2,3-dimethylphenyl)valine
N-(4-isopropylphenyl)valine
N-(3,5-dimethylphenyl)valine
N-(2,4-dimethylphenyl)valine
N-(4-hydroxyphenyl)valine
N-(2-methylthiophenyl)valine
N-(2,5-dichlorophenyl)valine
N-(3,4-methylenedioxyphenyl)valine
N-(3,4-dimethoxyphenyl)valine
N-(2,6-difluorophenyl)valine
N-(3,4-dichlorophenyl)valine
EXAMPLE 11
The a-halo acid chloride listed in column VIII is
reacted with m-phenoxybenzyl alcohol to prepare the respective
-halo ester in column IX according to procedures hereina~ove
such as Example 1.
VIII
2-bromo-3-methylpentanoyl chloride
2-bromo-4-methylpentanoyl chloride
2-bromobutanoyl chloride
-23-
1~774~
2-bromohexanoyl chloride
2-bromo-3-chloropropan~yl chloride
2,5-dichloropentanoyl chloride
2-chloro-4-trichloromethylbutanoyl chloride
IX
3-phenoxybenzyl 2-bromo-3-methylpentanoate
3-phenoxybenzyl 2-bromo-4-methylpentanoate
3-phenoxybenzyl 2-bromobutanoate
3-phenoxybenzyl 2-bromohexanoate
3-phenoxybenzyl 2-bromo-3-chloropropionate
3-phenoxybenzyl 2,5-dichloropentanoate
3-phenoxybenzyl 2,4,4,4-tetrachlorobutanoate
Following the pracedures hereinabove such as Example
4, 4-chloroaniline is reacted with each of the ~-halo esters
listed in column IX to yield the respective substituted amino
ester of column X,
X
3-phenoxybenzyl ester of N-(4-chlorophenyl)isoleucine
3-phenoxybenzyl ester of N-(4-chlorophenyl)leucine
3-phenoxybenzyl ester of 2-(4-chlorophenylamino)
butanoic acid
3-phenoxybenzyl ester of 2-(4-chlorophenylamino)
hexanoic acid
3-phenoxybenzyl ester of 2-(4-chlorophenylamino)-
3-chloropropionic acid
3-phenoxybenzyl ester of 2-(4-chlorophenylamino)-
S-chloropentanoic acid
3-phenoxybenzyl ester of 2-(4-chlorophenylamino)-
4,4,4-trichlorobutanoic acid
-24-
114~7745
ExAMæLE 12
To the m-phenoxybenzyl ester of valine (2 g, 0.0067
mole) in methanol ~30 ml) is added concantrated sulfuric acid
to brin~ to about pH 6. Cyclohexanone (0.6 g, 0.006 mole) is
then added ~ollowed by ~A molecular sieves and sodium cyano-
borohydride ~0.25 g, 0.004 mole). Additional sulfuric acid
is added to keep p~ at about 6. Ater about 24 hours, the
reaction is wor~ed up by removing methanol by rotoevaporation
ana the residue is poured into water and 10~ sodium carb~nate
followed by extraction with ether. The combined ether extracts
are filtered and conc~ntrated and the product LS isolated ~y
preparatory T~C (10% ether~hexane) to yield the m-phenoxy-
benzyl ester o~ N-cyclohexylvaline.
nmr ~CDC13~ ~ 0.89 ~m, 6, J - 7 ~z, (C~3)2CX~,
2.2S [m, 1, (CX3)2CX], 3.12 ~m, l "N-C~-~-), and 5.15 ppm
~s, ArCX2O). IR ~film) 1736 cm 1 ~C-O).
EX~NPLE 13
Each of the substituted aryl amines listed in column
XT ~s reacted with m-phenoxy~enzyl 2-~romoisovalerate using
the procedure of Example 4 to prepare '_he respective ~I-substituted
compound in column XII.
X~
2,4-dichloroaniline
3-methoxyaniline
3,4-dimethylaniline
2,3,5,6-tetrachloroaniline
3-methylaniline
3,5-dichloroaniline
3-acPtoaniline
-25-
1147745
2-acetoaniline
2-methylanili~e
XII
m-phenoxybenzyl ester of
N-~2,4-dichlorophenyl)valine
N-(3-methoxyphenyl)valine
N-(3,4-dimethylphenyl)valine
N- (2,3,5,6-tetrachlorophenyl)~aline
~-t3-methylphenyl)valine
N- (3,5-dichlorophenyl)valine
N - (3-ac~tophenyl)valine
N- (2-acetophenyl)valine
N-~2-methylphenyl)~alLne
T.~ 14
Followin~ the process of Example 1, each o~ the
.alcohols listed ln column XIII is reacted with the acid chloride
o~ a-~romoisovalesic a~id to yield the respective ester in
column X~V.
XIII
3-(2,2-dichlorovinyloxy)benzyl alcohol
3-~o-fluorophenoxy)benzyl alcohol
4-phenyl-2-butenyl alcohol
4-(4-methylphenoxy)-2-butynyl) alcohol
4-(4-methylphenyl)-2-~utenyl alcohol
3-phenylcarbonylbenzyl alcohol
l-ethynyl-2-methyl-2,5-hexadien-1-yl alcohol
l-ethynyl-2-methyl-2-penten-1-yl alcohol
l-ethynyl-2-methyl-3-phenyl-2-propen-1-yl alcohol
1-ethynyl-3-phenyl-2-propen-1-yl alcohol
2,4,6-trimethylbenzyl alcohol
-26-
1~47745
XIV
3-(2,2-dichlorovinyloxy)benzyl a-bromoisovalerate
3-(o-fluorophenoxy)benzyl a-bromoisovalerate
4-phenyl-2-butenyl a-bromoisovalerate
4-(4-methylphenoxy)-2-butynyl -bromoisovalerate
4-(4-methylphenyl)-2-butenyl a-bromoisovalerate
3-phenylcarbonylbenzyl a-bromoisovalerate
a-ethynyl-2-methyl-2,5-hexadienyl a-bromoisovalerate
a-ethynyl-2-methyl-2-pentenyl a-bromoisovalerate
a-ethynyl-2-methyl-3-phenyl-2-propenyl a-bromoiso-
valerate
a-ethynyl-3-phenyl-2-propenyl a-bromoisovalerate
2,4,6-trimethylbenzyl a-bromoisovalerate
Following the procedures hereinabove such as Example
5, p-methylaniline is reacted with each of the a-bromo esters
in column XIV to yield the respective ester of N-(p-methyl-
phenyl)valine in column XV.
X~
3-(2,2-dichlorovinyloxy)benzyl ester of N-(p-methyl-
phenyl)valine
3-(o-fluorophenoxy)benzyl ester of N-(p-methylphenyl)
valine
4-phenyl-2-butenyl ester of N-(p-methylphenyl)valine
4-(4-methylphenoxy)-2-butynyl ester of N-(p-methyl-
phenyl)valine
4-(4-methylphenyl)-2-butenyl ester of N-(p-methyl-
phenyl)valine
3-phenylcarbonylbenzyl ester of N-(p-methylphenyl)
valine
a-ethynyl-2-methyl-2,5-hexadienyl ester of N-(p-
methylphenyl)valine
1147745
-ethynyl-2-methyl-2-pentenyl ester of N-(p-methyl-
phenyl)valine
~-ethynyl-2-methyl-3-phenyl-2-propenyl ester of
N-(p-methylphenyl)valine
-ethynyl-3-phenyl-2-propenyl ester of N-(p-methyl-
phenyl)valine
2,4,6-trimethylbenzyl ester of N-(p-methylphenyl)~aline
EXAMPLE 15
Each of the ~-halo esters in column IX hereinabove
is reacted with p-methylaniline to yield the respective
3-phenoxybenzyl ester of the p-methylphenyl amino aci~ in
column XVI using the procedure of Example 5.
XVI
lS 3-phenoxybenzyl ester of N-(p-methylphenyl)isoleucine
3-phenoxybenzyl ester of N-(p-methylphenyl)leucine
3-phenoxybenzyl ester of 2-(p-methylphenylamino)
butanoic acid
3-phenoxybenzyl ester of 2-(p-methylphenylamino)
hexanoic acid
3-phenoxybenzyl ester of 2-(p-methylphenylamino)-
3-chloropropionic acid
3-phenoxybenzyl ester of 2-(p-methylphenylamino)-
5-chloropentanoic acid
3-phenoxybenzyl ester of 2-(p-methylphenylamino)-
4,4,4-trichlorobutanoic ~cid
EXAMPLE 16
Each of the ~-bromo esters listed in column IV is
reacted with p-methylaniline using the procedure of Example 5
-28-
~147745
to yield the respective ester of N-(p-methylphenyl)valine in
column XVII.
X~II
4-phenoxybenzyl ester of N-(p-methylphenyl)valine
3-benzylbenzyl ester of N-(p-methylphenyl)valine
4-propargylbenzyl ester of N-(p-methylphenyl)valine
4-allyl-2,6-dimethylbenzyl ester of N-(p-methyl-
phenyl)valine
p-allylbenzyl ester of N-(p-methylphenyl)valine
2,6-dimethyl-4-propargylbenzyl ester of N-(p-methyl-
phenyl)valine
a-ethynyl-3-trifluoromethylbenzyl ester of N-(p-
methylphenyl)valine
5-benzyl-3-furylmethyl ester of N-(p-methylphenyl)
valine
a-cyano-5-benzyl-3-furylmethyl ester of N-(p-methyl-
phenyl)valine
5-propargylfurfuryl ester of N-(p-methylphenyl)valine
2-methyl-5-propargyl-3-furylmethyl ester of N-(p-
methylphenyl)valine
5-propargyl-a-ethynylfurfuryl ester of N-(p-methyl-
phenyl)valine
5-benzyl-2-methyl-3-furylmethyl ester of N-~p-methyl-
phenyl)valine
2-methyl-3-propargyl-4-oxo-2-cyclopentene-1-yl ester
of N-(p-methylphenyl)valine
3-allyl-2-methyl-4-oxo-2-cyclopentene-1-yl ester of
N-(p-methylphenyl)valine
3-benzyl-4-oxo-2-cyclopentene-1-yl ester of N-(p-
methylphenyl)valine
-29-
~147745
3,4,5,6-tetrahydrophthalimidomethyl ester of N-(p-
methylphenyl)valine
phthalImidomethyl ester of N-(p-methylphenyl~valine
4-phenyl-3-chloro-2-butene-1-yl ester of N-(p-
methylphenyl)valine
5-propargyl-2-thiophenemethyl ester of N-(p-methyl-
phenyl)valine
5-benzyl-2-thiophenemethyl ester of N-(p-methyl-
phenyl)valine
5-~enzyl-3-thiophenemethyl ester of N-(p-methyl-
phenyl)valine
EXAMPLE 17
A. Two grams of a-~romoisovaleric acid (0.011 mole)
dissolvéd in 10 ml of methanol is titrated to the phenol-
phthalein end point at 0 with 2N sodium hydroxide/methanol.
The alcoho~ is then removed and 10 ml of d~methylformamide
and p-tri~luoromethylaniline (3,54 g, 0.022 mole) added.
Th- ~eact~on mixture is heated at 100 for 2 hours and left
at room te~perature a~out 18 hours. The reaction mixture is
poured into 50 ml af O.lN sodiu~ hydroxide, washed with
ethe~ and the aqueous phase adjusted to p~ 4 with c~nc. ~Cl
and then extrac~ed with chlor~orm ~3X). The e~tracts are
combined and washed with brine, dried, concentrated in a
rotoevapcrator and solvent removed u~der vacuum at about 50
to yield N-(p-trifluoromethylphenyl)valine.
B~ ~ mixt~e of the acid of part A (1.84 g, O.OOtl
mole) and potassium car~onate (1.95 g) in 10 ml of dry
dimethylformamide is stirred at room t~mperatn~e, under
~it~ogen, for 0.5 hours and then m-phenoxy~enzyl bromide
-30-
1147~45
(1.85 g, 0.0071 mole) is added at 0. The reaction mixture
is allowed to warm up to room temperature and is then stirred
about 18 hours. The reaction is then wor~ed up by pouring
into ice-water and extracting with ether (3X). The ether
extracts are comblned and washed with water and brine, dried
o~er calcium sulfate and evaporated under vacuum to yield
the m-phenoxybenzyl ester of N-(p-trifluorome~hylphenyl)valine.
MS m/e 443 (M , 5.9).
