GB1588111A - Esters and thiolesters of amino acids intermediates therefor processes for their production and compositions including them - Google Patents

Abstract

The new esters and thiolesters (thioesters) of amino acids are represented by the formula (A) <IMAGE> W and R<1> to R<5> are defined in the preceding Claim 1. The said compounds have insecticidal and acaricidal properties.

Description

(54) ESTERS AND THIOLESTERS OF AMINO ACIDS, PROCESSES FOR THEIR PRODUCTION, AND COMPOSITIONS INCLUDING THEM (71) We, ZOECON CORPORATION, a Corporation organised and existing under the laws of the State of Delaware, United States of America of 975 California Avenue, Palo Alto, California 94304, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to novel esters and thiolesters of amino acids, synthesis thereof and the use of said esters and thiolesters and compositions containing said esters of thiolesters for the control of pests.

The esters and thiolesters of amino acids of the present invention are represented by the following generic formula (A):

wherein, W is oxygen or sulfur; Rl is cycloalkyl, cycloalkenyl, cycloalkenyl substituted with halo or lower alkyl, or the group

in which t is zero, one, two, three or four; Y is independently selected from hydrogen, lower alkyl, lower haloalkyl, lower alkoxy, lower alkylthio, lower alkylcarbonyl, lower alkoxycarbonyl, lower acyloxy, halogen, cyano, nitro, and lower haloalkylthio; and Z is independently selected from the values of Y, cycloalkyl, and lower haloalkoxy; or Y and Z form a methylenedioxy group; R2 is hydrogen, lower alkyl, lower haloalkylcarbonyl, or formyl; R3 is alkyl of 2 to 5 carbon atoms, alkenyl of 2 to 5 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloalkenyl of 2 to 4 carbon atoms, or cycloalkyl of 3 or 4 carbon atoms; R4 is hydrogen or fluoro; and R5 is;

wherein, p is zero, one, two or three; R6 is hydrogen, cyano, methyl, trifluoromethyl, ethynyl, or

R7 is halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkylthio, lower alkenyl, or lower haloalkenyl; R8 is hydrogen or together with R7 forms a lower alkylenedioxy bridge across adjacent ring carbon atoms; R9 is hydrogen, lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower haloalkynyl, lower alkylcarbonyl, arylcarbonyl, substituted arylcarbonyl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, aralkyl, substituted aralkyl, cycloalkyl, cycloalkalkyl, lower acyloxy, aryloxycarbonyl, lower alkoxycarbonyl, or lower haloalkenyloxy; R'O is hydrogen or lower alkyl; R11 is hydrogen, lower alkenyl, lower alkynyl, or aralkyl; R12 and R'3 taken together form an alkylene bridge having 1 to 4 carbon atoms or an alkenylene bridge having 2 to 4 carbon atoms; R'4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or aralkyl; R'5 is hydrogen or lower alkyl; R16 is hydrogen, dichloro, fluoro, or methyl; R'7 is hydrogen, chloro, fluoro, methyl, or taken together with R16 forms a carbon-carbon bond; R18 is phenyl or phenyloxy; R'9 is hydrogen, halogen, methyl, or ethyl; R20 is allyl, propargyl, 3-butenyl, 3-butynyl, phenyl, or benzyl; 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 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. As such, the organic moiety (R5) is selected from the organo groups generally associated with the formation of pyrethrin esters and synthetic pyrethroid esters. Typical of such organo groups (R5) are the groups shown in, for example, U.S. Patents 3,973,035, 3,973,036, 3,996,244 and 4,003,945, Offenlegungsschrift 26 47 366, and Republic of South Africa Application No. 76/4622.

In the description hereinafter and the appended claims, each of R' through R20, W, Y, Z, p, and t is as defined hereinabove, unless otherwise specified.

As 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 or thiolester of formula (II) (X is bromo, chloro, or iodo).

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, dimethylformamide or dimethylsulfoxide at room temperature or above. The reaction generally proceeds rather slowly. 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).

The halo esters of formula II can be prepared from the acid halide thereof (11, wherein WR5 represents a brpmo or chloro) by reaction with an alcohol (Rs~OH).

The a-halo-substituted acid halide and a-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. Syn. 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 WR5 represents bromo or chloro) following the procedures of Harpp et al., J. Org. Chem. 40, 3420 (1975) and references cited therein. A method suitable when olefinic unsaturation is present is alkylation of acetoacetates 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 dichloro 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 a-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 or mercaptan HWR5.

The acid of formula (III) can be made from the halo acid or lower alkyl ester of formula (IV) (R2' is hydrogen or lower alkyl) using the conditions described hereinabove by reaction with the amine of formula (I).

Following reaction of a halo ester of formula (IV) wherein R2' is lower alkyl with an amine of formula (I), the resulting amino ester of formula (V)

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.

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 haloalkyl" refers to an alkyl group substituted with one to three halogen atoms such as chloromethyl, fluoromethyl, trifluoromethyl, 2,2,2 - trifluoroethyl, 6 - chlorohexyl and 2fluoroethyl. 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 and "haloalkylthio" refers to an alkylthio group substituted by up to three halogen atoms.

The term "lower alkenyl" refers to an ethylenically unsaturated hydrocarbon group, straight or branched, having a chain length of two to eight carbon atoms and one or two ethylenic bonds such as vinyl, allyl, 3 - butenyl, 2 - hexenyl, i propenyl and 2,4 - hexadienyl. The term "lower haloalkenyl" refers to a lower alkenyl group substituted with one to three halogen atoms. The term "lower alkenyloxy" refers to an alkenyloxy group, straight or branched, of two to eight carbon atoms. The term "lower haloalkenyloxy" refers to a lower alkenyloxy group substituted with one to three halogen atoms.

The term "lower alkynyl" refers to an alkynyl group, straight or branched, having a chain length of two to eight carbon atoms and one or two acetylinic bonds. The term "lower haloalkynyl" refers to a lower alkynyl group having one to three halogen atoms. The term "lower alkynyloxy" refers to an alkynyloxy group, straight or branched, of three to eight carbon atoms.

The term "cycloalkyl" refers to a cycloalkyl group of three to eight cyclic carbon atoms. The term "cycloalkalkyl" refers to a cycloalkyl group wherein one hydrogen atom is replaced by a lower alkyl group, the total number of carbon atoms being from four to twelve, such as cyclopropanemethyl, cyclobutaneethyl and, cyclohexanemethpl.

The term "aryl" refers to the aryl group phenyl or naphthyl. The term "aralkyl" refers to a lower alkyl group in which a hydrogen atom of the alkyl group is substituted by an aryl group, the total number of carbon atoms being from seven to twelve, such as benzyl and phenethyl. The terms "substituted aryl" and "substituted aralkyl" refer to an aryl group and an aralkyl group, respectively, substituted at one, two or three of the ring carbon atoms with a group selected from lower alkyl, lower haloalkyl, lower alkoxy, lower alkenyl, lower haloalkenyl, lower alkenyloxy, halogen, nitro, cyano and lower alkylthio.

The term "lower haloalkoxy" refers to a lower alkoxy group substituted with one to three halogen atoms.

The term "lower acyloxy" refers to a lower carboxylic acid acyloxy group of one to six carbon atoms, such as acetoxy.

The compounds of the present invention of formula (A) have one or more asymmetric carbon atoms. The present invention includes each of the optical isomers and racemic mixtures thereof. In the examples hereinafter, unless otherwise 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 and Lewis acids. 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 and alfalfa, a compound of formula A, or mixtures thereof, together with a carrier is 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 and emulsifiable concentrates. Suitable solid carriers include natural and synthetic silicates and clays, carbon or charcoal granules, natural and synthetic resins, and waxes. Suitable liquid carriers include water, aromatic hydrocarbons, alcohols, vegetable and mineral oils and ketones.

The amount of a compound of 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, compounds within the present invention are effective on many different insects and on acarids. They 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, they have a broad or relatively narrow spectrum of unusually high pesticidal activity on insects and acarids. Among the pests against which they 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 (Registered Trade Mark), dichlorvos, methoprene, kinoprene, hydroprene, cyhexatin and resmethrin.

The following examples are provided to illustrate the practice of the present invention. Temperature is given in degrees Centigrade. RT means room temperature.

