CH632232A5 - Esters and thiolesters (thioesters) of amino acids - Google Patents

Description

The present invention relates to novel esters and thiolesters of amino acids and their use in the fight against harmful insects.

The amino acid esters and thiglesters according to the invention are represented by the following generic formula (A):

R1V R3 O

\ I II .N-C-C-WR5 (A)

/ I

R2 R4

and their addition salts with strong mineral or organic acids; in this formula:

W is oxygen or sulfur,

R1 is a cycloalkyl, cycloalkenyl, cycloalkenyl group substituted by a halogenated or lower alkyl group, or the group of formula:

wherein t is 0.1, 2, 3 or 4; Y is independently selected from hydrogen, lower alkyl, lower haloalkyl, lower alkoxy, lower alkylthio, lower alkylcarbonyl, lower alkoxycarbonyl, lower aryloxy, halo, cyano, nitro and lower haloalkylthio; and Z is independently selected from the values of Y and cycloalkyl groups and lower haloalkoxy groups; or Y and Z form a methylene-dioxy group;

R2 is hydrogen, lower alkyl, haloalkyl-lower carbonyl or formyl;

R3 is a lower alkyl group having from 2 to 5 carbon atoms, lower alkenyl having from 2 to 5 carbon atoms, lower haloalkyl having from 1 to 4 carbon atoms, lower halo-noalkenyl having from 2 to 4 carbon atoms or lower cycloalkyl having 3 or 4 carbon atoms;

R4 is hydrotene or fluorine, and

Rs is a group chosen from:

-CHRe _ <^^ \ _ R8

V "

—CHi — N 11 w

R16R17

-CHR «- ^ D / dd r15

R19

I

—CH —C = CH —R20 I

CeeCH

or,

p is equal to 0,1,2 or 3

Rô is hydrogen, cyano, methyl, trifluoromethyl, ethynyl or

—C = S;

I

nh2

R7 is halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkylthio, lower alkenyl or lower haloalkenyl;

R® is hydrogen or, together with R7, forms a lower alkylenedioxy bridge between adjacent carbon atoms of a ring;

R9 is hydrogen, lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower haloalkynyl, lower alkylcarbonyl, arylcarbonyl, substituted arylcarbonyl, aryloxy,

632232

4

substituted aryloxy, arylthio, substituted arylthio, arylalkyl, arylalkyle the appended claims, have the meanings indicated below,

substituted, cycloalkyl, cycloalkalkyle, lower acyloxy, aryloxy- unless otherwise stated.

carbonyl, lower alkoxycarbonyl, or lower haloalkenyloxy The term lower alkyl denotes an alkyl group, with straight or branched chain, having a chain length of 1 to 8 atoms of

R10 is hydrogen or a lower alkyl group; 5 carbon. The term lower haloalkyl denotes an alkyl group

R11 is a lower alkenyl, lower alkynyl or aryl group substituted by 1 to 3 halogen atoms, such as chloromethyl, fluoro-

alkyl; methyl, trifluoromethyl, 2,2,2-trifluoroethyl, 6-chlorohexyIe,

R12 and R13 can together form lower alkylene or 2-fluoroethyl, and the like. The term lower alkoxy denotes a lower alkenylene bridge; alkoxy group, straight or branched chain, having a length of

R14 is hydrogen, lower alkyl, lower alkenyl, chain of 1 to 8 carbon atoms. The term lower alkylthio lower alkynyl or arylalkyl; denotes an alkylthio group, straight or branched chain, having a

R15 is hydrogen or lower alkyl; chain length from 1 to 8 carbon atoms.