EXaMPlE 18
~o a solution of a-bromoisovaleric acid (2 g, 0.110
mole) and S ml of methanol is added one drop of phenolphthalein
and then su~ficient sodium hydroxide/methanol until adjusted
to neutral p~. The sol~ent is then stripped off and p-chloro-
aniline (7 q, 0.05~ mole) added. The mixture is melted i~
a 100 bath and stirred at 100~ ~or 3 hours. The mixture is
cooled and taXen up in ether,and 10% aqueous sodium hydroxide
is added. The aque~us,phasë is acidified to pH 4 and extracted
wtth ether. The'ether extracts are combined and washed w~th
br~ne, d~ied over sodlum,sulfate and stripped to yield
N-~p-chlorophenyl)valine.
Following the proc2dure of Example 1, part A,
N-(p-chlorophenyl)valine is converted to the acid chloride
a~d then rea~ted with m-phenoxybenzyl alc~hol to yield the
m-phenoxybenzyl ester of N-(p-chlorophenyl)valine.
EXAMPIE 19
Following the procedure of Example 17, N-(2-fluoro-
4-chlorophenyl)valine (0.79 g) is reacted with a-ethynyl-m-
phenoxybenzyl bromide ~0.39 g) to yield the a-ethynyl-m-
phenoxybenzyl ester of N-(2-fluoro-4-chlorophenyl)valine,
~1~7745
MS m/e 451 (M ). N-(2-fluoro-4-chlorophenyl)valine is prepared
from 2-fluoro-4-chloroaniline and ~-bromoisovaleric acid using
the procedure of Example 17.
EXAMPLE 20
Following the procedure of Example 5, m-phenoxybenzyl
a-bromoisovalerate is reacted with each of the subs~ituted
phenyl amines in column XVIII to prepare the respective
N-substituted valine in column XIX.
XVIII
4-chloro-3-methylaniline
4-bromo-3-methylaniline
3-bromo-4-methylaniline
3,4-dibromoaniline
3-bromo-4-chloroaniline
4-(t-butyl)aniline
4-nitro-3-trifluoromethylaniline
3,5-di(trifluoromethyl)aniline
XIX
m-Phenoxybenzyl ester of
N-(4-chloro-3-methylphenyl)valine
N-(4-bromo-3-methylphenyl)valine
N-(3-bromo-4-methylphenyl)valine
N-(3,4-dibromophenyl)valine
N-(3-bromo-4-chlorophenyl)valine
N-(4-t-butylphenyl)valine
N-(4-nitro-3-trifluoromethylphenyl)valine
N-(3,5-ditrifluoromethylphenyl)valine
-32-
11477'~5
EXAMPLE 21
Following the procedure of Example 1, each of
m-(p-chlorophenoxy)benzyl alcohol, m-(p-methylphenoxy)benzyl
alcohol, and m-(m-trifluoromethylphenoxy)benzyl alcohol is
reacted with a-bromoisovaleric acid chloride to yield:
m-(p-chlorophenoxy)benzyl a-bromoisovalerate;
m-(p-methylphenoxy)benzyl ~-bromoisovalerate; and
m-(m-trifluoromethylphenoxy)benzyl u-bromoisovalerate.
Each of the above ~-bromo esters is reacted with
p-methylaniline to yield:
m-(p-chlorophenoxy)benzyl ester of N-(p-methyl-
phenyl)valine;
m-(p-methylphenoxy)benzyl ester of N-(p-methyl-
phenyl)valine; and
m-(m-trifluoromethylphenoxy)benzyl ester of
N-(p-methylphenyl)valine.
EXAMPLE 22
To m-phenoxybenzyl ~-bromoisovalerate (2 g, 0.0055
mole), 24, is added 2,6-dimethylaniline (3.33 g, 0.0275 mole)
followed by a catalytic amount of potassium iodide (20 mg).
The reaction mixture is heated at about 120 for 48 hours,
and then poured into ice-water (20 ml) and 2N sulfuric acid
(10 ml) and extracted with ether (3X 30 ml). The combined
ether extracts are washed with water (2X 20 ml) until neutral
and with brine (10 ml) followed by drying over calcium sulfate.
The reaction product is concentrated under vacuum and isolated
by prepaxative TLC to give m-phenoxybenzyl ester of N-(2,6-
dimethylphenyl)valine. MS m/e 403.2 (M+, 7.5).
-33-
i31 ~7~7~5
EXAMPLE 23
To m-phenoxybenzyl ~-bromoisovalerate (2 g, 0.0055
mole), 24, is added 2-methylaniline (2.95 g, 0.0275 mole)
followed by a catalytic amount of potassium iodide (20 mg).
The reaction mixture is heated, 110-115, for about 36 hours,
and then poured into ice-water (30 ml) and 2N sulfuric acid
~10 ml) and extracted with ether (3X 30 ml). The combined
ether extracts are washed with water (2X 30 ml) until neutral
and with brine (10 ml) followed by drying over calcium sulfate.
The reaction product is concentrated under vacuum and isolated
by preparative TLC to yield 3-phenoxybenzyl ester of N-(2-
methylphenyl)valine. MS m/e 389.2 (M+).
EXANPLE 24
To a-bromoisovaleric acid (1.2 g, 0.00603 mole) in
methanol ~2 ml) at 5, is added dropwise methanolic sodium
hydroxide to the phenolphthalein end point. The sodium salt
of the acid is isolated under vacuum, and to the acid salt is
added 2,6-dimethylaniline ~3.65 g, 0.03015 mole) and the
slurry heated in a pressure vessel at about 150 for 12 hours.
Upon cooling, water (20 ml) is added to the reaction mixture and
the excess 2,6-dimethylaniline extracted with ether (3X 20 ml).
The aqueous base layer is acidified with 2N sulfuric acid to
about pH 4 and the N-(2,6-dimethylphenyl)valine is extracted
with ether (3X 20 ml). The combined ether layers are washed
with water (2X 20 ml) until neutral and with brine (10 ml)
followed by drying over calcium sulfate. The N-(2,6-dimethyl-
phenyl)valine is isolated by concentration under vacuum.
To N-(2,6-dimethylphenyl)valine (1.07 g, 0.00486
mole) in THF:HMæT (3 ml: 3 ml) at 24 is added m-phenoxybenzyl
-34-
1147 745
bromide (1.28 g, 0.00486 mole) and potassium carbonate (0.670 g,
0.00486 mole), and the slurry is stirred at 24 for 16 hours.
The product is isolated by pouring the reaction mixture into
ice-water (20 ml) and extracting with ether (3X 20 ml). The
combined ether extracts are washed with water (2X 20 ml) and
brine (10 ml) and dried over calcium sulfate. The product is
concentrated under vacuum and purified by preparative TLC to
give m-phenoxybenzyl ester of N-(2,6-dimethylphenyl)valine,
MS m/e 403.2 (M+).
EXAMPLE 25
Following the procedure of Example 17 or 24, 3-fluoro-
4-methylaniline is reacted with a-bromoisovaleric acid to
prepare N-(3-fluoro-4-methylphenyl)valine, which is reacted with
a-ethynyl-m-phenoxybenzyl bromide to yield the ~-ethynyl-m-
phenoxybenzyl ester of N-(3-fluoro-4-methylphenyl)valine,
MS m/e 431 (M ).
N-(2-fluoro-4-methylphenyl)valine is prepared from
~-bromoisovaleric acid and 2-fluoro-4-methylaniline and then
reacted with a-ethynyl-m-phenoxybenzyl bromide to yield the
~-ethynyl-m-phenoxybenzyl ester of N-(2-fluoro-4-methylphenyl)
valine, MS m/e 431 (M+, 180).
EXAMPLE 26
To the m-phenoxybenzyl ester of N-(p-trifluoromethyl-
phenyl)valine (1.57 g) in about 15 ml benzene, with stirring
and under nitrogen, is added N-chlorosuccinimide (0.53 g). The
reaction mixture is heated to reflux for about 2 hours. The
reaction is cooled and partitioned between ether and water.
Aqueous phase is back-extracted with ether. The combined
114'77~5
ether phases are washed with water and brine, dried over sodium
sulfate, filtered and evaporated. The reaction product is put
on preparative TLC plates and eluted using 10% ether/hexane to
yield the m-phenoxybenzyl ester of N-(2-chloro-4-trifluoromethyl-
phenyl)valine, MS m/e 477.1 (M+).
Following the above procedure, there is prepa~ed
the m-phenoxy-~-cyanobenzyl ester of N-(2-chloro-4-trifluoro-
methylphenyl)valine, MS m/e 486.3 (M+), from the m-phenoxy-a-
cyanobenzyl ester of N-(p-trifluoromethylphenyl)valine.
EXAMPLE 27
To N-phenylvaline hydrochloride (0.1 mole) in ether-
THF at 5 is added dimethylformamide (0.06 mole) followed by
dropwise addition of thionylchloride (0.15 mole). The reaction
is stirred at 24 for 2.5 hours. The acid chloride hydro-
chloride is isolated and then in THF-ether, at 5, is added
~-cyano-3-phenoxybenzyl alcohol (0.09 mole) followed by slow
addition of pyridine (0.3 mole). The reaction mixture is
stirred at 24 for 17 hours and the product is worked up as in
Example 6 to yield the 3-phenoxy-~-cyanobenzyl ester of
N-phenylvaline.
EXAMPLE 28
Into a mixture of 1.0 g of the m-phenoxybenzyl ester
of N-(p-methylphenyllvaline and 10 ml of ether, with stirring
and cooled in an ice bath, is bubbled hydrogen chloride gas
for about 15 minutes. The reaction product is filtered, washed
with ether and recrystallized from hot ethanol to yield the
hydrogen chloride salt of the m-phenoxybenzyl ester of N-(p-
methylphenyl)valine, m.p. 151-153.
-36-
1147~745
Following the procedure of Example 6, 2-fluoro-4-
trifluoromethylaniline is reacted with ~-cyano-m-phenoxybenzyl
~-bromosiovalerate to yield the ~-cyano-m-phenoxybenzyl ester
of N-(2-fluoro-4-trifluoromethylphenyl)valine, MS m/e 502.1
(M ).
EXAMPLE 29
To a solution of 15.8 g (0.1 mole) ethyl 3,3-di-
methyl-2-oxo-butyrate ~Rabjohn et al., J Org. Chem. 35,
3726 (1970)] is added 12.7 g (0.1 mole) p-chloroaniline and
a catalytic amount (0.2 g) of p-toluenesulfonic acid. The
solution is heated under reflux and water removed with a
Dean-Stark trap. After 5 hours heating, the solution is
poured into ether and this fraction is washed with saturated
sodium bicarbonate and saturated brine solutions, and then
dried over calcium sulfate. Removal of solvent by rotoevap-
oration yield the desire imine ester.
Cl ~N~o~
To a solution of 13.4 g (0.05 mole) imine éster in
100 ml methanol at 10 is added excess (2 g, 0.032 mole)
sodium cyanoborohydride in portions. The pH of the solution
is maintained at about pH 6 during the course of the reduction
by adding concentrated sulfuric acid. After several hours,
the reaction is stopped, most of the alcohol is removed by
rotoevaporation, and the residue is poured into ether and water.
The organic fraction is washed with saturated brine solution
and dried over calcium sulfate. Removal of solvent by roto-
evaporation gives ethyl 2-(p-chlorophenylamino)-3,3-dimethyl-
butyrate.
1147745
A solution of 2.7 g (0.01 mole) of the above ethyl
amino ester and 0.4 g (0.01 mole) of sidum hydroxide in 17 ml
ethanol and 3 ml water is stirred at toom temperature for 2
days. The alcohol and water are removed by rotoevaporation
under high vacuum to give the sodium salt of 2-(p-chlorophenyl-
amino)-3,3-dimethylbutyric acid. To the sadium salt is added
50 ml HMPT and 2.63 g (0.01 mole) of m-phenoxybenzyl bromide.
After overnight stirring, the reaction is poured into water
and ether-hexane (1:1). The organic phase is washed several
times with water and then dried over calcium sulfate. Removal
of solvent by rotoevaporation gives the 3-phenoxybenzyl ester
of 2-(p-chlorophenylamino)-3,3-dimethylbutyric acid, MS m/e
423 (M+).
The process of this example is repeated using 0.1
mole of ethyl 3,3,3-trifluoro-2-oxo-propionate in place of
ethyl 3,3-dimethyl-2-oxo-butyrate to give as the final product
the 3-phenoxybenzyl ester of 2-(p-chlorophenylamino)-3,3,3-
trifluoropropionic acid.