EXAMPLE 1 A. To a - bromoisovaleric acid (10 g, 0.055 mole) in 60 ml ether, cooled to 100, is added dimethylformamide (DMF) (2.8 ml, 0.0332 mole), followed by slow addition of thionylchoride (5.9 ml, 0.0828 mole). After about one hour at 240, the acid chloride intermediate is isolated by decanting off the top ether layer from the oily residue and removing the ether under vacuum. To the acid chloride (0.055 mole) in 100 ml of ether, cooled to 100, is added m - phenoxybenzyl alcohol (11.49 g, 0.0495 mole) followed by addition of pyridine (9 ml, 0.11 mole) over about 15 minutes. The resulting white slurry is stirred at 240 for about 16 hours and then a trace of water is added to decompose excess 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 bicarbonate (10 ml), followed by water (2X 100 ml) and brine (25 ml) and dried over calcium sulfate to give m - phenoxybenzyl a - bromoisovalerate in quantitative yield.

nmr (CCl4 S 1.03 [m, 6, (CH3)2CH], 2.18 [m, 6, (CH3)2C111,

and 5.11 ppm (s, 2, ArCH2O-). IR (film) 1744 cm-' (C=O).

B. To m - phenoxybenzyl a - bromoisovalerate (3 g, 0.0083 mole) in 6 ml of hexamethylphosphorictriamide (HMPT), 24", is added aniline (0.0248 mole) followed by catalytic amount of potassium iodide (28 mg). The reaction mixture is heated at 650, for about 90 hours and then poured into ice-water (35 ml) and extracted with ether (3X 50 ml). The combined ether extract are washed with 2N sulfuric acid, water (2X 50 ml) until neutral, and with brine followed by drying over calcium sulfate. The product is concentrated under vacuum and isolated by preparative thin layer chromatography (TLC). m - Phenoxybenzyl ester of N phenylvaline.

nmr (CDCl3) a 1.00 [m, 6, (CH3)2CH], 2.07 [m, 1, (CH3)2-CHl, 3.95 [m, l,N-CH-CO2-], 4.00 (m, 1, NH), and 5.13 ppm (s, 2, ArCH2O). IR (film) 3400 cm-l (s) (NH) and 1738 cm-' (C=O).

EXAMPLE 2 To the m - phenoxybenzyl ester of N-phenylvaline (0.25 g) in HMPT (I ml) and tetrahydrofuran (1 ml), at 240, is added methyl iodide (0.12 ml) followed by potassium carbonate (0.092 g). The reaction mixture is heated at 600 for 4 days. The reaction is worked up by pouring into ice-water (5 ml) and extracting with ether (3X 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-Nmethylvaline.

nmr (CDCI3) a 0.92 [m, 6, (CH3)2CH], 2.3 [m, 1, (CH3)2CH], 2.88 (s, 3, CH,N), 3.96 (d, 1, N-CH-CO2), and 5.08 ppm (s, 2, ArCH2O). IR (film) 1740 (C=O).

EXAMPLE 3 A. To valine (11.7 g, 0.10 mole) in 88% formic acid (40 ml) is added acetic formylanhydride (26.3 g, 0.30 mole) over 0.5 hr at 5 . The reaction mixture is warmed to 240 and stirred for 17 hours. The reaction is worked up by distilling off (bath temp. 4550 ) the solvent, excess anhydride and acetic acid, to give, as a white solid, N-formylvaline, recrystallized from hot ethanol, m.p. 143--1450.

B. To 8 g (0.055 mole) of the product of part A in 55 ml of HMPT is added m phenoxybenzyl bromide (14.4 g, 0.055 mole) followed by anhydrous potassium carbonate (7.6 g, 0.055 mole). The reaction mixture is stirred, at 240, 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 calcium sulfate and evaporated under vacuum to give the m - phenoxybenzyl ester of N - formylvaline.

C. To the ester (26 g, 0.0835 mole) of part B, in 84 ml of anhydrous methanol is added IN methanolic HCI (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 aqueous layer is made basic by addition of 10% sodium bicarbonate and then extracted with ether (3X 200 ml). The combined ether phases are washed with water (2X 200 ml) until neutral and brine (100 ml) and then dried over calcium sulfate, filtered and rotoevaporated to give the m - phenoxybenzyl ester of valine.

nmr (CDCl3) a 0.91 [m, 6, (CH3)2CH], 1.37 (bs, 2, NH2), 2.00 [m, 1, (CH3)2CHl,

and 5.17 ppm (s, 2, ArCH2O-). IR (film) 3400 cm-' (NH2), 1740 cm-' (C=O).

EXAMPLE 4 To m - phenoxybenzyl a - bromoisovalerate (5 g, 0.0138 mole) in 9 ml of HMPT, 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 700 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 (2X 30 ml) and brine (10 ml), dried over calcium sulfate, filtered and evaporated. The crude product is purified by preparative TLC to yield the m phenoxybenzyl ester of N - (p - chlorophenyl)valine.

nmr (CDCl3) a 0.99 [m, 6, (CH3)2CH], 2.03 [m, 1, (CH3)2CHl, 3.93 (m, 2, NH and N-CH-CO2), and 5.10 ppm (s, 2, ArCH2O-). IR (film) 3410 cm-' (s) (NH), and 1740 cm-' (C=O).

EXAMPLE 5 To m - phenoxybenzyl a - bromoisovalerate (2 g, 0.0055 mole) in 4 ml of HMPT, at 24", is added toluidine (1.77 g, 0.0165 mole) and potassium iodide (25 mg). The reaction mixture is stirred at 60 for five days, cooled, and poured into ice-water (20 ml) plus 10 ml of 2N sulfuric acid. The reaction is worked up as in Example 4 yielding the m - phenoxybenzyl ester of N - (p - methylphenyl)valine.

nmr (CDCl3) 0.99 [m, 6, (CH3)2CH], 2.20 (s, 3, CH3-Ar), I 3.90 (m, 2, NH and # N-CH-CO2), and 5.11 ppm (s, 2, ArCH2O). IR (film) 3400 cm-' (s) (NH), and 1740 cm-' (C=O).

The above procedure is repeated using anisdine in place of toluidine to yield the m - phenoxybenzyl ester of N - (p - methoxyphenyl)valine.

nmr (CDCl3) a 0.98 [m, 6, (CH3)2CHI, 2.03 [m, 1, (CH3)2CHl, 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-' (s) (NH), and 1740 cm-' (C=O).

EXAMPLE 6 A. To a - bromoisovaleric acid (5.18 g, 0.0286 mole) in 30 ml of ether, cooled to 100, is added 1.3 ml of DMF followed by slow addition of 3 ml of thionyl chloride (0.0429 mole). After one hour at 240; the acid chloride is isolated in quantitative yield by decanting off top the ether layer and removing the solvent and excess thionyl chloride under vacuum.

To the acid chloride (5.7 g, 0.0286 mole) in 30 ml of ether at 100 is added 5.38 g of m - phenoxybenzaldehyde cyanohydrin (0.0257 mole) followed by slow addition of 4.6 ml of pyridine over 10 minutes. The reaction mixture is stirred at 240 for 17 hours and then a trace of water is added to destroy excess acid chloride. The reaction product is worked up by pouring into ice-water (50 ml) plus 2N sulfuric acid (30 ml) and extracting with ether (3X 30 ml). The combined ether extracts are washed with 10% sodium bicarbonate (10 ml), water (2X 50 ml) and brine (10 ml), dried over calcium sulfate and evaporated to yield m - phenoxy a - cyanobenzyl a - bromoisovalerate.

nmr (CDCl3) a 1.05 [m, 6, (CH3)2CH], 2.23 [m, 1, (CH3)2CHi,

and 6.41 ppm [s, 1, ArCH(CN)O]. IR (film) 1762 cm-' (C=O).

B. To m - phenoxy - a - cyanobenzyl a - bromoisovalerate (2.0 g, 0.0052 mole) in 4 ml of HMPT, at 240, is added aniline (1.5 g, 0.016 mole) and potassium iodide (21 mg). The reaction is stirred at 650 for 90 hours and then cooled and poured into ice-water (20 ml) plus 2N sulfuric acid (10 ml). The reaction is worked up as in Example 4 and purified by preparative TLC to give the m - phenoxy - a cyanobenzyl ester of N - phenylvaline.

nmr (CDCl3) a 1.02 [m, 6, (CH2)2CH], 2.10 [m, 1, (CH3)2CH], 4.0 (m, 2,-NH and N-CH-CO2), and 6.33 ppm [s, 1, ArCH(CN)O]. IR (film 3400 cm-' (s) (NH), 2260 cm-' (w) (CN), 1758 cm-' (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 respective ester under column II.