R16 is hydrogen, chloro, fluoro or methyl; The term lower alkenyl denotes a hydrocarbon group with

R17 is hydrogen, chloro, fluoro, methyl, or may, ethylenically unsaturated, straight or branched chain, having one with R16, form a carbon-carbon bond; 15 chain length from 2 to 8 carbon atoms and 1 or 2 bonds

Rla is a phenyl or phenyloxy group; ethylenic, such as vinyl, allyl, 3-butenyl, 2-hexenyl,

R! 9 is hydrogen, halogen or methyl or i-propenyl, 2,4-hexadienyl, and the like. The term halogeno-

ethyl; lower alkenyl denotes a lower alkenyl group substituted by 1

R20 is an allyl, propargyl, 3-butenyl, 3-butynyl group, with 3 halogen atoms. The term lower alkenyloxy denotes phenyl or benzyl. 20 alkenyloxy group, straight or branched chain, from 2 to 8 atoms

The compounds according to the invention, represented by the carbon formula. The term lower haloalkenyloxy denotes a generic group (A), are agents useful for combating lower alkenyloxy agents substituted by 1 to 3 halogen atoms.

pests, such as insects and mites. Without wishing to be limited to The term lower alkenyl designates an alkynyl group, chain to any theory and although the mode of action of straight or branched compounds, having a chain length of 2 to 8 atoms of formula (A), applied to control insects and mites, 25 carbon, and 1 or 2 acetylenic bonds. The term haloalkynyl is not fully understood, the compounds of formula (A) appear lower denotes a lower alkynyl group having from 1 to 3 atoms

be effective in the fight against insects and mites, due to halogen. The term lower alkynyloxy denotes an alkynyl-

mechanisms of the nature of known insecticidal agents, such as oxy, straight or branched chain, from 3 to 8 carbon atoms,

Pyrethrines and synthetic pyrethroids. As is, the group The term cycloalkyl denotes a cycloalkyl group from 3 to 8

organic (Rs) can be chosen from organic groups 30 cyclic carbon atoms. The term cycloalkalkyl denotes a generally associated with the formation of pyrethrin esters and cycloalkyl group esters in which a hydrogen atom is replaced

synthetic pyrethroids. Typical examples of these groups by a lower alkyl group, the total number of organic carbon atoms (Rs) are those mentioned in the US patents being from 4 to 12, such as cyclopropanemethyl, cyclobutane-ethyl,

Nos. 3973035.3973036.3996244 and 4003945, in the application for cyclohexanemethyl, and the like.

DE-OS Patent No. 2647366 and the Patent Application in the Republic 35 The term aryl designates the phenyl or naphthyl aryl group. South Africa N ° 76/4622. arylalkyl or aralkyl means a lower alkyl group in

The new compounds of formula (A) in which a hydrogen atom of the alkyl group is substituted by a

ß 1 r3 o aryl group, the total number of carbon atoms being from 7 to 12, such

1 11 as benzyl, phenethyl, and the like. The terms substituted aryl and

N — C — C — WR5 (A) 40 substituted arylalkyl denote an aryl group and a

/ arylalkyl group, substituted on 1,2 or 3 of the carbon atoms

R2 cyclic by a group chosen from lower alkyl groups,

with W, R1 to Rs as defined further, according to the invention, are lower haloalkyl, lower alkoxy, lower alkenyl,

characterized in the preceding claim 1; their use is lower haloalkenyl, lower alkenyloxy, halo, nitro,

presented in claim 24 above. 45 cyan0> lower alkylthio, and the like.

The acid of formula (III) can be obtained from the acid The term "lower haloalkoxy" denotes a halogenated alkoxy group or the lower alkyl ester of formula (IV) (R21 is lower substituted by 1 to 3 halogen atoms.

hydrogen or a lower alkyl group), applying the term "lower acyloxy" means an acyloxy group organi-

conditions described above by reaction with the amine of formula (I); 1ue lower having from 1 to 6 carbon atoms, such as acetoxy.

50 The compounds according to the invention, corresponding to formula (A),

R3 O have one or more asymmetric carbon atoms. The invention

X _ c — C — OR21 (IV) tion includes all optical isomers and their mixtures

I racemic. In the examples below, unless otherwise indicated, the

R4 compound prepared is a racemic mixture.