EXAMPLE 30
N-(4-chlorophenyl)valine is reacted with m-phenoxy-
-methylbenzyl bromide in THF/HMPT and potassium carbonate to
yield the m-phenoxy-a-methylbenzyl ester of N-(4-chlorophenyl)
valine, MS m/e 423 (M+). The m-phenoxy-a-methylbenzyl bromide
is prepared from m-phenoxybenzaldehyde by reaction with
methyllithium to the secondary alcohol which is brominated
using phosphorous tribromide.
EXAMPLE 31
A mixture of 10 g of 4-fluoronitrobenzene, 5 g of
-38-
~1477~5
valine and 10 g of sodium bicar~onate is dissolved in 200 ml
of ethanol and 100 ml of water. The reaction mixture is
refluxed for 3 hours and cooled. Excess 4-fluoronitrobenzene
is removed by ether extra~tion and the aqueous phase is brought
S to pH 3 to 4 with hydrochloric acid. The oily precipitate is
extracted with methylene chloride. After drying and removal
of solvent, the residue is treated with 3 equivalents of
sodium carbonate and 1 equivalent of m-phenoxybenzyl bromide
in dimethylformamide as solvent. After stirring 24 hours ~he
mixture is diluted with water and extracted with ether. The
organic phase is washed with water, dried and the solvent
removed. The crude ester is pl~rified by preparative TLC to
give the m-phenoxybenzyl ester of N-(p-nitrophenyl)valine.
EXAMPLE 32
To a solution of 1.51 g of N-phenylgly~ine in 10 ml
of dry dimethylformamide is added 2.76 g of dry potassium
car~onate and 1.04 g of 3,3-dimethyl-2-propenyl chloride.
The mixture is stirred overnight at room temperature and then
diluted with water and extracted with ether. The ether
extracts are combined and washed with water, dried over
magnesium sulfate and ether evaporated to give the 3,3-dimethyl-
2-propenyl ester of ~-phenylglycine.
To a solution of 2.19 g of the ester prepared above
in 20 ml of THF and 5 ml of HMPT is added a solution of 1.03
g of lithium diisopropylamide in TXF (prepared in situ from
1.01 g of diisopropylamine and 6.25 ml of 1.6M butyl lithium~
while maintaining temperature of about -60. The reaction is
allowed to reach -30, then 1. OQ g of trimethylsilyl chloride
in 5 ml of THF is added at -30 and then stirring for 20
-39-
~147745
minutes. The reaction is then cooled to -78 and an additional
1.03 g of lithium diisopropylamide in T~F added. The reaction
is stirred at -60 for 30 min. and 1.08 g of trimethylsilyl
chloride is added at -60. ~fter an hour at -60 the reaction
is allowed to reach room temperature and 1 hour thereafter
the ~eaction mixture is broùght to reflux for 30 minutes. The
reaction is cooled and poured into 10 ml of 2N sodium hydroxide.
T~e mixture is stirred for 20 minutes at room temperature and
then extracted with ether. The aqueous phase is acidified
t~ pH 3-4 and re-extracted with ether. The ether extracts are
combined and washed with water, dried and evaporated to give
2-phenylamino-3,3-dimethyl-4-pentenoic acid which is esterified
using m-phenoxybenzyl bromide by procedures hereinabove to
yield m-p;.enoxybenzyl 2-phe~ylamino-3,3-dimethyl-4-pentenoate
tm-phenoxybenzyl 2-phenylamino-2-t2-methyl-3-~uten-2-yl)-
acetate].
E~AMPLE 33
A solution of 2 g of a-bromoisovaleric acid and 10
ZO ml o~ methanol is titrated, at 0, to the phenolph~halein end
point with sodium hydroxide~methanol solution. The solvent
is then removed, 6 ml of dimethylformamide and 2.97 g of
p-acstylaniline added. The resulti~g clear reaction mixture
is heated at 100~ for 3 hours and then stirred overnight at
room temperature. The reaction is poured into 50 ml o~ O.lN
sodium hydroxide and washed with ether. The aqueous phase is
acidified to pH 4 with concentrated hydrochloric acid and
extracted 3X with chloroform. The chloroform extracts are
dried and concentrated. The concentrate is taken up with
0.lN sodium hydroxide and washed with-ether. The aqueous
-40-
114~745
phase is acidified and worked up as before to give l.0 g of
N-(p-acetylphenyl)valine which is reacted with 1.05 g of
m-phenoxybenzyl bromide in dimethylformamide with potassium
carbonate by procedures hereinabove to yield the m-phenoxybenzyl
ester of N-(p-acetylphenyl)valine, MS m/e 417.1 (M+).
Following the above procedure, N-(p-cyanophenyl)valine
is prepared from 0.011 mole of ~-bromoisovaleric acid and
0.022 mole of p-cyanoaniline. Then 0.01 mole of N-(p-cyano-
phenyl)valine is esterified using 0.01 mole of m-phenoxybenzyl
bromide and 0.020 mole of potassium carbonate in dimethyl-
formamide to prepare the m-phenoxybenzyl ester of N-(p-cyano-
phenyl)valine, MS m/e 400.1 (M+).
EXAMPLE 34
The process of Example 29 is repeated using 0.1 mole
of ethyl 3,3,3-trichloro-2-oxopropionate in place of ethyl
3,3-dimethyl-2-oxo-butyrate to give as the final product the
3-phenoxybenzyl ester of 2-(p-chlorophenylamino)-3,3,3-tri-
chloropropionic acid.
EXAMPLE 35
A 100 ml flask is flushed with nitrogen and to it is
added 25 ml of a lM THF solution of lithium N-isopropylcyclo-
hexylamide (0.025 mole) followed by HMPT (5 ml). The flask is
cooled to -78 and 7.1 g ~0.025 mole) of m-phenoxybenzyl 3-
methyl-2-butenoate in THF (25 ml) is added dropwise over 5
minutes. After the addition the mixture is stirred at -20 for
l hour. This cold solution is then added dropwise to l-l
equivalent of bromine in THF at -78. After a further 1 hour at
-78, 5 ml of concentrated hydrochloric acid is added and the
1147745
mixture allowed to come to RT and poured into ether plus cold
a~ueous hydrochloric acid. The ether layer is washed with water
and brine and dried over calcium sulfate. Removal of the
solvent gives m-phenoxybenzyl 2-bromo-3-methyl-3-butenoate,
which is reacted with p-methylaniline by the process of Example
5 to give m-phenoxybenzyl ester of 2-~p-methylphenylamino)-3-
methyl-3-butenoate.
EXAMPLE 36
Following the procedure of Example 1, the m-phenoxy-
benzyl ester of ~-bromoisovaleric acid is reacted with 3,4-
methylenedioxyaniline (3 equivalents) at about 75 for about
14 hours to yield the m-phenoxybenzyl ester of N-(3,4-methylene-
dioxyphenyl)valine, MS m/e 419 (M , 13.2), 192 (100).
Following the above procedure, the m-phenoxybenzyl
ester of N-(3-methoxyphenyl)valine, MS m/e 405 (M+, 4.1), 178
(100), is prepared from m-anisidine.
EXAMPLE 37
A mixture of N-chlorosuccinimide (1.17 mmole),
m-phenoxybenzyl ester of N-(p-methoxyphenyl)valine (1.23 mmole)
and benzene (20 ml) is refluxed under nitrogen for about 60
hours. The reaction is worked up in water/ether. The ether
layer is washed with water and brine and dried over sodium
sulfate. The crude product is purified by preparatory TLC
eluting with 15% ether/hexane to gi~e the m-phenoxybenzyl ester
of N-(2-chloro-4-methoxyphenyl)valine, MS m/e 439 (M+, 7.4),
212 (100).
-42-
~14'7745
EXAMPLE 38
A solution of ~-bromoisovaleric acid (8.17 mmole) in
methanol is titrated to the phenophthalein end point using
sodium methoxide. The solvent is removed by rotoevaporation
and then there is added potassium carbonate (1.69 g), 2-fluoro-
4-methylaniline (16.38 mmole) and 3 ml HMæT. The reaction is
heated at 60 for about 5 hours and then worked up with 5%
sodium hydroxide/ether and washed with water (3X). The basic
layer is acidified and extracted with ether, washed with water
and brine, dried over sodium sulfate and rotoevaporated to
yield ~-(2-fluoro-4-methylphenylamino)isovaleric acid.
(2-Fluoro-4-methylaniline is prepared from 3-fluoro-4-nitro-
toluene in a Parr bottle using platinum oxide and hydrogen
lS in ethanol.)
To a mixture of 5.15 mmole of ~-(2-fluoro-4-methyl-
phenylamino)isovaleric acid, potassium carbonate (6.44 mmole),
4 ml of HMPT and 3 ml of THF, stirred, is added 5.13 mmole of
m-phenoxybenzyl bromide. The reaction is stirred overnight at
RT. The reaction is poured into 5% sodium hydroxide/ether,
extracted with water (2X) and then washed with water (2X),
dried over sodium sulfate and rotoevaporated under vacuum.
The crude product is subjected to preparatory TLC eluting with
10% ether/hexane to give m-phenoxybenzyl ester of N-(2-fluoro-
4-methylphenyl)valine.
nmr (CDC13) ~ 0.98 [d, 3, J - 7 Hz, CH(CH3)2], 1.02
[d, 3, J a 7 Hz, CH(CH3)2], 2.22 (s, 3, F ~ CH3), and 5.13 ppm
(s, 2, ArCH2O). IR (neat))1734 cm 1 (C=O).
-43-
~147745
Following the above procedure, N-(4-tert-butyl-
phenyl)valine is reacted with m-phenoxybenzyl bromide to yield
the m-phenoxybenzyl ester of N-(4-tert-butylphenyl)valine.
nmr (CDC13) ~ centered at 0.99 [d, 6, J = 7 Hz,
(CH3)2CH~, 1.28 [s, 9, (CH3)3C-Ar], 3.93 (m, 2, NH and HN-CH-~-),
and 5.11 ppm (s, 2, ArCH2O). IR (film) 1743 cm 1 (C=O).
The procedure of this example is used to prepare
N-(3-chloro-4-fluorophenyl)valine and N-(3-fluoro-4-methyl-
phenyl)valine, each of which is reacted with m-phenoxybenzyl
bromide to yield the m-phenoxybenzyl ester of N-(3-chlaro-4-
fluorophenyl)valine ~MS m/e 427 (M+, 3.2), 200 (100)] and the
m-phenoxybenzyl ester of N-(3-fluoro-4-methylphenyl)valine.
nmr (CDC13) ~ centered at 0.97 ~d, 6, J = 7 Hz, CH(CH3)2], 2.11
(d, 3, J s 2 Hz, ~ CH3), and 5.10 ppm (s, 2, ArCH2O). IR (neat
1732 cm 1 (C=O). N F
EXAMPIE 39
~ mixture of 5 g of p-trifluoromethylaniline, 2.25 g
of -bromoisovaleric acid and 2.0 g of potassium carbonate is
heated at 100 for 1 hour. After 1.5 hour, 5 ml of HMPT is
added and the mixture heated at 100~ for 15 hr. The mixture is
then poured into water and potassium carbonate added to about
pH 11. The mixture is washed with ether, methylene chloride
and the aqueous phase acidified to about pH 3 and washed with
ether and concentrated. The residue is recrystallized from
hexane/ether to yield N-(4-trifluoromethylphenyl)valine, which
is reacted with m-phenoxybenzyl bromide to yield the m-phenoxy-
benzyl ester of N-(4-triflurormethylphenyl)valine. MS m/e 443
(l~+, 5.9).
-44-
11~77~s
The acid, N-(4-triflusromethylphenyl)valine, is reacted,
at RT in DMF/THF and potassium carbonate, with m-phenoxy-a-
ethynylbenzyl bromide to yield the m-phenoxy-a-ethynylbenzyl
ester of N-(4-trifluoromethylphenyl)valine. MS m/e 467 (M+,
1.3), 216 (lO0).
The acid, N-(4-fluorophenyl)valine is prepared as
above from 4-fluoroaniline and a-bromoisovaleric acid and then
reacted with m-phenoxybenzyl bromide, as above, to yield the
m-phenoxybenzyl ester of N-(4-fluorophenyl)valine. nmr (CDCl3)
~ centered at 0.90 ~m, 6, (CX3)2CH], 2.0 [m, l, (CH3)2CH], 3.80
(m, 2, NH and N-CH-~-), and 5.15 ppm (s, 2, ArCH2O). IR (film)
3400 cm 1 (N~).
N-(3-fluorophenyl)valine (prepared by reacting
a-bromoisovaleric acid and 3-fluoroaniline at 140, under
nitrogen, for 3.5 hr) is reacted with m-phenoxybenzyl bromide
in HMPT/THF and potassium carbonate at RT to yield the m-phenoxy-
benzyl ester of N-(3-fluorophenyl)valine. MS m/e 393 (M , 2),
166 (100).