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 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 II 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 N - (3 - cyanophenyl)valine N - (2 - cyanophenyl)valine N - (2,6 - dimethylphenyl)valine N - (2,5 - dimethylphenyl)valine EXAMPLE 8 Following the procedure of Example 1, a - 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 - trifluoromethylbenzyl 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 - 4 - ol 2 - allyl - 3 - methyl - 2 - cyclopentene - 1 - 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 5 - benzyl - 2 - thiophenemethanol 5 - benzyl - 3 - thiophenemethanol IV p - phenoxybenzyl a - bromoisovalerate m - benzylbenzyl a - bromoisovalerate p - propargyl - benzyl - bromoisovalerate 4 - allyl - 2,6 - dimethylbenzyl a - bromoisovalerate p - allylbenzyl a - bromoisovalerate 2,6 - dimethyl - 4 - propargyl - benzyl a - bromoisovalerate a - ethynyl - 3 - trifluoromethylbenzyl a - bromoisovalerate 5 - benzyl - 3 - furylmethyl a - bromoisovalerate a - cyano - 5 - benzyl - 3 - furylmethyl a - bromoisovalerate 5 - propargylfurfuryl d - bromoisovalerate 2 - methyl - 5 - propargyl - 3 - furylmethyl a - bromoisovalerate 5 - propargyl - a - ethynylfurfuryl a - bromoisovalerate 5 - benzyl - 2 - methyl - 3 - furylmethyl a - bromoisovalerate 2 - methyl - 3 - propargyl - 4 - oxo - 2 - cyclopentene - 1 - yl methyl - bromoisovalerate 3 - allyl - 2 - methyl - 4 - oxo - 2 - cyclopentene - 1 - yl methyl a bromoisovalerate 3 - benzyl - 4 - oxo - 2 - cyclopentene - 1 - yl methyl a - bromoisovalerate 3,4,5,6 - tetrahydrophthalimidomethyl cr - bromoisovalerate phthalimidomethyl a - bromoisovalerate 4 - phenyl - 3 - chloro - 2 - butene - 1 - yl - bromoisovalerate 5 - propargyl - 2 - thiophenemethyl a - bromoisovalerate 5 - benzyl - 2 - thiophenemethyl cr - bromoisovalerate 5 - benzyl - 3 - thiophenemethyl a - bromoisovalerate EXAMPLE 9 Each of the a - bromo ester intermediates listed under column IV is reacted with 4 - chloraniline 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.

V 4 - phenoxybenzyl ester of N - (4 - chlorophenyl)valine 3 - benzylbenzyl ester of N - (4 - chlorophenyl)valine 4 - propargylbenzyl ester of N - (4 - chlorophenyl)valine 4 - allyl - 2,6 - dimethylbenzyl ester of N - (4 - chlorophenyl)valine p - allylbenzyl ester of N - (4 - chlorophenyl)valine 2,6 - dimethyl - 4 - propargylbenzyl ester of N - (4 - chlorophenyl)valine a - ethynyl - 3 - trifluoromethylbenzyl 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 - chlorophenyl)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 - chlorophenyl)valine 5 - benzyl - 2 - methyl - 3 - furylmethyl ester of N (4 - chlorophenyl)valine 2 - methyl - 3 - propargyl - 4 - oxo - 2 - cyclopentene - 1 - yl methyl ester of N - (4 - chlorophenyl)valine 3 - allyl - 2 - methyl - 4 - oxo - 2 - cyclopentene - 1 - yl methyl ester of N (4 - chlorophenyl)valine 3 - benzyl - 4 - oxo - 2 - cyclopentene - 1 - yl methyl 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 chlorophenyl)valine 5 - propargyl - 2 - thiophenemethyl ester of N - (4 - chlorophenyl)valine 5 - benzyl - 2 - thiophenemethyl ester of N - (4 - chlorophenyl)valine 5 - benzyl - 3 - thiophenemethyl ester of N - (4 - chlorophenyl)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 - trifluoromethylaniline 3 - trifluoromethylaniline 3,5 - dichloro - 4 - hydroxyaniline 4 - chloro - 3 - nitroaniline 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 - (4 - 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 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 - (2,3 - 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 a - halo ester in column IX according to procedures hereinabove such as Example 1.

VIII 2 - bromo - 3 - methylpentanoyl chloride 2 - bromo - 4 - methylpentanoyl chloride 2 - bromobutanoyl chloride 2 - bromohexanoyl chloride 2 - bromo - 3 - chloropropanoyl 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 procedures hereinabove such as Example 4, 4 - chloroaniline is reacted with each of the a - 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) - 5 - chloropentanoic acid 3 - phenoxybenzyl ester of 2 - (4 - chlorophenylamino) - 4,4,4 trichlorobutanoic acid EXAMPLE 12 To the m - phenoxybenzyl ester of valine (2 g, 0.0067 mole) in methanol (30 ml) is added concentrated sulfuric acid to bring to about pH 6. Cyclohexanone (0.6 g, 0.006 mole) is then added followed by 3A molecular sieves and sodium cyanoborohydride (0.25 g, 0.004 mole). Additional sulfuric acid is added to keep pH at about 6. After about 24 hours, the reaction is worked up by removing methanol by rotoevaporation and the residue is poured into water and 10% sodium carbonate followed by extraction with ether. The combined ether extracts are filtered and concentrated and the product is isolated by preparatory TLC (10% ether/hexane) to yield the m - phenoxybenzyl ester of N - cyclohexylvaline.

nmr (CDCl3) 0.89 [m, 6, J-7 Hz, (CH3)2CH], 2.26 [m, 1, (CH3)2C!I1,

and 5.15 ppm (s, ArCH2O). IR (film) 1736 cm-' (C=O).

EXAMPLE 13 Each of the substituted aryl amines lisfed in column XI is reacted with m phenoxybenzyl 2 - bromoisovalerates using the procedure of Example 4 to prepare the respective N - substituted compound in column XII.

XI 2,4 - dichloroaniline 3 - methoxyaniline 3,4 - dimethylaniline 2,3,5,6 - tetrachloroaniline 3 - methylaniline 3,5 - dichloroaniline 3 - acetoaniline 2 - acetoaniline 2 - methylaniline 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)valine N - (3 - methylphenyl)valine N - (3,5 - dichlorophenyl)valine N - (3 - acetophenyl)valine N - (2 - acetophenyl)valine N - (2 - methylphenyl)valine EXAMPLE 14 Following the process of Example I, each of the alcohols listed in column XIII is reacted with the acid chloride of a - bromoisovaleric acid to yield the respective ester in column XIV.

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 - butenyl alcohol 3 - phenylcarbonylbenzyl alcohol I - ethynyl - 2 - methyl - 2,5 - hexadien - I - yl alcohol 1 - ethynyl - 2 - methyl - 2 - penten - 1 - yl alcohol 1 - ethynyl - 2 - methyl - 3 - phenyl - 2 - propen - I - yl alcohol 1 - ethynyl - 3 - phenyl - 2 - propen - I - yl alcohol 2,4,6 - trimethylbenzyl alcohol XIV 3 - (2,2 - dichlorovinyloxy)benzyl a - bromoisovalerate 3 - (o - fluorophenoxy)benzyl a - bromoisovalerate 4 - phenyl - 2 - butenyl sx - bromoisovalerate 4 - (4 - methylphenoxy) - 2 - butynyl a - 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 - bromoisovalerate 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 - methylphenyl)valine in column XV.

XV 3 - (2,2 - dichlorovinyloxy)benzyl ester of N - (p. - methylphenyl)valine 3 - (o - fluorophenoxy)benzyl ester of N - (p - methylphenyl)valine 4 - phenyl - 2 - butenylester of N - (p - methylphenyl)valine 4 - (4 - methylphenoxy) - 2 - butynyl ester of N - (p - methylphenyl)valine 4 - (4 - methylphenyl) - 2 - butenyl ester of N - (p - methylphenyl)valine 3 - phenylcarbonylbenzyl ester of N - (p - methylphenyl)valine a- ethynyl - 2- methyl - 2,5 - hexadienyl ester of N- (p methylphenyl)valine a - ethynyl - 2 - methyl - 2 - pentenyl ester of N - (p - methylphenyl)valine a - ethynyl - 2 - methyl - 3 - phenyl - 2 - propenyl ester of N - (p methylphenyl)valine a - ethynyl - 3 - phenyl - 2 - propenyl ester of N - (p - methylphenyl)valine 2,4,6 - trimethylbenzyl ester of N - (p - methylphenyl)valine EXAMPLE 15 Each of the a - halo esters in column IX hereinabove is reacted with p methylaniline to yield the respective 3- phenoxybenzyl ester of the pmethylphenyl amino acid in column XVI using the procedure of Example 5.

XVI 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 acid EXAMPLE 16 Each of the a - bromo esters listed in column IV is reacted with p methylaniline using the procedure of Example 5 to yield the respective ester of N (p - methylphenyl)valine in column XVII.