After the reaction of a halogenated ester of formula (IV) where R21 is 55 The salts of the compounds of formula (A) also enter the lower alkyl group, with an amine of formula (I), the amino-framework of 1 invention. The salts are obtained from inorganic acids.

ester of formula (V) resulting therefrom: <strong or strong organic acids, such as hydrochloric acid,

sulfuric acid, phosphoric acid, p-toluenesulfonic acid,

\ R3 O p-benzenesulfonic acid, methanesulfonic acid, an acid of

N_C — C — OR21 (V) 60 Lewis, and the like. Many compounds of formula A are

/ I oils which are advantageously converted into salt for reasons of

R2 R4 handling and formulation, and superior stability. The salts can be used as pesticides, in the same way as the compounds are saponified by conventional methods into the amino acid of formula of formula A.

(III) or one of its reactive derivatives, such as acid chloride, 65 The compounds according to the invention, corresponding to formula (A), are acid bromide or one of its inorganic salts, such as the salt of useful pesticidal agents, especially to combat sodium or potassium. insects and mites. When using the compounds of formula A

The following terms, used in the description below or in to fight insects and mites for the protection of

V

632232

agricultural crops, for example, soybeans, cotton, alfalfa, etc., an effective amount is applied locally, as regards its pesticidal effect, of a compound of formula (A) or mixtures of these compounds, with a support. The carrier can be liquid or solid and includes adjuvants, such as wetting agents, dispersing agents and other surfactants. The compounds of formula A can be used in formulations such as wettable powders, solutions, powders, granules, emulsifiable concentrates, and the like. Suitable solid carriers include natural and synthetic silicates and clays, carbon or coal granules, natural and synthetic resins, waxes, and the like. Suitable liquid carriers include water, aromatic hydrocarbons, alcohols, vegetable and mineral oils, ketones, and the like. The amount of a compound of formula (A), the formulation of which can vary within wide limits, generally between about 0.01 and 90.0% by weight.

As will be demonstrated below, the compounds according to the invention are effective against many different insects and mites. The compounds are effective pesticides against insects, such as mosquitoes, flies, aphids, weevils, and mites, such as spiders, mites and ticks. Depending on the particular combination of the substituents of formula (A), the compounds have a broad or relatively narrow spectrum of extraordinarily high pesticidal activity against insects and mites. Among the insects against which the compounds according to the invention prove to be effective pesticides, mention may be made of insects of the order Lepidoptera, Orthoptera, Heteroptera, Homoptera, Diptera, Coleoptera or Hymenoptera, and the mites of the order of the mites including the mites of the family of the spider mites or of the tarsonemids and the ticks, such as Ornithodoros. 30

The compounds according to the invention can be used in combination with other pesticides, such as carbamates, phosphates and insect growth regulators, for example the products known under the trade names: Propoxur, Carbaryle, Naled, Dichlorvos, Methoprene, Kinoprene, Hydroprene, Cyhexatin and Resmethrine.

The following examples are given by way of illustration of the methods for obtaining the compounds according to the invention. The temperatures are indicated in degrees centigrade.

40

Example 1:

A. To 10 g (0.055 mol) of α-bromo-isovaleric acid in 60 ml of ether, cooled to 10 ° C., 2.8 ml (0.0332 mol) of dimethylformamide (DMF) were added , then more slowly 5.9 ml (0.0828 mol) of thionyl chloride. After about 1 hour at 24 ° C., the intermediate acid chloride was isolated by decantation of the upper ethereal layer from the oily residue and vacuum distillation of the ether. To acid chloride (0.055 mol) in 100 ml of ether, cooled to 10 ° C, was added

11.49 g (0.0495 mol) of m-phenoxybenzyl alcohol, then 9 ml (0.11 mol) of Pyridine in approximately 15 min. The white suspension thus obtained was stirred at 24 ° C for about 16 h and a trace of water was added to decompose the excess acid chloride. The ester was isolated by pouring the suspension of reaction products into a water-ice mixture (100 ml), acidifying with 60 ml of 2N sulfuric acid and extracting with 3 times 100 ml of ether. The combined extracts were washed with ether with 10 ml of 10% sodium bicarbonate, then with 2 times 100 ml of water and finally with 25 ml of brine,

then it was dried over calcium sulfate in order to obtain the m-phenoxybenzyl α-bromo-isovalerate with a quantitative yield.