N-(2-chloro-4-methylphenyl)valine is prepared as above
from a-bromoisovaleric acid and 2-chloro-4-methylaniline and
then reacted with m-phenoxybenzyl bromide, as above, to yield
the m-phenoxybenzyl ester of N-(2-chloro-4-methylphenyl)valine.
MS m/e 423 (M+, 4), 196 (100).
Similarly, there is prepared the m-phenoxybenzyl
ester of N-(3-nitrophenyl)valine from N-(l-nitrophenyl)valin~
and m-phenoxyben2yl bromide. MS m/e 420 (M , 4), 193 (lO0).
EXAMPLE 40
To 1.21 mmole of triethyl oxonium tetrafluoroborate
in about 5 ml methylene chloride under nitrogen is added 1.05
-45-
1147745
mmole of the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine.
The reaction is stirred at RT o~ernight and then poured into
ether/water. The organic phase is washed with water and brine,
dried over calcium sulfate, and solvent removed. The crude
product is applied to preparatory T~C eluting with 20~ ether/hexane,
to give the m-phenoxybenzyl ester N-ethyl,N-(4-chlorophenyl)valine.
MS m/e 437 ~M , 3), 210 (100).
EXAMPLE 41
N-(4-fluoro-2-methylphenyl)valine prepared from
4-fluoro-2-methylaniline and -bromoisovaleric acid is reacted
with m-phenoxybenzyl bromide as in Example 38 to give the
m-phenoxybenzyl ester of N-(4-fluoro-2-methylphenyl)valine.
MS m/e 407.2 (M , 4.5), 180 (100).
EXAMPT~ 42
To a mixture of 0.47 g of N-(4-methylphenyl)valine,
5 ml of HMPT, and 0.36 g of potassium carbonate, with stirring,
i8 added 0.82 g of m-(3,4-dichlorophenoxy)benzyl bromide. The
reaction mixture is stirred overnight at RT and then wor~ed up
by partition between water/ether The aqueous phase is extracted
with ether (2X) and then the combined ether phases are washed
with water and brine, dried over sodium sulfate, filtered and
evaporated. The concentrate is subjected to preparatory T~C
eluting with 10% ether/hexane to yield the m-(3,4-dichloro-
phenoxy)benzyl ester of N-(4-methylphenyl)valine. ~S m/e 459.1
(M , 2.4), 162.1 (100).
The m-phenoxybenzyl ester of N-(2-nitrophenyl)valine,
YS m/e 420.1 ~M , 2.7~, 193 (100), is prepared from the reaction
-46-
11477~5
of m-phenoxybenzyl bromide and N-(2-nitrophenyl)valine as aoove.
N-(4-methylphenyl)valine is reacted with m-phenoxy-
a-ethynylbenzyl bromide in DMF/THF and potassium carbonate at
RT, as above, to give the m-phenoxy--ethynylbenzyl ester of
S of N-(4-methylphenyl)valine. MS m/e 413.1 ~M+, 3.8), 162.1
(100). ~ / 3
H CjH 3 ~ ~
C ~
N-(3,4,5-trichlorophenyl)valine, prepared from 3,4,5-
trichloroaniline and ~-bromoisovaleric acid, is reacted with
m-phenoxy~enzyl bromide in H~PT/THF and potassium carbonate at
RT to yield the m-phe~oxy~enzyl ester of N-(3,4,5-trichloro-
phenyl)valine. MS m/e 477.1 (M+, 9.8), 250 (100).
EXAMPLE 43
A mixture of 3,5-dimethoxyaniline (2.1 g), the m-
phenoxybenzyl ester of a-bromoisovaleric acid (1.0 g), potassium
iodide (72.9 mg) and 5 ml of HMæT is heated overnight at
70-80. The reaction is then worked up by partition between
100 ml of 2N sulfuric acid and 100 ml of ether. The aqueous phase
is extracted with e~her and then the combined ether phases are
washed with 2N sulfuric acid, satuxated sodium bicarbonate and
brine, dried over potassium car~onate, filtered and evaporated.
The residue is subjected to prep. TLC eluting with ether/hexane
to yield the m-phenoxybenzyl ester of N-(3,5-dimethoxyphenyl)-
valine. MS m/e 435.2 (M , 11.7), 208.1 (100).
By the above procedure, 3,4,5-trimethoxyaniline is
reacted with m-phenoxybenzyl a-~romoisovalerate to yield ~he
m-phenoxybenzyl ester of N-(3,4,5-trimethoxyphenyl)valine.
1147 745
MS m/e 465.2 (M , 39.0), 182.9 (100~.
Following the procedures of Example 42, N-(4-chloro-
phenyl)valine is reacted with m-benzylbenzyl bromide to yield
the m-benzylbenzyl ester of N-(4-chlorophenyl)valine. MS m/e
407.L (M , 6.2), 182 (100).
EXAMæLE 44
To m-phenoxybenzyl 3-methyl-2-butenoate (5.80 mmole)
and carbon tétrachloride (30 ml), under nitrogen, is slowly
added bromine (5.99 mmole) in carbon tetrachloride with the
reaction flask in an ice-bath. After about 3 hr, the reaction
is worked up by partition between water/ether. The aqueous
phase is extracted with ether and then the combined ether
phases are washed with water and brine, dried over potassium
carbonate, filtered and evaporated to yield m-phenoxy~enzyl
2,3-dibromo-3-methylbutanoate.
A mixture of the above dibromo ester ~4.1 mmole),
4-methylaniline (12.6 mmole), triethylamine (8.6 mmole), THF
(20 ml) and HMPT (2 ml) is heated at 50 under nitrogen. After
9 days, the reaction is wor~ed up by partition between ether/2N
HCl. The aqueous phase is extracted with ether and then the
combined ether phases are washed with 2N HCl and brine, dried
o~er potassium carbonate, filtered and evaporat~d. The residue
is subjected to prep. TLC eluting with 10% ether/hexane to
yield the m-phenoxybenzyl ester of a-(4-methylphenylamino)-
3-methyl-3-butenoic acid. MS m/e 387.2 (M , 2.7), 160 (100).
EXAMPLE 45
To N-~4-chlorophenyl)isoleucine (0.57 g) in about 5 ml
of HMoeT is added potassium carbonate (0.54 g) and then
-48-
~147745
m-phenoxybenzyl bromude (1.09 g). The reaction mixture is
stirred overnight at RT. The reaction is worked up by partition
between water/ether. The aqueous phase is extracted with ether
and then the combined ether phases are washed with water and
brine, dried over potassium carbonate, filtered and evaporated.
The residue is subjected to prep. TLC eluting with 10% ether/hexane
to yield the m-phenoxybenzyl ester of N-(4-chlorophenyl)iso-
leucine. MS m~e 423 (M+, 3.7), 196 (100).
N-(4-chlorophenyl)isoleucine is prepared by the
reaction of 4-chloroaniline with the sodium salt of ~-bromo-3-
methylpentanoic acid neat at 100.
By the above procedure, m-phenoxybenzyl bromide is
reacted with N-(4-methylphenyl)isoleucine to prepare the
m-phenoxybenzyl ester of N-(4-methylphenyl)isoleucine. MS m/e
403.3 (M+, 3.3), 176.1 (100).
EXAMPT~ 46
N-~4-methylphenyl)valine is reacted with m-(4-methoxy-
phenoxy)benzyl bromide in THF/HMPT and potassium carbonate at
RT overnight to yield the m-(4-methoxyphenoxy)benzyl ester of
N-(4-methylphenyl)valine. IR (film) 3380 cm 1 (NH) and 1735 cm 1
(~=0) .
EXAMPLE 47
2S To the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine
(1.19 mmole) in ether (4.5 ml), under nitrogen, is added dimethyl-
aminopyridine (4.25 mmole) which is cooled in an ice-bath and
then trichloroacetyl chloride (3.58 mmole) in ether added slowly.
The reaction mixture is heated at 40~ for 3 days. The reaction
is wor~ed up with ether/water. The aqueous phase is extracted
-49-
11~774S
with ether and then the combined ether phases are washed with
water and brine and dried over sodium sulfate. The residue is
subjected to prep. TLC eluting with 10% ether/hexane to yield
the m-phenoxybenzyl ester of N-trichloroacetyl,N-(4-chloro-
phenyl)valine. MS m/e 553 (M+, 1.8), 183 (100).
EXAMPLE 48
Following the procedure of Example 47, the m-phenoxy-
benzyl ester of N-acetylformyl,N-(4-chlorophenyl)valine ~MS m/e
479 (M , 0.5), 183 (100)] is prepared by the reaction of the
acid chloride of pyruvic acid with the m-phenoxybenzyl ester of
N-(4-chlorophenyl)valine.
EXAMPLE 49
Following ~he procedure of Example 42, N-(4-chloro-
phenyl)valine is reacted with m-(3,4-dichlorophenoxy)benzyl
bromide to yield the m-(3,4-dichlorophenoxy)benzyl estex of
N-(4-chlorophenyl)valine. MS m/e 477 (M , 2.1), 182 (100).
EXAMoeLE 50
To the m-phenoxybenzyl ester of N-(4-methoxyphenyl)-
valine (0.89 mmol) in ether is added tri~luoroacetic anhydride
(4.46 mmol), under nitrogen. The reaction mixture is stirred
for 2.5 hr and then wor~ed up with ether/water. The combined
ether layers are washed with saturated sodium bicarbonate and
brine, dried over sodium sulfate and evaporated to yield the
m-phenoxybenzyl ester of N-trifluoroacetyl,N-(4-methoxyphenyl)-
valine. MS m/e 501 (M , 22.5), 183 (100).
-50-
114774S
EXAMPLE 51
A mixture of the m-phenoxybenzyl ester of N-(4-
chlorophenyl)valine (1.22 mmole), acetic formic anhydride in
acetic acid (23.8 mmole, 2.1 g) and formic acid (1.5 ml) is
stirred overnight at RT under nitrogen. The reaction product
is concentrated and then subjected to prep. TLC eluting with
20% ethylacetate/hexane to yield the m-phenoxybenzyl ester of
N-formyl,N-(~-chlorophenyl)valine, MS m/e 437 (M , 8.1),
182 (100).
EXAMPLE 52
Following the procedure of Example 50, trifluoroacetic
anhydride and the m-phenoxybenzyl ester of N-(4-chlorophenyl)-
valine are reacted to yield the m-phenoxybenzyl ester of N-
trifluoroacetyl,N-(4-chlorophenyl)valine, MS m/e 505 (M+, 14.9),
278 (100).
Following the procedure of, for example, Example 42,
~-ethynyl-m-phenoxybenzyl bromide and N-(4-chlorophenyl)valine
are reacted to yield the ~-ethynyl-m-phenoxybenzyl ester of
N-(4-chlorophenyl)valine, MS m/e 433 (M+, 2.2), 182 (100).
EXAMPLE 53
To the m-phenoxybenzyl ester of N-phenyl valine
(1.2 mmole) is added 12.5% phosgene in benzene (2.3 mmole),
cooled in an ice bath, and then dimethylaminopyridine (1.22
mmole). The reaction mixture is stirred at RT for 3 days. Then
one ml of benzene, 0.15 g of dimethylaminopyridine and 2 ml of
phosgene are added and the reaction stirred overnight at RT.
The reaction is worked up using chloroform/water. The chloro-
form layer is washed with dilute sulfuric acid, water and brine,
-51-
1147745
dried over sodium sulfate and filtered. The solvent is
removed by rotoevaporation to yield the m-phenoxybenzyl ester
of N-chloroformyl,N-phenyl valine.
A mixture o 0.89 mmole of the foregoing ester, one
ml of pyridine and methanol (0.91 mmole) is stirred at RT for
4 days. The reaction is then worked up using dilute HCl/ether.
The ether layer is washed with aqueous HCl, water and brine,
dried over sodium sulfate and filtered. Solvent is removed
and residue plated on prep. TLC plate eluting with 8%, 20~
ether-hexane to yield the m-phenoxybenzyl ester of N-methoxy-
carbonyl,N-phenyl valine, MS m/e 433 (M , 6.7), 206 (100).
EXAMPLE 54
N-(2-chloro-4-cyanophenyl)valine and m-phenoxybenzyl
bromide in THF/HMPT with potassium carbonate are reacted using
the procedure of Example 42 to prepare the m-phenoxybenzyl
ester of N-(2-chloro-4-cyanophenyl)valine, MS m/e 434 ~M+,
3.7), 207 (100). N-(2-chloro-4-cyanophenyl)valine is prepared
by the reaction of 2-chloro-4-cyanoaniline with ~-bromoiso-
valeric acid using the process of, for example, Example 18.