XVII 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 - methylphenyl)valine p - allylbenzyl ester of N - (p - methylphenyl)valine 2,6 - dimethyl - 4 - propargylbenzyl ester of N - (p - methylphenyl)valine a - ethynyl - 3 - triflouromethylbenzyl 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 - methylphenyl)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 - methylphenyl)valine 5 - benzyl - 2 - methyl - 3 - furylmethyl ester of N - (p - methylphenyl)valine 2 - methyl - 3 - propargyl - 4 - oxo - 2 - cyclopentene - I - yl methyl ester of N - (p - methylphenyl)valine 3 - allyl - 2 - methyl - 4 - oxo - 2 - cyclopentene - 1 - yl methyl ester of N (p - methylphenyl)valine 3 - benzyl - 4 - oxo - 2 - cyclopentene - 1 - yl methyl ester of N - (p methylphenyl)valine 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 - methylphenyl)valine 5 - benzyl - 2 - thiophenemethyl ester of n - (p - methylphenyl)valine 5 - benzyl - 3 - thiophenemethyl ester of N - (p - methylphenyl)valine EXAMPLE 17 A. Two grams of a - bromoisovaleric acid (0.011 mole) dissolved in 10 ml of methanol is titrated to the phenolphthalein end point at 00 with 2N sodium hydroxide/methanol. The alcohol is then removed and 10 ml of dimethylformamide and p - trifluoromethylaniline (3.54 g, 0.022 mole) added. The reaction mixture is heated at 1000C for 2 hours and left at room temperature about 18 hours. The reaction mixture is poured into 50 ml of 0. IN sodium hydroxide, washed with ether and the aqueous phase adjusted to pH 4 with conc. HCI and then extracted with chloroform (3X). The extracts are combined and washed with brine, dried, concentrated in a rotoevaporator and solvent removed under vacuum at about 50 to yield N - (p - triflouromethylphenyl)valine.

B. A mixture of the acid of part A (1.84 g, 0.0071 mole) and potassium carbonate (1.95 g) in 10 ml of dry dimethylformamide is stirred at room temperature, under nitrogen, for 0.5 hours and then m - phenoxybenzyl bromide (1.85 g, 0.0071 mole) is added at 00. The reaction mixture is allowed to warm up to room temperature and is then stirred about 18 hours. The reaction is then worked up by pouring into ice-water and extracting with ether (3X). The ether extracts are combined and washed with water and brine, dried over calcium sulfate and evaporated under vacuum to yield the m-phenoxybenzyl ester of N - (p trifluoromethylphenyl)valine. MS m/e 443 (M+, 5.9).

EXAMPLE 18 To a solution of a - bromoisovaleric acid (2 g, 0.110 mole) and 5 ml of methanol is added one drop of phenolphthalein and then sufficient sodium hydroxide/methanol until adjusted to neutral pH. The solvent is then stripped off and p - chloroaniline (7 g, 0.055 mole) added. The mixture is melted in a 100" bath and stirred at 1000 for 3 hours. The mixture is cooled and taken up in ether, and 10% aqueous sodium hydroxide is added. The aqueous phase is acidified to pH 4 and extracted wtih ether. The ether extracts are combined and washed with brine, dried over sodium sulfate and stripped to yield N - (p - chlorophenyl)valine.

Following the procedure of Example 1, part A, N - (p - chlorophenyl)valine is converted to the acid chloride and then reacted with m - phenoxybenzyl alcohol to yield the m - phenoxybenzyl ester of N - (p - chlorophenyl)valine.

EXAMPLE 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, MS m/e 451 (M+). N - (2 - fluoro - 4 chlorophenyl)valine is prepared from 2 - fluoro - 4- chloroaniline and abromoisovaleric 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 substituted 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 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 a - bromoisovalerate; and m - (m - trifluoromethylphenoxy)benzyl a - bromoisovalerate.

Each of the above a - bromo esters is reacted with p - methylaniline to yield: m - (p - chlorophenoxy)benzyl ester of N - (p - methylphenyl)valine; m - (p - methylphenoxy)benzyl ester of N - (p - methylphenyl)valine; and m - (m - trifluoromethylphenoxy)benzyl ester of N - (p methylphenyl)valine.

EXAMPLE 22 To m - phenoxybenzyl a - bromoisovalerate (2 g, 0.0055 mole), 240, 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 1200 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 preparative TLC to give m - phenoxybenzyl ester of N - (2,6 dimethylphenyl)valine. MS m/e 403.2 (m+, 7.5).

EXAMPLE 23 To m - phenoxybenzyl a - 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, 110115 , 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+).

EXAMPLE 24 To a - bromoisovaleric acid (1.2 g, 0.00603 mole) in methanol (2 ml) at 50, 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 1500 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 - dimethylphenyl)valine is isolated by concentration under vacuum.

To N - (2,6 - dimethylphenyl)valine (1.07 g, 0.00486 mole) in THF:HMPT (3 ml:3 ml) at 24 is added m - phenoxybenzyl 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 procedures 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 a - 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 abromoisovaleric acid and 2 - fluoro - 4 - methylaniline and then reacted with a ethynyl - m - phenoxybenzyl bromide to yield the ce- ethynyl - m phenoxybenzyl ester of N - (2 - fluoro - 4 - methylphenyl)valine, MS m/e 431 (M+, 180).

EXAMPLE 26 To them - phenoxybenzyl ester of N - (p - trifluoromethylphenyl)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 ether phased 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 trifluoromethylphenyl)valine, MS m/e 477.1 (M+).

Following the above procedure, there is prepared the m - phenoxy - a cyanobenzyl ester of N - (2 - chloro - 4 - trifluoromethylphenyl)valine, MS m/e 486.3 (M+), from the m - phenoxy - cw- cyanobenzyl ester of N- (p trifluoromethylphenyl)valine.

EXAMPLE 27 To N - phenylvaline hydrochloride (0.1 mole) in ether-THF at 50 is added dimethylformamide (0.06 mole) followed by dropwise addition of thionylchloride (0.15 mole). The reaction is stirred at 24C for 2.5 hours. The acid chloride hydrochloride is isolated and then in THF-ether, at 50, is added a - 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 - a - cyanobenzyl ester of N phenylvaline.

EXAMPLE 28 Into a mixture of 1.0 g of the m - phenoxybenzyl ester of N - (p methylphenyl)valine 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--1530.

Following the procedure of Example 6, 2 - fluoro - 4 - trifluoromethylaniline is reacted with a - cyano - m - phenoxybenzyl a - bromoisovalerate 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 rotoevaporation yield the desire imine ester.

To a solution of 13.4 g (0.05 mole) imine ester 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 - dimethylbutyrate.

A solution of 2.7 g (0.01 mole) of the above ethyl amino ester and 0.4 g (0.01 mole) of sodium hydroxide in 17 ml ethanol and 3 ml water is stirred at room temperature for 2 days. The alcohol and water are removed by rotoevaporation under high vacuum to give the sodium salt of 2 - (p - chlorophenylamino) - 3,3 dimethylbutyric acid. To the sodium 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 - a - 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 valine and 10 g of sodium bicarbonate 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 extraction and the aqueous phase is brought 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 the 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 purified 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 - phenylglycine in 10 ml of dry dimethylformamide is added 2.76 g of dry potassium carbonate 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 N - 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 THF (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 1.08 g of trimethylsilyl chloride in 5 ml of THF is added at --300 and then stirring for 20 minutes. The reaction is then cooled to 780 and an additional 1.03 g of lithium diisopropylamide in THF added. The reaction is stirred at 600 for 30 iiiin. and 1.08 g of trimethylsilyl chloride is added at 600. After an hour at -600 the reaction is allowed to reach room temperature and 1 hour thereafter the reaction mixture is brought to reflux for 30 minutes. The reaction is cooled and poured into 10 ml of 2N sodium hydroxide. The mixture is stirred for 20 minutes at room temperature and then extracted with ether. The aqueous phase is acidified to 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 - phenoxybenzyl 2 - phenylamino - 3,3 - dimethyl - 4 pentenoate [m - phenoxybenzyl 2 - phenylamino - 2 - (2 - m 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 give the m - phenoxybenzyl ester of N - (2 - chloro - 4 - methoxyphenyl)valine, MS m/e 439 (M+, 7.4), 212 (100).

EXAMPLE 38 A solution of a - bromoisovaleric acid (8.17 mmole) in methanol is titrated to the phenolphthalein 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 HMPT. The reaction is heated at 600 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 a - (2 fluoro - 4 - methylphenylamino)isovaleric acid. (2 - Fluoro - 4 - methylaniline is prepared from 3 - fluoro - 4 - nitrotoluene in a Parr bottle using platinum oxide and hydrogen in ethanol.) To a mixture of 5.15 mmole of (x - (2 - fluoro - 4 methylphenylamino)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 (CDCl3) a 0.98 [d, 3 J-7 Hz, CH(CH3)2], 1.02 [d, 3, J=7 Hz, CH(CH3)2], 2.22

and 5.13 ppm (s, 2, ArCH2O). IR (neat))1734 cm-' (C=O).