NMR (CCI *) S 1.03 [m, 6, (Œ3) 2CH], 2.18 [m, 6. (CH3) 2ÇH), 3.94 (d, 1, J = 8 Hz, Br— ( ^ H - C—), and 5.11 ppm (s, 2, ArCH20—).

O

IR (film) 1744 cm "1 (C = 0).

B. To 3 g (0.0083 mol) of m-phenoxybenzyl α-bromo-isovalerate in 6 ml of hexamethylphosphoric triamide (HMPT) at 24 "C, 0.0248 mol of aniline was added, then an amount potassium iodide catalyst (28 mg) The reaction mixture was heated at 65 ° C for about 90 h, then poured into 35 ml of an ice-water mixture and extracted with 3 times 50 ml of The combined extracts were washed with ether, with 2N sulfuric acid, then with

2 times 50 ml of water until neutral and with brine before drying over calcium sulphate. The product was concentrated in vacuo and isolated by preparative thin layer chromatography. The m-phenoxybenzyl ester of N-phenylvaline was obtained, the characteristics of which are as follows:

NMR (CDC13) S 1.00 [m, 6, (ÇH3) 2CH], 2.07 [m, 1, (CH3) 2-CH], 3.95 [m, 1, ^ N — CH — C02— ], 4.00 (m, 1, NH), and 5.13 ppm (s, 2, ArCH, Q). IR (film) 3400 cm-1 (s) (NH) and 1738 cm "1 (C = 0). Example 2:

0.25 g of N-phenylvaline m-phenoxybenzyl ester in

1 ml of HMPT and 1 ml of tetrahydrofuran, at 24 ° C., 0.12 ml of methyl iodide was added, then 0.092 g of potassium carbonate. The reaction mixture was heated at 60 ° C for 4 d. The reaction mixture was poured into a water-ice mixture (5 ml) and extracted with

3 times 10 ml of ether. The combined extracts were washed with ether with

2 times 10 ml of water and with 1 time 5 ml of brine, and dried over calcium sulphate. The product was isolated and purified by preparative thin layer chromatography to obtain the m-phenoxybenzyl ester of N-phenyl-N-methylvaline.

NMR (CDC13) S 0.92 [m, 6, (CH3) 2CH], 2.3 [m, 1, (CH,), - CH |,

..VAf

2.88 (s, 3, CH3N), 3.96 (d,

X

_H — C02), and 5.08 ppm (s, 2,

ArCH20). IR (film) 1740 cm "1 (C = 0).

Example 3:

A. To 11.7 g (0.10 mol) of valine in 40 ml of 88% formic acid, 26.3 g (0.30 mol) was added over 0.5 h at 5 ° C. formyl acetic anhydride. The reaction mixture was heated to 24 ° C and stirred for 17 h. The solvent, anhydride and excess acetic acid were separated from the reaction mixture by distillation (bath temperature 45-50 ° C), in order to obtain a white solid, N-formyl-valine, which recrystallized from hot ethanol, mp: 143-145 ° C.

B. To 8 g (0.055 mol) of product A in 55 ml of HMPT, 14.4 g (0.055 mol) of m-phenoxybenzyl bromide was added, then 7.6 g (0.055 mol) of potassium carbonate anhydrous. The reaction mixture was stirred at 24 ° C for 48 h and poured into 250 ml of a water-ice mixture, then extracted with 3 times 100 ml of ether. The combined extracts were washed with ether with 2 times 100 ml of water and 1 time 25 ml of brine and dried over calcium sulphate before evaporating in vacuo to obtain the m-phenoxybenzyl ester of N-formyl-valine.