Similarly, there is prepared N-(2,4-difluorophenyl)-
valine from 2,4-difluoroaniline and ~-bromoisovaleric acid.
The N-(2,4-difluorophenyl)valine is esterified using m-phenoxy-
benzyl bromide to prepare the m-phenoxybenzyl ester of N-(2,4-
difluorophenyl)valine, MS m/e 411 (M , 3.5), 184 (lO0).
EXAMPLE 55
N-(2-fluoro-4-chlorophenyl)valine and m-phenoxybenzyl
bromide are reacted using the process of Example 42 to yield
the m-phenoxybenzyl ester of N-(2-fluoro-4-chlorophenyl)valine,
-52-
1~4774S
MS m/e 427.1 (M , 4.1), 200 (100). N-(2-fluoro-4-chlorophenyl)-
valine is prepared by heating the potassium salt of a-bromoiso-
valeric acid and 2-fluoro-4-chloroaniline neat at 130 for
about 2 hours.
Similarly, there is prepared N-(3-methyl-4-fluoro-
phenyl)valine which is esterified using m-phenoxybenzyl bromide
to yield the m-phenoxybenzyl ester of N-(3-methyl-4-fluoro-
phenyl)valine, MS m/e 407.3 (M+, 0.3), 180 (100).
In the same way, there is prepared N-(3-methyl-6-
fluorophenyl)valine and N-(3-fluoro-6-methylphenyl)valine, each
of which is esterified using m-phenoxybenzyl bromide to yield
the m-phenQxybenzyl ester of N-(3-methyl-6-fluorophenyl)valine
~MS m/e 407.3 (M+, 4.3), 180 (100)] and the m-phenoxybenzyl
ester of N-(3-fluoro-6-methylphenyl)valine ~MS m/e 407.3 (M+,
3.9), 180 (100)].
EXAMPLE 56
To a mixture of the ~-cyano-m-phenoxybenzyl ester of
N-(4-chlorophenyl)valine (0.79 g) and about 20 ml of dry DMF
2 0 i8 added about one ml of triethanolamine at RT. Into the
mixture is slowly bubbled H2S gas for about 3 hours. The
reaction is then stirred overnight. The reaction is worked up
by partition with ether/water. The organic phase is washed with
brine (3X), dried over sodium sulfate, filtered and evaporated.
The residue is plated on a prep. TLC plate eluting with 20%
ethyl acetate/hexane to yield the desired thioamide, MS m/e
181.9 (100), IR (film) 3180 cm 1 (NH) and 1740 cm 1 (C-O).
_~N X-- ~0
Cl O S
NH2
-53-
~147'745
EXAMpT~ 57
N-(2-cyano-4-chlorophenyl)valine is reacted with
m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of
N-(2-cyano-4-chlorophenyl)valine using the procedure of
Example 42. MS m/e 434.1 (M+, 3.5).
Similarly, there is prepared the ~-cyano-m-phenoxy-
benzyl ester of N-(2-methylphenyl)valine, MS m/e 414.1 (M+,
5.8), from a-cyano-m-phenoxybenzyl bromide and N-(2-methyl-
phenyl)valine.
Likewise, there is prepared the m-phenoxybenzyl ester
of N-(2-methyl-4-chlorophenyl)valine, MS m/e 423.1 (M , 16.9),
from m-phenoxybenzyl bromide and N-(2-methyl-4-chlorophenyl)-
valine.
In the same way, N-(pentafluorophenyl)valine is
reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl
ester of N-(pentafluorophenyl)valine, MS m/e 465 (M+, 4.2).
EXAMPLE 58
m-Phenoxybenzyl bromide is reacted with each of
N-(2,4-dimethoxyphenyl)valine and N-(2-methyl-6-chlorophenyl)-
valine following the procedure of Example 42 to yield the
m-phenoxybenzyl ester of N-(2,4-dimethoxyphenyl)valine, MS m/e
435.2 (M+, 12.4), and the m-phenoxybenzyl ester of N-(2-methyl-
6-chlorophenyl)valine, MS m/e 423.1 (M , 3.7).
EXAMPLE 59
A mixture of 0.5 g of the m-phenoxyben2yl ester of
N-(2,6-dimethylphenyl)valine, 0.21 g of N-chlorosuccinimide
and 3 ml of benzene is heated at reflux for 2 hours. The
reaction is diluted with hexane, washed with water (2X) and
-54-
114774S
solvent stripped to give the crude product. To the crude
product is added 0.1 g of N-chlorosuccinimide and 3 ml benzene.
The mixture is heated at reflux for 30 min and then allowed to
stand overnight at RT. The reaction is worked up by diluting
with hexane, washing with water and stripping off solvent to
yield the m-phenoxybenzyl ester of N- (2, 6-dimethyl-4-chloro-
phenyl)valine, MS m/e 437.1 (M , 15.3).
EXAMPLE 60
N-(4-bromophenyl)valine, prepared from 4-bromoaniline
and a-bromoisovaleric acid, is esterified using m-phenoxybenzyl
bromide to yield the m-phenoxybenzyl ester of N-(4-bromophenyl)-
valine, MS m/e 454 (M+).
The sodium salt of ~-bromoisovaleric acid is reacted
with p-ethylaminobenzoate, neat, at 140 for 3 hr to yield
N-(4-ethoxycarbonylphenyl)valine, which is reacted with m-
phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of
N-(4-ethoxycarbonylphenyl)valine, MS m/e 447 (M+).
The m-phenoxybenzyl ester of N-(3-trifluoromethyl-
phenyl)valine, MS m/e 443 (M+), is prepared from N-(3-trifluoro-
methylphenyl)valine and m-phenoxybenzyl bromide. The reaction
of 3-trifluoromethylaniline with the sodium salt of ~-bromoiso-
valeric acid provides the starting material.
Each of N-(3,4-dimethylphenyl)valine, N-(3-methyl-
phenyl)valine, N-(2,4,6-trimethylphenyl)valine, N-(2-chloro-
5-trifluoromethylphenyl)valine and N-(2,6-difluoro-4-chloro-
phenyl)valine is esterified using m-phenoxybenzyl bromide with
potassium carbonate in THF/HMPT at RT to yield the respective
ester below.
-55-
114774S
The m-phenoxybenzyl ester of
N-(3,4-dimethylphenyl)valine, MS m/e 403.2 (M+),
N-(3-methylphenyl)valine, MS m/e 389.2 (M ),
N-(2,4,6-trimethylphenyl)valine, MS m/e 417.1 (M+),
N-(2-chloro-5-trifluoromethylphenyl)valine,
MS m/e 477 (M+), and
N-(2,6-difluoro-4-chlorophenyl)valine, MS m/e 445.1 (M+) .
The starting material is prepared by the reaction of
the sodium salt of a-bromoisovaleric acid with each of
3,4-dimethylaniline, 3-methylaniline, 2,4,6-trimethylaniline,
3-chloro-5-trifluoromethylaniline and 2,6-difluoro-4-chloro-
aniline according ~o the procedure of Example 18.
Following the procedure of Example 1, each of 4-n-
butylaniline and 4-cyclopropylaniline is reacted with m-phenoxy-
benzyl ~-bromoisovalerate to yield the m-phenoxybenzyl ester
of N-(4-n-butylphenyl)valine, MS m/e 431.2 (M ), and the
m-phenoxybenzyl ester of N-(4-cyclopropylphenyl)valine, MS
m/e 415.1 (M+).
Each of the m-phenoxybenzyl ester of N-(4-chloro-
phenyl)valine and N-(4-methylphenyl)valine is methylated using
the procedure of Example 2 to yield the m-phenoxybenzyl ester
of N-methyl,N-(4-chlorophenyl)valine, MS m/e 423 (M ), and the
m-phenoxybenzyl ester of N-methyl,N-(4-methylphenyl)valine,
MS m/e 403.2 (M ).
EXAMPLE 61
To a mixture of 10 g of ethyl crotonate, 40 ml of
dioxane and 60 ml of water, at 0, is slowly added 15 g of
N-bromosuccinimide After addition is complete, the reaction
is allowed to stand at RT for 17 hr with stirring. The
-56-
il4~745
reaction is taken up in ether, washed with water and saturated
sodium sulfite, dried over magnesium sulfate and evaporated
under reduced pressure to yield ethyl 2-bromo-3-hydroxybutanoate.
To a mixture of ethyl 2-bromo-3-hydroxybutanoate
(10 g) and 15 ml of HMPT is added 13.2 g of aniline~ The
reaction is stirred at RT for 3 days and then taken up in ether
followed by washing with dilute sulfuric acid, pH 3, and water.
The ether phase is dried over magnesium sulfate and evaporated
to yield ethyl 2-phenylamino-3-hydroxybutanoate, which is
saponified using 1.6 g of sodium hydroxide, 40 ml of methanol
and 20 ml of water with stirring overnight at RT. The acid
2-phenylamino-3-hydroxybutanoic acid (3.0 g) is reacted with
m-phenoxybenzyl bromide (3.4 g) in HMPT (20 ml) and potassium
carbonate (2.12 g) at 35 for a few hours and worked up using
ether/water to yield the m-phenoxybenzyl ester of 2-phenylamino-
3-hydroxybutanoic acid.
To a solution of N-chlorosuccinimide (1.24 g) and
dry THF (60 ml), stirring at RT, is slowly added triphenyl-
phosphine (2.43 g) in 50 ml of THF. Then the m-phenoxybenzyl
ester of 2-phenylamino-3-hydroxybutanoate (3.5 g) in 30 ml of
THF is added slowly. The reaction mixture is stirred overnight.
The reaction is then concentrated under reduced pressure. The
residue (oil) is taken up in ether, washed with water, dried
over magnesium sulfate and evaporated to yield the m-phenoxy-
benzyl ester of 2-phenylamino-3-chloro-butanoic acid, MS m/e
395 (M ).
The above prepared ester is methylated using the
procedure of Example 2 to yield m-phenoxybenzyl 2-(methyl,phenyl-
amino)-3-chlorobutanoate, MS m/e 409 (M+).
-57-
11~774~
EXAMPLE 62
A mixture of 0.5 g of m-phenoxybenzyl 2-oxo-3-
methylbutanoate, 0.39 g of 2,4,6-trichloroaniline, 0.02 g of
p-toluenesulfanylacetate and 10 ml of benzene is heated to
reflux for about 5.5 hr. A Dean-Stark trap is used to remove
water. The reaction is worked by pouring into ether/sodium
bicarbonate solution. The organic phase is washed with water
and brine, dried over magnesium sulfate and evaporated. To
the reaction product (0.79 g) is added 3 ml of methanol, l ml
of THF and 0.19 g of NaCNBH3. The reaction mixture is stirred
at RT and then adjusted to pH 3 to 4 with concentrated sulfuric
acid. Stirring ~t RT is continued overnight. The reaction is
worked up as before using ether/sodium bicarbonate solution and
subjected to prep. TLC eluting with 20% ether/hexane to yield
the m-phenoxybenzyl ester of N-(2,4,6-trichlorophenyl)valine,
MS m/e 477 (M+).
N-(2,4-dichlorophenyl)valine, prepared ~rom 2,4-di-
chloroaniline and sodium salt of a-bromoisovaleric acid, is
reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl
ester of N-(2,4-dichlorophenyl)valine, MS m/e 443 (M ).
Following the procedure of Example 6, a-cyano-m-
phenoxybenzyl a-bromoisovalerate is reacted with each of 4-chloro-
aniline, 4-methoxyaniline and 4-methylaniline to prepare the
a-cyano-m-phenoxybenzyl ester of
N-(4-chlorophenyl)valine, MS m/e 434.1 (M ),
N-(4-methoxyphenyl)valine, MS m/e 430.1 (M+), and
N-(4-methylphenyl)valine, MS m/e 414.2 (M ).
The a-cyano-m-phenoxybenzyl ester of N-(4-chloro-
phenyl)valine is reacted with methyl iodide using the procedure
of Example 2 to yield the a-cyano-m-phenoxybenzyl ester of
-58-
1147745
N-methyl,N-(4-chlorophenyl)valine, MS m/e 448.1 (M ).
N-(2,3-dichlorophenyl)valine, prepared from 2,3-di-
chloroaniline and sodium salt of ~-bromoisovaleric acid, is
reacted with m-phenoxybenzyl bromide to yield the m-phenoxy-
benzyl ester of N-(2,3-dichlorophenyl)valine, MS m/e 443 (M+~.