Following the above procedure, N - (4 - tert - butylphenyl)valine is reacted with m - phenoxybenzyl bromide to yield the m - phenoxybenzyl ester of N - (4 tert - butylphenyl)valine.

nmr (CDCl3) a centered at 0.99 [d, 6, J=7 Hz. (CH3)2CH], 1.28 [s, 9, (CH2)2C- Ar],

and 5.11 ppm (s, 2, ArCH2O). IR (film) 1743 cm-' (C=O).

The procedure of this example is used to prepare N - (3 - chloro - 4 fluorophenyl)valine and N - (3 - fluoro - 4 - methylphenyl)valine, each of which is reacted with m - phenoxybenzyl bromide to yield the m - phenoxybenzyl ester of N - (3 - chloro - 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 (CDCl2) S centered at 0.97 [d, 6, 5=7 Hz, CH(CH3)2], 2.11 (d, 3, 5=2 Hz,

and 5.10 ppm (s, 2, ArCH2O). IR (neat 1732 cm-' (C=O).

EXAMPLE 39 A mixture of 5 g of p - trifluoromethylaniline, 2.25 g of a - bromoisovaleric acid and 2.0 g of potassium carbonate is heated at 1000 for I hour. After 1.5 hour, 5 ml of HMPT is added and the mixture heated at 1000 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 - phenoxybenzyl ester of N - (4 trifluoromethylphenyl)valine. MS m/e 443 (M+, 5.9).

The acid, N - (4 - trifluoromethylphenyl)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 (100).

The acid, N - (4 - fluorophenyl)valine is prepared as above from 4fluoroaniline 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) a centred at 0.90 [m, 6, (CH3)2CH], 2.0 [m, 1, (CH3)2CHI,

and 5.15 ppm (s, 2, ArCH2O). IR (film) 3400 cm-' (NH).

n - (3 - fluorphenyl)valine (prepared by reacting a - bromoisovaleric acid and 3 - fluoroaniline at 1400, under nitrogen, for 3.5 hr) is reacted with m phenoxybenzyl bromide in HMPTtTHF and potassium carbonate at RT to yield the m - phenoxybenzyl 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 - (3 - nitrophenyl)valine and m - phenoxybenzyl bromide. MS m/e 420 (M+, 4), 193 (100).

EXAMPLE 40 To 1.21 mmole of triethyl oxonium tetrafluoroborate in about 5 ml methylene chloride under nitrogen is added 1.05 mmole of the m - phenoxybenzyl ester of N (4 - chlorophenyl)valine. The reaction is stirred at RT overnight 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 TLC 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 a - bromoisovaleric acid is reacted with m - phenoxybenzyl ester of N - (4 - fluoro - 2 - methylphenyl)valine. MS m/e 407.2 (M+, 4.5), 180 (100).

EXAMPLE 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, is added 0.82 g of m - (3,4 dichlorophenoxy)benzyl bromide. The reaction mixture is stirred overnight at RT and then worked 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 TLC eluting with 10% ether/hexane to yield the m - (3,4 - dichlorophenoxy)benzyl ester of N - (4 - methylphenyl)valine. MS m/e 459.1 (M+, 2.4), 162.1 (100).

The m - phenoxybenzyl ester of N - (2 - nitrophenyl)valine, MS m/e 420. I (M+, 2.7), 193 (100), is prepared from the reaction of m - phenoxybenzyl bromide and N - (2 - nitrophenyl)valine as above.

N - (4 - methylphenyl)valine is reacted with m - phenoxy - a - ethynylbenzyl bromide in DMFtTHF and potassium carbonate at RT, as above, to give the m phenoxy - a - ethynylbenzyl ester of N - (4 - methylphenyl)valine. MS m/e 413.1 (M+, 3;8), 162.1(100).

N - (3,4,5 - trichlorophenyl)valine, prepared from 3,4,5 - trichloroaniline and a- bromoisovaleric acid is reacted with m - phenoxybenzyl bromide in HMPT/THF and potassium carbonate at RT to yield the m - phenoxybenzyl ester of N - (3,4,5 - trichlorophenyl)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 HMPT is heated overnight at 70--800. 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 ether and then the combined ether phases are washed with 2N sulfuric acid, saturated sodium bicarbonate and brine, dried over potassium carbonate, 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 - bromoisovalerate to yield the m - phenoxybenzyl ester of N (3,4,5 - trimethoxyphenyl)valine. MS m/e 465.2 (M+, 39.0), 182.9 (100).

Following the procedure of Example 42, N - (4 - chlorophenyl)valine is reacted with m - benzylbenzyl bromide to yield the m - benzylbenzyl ester of N (4 - chlorophenyl)valine. MS m/e 407.1 (M+, 6.2), 182 (100).

EXAMPLE 44 To m - phenoxybenzyl 3 - methyl - 2 - butenoate (5.80 mmole) and carbon tetrachloride (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 phenoxybenzyl 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 worked up by partition between ether/2N HCI. The aqueous phase is extracted with ether and then the combined ether phases are washed with 2N HC1 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 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 HMPT is added potassium carbonate (0.54 g) and then m - phenoxybenzyl bromide (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)isoleucine. MS m/e 423 (M+, 3.7), 196 (100).

N- (4 - chlorophenyl)isoleucine is prepared by the reaction of 4chloroaniline with the sodium salt of a - 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).

EXAMPLE 46 N - (4 - methylphenyl)valine is reacted with m - (4 - methoxyphenoxy)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 cam~' (NH) and 1735 cm-' (C=O).

EXAMPLE 47 To the m - phenoxybenzyl ester of N - (4 - chlorophenyl)valine (1.19 mmole) in ether (4.5 ml), under nitrogen, is added dimethylaminopyridine (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 400 for 3 days. The reaction is worked up with ether/water. The aqueous phase is extracted 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 chlorophenyl)valine. MS m/e 553 (M+, 1.8), 183 (100).

EXAMPLE 48 Following the procedure of Example 47, the m - phenoxybenzyl 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 or pyruvic acid with the m phenoxybenzyl ester of n - (4 - chlorophenyl)valine.

EXAMPLE 49 Following the procedure of Example 42, N - (4 - chlorophenyl)valine is reacted with m - (3,4 - dichlorophenoxy)benzyl bromide to yield the m - (3,4 dichlorophenoxy)benzyl ester of N - (4 - chlorophenyl)valine. MS m/e 477 (M+, 2.1), 182 (100).

EXAMPLE 50 To the m - phenoxybenzyl ester of N (4 - methoxyphenyl)valine (0.89 mmol) in ether is added trifluoroacetic anhydride (4.46 mmol), under nitrogen. The reaction mixture is stirred for 2.5 hr and then worked 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).

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 - (4 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, a - ethynyl - m phenoxybenzyl bromide and N - (4 - chlorophenyl)valine are reacted to yield the a - 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 chloroform layer is washed with dilute sulfuric acid, water and brine, 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 of 0.89 mmole of the foregoing ester, 1 ml of pyridine and methanol (0.91 mmole) is stirred at RT for 4 days. The reaction is then worked up using dilute HCI/ether. The ether layer is washed with aqueous HCI, 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 - methoxycarbonyl,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 - 4cyanophenyl)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 a - bromoisovaleric acid using the process of, for example, Example 18.

Similarly, there is prepared N - (2,4 - difluorophenyl)valine from 2,4 difluoroaniline and a - bromoisovaleric acid. The N - (2,4 - difluorophenyl)valine is esterified using m - phenoxybenzyl bromide to prepare the m - phenoxybenzyl ester of N - (2,4 - difluorophenyl)valine. MS m/e 411 (M+, 3.5), 184 (100).

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. 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 - bromoisovaleric acid and 2 - fluoro - 4 - chloroaniline neat at 1300 for about 2 hours.

Similarly, there is prepared N - (3 - methyl - 4 - fluorophenyl)valine which is esterified using m - phenoxybenzyl bromide to yield the m - phenoxybenzylester of N - (3 - methyl - 4 - fluorophenyl)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 - phenoxybenzyl 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 a - cyano - m - phenoxybenzyl ester of N - (4 chlorophenyl)valine (0.79 g) and about 20 ml of dry DMF is added about 1 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-' (C=O).

EXAMPLE 57 N - (2 - cyano - 4 - chlorophenyl)valine is reacted with m - phenoxybenzyl bromide to yield the m - phenoxybenzyl ester of N - (2 - cyano - 4chlorophenyl)valine using the procedure of Example 42. MS m/e 434.1 (M+, 3.5).