I

C. To 26 g (0.0835 mol) of ester of B in 84 ml of anhydrous methanol, 92 ml (0.092 mol) of IN methanolic HCL were added. The reaction mixture was stirred at 24 ° C for 18 h and the methanol was distilled off in vacuo. We poured the residue into

200 ml of a water-ice mixture, then remove the neutral impurities with ether. The aqueous layer was made basic by the addition of 10% sodium bicarbonate and extracted with 3 times 200 ml of ether. The extracts were combined with ether and washed with twice 200 ml of water until neutral, then with 100 ml of brine before drying over calcium sulphate, filter and evaporate on a rotary evaporator to obtain 1 m-phenoxybenzyl ester of valine, the characteristics of which are as follows:

NMR (CDC13) S 0.91 [m, 6, (CH3) 2CH], 1.37 (bs, 2, NH2),

2.00 [m, 1, (CH3) 2CH], 3.31 (d, l ^ N- ^ H-C-) and 5.17 ppm (s, 2,

'O

ArCH20—). IR (film) ~ 3400 cm "1 (NH2), 1740 cm-1 (C = 0).

632232

6

Example 4:

To 5 g (0.0138 mol) of m-phenoxybenzyl α-bromo-isovalerate in 9 ml of HMPT at 24 ° C., 5.27 g (0.0413 mol) of p-chloroaniline and an amount were added. potassium iodide catalytic (60 mg). The reaction mixture was stirred at 70 ° C for 4 d. The reaction mixture was then poured into 30 ml of a water-ice mixture and 10 ml of 2N sulfuric acid and extracted with 3 times 30 ml of ether. The ethereal extracts were combined and washed with twice 30 ml of water and once with 10 ml of brine, dried over calcium sulphate, filtered and evaporated. The crude product was purified by preparative thin layer chromatography in order to obtain the m-phenoxy-benzyl ester of N- (p-chlorophenyl) valine, the characteristics of which are as follows:

NMR (CDC13) S 0.99 [m, 6, (CH3) 2CH], 2.03 [m, 1, (CH3) 2CH], 15 3.93 (m, 2, NH and ^ N- ^ H -

IR (film) 3410 cm "1 (s) (NH), and 1740 cm" 1 - (C = 0).

-C02), and 5.10 ppm (s, 2, ArCH20—).

-C02), and 5.10 ppm

4.06 (d, 1, J = 8 Hz, Br-CH-C-), and 6.41 ppm [s, 1,

O

ArCH (CN) 0]. IR (film) 1762 cm-1 (C = O).

B. To 2.0 g (0.0052 mol) of m-phenoxy-a-cyanobenzyl a-bromo-isovalerate in 4 ml of HMPT at 24 ° C., 1.5 g of aniline (0.016) were added mol) and 21 mg potassium iodide. The reaction mixture was stirred at 65 ° C for 90 h, then cooled and poured into 20 ml of an ice-water mixture and 10 ml of 2N sulfuric acid. The reaction mixture was treated according to the method described in Example 4 and purified by preparative thin layer chromatography in order to obtain the m-phenoxy-a-cyanobenzyl ester of N-phenylvaline, the characteristics of which are as follows :

NMR (CDCI3) 8 1.02 [m, 6, (CH3) 2CH], 2.10 [m, 1, (CH3) 2CH],

tNsr-èi

4.0 (m, 2, —NHet

/

-H — C02), and 6.33 ppm [s, 1,

20

Example 5:

To 2 g (0.0055 mol) of m-phenoxybenzyl α-bromo-isovalerate in 4 ml of HMPT at 24 ° C. was added 1.77 g (0.0165 mol) of toluidine and 25 ml of iodide potassium. The reaction mixture was stirred at 60 ° C for 5 d, cooled and poured into 20 ml of a water-ice mixture and 10 ml of 2N sulfuric acid. The reaction mixture was treated according to the process described in Example 4, in order to obtain the m-phenoxybenzyl ester of N- (p-methylphenyl) -valine, the characteristics of which are as follows:

NMR (CDCI3) S 0.99 [m, 6, (CH3) 2CH], 2.20 [s, 3, CH3 - Ar), 3.90 (m, 2, NH and ^ N-èlî — C02) , and 5.11 ppm (s, 2, ArCH20).

IR (film) 3400 cm "1 (s) (NH), and 1740 cm" 1 (C = 0).

The above method was applied, replacing toluidine with anisidine, in order to obtain the m-phenoxybenzyl ester of N- (p-methoxyphenyl) valine, the characteristics of which are given below:

NMR (CDCI3) S 0.98 [m, 6, (CH3) 2CH], 2.03 [m, 1, (CH3) 2CH], 40 3.73 (s, 3, OCH3), 3.77 (m , 2, NH and ^ N-èlI

(s, 2, ArCH20—). IR (film) 3400 cm-1 (s) (NH), and 1740 cm "1 (C = 0).

Example 6:

A. To 5.18 g (0.0286 mol) of α-bromo-isovaleric acid in 30 ml of ether cooled to 10 ° C., 1.3 ml of dimethylformamide (DMF) was added, then, more slowly, 3 ml (0.0429 mol) of thionyl chloride. After 1 h at 24 ° C, the acid chloride was isolated in quantitative yield by decanting the upper ether layer and removing the solvent and excess thionyl chloride by vacuum distillation.

To 5.7 g (0.0286 mol) of the acid chloride in 30 ml of ether at 10 ° C., 5.38 g of m-phenoxybenzaldehyde cyanohydrin (0.0257 mol) was added, then, more slowly, 4.6 ml of pyridine in 10 min. The reaction mixture was stirred at 24 ° C for 17 h and a trace of water was added to destroy the excess acid chloride. The reaction mixture was poured into 50 ml of a water-ice mixture and 30 ml of 2N sulfuric acid and extracted with 3 times 30 ml of ether. The ethereal extracts were pooled and washed with 10 ml of 10% sodium bicarbonate, 2 times 50 ml of water and 10 ml of brine, dried over calcium sulfate and evaporated to obtain a -bromo-isovalerate of m-phenoxy-a-cyanobenzyl, the characteristics of which are as follows:

NMR (CDCI3) S 1.05 [m, 6, (CH3) 2CH], 2.23 [m, 1, (CH3) 2CH],

ArCH (CN) 0]. IR (film) 3400 cm "1 (s) (NH), 2260 cm" 1 (w) (C = N), 1758 cm "1 (C = 0).

Example 7;

According to the method of Example 5, each of the compounds of column I was reacted with the m-phenoxybenzyl α-bromo-isovalerate in order to obtain the respective esters listed in column II.