EXAMPLE 63
Following the procedure of Example l, m-phenoxybenzyl
a-bromoisovalerate is reacted with each of 4-ethylaniline and
4-isopropylaniline to yield the m-phenoxybenzyl ester of N-(4-
ethylphenyl)valine, MS m/e 403.2 (M+), and N-(4-isopropylphenyl)-
valine, MS m/e 417.2 (M+).
Following the procedure of Example 18, m-phenoxybenzyl
bromide is reacted with each of N-(4-nitrophenyl)valine and
N- (2,6-dichlorophenyl)valine to yield the respective m-phenoxy-
benzyl ester of N-(4-nitrophenyl)valine, MS m/e 420.1 (M+), and
N-(2,6-dichlorophenyl)valine, MS m/e 443 (M+).
EXAM~LE 64
Following the procedure of Example l, m-phenoxybenzyl
~-bromoisovalerate is reacted with 3-chloroaniline to yield the
m-phenoxybenzyl ester of N-(3-chlorophenyl)valine, MS m/e
409.2 (M+).
Following the procedure of Example 18, m-phenoxybenzyl
bromide is reacted with each of N-(3-trifluoromethyl-4-chloro-
phenyl)valine, N-(2-chlorophenyl)valine, and N-(2,6-difluoro-
phenyl)valine to yield the respective ester - the m-phenoxybenzyl
ester of
N-(3-trifluoromethyl-4-chlorophenyl)valine,
MS m/e 477.1 (M+),
-59-
-
1147745
N-(2-chlorophenyl)valine, MS m/e 409 (M+), and
N-(2,6-difluorophenyl)valine, MS m/e 411.1 (M ).
N-(4-t-butylphenyl)valine is reacted with benzyl
bromide using the procedure of Example 18 to yield the benzyl
ester of N-(4-t-butylphenyl)valine, MS m/e 431 (M ).
Following the procedure of Example 24, N-(4-chloro-
phenyl)valine is esterified using each of 4-allylbenzyl bromide,
m-(3-trifluoromethylphenoxy)benzyl bromide, m-(4-chlorophenoxy)-
benzyl bromide, m-(4-methylphenoxy)benzyl bromide, m-(4-methoxy-
phenoxy)benzyl bromide, and m-(4-t-butylphenoxy)benzyl bromide
to yield the respective esters -- the 4-allylbenzyl ester of
N-(4-chlorophenyl)valine, MS m/e 357.1 (M+); the m-(3-trifluoro-
methylphenoxy)benzyl e~ter of N-(4-chlorophenyl)valine, MS m/e
477 (M+); the m-(4-chlorophenoxy)benzyl ester of N-(4-chloro-
phenyl)valine, MS m/e 443 (M+); the m-(4-methylphenoxy)benzyl
ester of N-(4-chlorophenyl)valine, MS m/e 423 (M+); the m-t4-
methoxyphenoxy)benzyl ester of N-(4-chlorophenyl)valine, MS
m/e 439 (M+); and the m-(4-t-butylphenoxy)benzyl ester of
N-(4-chlorophenyl)valine, MS m/e 465.2 (M+).
Following the procedure of Example 42, N-(4-methyl-
phenyl)valine is reacted with each of 4-allylbenzyl bromide,
m-(3-trifluoromethylphenoxy)benzyl bromide, m-(4-methylphenoxy)-
benzyl bromide, m-(4-chlorophenoxy)benzyl bromide and m-(4-t-
butylphenoxy~benzyl bromide to yield the respective esters --
the 4~allylbenzyl ester of N-(4-methylphenyl)valine, MS m/e
337.1 (M+); the m-(3-trifluoromethylphenoxy)benzyl ester of
N-(4-methylphenyl)valine, MS m/e 457.1 (M+); the m-(4-methyl-
phenoxy)benzyl ester of N-(4-methylphenyl)valine, MS m/e
403.2 (M+); the m-(4-chlorophenoxy)benzyl ester of N-(4-methyl-
phenyl)valine, MS m/e 423 (M+); and the m-(4-t-butylphenoxy)-
benzyl ester of N-(4-methylphenyl)valine, MS m/e 445.2 (M+).
-60-
114'~7'~S
ExAMæLE 65
To a mixture of N-~4-methylphenyl)valine (2.77 mmol),
potassium carbonate (3.25 mmol) and HMPT (3 ml), with stirring
and under nitrogen, at RT, is added 5-benzyl-3-furylmethyl
S bromide (2.77 mmol) in THF. The reaction is stirred at ~T for
about 48 hr and then wor~ed up by partition between water/ether.
The organic phase is washed with water and brine, dried over
potassium carbonate, filtered and evaporated. The residue is
plated on prep. T~C plate eluting with 10% ether/hexane to
yield the 5-~enzyl-3-furylmethyl ester of N-(4-methylphenyl)-
valine, MS m/e 377.1 (M ).
Following the procedure of Example 17, N-(2- trifluoro-
methylphenyl)valine, prepared from 2-trifluoromethylaniline and
sodium salt of a-bromoisovaleric acid by the procedure of
Example 18, is reacted with m-phenoxybenzyl bromide to yield
the m-phenoxybenzyl ester of N-~2-trifluoromethylphenyl)valine,
MS m/e 443 (M+).
Using the procedure of Example 1, each of 2-methoxy-
aniline and 4-ethoxyaniline is reacted with m-phenoxybenzyl
-bromoisovalerate to yie~d the m-phenoxybenzyl ester of N-(2-
methoxyphenyl)valine, MS m/e 405.2 (M ), and the m-phenoxybenzyl
ester of N-(4-ethoxyphenyl)valine, MS m/e 419.1 (M ).
Following the procedure of Example 42, N-(3,4-dichloro-
phenyl)valine is reacted with m-phenoxybenzyl bromide to yield
the m-phenoxybenzyl ester of N-(3,4-dichlorophenyl)valine, MS
m/e 443 (M ).
Each of N-(3-cyanophenyl)valine and ~-(3,4-dimethoxy-
phenyl)valine is reacted with m-phenoxybenzyl bromide using the
procedure of Example 17 to yield the m-phenoxybenzyl ester of
N-(3-cyanophenyl)valine, MS m/e 400.1 (M+), and the m-phenoxybenzyl
-61-
11477~5
ester of N-~3,4-dimethoxyphenyl)valine, MS m/e 435 (M ).
Following the procedure of Example 6, 4-trifluoro-
methylaniline is reacted with -cyano-m-phenoxybenzyl a-bromo-
isovalerate to yieId the a-cyano-m-phenoxybenzyl ester of
N-(4-trifluoromethylphenyl)valine, MS m/e 468.2 (M+).
EXAMPLE 66
To p-nitrothiophenol (14.1 g) suspended in water (100 ml)
at RT is added 2N sodium hydroxide (52 ml). The mixture is
stirred for 15 min and methyl iodide (9.4 ml) added slowly at 10.
The reaction mixture is warmed to RT and stirred for 2 hr. The
reaction is wor~ed up by extracting into ether (3X 80 ml), washing
with water and brine, drying over calcium sulfate and evaporating
to give p-nitrophenyl methylsulfide (12.2 g).
To p-nitrophenyl methylsulfide (10.5 g) in chloroform
(120 ml), cooled to 10-17, under nitrogen, is bubbled chlorine
while illuminating with a lamp ~150 watt). A trace of 2,2'-
azobis-(2-methylpropionitrile) is added. After about 3 hr of
passing chlorine through the solution, the reaction is terminated
and nitrogen passed throu~h for 0.5 hr. The solution is
concentrated and the product, p-nitrophenyl trichloromethyl
sulftde recrystallized out of hot acetone, m.p. 94-96.
p-Nitrophenyl trichloromethylsulfide (1.5 g) and purified
SbF3 (1.96 g) is 3tirred under nitrogen in a Claisen flask and
heated to 110-120. After about 0.5 hr, the product is di~tilled
off at 85-90 (5 mm~. The distillate is taken up in ether (50 ml)
and the ether layer washed with 10~ HCl until cloudiness no
longer occurs on addition of water. The ether layer is washed
with water until neutral and wi~h brine, dried over calcium sulfate
and evaporated to yield p-nitrophenyl trifluoromethyl sulfide.
-62-
1147745
To p-nitrophenyl trifluoromethyl sulfide (3.0 g) in
absolute ethanol (30 ml) is added Adams catalyst (Pt2O, 0.026 g).
The mixture is hydrogenated in a Parr vessel at 50 lbs/sq. in.
for about 15 min. The reaction is worked up by filtering through
Celite and evaporating to yield p-aminophenyl trifluoromethyl
qulfide.
Following the procedure of Example 43, p-aminophenyl
trifluoromethyl sulfide is reacted with m-phenoxybenzyl ~-bromo-
isovalerate to yield the m-phenoxybenzyl ester of N-(4-trifluoro-
methylthiophenyl)valine, MS m/e 475 (M+).
Alternatively, using the procedure of Example 38,
p-aminophenyl trifluoromethyl sulfide is reacted with the sodium
salt of a-bromoisovaleric acid to yield N-(4-trifluoromethyl-
thiophenyl)valine, which is esterified to yield the m-phenoxy-
benzyl ester of N-(4-trifluoromethylthiophenyl)valine.
EXAMPLE 67
To a 100 ml, 3-necked flask equipped with addition
funnel and reflux condensor to which is attached a water-gas
trap, are placed 10.08 g (65 mmole) of 2-fluoro,4-nitrotoluene.
The addition funnel is charged with 7.0 ml (22.3 g; 138 mmole)
of bromine and the flask is heated. When the temperature (oil
bath) is approximately 100, the bromine is introduced slowly
while illuminating the flask with a 150 watt light bulb. The
bromination starts readily as the temperature is increased to
approx. 160-170 and HBr is smoothly evolved. After 4 hr, heating
is discontinued. The cooled mixture is worked up by pouring
into ice and saturated sodium bisulfite and extracting with
ether (3X). The combined organic layers are washed once more
with saturated NaHSO3, brine (lX), and dried over sodium sulfate.
1~7t745
Filtration and evaporation of the solvent yields 17.0 g of a
mixture of the benzal bromide and benzyl bromide (1.7:1 by nmr
analysis). The crude material is suspended in a hypobromite
solution prepared by combining 60 g of sodium hydroxide and
20 ml of bromine in 600 ml of water. This mixture is stirred
for 6 days at RT and then filtered to yield 2-fluoro,4-nitro-
a,~,a-tribromotoluene, which may be recrystallized from
methanol.
A mixture of 8.5 g of 2-fluoro,4-nitro-~,a,~-tribromo-
toluene (22 mmole) and 4.7 g (26 mmole) of antimony trifluoride
are placed in a small flask equipped with a condensor set for
distillation. The flask is heated slowly and the mixture
distilled both at atmospheric pressure and then under reduced
pressure until no further material distills. The distillate
is partitioned between 6N hydrochloric acid and ether. The
organic layer is then washed with 6N sodium hydroxide (lX) and
brine (lX) and dried over sodium sulfate. Filtration and
evaporation of the solvent yielded 2-fluoro,4-nitrobenzotri-
fluoride.
To a solution of 20 ml of concentrated hydrochloric
acid and 15 ml of 95% ethanol is added 5.0 g (24 mmole) of
2-fluoro,4-nitrobenzotrifluoride. The mixture is stirred and
20 g (88 mmole) of stannous chloride dihydrate is added in por-
tions over a 30 min period. The reaction is exothermic and
during the addition the temperature is maintained at 60. When
the addition is complete, the mixture is stirred at 60 for an
additional 30 min. The reaction is cooled and poured onto a
mixture of ice and 36~ sodium hydroxide, which is extracted with
ether (3X). The combined ether layers are washed once with
brine and dried over sodium sulfate. Filtration and evaporation
-64-
~14'7745
of the solvent gave 4-amino,2-fluorobenzotrifluoride (3-fluoro-
4-trifluoromethylaniline).
Following the procedure of Example 38, 3-fluoro-4-
trifluoromethylaniline is reacted with the sodium salt of
a-bromoisovaleric acid to yield N-(3-fluoro-4-trifluoromethyl-
phenyl)valine, which is esterifed to yield the m-phenoxybenzyl
ester of N-(3-fluoro-4-trifluoromethylphenyl)valine.
N-t2,4-dinitrophenyl)valine is reacted with m-phenoxy-
benzyl bromide using the procedure of Example 38 to yield the
m-phenoxybenzyl ester of N-(2,4-dinitrophenyl)valine.