Similarly, there is prepared the a - cyano - m - phenoxybenzyl ester of N - (2 methylphenyl)valine. MS m/e 414.1 (M+, 5.8), from a - cyano - m - phenoxybenzyl bromide and N - (2 - methylphenyl)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 - (2,4dimethoxyphenyl)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 - phenoxybenzyl 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 solvent stripped to give 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 - chlorophenyl)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 cg- bromoisovaleric acid is reacted with ethyl p aminobenzoate, neat, at 1400 for 3 hr to yield N - (4 ethoxycarbonylphenyl)valine, which is reacted with m - phenoxybenzyl bromide to yield the m - phenoxy benzyl ester of N - (4 - ethoxycarbonylphenyl)valine.

MS m/e 447 (M+).

The m - phenoxybenzyl ester of N - (3 - trifluoromethylphenyl)valine. MS m/e 443 (M+), is prepared from N - (3 - trifluoromethylphenyl)valine and m phenoxybenzyl bromide. The reaction of 3 - trifluoromethylaniline with the sodium salt of a - bromoisovaleric acid provides the starting material.

Each of N - (3,4 - dimethylphenyl)valine, N - (3 - methylphenyl)valine, N (2,4,6 - trimethylphenyl)valine, N - (2 - chloro - 5 - trifluoromethylphenyl)valine and N - 2,6 - difluoro - 4- chlorophenyl)valine is esterified using m phenoxybenzyl bromide with potassium carbonate in THF/HMPT at RT to yield the respective ester below.

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 chloroaniline according to the procedure of Example 18.

Following the procedure of Example 1, each of 4 - n - butylaniline and 4 cyclopropylaniline is reacted with m - phenoxybenzyl a - bromoisovalerate to yield the m - phenoxybenzyl ester of N - (4 - butylphenyl)valine. MS m/e 431.2 (M+), and the m - phenoxybenzyl ester of N - (4 - cyclopropylphenyl)valine. MS m/e 415.1 (my ).

Each of the m - phenoxybenzyl ester of N - (4 - chlorophenyl)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- (4methylphenyl)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 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 35C 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 triphenylphosphine (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 TMF 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 phenoxybenzyl ester of 2 - phenylamino - 3 - chloro - butanoic acid. MS m/e 395 (me).

The above prepared ester is methylated using the procedure of Example 2 to yield m - phenoxybenzyl 2 - (methyl,phenylamino) - 3 - chlorobutanoate. MS m/e 409 (M+).

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 - toluenesulfonylacetate 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 up 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, 1 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 at 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 from 2,4 - dichloroaniline 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 - chloroaniline, 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 - chlorophenyl)valine is reacted with methyl iodide using the procedure of Example 2 to yield the a cyano - m - phenoxybenzyl ester of N - methyl,N - (4 - chlorophenyl)valine. MS m/e 448.1 (M+).

N - (2,3 - dichlorophenyl)valine, prepared from 2,3 - dichloroaniline and sodium salt of a - bromoisovaleric acid, is reacted with m - phenoxybenzyl bromide to yield the m - phenoxybenzyl ester of N - (2,3 - dichlorophenyl)valine.

MS m/e 443 (M+).

EXAMPLE 63 Following the procedure of Example 1, 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 - phenoxybenzyl ester of N - (4 nitrophenyl)valine. MS m/e 420.1 (M+), and N - (2,6 - dichlorophenyl)valine. MS m/e 443 (M+).

EXAMPLE 64 Following the procedure of Example 1, m - phenoxybenzyl a - 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 - chlorophenyl)valine, N - (2 chlorophenyl)valine, and N - (2,6 - difluorophenyl)valine to yield the respective ester-the m - phenoxybenzyl ester of N - (3 - trifluoromethyl - 4 - chlorophenyl)valine. MS m/e 477.1 (M+), 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 benzylbromide 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 - chlorophenyl)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 methoxyphenoxy)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 trifluoromethylphenoxy)benzyl ester of N - (4 - chlorophenyl)valine. MS m/e 477 (M+); the m - (4 - chlorophenoxy)benzyl ester of N - (4 - chlorophenyl)valine.

MS m/e 443 (M+); the m - (4 - methylphenoxy)benzyl ester of N - (4 chlorophen with a - cyano - m - phenoxybenzyl a - bromoisovalerate to yield 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 from 15 min and methyl iodide (9.4 ml) added slowly at 100. The reaction mixture is warmed to RT and stirred for 2 hr. The reaction is worked 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 methylsuffide (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 through for 0.5 hr. The solution is concentrated and the product, p-nitrophenyl trichloromethyl sulfide recrystallized out of hot acetone, m.p. 9496 .

p-Nitrophenyl trichloromethylsulfide (1.5 g) and purified SbF3 (1.96 g) is stirred under nitrogen in a Claisen flask and heated to l 11200. After about 0.5 hr, the product is distilled off-at 8590 (5 mm). The distillate is taken up in ether (50 ml) and the ether layer washed with -10% HCI until cloudiness no longer occurs on addition of water. The ether layer is washed with water until neutral and with brine, dried over calcium sulfate and evaporated to yield p-nitrophenyl trifluoromethyl sulfide.

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 Ibs/sq. in. for about 15 min. The reaction is worked up by filtering through Celite and evaporating to yield p - aminophenyl trifluoromethyl sulfide.

Following the procedure of Example 43, p-aminophenyl trifluoromethyl sulfide is reacted with m-phenoxybenzyl a-bromo-isovalerate to yield the mphenoxybenzyl ester of N-(4-trifluoromethylthiophenyl)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-trifluoromethylthiophenyl)valine, which is esterified to yield the mphenoxybenzyl 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 2fluoro-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 1000, 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--1700 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 (1X), and dried over sodium sulfate. 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,a-tribromotoluene, which may be recrystallized from methanol.

A mixture of 8.5 g of 2 - fluoro - 4 - nitro - a,a,a x - tribromotoluene (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 (1X) and brine (1X) and dried over sodium sulfate. Filtration and evaporation of the solvent yielded 2-fluoro-4-nitrobenzotrifluoride.

To a solution of 20 ml of concentrated hydrochloric acid and 15 ml of 95 /n 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 portions over a 30 min period. The reaction is exothermic and during the addition the temperature is maintained at 600. When the addition is complete, the mixture is stirred at 600 for an additional 30 min. The reaction is cooled and poured onto a mixture of ice and 36 /n 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 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 - trifluoromethylphenyl)valine, which is esterified to yield the m phenoxybenzyl ester of N - (3 - fluoro - 4 - trifluoromethylphenyl)valine.

N-(2,4-dinitrophenyl)valine is reacted with m-phenoxybenzyl bromide using the procedure of Example 38 to yield the m-phenoxybenzyl ester of N-(2,4dinitrophenyl)valine.

This procedure is repeated using 3-fluoro-4-nitrotoluene in place of 2-fluoro-4nitrotoluene to prepare 2-fluoro-4-trifluoromethyaniline, which is converted into N-(2-fluoro-4-trifluoromethylphenyl)valine and then esterified to yield the mphenoxybenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine. MS m/e 461.1 (M+).

EXAMPLE 68 A mixture of 2 - fluoro - 4 - chlorotoluene (25.05 g), KM nO4 (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 (Registered Trade Mark) and the filtrate is acidified with 2N HCI. White crystals are filtered off, dissolved in ether and washed with water and brine, dried over sodium sulfate, filtered and evaporated to yield 2fluoro-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 1300. 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 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 1500, 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--1050.

The above process is repeated using N-(4-methylphenyl)valine to yield the mphenoxybenzyl thiolester of N-(4-methylphenyl)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, the reaction mixture is poured into 15% NaOH solution. The layers are separated and the organic fraction shaken with 15% NaOH solution. The methylene chloride fraction is washed with saturated NaCI solution, dried over calcium sulfate and evaporated to yield 4bromo-2-fluoroaniline.

To the potassium salt of cu-bromoisovaleric acid (1.42 g) is added 4-bromo-2fluoroaniline (1.9 g). The mixture is heated at 1250 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. HCI and then extracted into ether, washed with saturated NaCI 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-a-cyanobenzyl mesylate (0.43 g) is stirred for about 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 the 25% methylene chloride/hexane once and then 30% methylene chloride/hexane and the major band collected to yield the m-phenoxy-(x- cyanobenzyl 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 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 in vacuo to yield 3-(4-chlorophenyl)-4isopropyloxazoladine-2,5-dione, m.p. 137138 .

To a mixture of m-naphthoxybenzaldehyde (0.43 g), 3-(4-chlorophenyl)-4isopropyloxazolidine-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 mixture 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 evaporating. The concentrate is plated, prep. TLC, eluting with 20% ether/hexane to yield the m-naphthoxy-cr-cyanobenzyl ester of N-(4-chlorophenyl)valine. MS m/e 484 (M+).

nmr (CDCl2) a centered at 1.0 [m, 6, (CH3)2CH], 2.10 [m, 1, (CH3)2CH1, 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-4trifluoromethylphenyl)valine, N-(4-chloro-2-fluorophenyl)valine, N-(2-fluoro-4trifluoromethylphenyl)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.