Column I

3,4,5-trimethoxyaniline 4-phenetidine 2,4-dimethoxyaniline 3,5-dimethoxyaniline

2-anisidine 4-ethxlaniline

2,4,6-trimethxlaniline

4-nitroaniline

2,4,6-trichloroaniline

4-fluoroaniline

4-bromoaniline

3-chloro-2-methoxyaniline

2-chloro-4-methxlaniline 2,6-dichloroaniline

4-chloro-2-nitroaniline

2,6-dichloro-4-nitroaniline 4-aminoacetophenone

3-aminobenzonitrile 2-aminobenzonitrile 2,6-dimethylaniline 2,5-dimethylaniline

, Column II

The m-phenoxybenzyl esters of: la- (3,4,5-trimethoxyphenyl) valine N- (4-ethoxyphenyl) valine la N- (2,4-dimethoxyphenyl) valine la N- (3,5-dimethoxyphenyl) valine N- (2-methoxyphenyl) valine N- (4-ethylphenyl) valine N- (2,4,6-trimethylphenyl) valine N- (4-nitrophenyl) valine 1 N- (2,4, 6-trichlorophenyl) valine N- (4-fluorophenyl) valine N- (4-bromophenyl) valine laN- (3-chloro-2-methoxyphenyl) valine laN- (2-chloro-4-methylphenyl) valine 'N - (2,6-dichlorophenyl) valine laN- (4-chloro-2-nitrophenyl) valine laN- (2,6-dichloro-4-nitrophenyl) valine laN- (4-methylcarbonylphenyl) valine

7

632232

N- (3-cyanophenyl) valine N- (2-cyanophenyl) valine N- (2,6-dimethylphenyl) valine N- (2,5-dimethylphenyl) valine

Example 8:

According to the method of Example 1, the œ-bromo-isovaleric acid was reacted in the form of its acid chloride with the alcohols listed in column III, in order to obtain the respective esters of column IV .

Column 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 alcohol -ethynylfurfuryl alcohol 5-benzyl-2-methyl-3-furylmethyl

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.

Column IV

p-phenoxybenzyl a-bromo-isovalerate a-m-benzylbenzyl a-bromo-isovalerate p-propargylbenzyl a-bromo-isovalerate 4-allyl-2,6-dimethylbenzyl a-bromo-isovalerate a-bromo-isovalerate 2,6-dimethyl-4-propargylbenzyl 2-bromo-3-trifluoromethylbenzyl a-bromo-5-benzyl-3-fury allylbenzyl a-bromo-isovalerate a-bromo-isovalerate 2-bromo-isovalerate cyano-5-benzyl-3-furylmethyl a-bromo-5-propargylfurfuryl a-bromo-2-methyl-5-propargyl-3-furylmethyl a-bromo-isovalerate a-5-propargyl-a-ethynylfurfuryl a- 5-benzyl-2-methyl-3-furylmethyl bromo-isovalerate a-2-methyl-3-propargyl-4-oxo-2-cyclopentene bromo-isovalerate

3-allyl-2-methyl-4-oxo-2-cyclopentene-1-yl a-bromo-isovalerate-3-allyl-2-methyl-4-oxo-2-cyclopentene-1-yl

3,4,5,6-tetrahydrophthalimidomethyl 2-bromo-isovalerate phthalimidomethyl a-bromo-isovalerate 4-phenyl-3-chloro-2-butene-1-yl a-bromo-isovalerate -propargyl-2-thiophenemethyl a-bromo-5-benzyl-2-thiophenemethyl a-bromo-5-benzyl-3-thiophenemethyl a-bromo-isovalerate

Example 9:

Each intermediate α-bromoester listed in column IV was reacted with 4-chloroaniline according to the above process, for example according to the procedures of Examples 1,4 or 5, in order to obtain the respective esters of the N- (4-chlorophenyl) valine listed in column V.

Column 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 ester N- (4-chlorophenyl) valine dimethylbenzyl ester p- allylbenzyl N- (4-chlorophenyl) valine ester 2,6- dimethyl-4-propargylbenzyl ester of N- (4-

chlorophenyl) valine a-ethynyl-3-trifluoromethylbenzyl ester of N- (4-chloro-phenyl) valine ester 5-benzyl-3-furylmethyl of N- (4-chlorophenyl) valine ester a-cyano-5-benzyl- N- (4-chlorophenyl) -valine 3-furylmethyl N-(4-chlorophenyl) valine 5-propargylfurfuryl ester 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 ester -4-oxo-2-cyclopentene-1-yl of N- (4-chlorophenyl) valine ester 3-allyl-2-methyl-4-oxo-2-cyclopentene-1-yl of N- (4-chlorophenyl ) valine ester 3-benzyl-4-oxo-2-cyclopentene-l-ylique from N- (4-chloro-phenyl) valine ester 3,4,5,6-tetrahydrophthalimidomethyl from N- (4-chloro-phenyl ) phthalimidomethyl valine ester of N- (4-chlorophenyl) valine ester 4-phenyl-3-chloro-2-butene-1-ylique of N- (4-chlorophenyl) -