This procedure is repeated using 3-fluoro-4-nitro-
toluene in place of 2-fluoro-4-nitrotoluene to prepare 2-fluoro-
4-trifluoromethylaniline, which i8 converted into N-(2-fluoro-
4-trifluoromethylphenyl)valine and then esterified to yield
the m-phenoxybenzyl ester of N-(2-fluoro-4-trifluoromethyl-
phenyl)valine, MS m/e 461.1 (M+).
EXAMPLE 68
A mixture of 2-fluoro-4-chlorotoluene (25.05 g),
KMnO4 (55.04 g) and water (400 ml) is heated to reflux for
about 5 hr. The reaction is then worked up by filtering while
hot through Celite and the filtrate is acidified with 2N HCl.
White crystals are filtered off, dissolved in ether and washed
with water and brine, dried over sodium sulfate, filtered and
evaporated to yield 2-fluoro-4-chlorobenzoic acid.
A mixture of 2-fluoro-4-chlorobenzoic acid (6.05 g),
polyphosphoric acid (62.51 g) and CH3NO2 (5.1 g) is heated at
130. After about 2.5 hr, the reaction mixture is poured onto
ice and made basic by addition of dilute sodium hydroxide. The
reaction is then worked up by extracting with ether. The
1147745
combined ether extracts are washed with water and brine, dried
over sodium sulfate, filtered and evaporated to yield 2-fluoro-
4-chloroaniline.
EXAMPLE 69
A mixture of N-(4-chlorophenyl)valine (0.6 g),
m-phenoxybenzyl sulfide (0.57 g) and tetra(t-butoxy)titanate
(0.9 g~, in a flask fitted with a short path distillation head
under nitrogen, is heated to about 150, with stirring for
about 7 hr, under vacuum (about 50 mm). The reaction mixture
is allowed to cool and let stand for several hours. The
reaction is worked up by adding ether and 2N sulfuric acid,
which is extracted with ether. The combined ether layers are
washed with water, 10~ sodium bicarbonate, water, brine, dried
over calcium sulfate and rotoevaporated. The concentrate is
placed on prep. TLC, eluting with 10% ether/hexane, and the
main band collected to yield the m-phenoxybenzyl thiolester
of N-(4-chlorophenyl)valine, m.p. 103.5-105.
The above process is repeated using N-(4-methylphenyl)-
valine to yield the m-phenoxybenzyl thiolester of N-(4-methyl-
phenyl)valine, MS m/e 405 (M ).
EXAMPLE 70
To a solution of o-fluoroaniline (3.9 g) in methylene
chloride (50 ml), cooled to -20 under nitrogen, is added a
solution of 2,4,4,6-tetrabromocyclohexadienone (35 mmol) in
methylene chloride. After several hours, reaction is poured
into 15% NaOH solution. The layers are separated and the organic
fraction shaken against 15% NaOH solution. The methylene
chloride fraction is washed with saturated NaCl solution, dried
-66-
~14'77~5
over calcium sulfate and evaporated to yield 4-bromo-2-fluoro-
aniline.
To the potassium salt of a-bromoisovaleric acid
(1.42 g) is added 4-bromo-2-fluoroaniline (1.9 g). The mixture
is heated at 125 under nitrogen for 3.5 hr and then cooled to
RT. The reaction product is poured into 2M NaOH and ether/
chloroform. The basic phase is separated and acidified with
conc. HCl and then extracted into ether, washed with saturated
NaCl solution, dried over calcium sulfate and evaporated to
yield N-(4-bromo-2-fluorophenyl)valine.
A mixture of N-(4-bromo-2-fluorophenyl)valine (0.45 g),
potassium carbonate (0.25 g), THF (4 ml), DMF (4 ml) and m-
phenoxy-~-cyanobenzyl mesylate (0.43 g) is stirred for abouk
60 hr and then poured into water and hexane/ether (9:1). The
organic phase is washed with water and saturated sodium chloride
solution, dried over calcium sulfate and evaporated. The
residue is placed on prep. TLC eluting with 25% methylene
chloride/hexane once and then 30% methylene chloride/hexane
and the major band collected to yield the m-phenoxy-a-cyano-
benzyl ester of N-(4-bromo-2-fluorophenyl)valine, MS m/e
496 (M ).
EXAMPLE 71
To 4.9 g of N-(4-chlorophenyl)valine (0.0215 mole)
in 50 ml of 1,4-dioxane is slowly passed a stream of phosgene
gas as the solution is stirred. Cooling is applied to keep the
solution at RT. When the solution is saturated with phosgene,
the phosgene is shut off and the mixture is allowed to stir
under nitrogen at RT. After 45 hr, about two-thirds of the
dioxane is removed by distilling at aspirator pressure. The
-67-
~147~7~5
residue is diluted with hexane, then allowed to crystallize
overnight at RT. The solid is collected by filtration and
washed with hexane, with care being taken to minimize exposure
to air. The solid is dried _ vacuo to yield 3-(4-chlorophenyl)-
4-isopropyloxazolidine-2,5-dione, m.p. 137-138.
To a mixture of m-naphthoxybenzaldehyde (0.43 g),
3-(4-chlorophenyl)-4-isopropyloxazolidine-2,5-dione (0.5 g), and
potassium cyanide (0.23 g) in benzene (about 10 ml), with
stirring, is added benzyl triethyl ammonium chloride (about
0.1 g). The reaction mi~ture is stirred for about 50 hr. The
reaction is then worked up by taking up in ether, washing with
water and brine, drying over sodium sulfate and euaporating.
The concentrate is plated, prep. TLC, eluting with 20% ether/
hexane to yield the m-naphthoxy--cyanobenzyl ester of N-(4-
chlorophenyl)valine, MS m/e 484 (M+).
nmr (CDC13) ~ centered at 1.0 [m, 6, (CH3)2CH], 2~10
~m, 1, (CH3)2CH], and 4.0 ppm (m, 2, NH and,N-CH).
EXAMPLE 72
The process of Example 69 is repeated using each of
N-(2-chloro-4-trifluoromethylphenyl)valine, N-(4-chloro-2-
fluorophenyl)valine, N-(2-fluoro-4-trifluoromethylphenyl)valine
and N-(4-bromo-2-fluorophenyl)valine as the starting material
to yield the m-phenoxybenzyl thiolester of
N-(2-chloro-4-trifluoromethylphenyl)valine,
N-(4-chloro-2-fluorophenyl)valine,
N-(2-fluoro-4-trifluoromethylphenyl)valine, and
N-(4-bromo-2-fluorophenyl)valine.
-68-
1147~745
EXAMPLE 73
N-(2-fluorophenyl)valine, prepared by the reaction of
2-fluoroaniline and a-bromoisovaleric acid, is reacted with
m-phenoxybenzyl bromide, as in Example 17, to yield the m-phen-
oxybenzyl ester of N-(2-fluorophenyl)valine, MS m/e 493.2 (M+).
Following the procedure of Example 28, there is prepared
the hydrogen chloride salt of the m-phenoxybenzyl ester of
N-(4-chlorophenyl)valine, m.p. 126-130.
EXAMPLE 74
Following the procedure of Example 6, 2-fluoro-4-chloro-
aniline is reacted with m-phenoxy-a-cyanobenzyl a-bromoisovalerate
to give the m-phenoxy--cyanobenzyl ester of N-(2-fluoro-4-
chlorophenyl)valine, MS m/e 452 (M+). Alternatively 2-fluoro-
4-chloroaniline is reacted with the sodium salt of a-bromo-
isovaleric acid to give N-(2-fluoro-4-chlorophenyl)valine,
which is then esterified using m-phenoxy-~-cyanobenzyl bromide
or mesylate.
N-(4-chlorophenyl)valine is reacted with m-phenylcarbonyl-
benzyl bromide or the mesylate following the procedure of
Example 24 to yield the m-phenylcarbonylbenzyl ester of N-(4-
chlorophenyl)valine, MS m/e 421 (M+).
EXAMPLE 75
Each of N-(2-chloro 4-fluorophenyl)valine, N-(4-methyl-
thiophenyl)valine, N-(4-chloro-3-fluorophenyl)valine, N-(4-
cyano-2-fluorophenyl)valine, N-(4-bromo-2-fluorophenyl)valine
and N-(4-trifluoromethoxyphenyl~valine is reacted with m-phenoxy-
benzyl bromide using the procedure of Example 24 to yield
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m-phenoxybenzyl ester of
N-(2-chloro-4-fluorophenyl)valine, MS m/e 427 (M+);
N-(4-methylthiophenyl)valine, MS m/e 421 (M+);
N-(4-chloro-3-fluorophenyl)valine, MS m/e 427 (M+, 200);
N-(4-cyano-2-fluorophenyl)valine, MS m/e 418 (M+);
N-(4-bromo-2-fluorophenyl)valine, MS m/e 471 (M+); and
N-(4-trifluoromethoxyphenyl)valine, MS m/e 459 (M+).
Following the procedure of Example 70, each of m-phen-
oxy-a-cyanobenzyl ester of N-(4-chloro-3-fluorophenyl)valine,
MS m/e 452 (M+), and the m-phenoxy--cyanobenzyl ester of
N-(2-fluoro-4-methylphenyl)valine, MS m/e 432 (M+), is prepared
from N-(4-chloro-3-fluorophenyl)valine and N-(2-fluoro-4-methyl-
phenyl)valine and m-phenoxy-a-cyanobenzyl mesylate or bromide.
The starting materials are prepared by the reaction of 4-chloro-
3-fluoroaniline and 2-fluoro-4-methylaniline, respectively,
with the potassium salt of a-bromoisovaleric acid.
3-(Trifluoroacetyl)diphenyl ether (0.984 g) is
dissolved in 5 ml methanol and reduced with 0.25 g sodium
borohydride to give the corresponding alcohol. To 0.27 g
of this alcohol (1.0 mole) is added 2 ml of pyridine and 0.5 g
of 3-(4-chlorophenyl)-4-isopropyloxazolidine-2,5-dione (1.97 mole).
The solution is heated at 80 for 15 hr under nitrogen. The
reaction mixture is diluted with ether-hexane and washed with
dilute hydrochloric acid followed by aqueous sodium bicarbonate.
The organic phase is stripped and chromatographed on a 1 m silica
plate eluted with 10% ether-hexane to give the 3-phenoxy-a-tri-
fluoromethylbenzyl ester of N-(4-chlorophenyl)valine, MS m/e
477.1 (M+), 182 (100).
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EXAMPLE 76
Following the procedure of Example 65, N-(4-chloro-
phenyl)valine is reacted with each of 5-benzyl-3-furylmethyl
bromide, m-allyloxybenzyl bromide and m-propargyloxybenzyl
bromide to yield the 5-benzyl-3-furylmethyl ester of N-(4-
chlorophenyl)valine, MS m/e 397 (M+), the m-allyloxybenzyl
ester of N-(4-chlorophenyl)valine, MS m/e 373 (M+), and the
m-propargyloxybenzyl ester of N-(4-chlorophenyl)valine, MS
m/e 371 (M+).
4-Chloroaniline is reacted with m-phenoxybenzyl
2-bromobutanoate using the process of Example 4 to yield
m-phenoxybenzy~ 2-(4-chlorophenylamino)butanoate, MS m/e
395 (M ).
Following the procedure of Example 6, 4-chloroaniline
is reacted with each of p-benzylbenzyl a-bromoisovalerate and
m-benzyl--cyanobenzyl -bromoisovalerate to yield the p-benzyl-
benzyl ester of N-(4-chlorophenyl)valine, MS m/e 407 (M+), and
the m-benzyl-a-cyanobenzyl ester of N-(4-chlorophenyl)valine,
MS m/e 432 (M+).
Following the procedure of Example 60, N-(4-isoprop-
oxycarbonylphenyl)valine is prepared and reacted with m-phenoxy-
benzyl bromide to yield the m-phenoxybenzyl ester of N-(4-iso-
propoxycarbonylphenyl)valine, MS m/e 461 (M+).
EXAMPLE 77
To a slurry of 0.50 g of sodium hydride in 25 ml of
dioxane under argon is added 2.80 g of 2-(2-fluoro-4-trifluoro-
methylphenylamino)-3-methylbutanoic acid in small portions.
When hydrogen evolution is ceased, the mixture is cooled in
an ice bath and phosgene is passed over the surface of the
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stirring mixture. An obvious reaction ensues, with dissolution
of the sodium salt and evolution of more hydrogen. When the
hydrogen evolution appears to have ceased, the ice bath is
removed and the addition of phosgene is continued until the
solution appears nearly saturated. The reaction mixture is
then filtered through a glass frit to remove insoluble salts
and the filtrate is distilled at 15-20 mm pressure to remove
phosgene and about 15 ml of the dioxane solvent. The residue
is then diluted with hexane and allowed to stand at RT until
crystallization is complete. The anhydride is collected by
filtration, washed with hexane and dried under vacuum, with
care being taken to minimize exposure to moisture, to yield
3-(2-fluoro-4-trifluoromethylphenyl)-4-isopropyloxazolidine-
2,5-dione.