EXAMPLE 73 N-(2-fluorophenyl)valine, prepared by the reaction of 2-fluoroaniline and abromoisovaleric acid, is reacted with m-phenoxybenzyl bromide, as in Example 17, to yield the m-phenoxybenzyl 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 Folloing the procedure of Example 6, 2-fluoro-4-chloroaniline is reacted with m-phenoxy-a-cyanobenzyl a-bromoisovalerate to give the m-phenoxy-a- 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- bromoisovaleric acid to give. N-(2-fluoro-4-chlorophenyl)valine, which is then esterified using m-phenoxy-a-cyanobenzyl bromide or mesylate.

N-(4-chlorophenyl)valine is reacted with m-phenylcarbonylbenzyl bromide or the.

mesylate following the procedure of Example 24 to yield the mphenylcarbonylbenzyl ester of N-(4-chlorophenyl)valine. MS m/e 421 (M+).

EXAMPLE 75 Each of N - (2 - chloro - 4 - fluorophenyl)valine, N - (4 methylthiophenyl)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-phenoxybenzyl bromide using the procedure of Example 24 to yield 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 the m - phenoxy-acyanobenzyl ester of N-(4-chloro-3-fluorophenyl)valine MS m/e 452 (M+), and the m-phenoxy-cr-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 - methylphenyl)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 etherhexane and washed with dilute hydrochloric acid followed by aqueous sodium bicarbonate. The organic phase is stripped and chromatographed on a I m silica plate eluted with 10% ether-hexane to give the 3 - phenoxy - a - trifluoromethylbenzyl ester of N - (4 - chlorophenyl)valine. MS m/e 477.1 (M+), 182 (100).

EXAMPLE 76 Following the procedure of Example 65, N-(4-chlorophenyl)valine is reacted with each of 5-benzyl-3-furylmethyl bromide, m-allyloxybenzyl bromide and mpropargyloxybenzyl bromide to yield the 5-benzyl-3-furylmethyl ester of N-(4chlorophenyl)valine. MS m/e 397 (M+), the m-allyloxybenzyl ester of N-(4chlorophenyl)valine. MS m/e 373 (M+), and the m-propargyloxybenzyl ester of N (4-chlorophenyl)valine. MS m/e 371 (M+).

4-Chioroaniline is reacted with m-phenoxybenzyl 2-bromobutanoate using the process of Example 4 to yield m-phenoxybenzyl 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 - cr- cyanobenzyl a bromoisovalerate to yield the p - benzylbenzyl ester of N-(4-chlorophenyl)valine.

MS m/e 407 (M+), and the m-benzyl-a-cyanobenzyl ester of N-(4chlorophenyl)valine. MS m/e 432 (M+).

Following the procedure of Example 60, N - (4 - isopropoxycarbonylphenyl)valine is prepared and reacted with m-phenoxybenzyl bromide to yield the m - phenoxybenzyl ester of N - (4 - isopropoxycarbonylphenyl)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 - trifluoromethylphenylamino) - 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 stirring mixture. A 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 - isopropyloxazolidine - 2,5 dione is reacted with phenol using the procedure of Example 75 to give the phenyl ester of N-(2-fluoro-4-trifluoromethylphenyl)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.

The thioacid is reacted with m - phenoxy - a - cyanobenzyl bromide or mesylate using the procedure of Example 70 to yield the m-phenoxy-a-cyanobenzyl thiolester of N-(2-fluoro-4-trifluoromethylphenyl)valine.

EXAMPLE 78 Following the procedure of Example 38, N - (4 - trifluoromethylphenyl)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 - isopropyloxazolidine - 2,5dione 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-a-cyanobenzyl ester of N - (2 - fluoro - 4 - trifluoromethylphenyl)valine and the m - benzoyl - a - cyanobenzyl ester of N - (4 trifluoromethylphenyl)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 to 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 - fluorophenoxy)benzyl bromide as the esterification reagent, the respective m-(p-fluorophenoxy)benzyl ester of the listed amino acids are prepared.

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-acyanobenzyl bromide to yield the m-phenoxybenzyl ester of N - (2 - 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 - 4methoxyphenyl)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.

EXAMPLE 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 - propargylbenzyl bromide, 4 - propargylbenzyl bromide, 4 - phenyl - 3 - chloro - 2 - butene - 1 - yl bromide, 3,4 - dichloro - cr - ethynylbenzyl bromide, 3 - trifluoromethoxybenzyl bromide, 3 - trifluoromethyl a - ethynylbenzyl bromide, 4 - (p - fluorophenyl) - 3 - chloro - 2 - butene - I - 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 - trifluoromethyl phenyl)valine, 2,6 - dimethyl - 4 - propargylbenzyl ester of N - (2 - fluoro - 4 - trifluoro methylphenyl)valine, 4 - piopargylbenzyl ester of N - (2 - fluoro - 4 - trifluoro methylphenyl)valine, 4 - phenyl - 3 - chloro - 2 - butene - I - yl ester of N - (2 - fluoro - 4 trifluoromethylphenyl)valine, 3,4 - dichloro - a - ethynylbenzyl ester of N - (2 - fluoro - 4 - trifluoro methylphenyl)valine, 3 - trifluoromethoxybenzyl ester of N - (2 - fluoro - 4- trifluoro methylphenyl)valine, 3 - trifluoromethyl - a - 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 3,979,519, the 3 - trifluoromethoxy - a cyanobenzyl ester of N - (2 - fluoro - 4 - trifluoromethylphenyl)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 m - phenoxy - a - cyanobenzyl ester of N - phenylvaline diluted to three different concentrations in aqueous carrier containing 0.025% Tween (Registered Trade Mark) 20 and 0.1% wetting agent. The treated leaves are maintained at 24C and 16 hr photoperiod for 2 days. Live adult mites are then counted and subtracted 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 LCso of less than 0.1%.

Individual fava bean leaves are dipped in m - phenoxybenzyl ester of Nphenyl-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 24C 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 LCso 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 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 milksaturated 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 LCso 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 0.5 ml of water containing the m phenoxybenzyl ester 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 LCso of the compounds was less than 0.01%.

Two groups of 10 each of 0-24 hr III instar Heliothis virescens larvae were treated with 1 y1 of the m - phenoxybenzyl ester of N - (p - methoxyphenyl)valine in acetone at three different concentrations by application of 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 250 and 16 hr photoperiod. After 72 hr the number of dead is calculated as a percentage of the tqtal number originally treated and then corrected for any mortality in the control groups using Abbott's formula. The LCso 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 LC,, of less than fifteen parts per million (ppm).

m - phenoxy - a - cyanobenzyl ester of N - (2 - chloro - 4 - trifluoromethyl phenyl)valine, m - phenoxy - a - cyanobenzyl ester of N - (2 - fluoro - 4 - trifluoromethyl phenyl)valine, m - phenoxybenzyl ester of N- (2- fluoro - 4- trifluoromethyl phenyl)valine, m - phenoxybenzyl ester of N - (4 - trifluoromethylphenyl)valine.

A 4E emulsive concentrate was prepared using the m - phenoxybenzyl ester of N - (4 - trifluoromethyl-phenyl)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 LCso value was less than 10 ppm.

"Atlox" is a Registered Trade Mark.

The compounds listed below were used to treat tick nymphs (Ornithodoros nymph I) using the method described above and exhibited an LC > o of less than 15 ppm.

m - phenoxy - a - cyanobenzyl ester of N - (2 - chloro - 4 - trifluoromethyl phenyl)valine, m - phenoxy - a - cyanobenzyl ester of N - (2 - fluoro - 4 - trifluoromethyl phenyl)valine, m - phenoxy - a - methylbenzyl ester of N - (4 - chlorophenyl)valine, m - phenoxy - a - ethynylbenzyl ester of N - (4 - chloro - 2 - fluoro phenyl)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 - fluoro - 4

Claims (42)

**WARNING** start of CLMS field may overlap end of DESC **. 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 LC,, of less than fifteen parts per million (ppm). m - phenoxy - a - cyanobenzyl ester of N - (2 - chloro - 4 - trifluoromethyl phenyl)valine, m - phenoxy - a - cyanobenzyl ester of N - (2 - fluoro - 4 - trifluoromethyl phenyl)valine, m - phenoxybenzyl ester of N- (2- fluoro - 4- trifluoromethyl phenyl)valine, m - phenoxybenzyl ester of N - (4 - trifluoromethylphenyl)valine. A 4E emulsive concentrate was prepared using the m - phenoxybenzyl ester of N - (4 - trifluoromethyl-phenyl)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 LCso value was less than 10 ppm. "Atlox" is a Registered Trade Mark. The compounds listed below were used to treat tick nymphs (Ornithodoros nymph I) using the method described above and exhibited an LC > o of less than 15 ppm. m - phenoxy - a - cyanobenzyl ester of N - (2 - chloro - 4 - trifluoromethyl phenyl)valine, m - phenoxy - a - cyanobenzyl ester of N - (2 - fluoro - 4 - trifluoromethyl phenyl)valine, m - phenoxy - a - methylbenzyl ester of N - (4 - chlorophenyl)valine, m - phenoxy - a - ethynylbenzyl ester of N - (4 - chloro - 2 - fluoro phenyl)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 - fluoro - 4 methylphenyl)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, m - phenoxy - a - cyanobenzyl ester of N - (4 - chloro - 2 - fluoro phenyl)valine, m - phenoxybenzyl ester of N - (2 - fluoro - 4 - trifluoromethylphenyl)valine, m - phenoxy - a - cyanobenzyl ester of N - (4 - bromo - 2 - fluoro phenyl)valine, m - phenoxybenzyl ester of No (2- chloro - 4 - trifluoromethyl phenyl)valine, m - phenoxy - a - cyanobenzyl ester of N - (2 - fluoro - 4 - trifluoromethyl phenyl)valine, m - phenoxy - a - cyanobenzyl ester of N - (2 - chloro - 4 - trifluoromethyl phenyl)valine, m - phenoxybenzyl ester of N - (2 - fluoro - 4 - methylphenyl)valine. WHAT WE CLAIM IS:

1. A compound of the formula (A):

wherein, W is oxygen or sulfur; R' is cycloalkyl, cycloalkenyl, cycloalkenyl substituted with halo or lower alkyl, or the group

in which t is zero, one, two, three or four; Y is independently selected from hydrogen, lower alkyl, lower haloalkyl, lower alkoxy, lower alkylthio, lower alkylcarbonyl, lower alkoxycarbonyl, lower acyloxy, halogen, cyano, nitro, and lower haloalkylthio; and Z is independently selected from the values of Y, cycloalkyl, and lower haloalkoxy; or Y and Z form a methylenedioxy group; R2 is hydrogen, lower alkyl, lower haloalkylcarbonyl, or formyl; R3 is alkyl or 2 to 5 carbon atoms, alkenyl of 2 to 5 carbon atoms, haloalkyl of I to 4 carbon atoms, haloalkenyl of 2 to 4 carbon atoms, or cycloalkyl of 3 or 4 carbon atoms; R4 is hydrogen or fluoro; and R5 is;

wherein, p is zero, one, two or three; R6 is hydrogen, cyano, methyl, trifluoromethyl, ethynyl, or

R7 iS halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkylthio, lower alkenyl, or lower haloalkenyl; R6 is hydrogen or together with R7 forms a lower alkylenedioxy bridge across adjacent ring carbon atoms; R9 is hydrogen, lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower haloalkynyl, lower alkylcarbonyl, arylcarbonyl, substituted arylcarbonyl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, aralkyl, substituted aralkyl, cycloalkyl, cycloalkalkyl, lower acyloxy, aryloxycarbonyl, lower alkoxycarbonyl, or lower haloalkenyloxy; R'O is hydrogen or lower alkyl; R" is hydrogen, lower alkenyl, lower alkynyl or aralkyl; R12 and R13 taken together form an alkylene bridge having I to 4 carbon atoms or a lower alkenylene bridge having 2 to 4 carbon atoms; R14 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or aralkyl; R15 is hydrogen or lower alkyl; R16 is hydrogen, chloro, fluoro, or methyl; R17 is hydrogen, chloro, fluoro, methyl, or taken together with R16 forms a carbon-carbon bond; Ris is phenyl or phenyloxy; Rl9 is hydrogen, halogen, methyl or ethyl; R20 is allyl, propargyl, 3 - butenyl, 3 - butynyl, phenyl, or benzyl; and the salts thereof of strong inorganic acids or organic acids.

2. A compound according to Claim 1 of the formula:

wherein R3 is isopropyl, isopropenyl, or trifluoromethyl.

3. A compound according to Claim 1 of the formula:

wherein, Z is hydrogen, trifluoromethyl, fluoro, chloro, bromo, cyclopropyl or lower alkyl of I to 4 carbon atoms; R2 is hydrogen, methyl or ethyl; R6 is hydrogen, cyano, ethynyl or

and R9 is phenoxy or p-fluorophenoxy.

4. A compound according to Claim 3 wherein each of R2 and R6 is hydrogen and R9 is phenoxy.

5. A compound according to Claim 1 of the formula:

wherein, R2 is hydrogen, methyl or ethyl; R6 is hydrogen, cyano, ethynyl or

R9 is phenoxy or p - fluorophenoxy; Y is hydrogen, trifluoromethyl, fluoro, dichloro, bromo, lower alkyl of 1 to 4 carbon atoms, lower alkoxy of 1 to 4 carbon atoms or lower alkythio of 1 to 3 carbon atoms; Z is independently selected from the values of Y, and cyclopropyl; and t is zero, one or two.

6. A compound according to Claim 5 wherein t is one or two.

7. A compound according to Claim 5 wherein t is zero.

8. A compound according to Claim 5 wherein t is zero and Z is in the meta position.

9. A compound according to Claim 5 wherein t is zero and Z is in the ortho position.

'

10. A compound according to Claim 5 wherein t is one, Y is in the ortho position and Z is in the para position.

II. A compound according to Claim 5 wherein t is one, Y is in the meta position and Z is in the para position.

12. A compound according to Claim 11 wherin Y is fluoro.

13. A compound according to Claim 10 wherein Y is fluoro.

14. A compound according to Claim 5 wherein Z is lower alkyl of I to 4 carbon atoms, chloro, fluoro, bromo, trifluoromethyl or cyclopropyl; Z is the para position; Y is in the ortho position; and t is one.

15. A compound according to Claim 14 wherein Y is fluoro.

16. A compound according to Claim 15 wherein each of R2 and R6 is hydrogen.

17. A compound according to Claim 16 wherein R9 is phenoxy.

18. A compound according to Claim 15 wherein Z is lower alkyl of I to 4 carbon atoms.

19. A compound according to Claim 18 wherein each of R2 and R6 is hydrogen.

20. A compound according to Claim 19 wherein R9 is phenoxy.

21. A compound according to Claim 1 of the formula:

wherein R3 is isopropyl, isopropenyl or trifluoromethyl.

22. A compound according to Claim 21 wherein R2 is hydrogen, R3 is isopropyl, R6 is hydrogen or cyano, R9 is phenoxy, W is oxygen, and Y is bromo, chloro or fluoro.

23. A compound according to Claim I of the formula:

wherein R6 is hydrogen or cyano.

24. A compound according to Claim 23 wherein Y is fluoro and Z is dichloro, bromo, fluoro, trifluoromethyl, or alkyl of one to four carbon atoms.

25. A compound according to Claim 23 wherein Y is fluoro and Z is trifluoromethyl.

26. The m - phenoxy - a - cyanobenzyl ester of N - (2 - fluoro - 4 - trifluoromethylphenyl)valine.

27. A compound according to Claim 23 wherein Y is fluoro and Z is chloro.

28. A compound according to Claim 23 wherein Y is chloro and Z is trifluoromethyl.

29. The m - phenoxy - a - cyanobenzyl ester of N - (2 - chloro - 4 trifluoromethylphenyl)valine.

30. A salt of any of the foregoing compounds and a strong inorganic or organic acid.

31. A salt of any of the foregoing compounds formed from an acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, pbenzenesulfonic acid, and methanesulfonic acid.

32. The salt of any of the foregoing compounds formed from hydrochloric acid.

33. A process for the manufacture of the compounds of formula A as defined herein and the salts thereof formed from a strong inorganic or organic acid according to the processes described herein.

34. A method for the control of pests such as insects and acarids which comprises treating said pests with a pesticidally effective amount of a compound of formula A, or the salt thereof, as defined herein.

35. The method according to Claim 34 wherein the pest is an insect of the order Lepidoptera, Orthoptera, Heteroptera, Homoptera, Diptera, Coleoptera, or Hymenoptera.

36. The method according to Claim 34 wherein the pest is a mite or a tick of the order Acarina.

37. The method according to Claim 36 wherein the mite is of the family Tetranychidae or Tarsomemidae.

38. A composition for the control of pests such as insects and acarids which comprises a suitable liquid or solid carrier and pesticidally effective amount of a compound of formula A or the salt thereof as defined herein.

39. Each compound of the formula (A) given and defined in Claim 1 which is specifically disclosed herein

40. Pest control methods substantially as herein described and exemplified.

41. Pest control compositions substantially as herein described and exemplified.

42. A compound of the formula (A) given and defined in Claim I whenever produced by a process according to Claim 33.