3-(2-Fluoro-4-trifluoromethylphenyl)-4-isopropyl-
oxazolidine-2,5-dione is reacted with phenol using the procedure
of Example 75 to give the phenyl ester of N-(2-fluoro-4-tri-
fluoromethylphenyl)valine, which is reacted with NaHS
using the method of Hirakayaski et al., Bull. Chem. Soc. Japan
38, 320 (1965) to give the sodium salt of the thioacid.
F ~
3 ~ NH ~ SNa
The thioacid is reacted with m-phenoxy-~-cyanobenzyl
bromide or mesylate using the prcedure of Example 70 to yield
the m-phenoxy-~-cyanobenzyl thiolester of N-(2-fluoro-4-trifluoro-
methylphenyl)valine.
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EXAMPLE 78
Following the procedure of Example 38, N-(4-trifluoro-
methylphenyl)valine is reacted with p-benzoylbenzyl bromide to
yield the p-benzoylbenzyl ester of N-(4-trifluoromethylphenyl)-
valine.
Each of 3-(2-fluoro-4-trifluoromethylphenyl)-4-iso-
propyloxazolidine-2,5-dione and 3-(4-trifluoromethylphenyl)-4-
isopropyloxazolidine-2,5-dione, prepared by the procedure of
Example 77, is reacted with m-benzoylbenzaldehyde and potassium
cyanide using the procedure of Example 71 to yield the m-benzoyl-
~-cyanobenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine
and the m-benzoyl-a-cyanobenzyl ester of N-(4-trifluoromethyl-
phenyl)valine.
EXAMPLE 79
Each of N-(2-fluoro-4-trifluoromethylphenyl)valine,
N-(2-chloro-4-trifluoromethylphenyl)valine, N-(4-chloro-2-
fluorophenyl)valine and N-(4-bromo-2-fluorophenyl)valine is
esterified using m-(o-fluorophenoxy)benzyl bromide according to0 the procedure of Example 42 to yield
the m-(o-fluorophenoxy)benzyl ester of
N-(2-fluoro-4-trifluoromethylphenyl)valine,
N-(2-chloro-4-trifluoromethylphenyl)valine,
N-(4-chloro-2-fluorophenyl)valine, and
N-(4-bromo-2-fluorophenyl)valine.
By repeating the above procedure using m-(p-fluoro-
phenoxy)benzyl bromide as the esterification reagent, the
respective m-(p-fluorophenoxy)benzyl ester of the listed amino
acids are prepared.
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EXAMPLE 80
Following the procedure of Example 38, N-(2-fluoro-
4-methoxyphenyl)valine is prepared and reacted with each of
m-phenoxybenzyl bromide and m-phenoxy-~-cyanobenzyl bromide to
yield the m-phenoxybenzyl ester of N-(~-fluoro-4-methoxyphenyl)-
valine and the m-phenoxy-a-cyanobenzyl ester of N-(2-fluoro-4-
methoxyphenyl)valine.
Using the process of Example 42, each of N-(2-fluoro-
4-methoxyphenyl)valine and N-(2-fluoro-4-trifluoromethylphenyl)-
valine is reacted with m-(p-fluorophenoxy)benzyl bromide to
yield the m-(p-fluorophenoxy)benzyl ester of N-(2-fluoro-4-
methoxyphenyl~valine and the m-(p-fluorophenoxy)benzyl ester of
N-(2-fluoro-4-trifluoromethylphenyl)valine.
EXA~PLE 81
Following the procedure of Example 17 or 42, N-~2-
fluoro-4-trifluoromethylphenyl)valine is esterified using each
of 2,6-dimethyl-4-allylbenzyl bromide, 2,6-dimethyl-4-propargyl-
benzyl bromide, 4-propargylbenzyl bromide, 4-phenyl-3-chloro-
2-butene-1-yl bromide, 3,4-dichloro-a-ethynylbenzyl bromide,
3-trifluoromethoxybenzyl bromide, 3-trifluoromethyl-a-ethynyl-
benzyl bromide, 4-(p-fluorophenyl)-3-chloro-2-butene-1-yl
chloride, 4-(o-fluorophenyl)-3-chloro-2-butene-1-yl chloride and
3-(2,2-dichlorovinyloxy)benzyl bromide to yield
2,6-dimethyl-4-allylbenzyl ester of N-(2-fluoro-4-
trifluoromethylphenyl)valine,
2,6-dimethyl-4-propargylbenzyl ester of N-(2-fluoro-
4-trifluoromethylphenyl)valine,
4-propargylbenzyl ester of N-(2-fluoro-4-trifluoro-
methylphenyl)valine
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4-phenyl-3-chloro-2-butene-1-yl ester of N-(2-fluoro-
4-trifluoromethylphenyl)valine,
3,4-dichloro-~-ethynylbenzyl ester of N-(2-fluoro-4-
trifluoromethylphenyl)valine,
3-trifluoromethoxybenzyl ester of N-(2-fluoro-4-tri-
fluoromethylphenyl)valine,
3-trifluoromethyl-~-ethynylbenzyl ester of N-(2-fluoro-
4-trifluoromethylphenyl)valine,
4-(p-fluorophenyl)-3-chloro-2-butene-1-yl ester of
N-(2-fluoro-4-trifluoromethylphenyl)valine,
4-(o-fluorophenyl)-3-chloro-2-butene-1-yl ester of
N-(2-fluoro-4-trifluoromethylphenyl)valine,
and 3-(2,2-dichlorovinyloxy)benzyl ester of N-(2-fluoro-
4-trifluoromethylphenyl)valine.
Using the procedure of U.S. Patent 3979519, the
3-trifluoromethoxy-a-cyanobenzyl ester of N-(2-fluoro-4-tri-
fluoromethylphenyl)valine is prepared by the reaction of the
acid chloride of N-(2-fluoro-4-trifluoromethylphenyl)valine and
3-trifluoromethoxybenzaldehyde cyanohydrin. Alternatively,
3-trifluoromethoxybenzaldehyde is reacted with 3-(2-fluoro-4-
trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione and
potassium cyanide using the procedure of Example 71 herein to
yield the 3-trifluoromethoxy-a-cyanobenzyl ester of N-(2-fluoro-
4-trifluoromethylphenyl)valine.
Young lima bean leaves (in water) infested with
approximately 50 adult Tetranychus urticae are sprayed to
runoff with the compound (m-phenoxy-~-cyanobenzyl ester of
N-phenylvaline) diluted to three different concentrations in
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aqueous carrier containing 0.025% Tween 20 and 0.1% wetting
agent. The treated leaves are maintained at ~4 and 16 hr
photoperiod for 2 days. Live adult mites are then counted and
substracted from the original total to obtain the number affected,
which is stated as a percentage of the total. Correction is
made for any control mortality using Abbott's formula. The
compound had an LC50 of less than 0.1%.
Individual fava bean leaves are dipped in the compound
(the m-phenoxybenzyl ester of N-phenyl-N-methylvaline) diluted
to three different concentrations in acetone with 0.025% Tween
20 and 0.1% wetting agent. The leaves are allowed to dry for
2 hr, then infested with 10 adult Aphis fabae caged on the upper
surface of the leaves. The treated leaves are maintained for
48 hours at 24 and 16 hr photoperiod. The effect is stated as
the number dead calculated as a percentage of the total aphids.
This is corrected for control mortality, if any, using Abbott's
formula. The compound had an LC50 of less than 0.05%.
Fifteen 72-hr-old adult female Musca domestica L. are
anesthetized with ether vapor. These are then treated with 1 ul
of the compound [m-phenoxybenzyl ester of N-(p-methylphenyl)-
valine] diluted to three different concentrations in acetone
applied to the dorsal surface of the prothorax. They are held
in an assay container with milk-saturated cotton at 25, 16 hr
,photoperiod for 24 hours. The effect is stated as the number
dead calculated as a percentage of the total, corrected for any
control mortality using Abbott's formula. The compound gave an
LC50 of less than 0.01%.
Into a mixture of 45 mg of wettable powder [Attaclay
(60%), Marosperse N-22 (26.7%) and Igepon T-77 (13.3%)] and
3~ ~.5 ml of water containing the compound ~m-phenoxybenzyl ester
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'~'
.,... - .,
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of N-(p-chlorophenyl)valine] at three different concentrations
is dipped fifteen fed tick nymphs (Ornithodoros nymph I). The
treated nymphs are maintained on filter paper for 7 days at
28, 64% humidity, 16 hr photoperiod and then observed.
Correction is made for any mortality in the control using
Abbott's formula. The LC50 of the compound was less than 0.01%.
Two groups of 10 each of 0-24 hr III instar Heliothis
virescens larvae were treated with 1 ul of the compound [the
m-phenoxybenzyl ester of N-(p-methoxyphenyl)valine] in acetone
at three different concentrations by application to the dorsum
of the thorax. Two groups of 10 each are treated identically
with 1 ul acetone as controls. Larvae are held individually in
30 ml plastic cups provided with artificial medium for 72 hours
at 25 and 16 hr photoperiod. After 72 hr the number of dead
is calculated as a percentage of the total number originally
treated and then corrected for any mortality in the control
groups using Abbott's formula. The LC50 of the compound was
less than 0.5~.
Each of the compounds listed below were used to treat
aphids (adult Aphis fabae) using the method described above.
Each of the compounds gave an LC50 of less than fifteen parts
per million (ppm).
m-phenoxy-a-cyanobenzyl ester of N-(2-chloro-4-tri-
fluoromethylphenyl)valine
m-phenoxy-~-cyanobenzyl ester of N-(2-fluoro-4-tri-
fluoromethylphenyl)valine
m-phenoxybenzyl ester of N-(2-fluoro-4-trifluoromethyl-
phenyl)valine
m-phenoxybenzyl ester of N-(4-trifluoromethylphenyl)-
valine
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A 4E emulsive concentrate was prepared using the
m-phenoxybenzyl ester of N-(4-trifluoromethylphenyl)valine
(51.3%), Atlox 3404F ~3%), Atlox 3403F (3%) and Tenneco 500-100
(42.7~), was diluted with water and applied to Tetranychus
urticae as described above. The LC50 value was less than
10 ppm.
The compounds listed below were used to treat tick
nymphs (Ornithodoros nymph I) using the method described above
and exhibited an LC50 f less than 15 ppm.
m-phenoxy-a-cyanobenzyl ester of N-(2-chloro-4-tri-
fluoromethylphenyl)valine
m-phenoxy-a-cyanobenzyl ester of N-(2-fluoro-4-tri-
fluoromethylphenyl)valine
m-phenoxy--methylbenzyl ester of N-(4-chlorophenyl)-
valine
m-phenoxy--ethynylbenzyl ester of N-(4-chloro-2-
fluorophenyl)valine
m-phenoxy-a-ethynylbenzyl ester of N-(3-fluoro-4-
methylphenyl)valine
m-phenoxy-a-ethynylbenzyl ester of N-(2-fluoro-4-
methylphenyl)valine
m-phenoxy-a-cyanobenzyl ester of N-(2~1uoro-4-methyl-
phenyl)valine
m-phenoxy-a-cyanobenzyl ester of N-(4-chloro-2-fluoro-
phenyl)valine
Each of the compounds listed below was applied to
Heliothis virescens larvae using the method described above and
_ _
gave an LC50 value of less than 0.1%.
m-phenoxybenzyl ester of N-(4-chloro-2-fluorophenyl)-
valine
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m-phenoxy-~-cyanobenzyl ester of N-(4-chloro-2-
- fluorophenyl)valine
m-phenoxybenzyl ester of N-(2-fluoro-4-trifluoro-
- methylphenyl)valine
5m-phenoxy-~-cyanobenzyl ester of N-(4-bromo-2-fluoro-
phenyl)valine
m-phenoxybenzyl ester of N-(2-chloro-4-trifluoro-
methylphenyl)valine
m-phenoxy-~-cyanobenzyl ester of N-(2-fluoro-4-tri-
lOfluoromethylphenyl)valine
m-phenoxy-~-cyanobenzyl ester of N-(2-chloro-4-tri-
fluoromethylphenyl)valine
m-phenoxybenzyl ester of N-(2-fluoro-4-methylphenyl)-
valine
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