5- propargyl-2-thiophenemethyl ester of N- (4-chlorophenyl) -valine 5-benzyl-2-thiophenemethyl ester of N- (4-chlorophenyl) 5-benzyl-3-thiophenemethyl ester of N- (4-chlorophenyl) valine

Example 10:

According to the method described in Example 5, each amino compound listed in column VI was reacted with the m-phenoxybenzyl α-bromoiso-valerate to obtain the respective N-substituted esters listed in column VII.

Column 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

5

io

15

20

25

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3,4-methylenedioxyaniline 3,4-dimethoxyaniline 2,6-difluoroaniline 3,4-dichloroaniline

Column VII

M-Phenoxybenzyl esters of the following compounds: N- (2-chloro-6-methylphenyl) valine, N- (4-chloro-2-methylphenyl) valine N- (4-chloro-3-trifluoromethylphenyl) valine N- ( 2-choro-5-trifluoromethylphenyl) valine N- (2-trifluoromethylphenyl) valine N- (3-trifluoromethylphenyl) valine N- (3,5-dichloro-4-hydroxyphenyl) valine N- (4-chloro-3-nitrophenyl) vaiine N- (2,3-dichlorophenyl) vaIine N- (2-fluorophenyl) valine N- (2,6-diiodo-4-nitrophenyl) valine N- (3,4,5-trichlorophenyl) valine N- (4- ethoxycarbonylphenyl) vaiin 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) vaIine

Example 11:

The α-haloacid chlorides listed in column VIII were reacted with the m-phenoxybenzyl alcohol, in order to prepare the respective α-haloesters from column IX, according to the methods described above, as in example 1.

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 chloride 4-trichloromethylbutanoyl

Column IX

3-phenoxybenzyl 2-bromo-3-methylpentanoate 2-bromo-4-methylpentanoate 3-phenoxybenzyl 2-bromobutanoate 3-phenoxybenzyl 2-bromohexanoate 3-phenoxybenzyl 2-bromo-3-chloropropionate 2, 3-phenoxybenzyl 2,4-dichloropentanoate 2,4,4,4-3-phenoxybenzyl tetrachlorobutanoate

According to the methods described above, such as in Example 4, 4-chloroaniline was reacted with each α-haloester ester listed in column IX in order to obtain the respective substituted amino esters of column X.

Column 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 ester 3-phenoxybenzyl ester 2- (4-chlorophenylamino) -hexanoic acid 3-phenoxybenzylic ester of 2- (4-chlorophenylamino) -3-chloropropionic acid 3-phenoxybenzylic ester of 2- (4-chlorophenylamino) acid -5- chloropentanoic 3-phenoxybenzylic ester of 2- (4-chlorophenylamino) -4,4,4-trichloronutanoic acid

10 Example 12:

To 2 g (0.0067 mol) of m-methoxybenzyl ester of valine in 30 ml of methanol, concentrated sulfuric acid was added to obtain a pH of approximately 6. Then 0.6 g (0.006 mol) of cyclohexanone, 3A molecular sieves and 0.25 g of sodium cyanoborohydride (0.004 mol) were added. Sulfuric acid was added again to maintain the pH at about 6. After approximately 24 h, the methanol was removed by rotoevaporation, the residue poured into water and 10% sodium carbonate, then extracted with ether. The ethereal extracts were pooled and the product which was isolated was filtered and concentrated by preparative thin layer chromatography (10% ether / hexane) to obtain the m-phenoxybenzyl ester of N-cyclohexylvaline with the following characteristics:

NMR (CDCy S 0.89 [m, 6, J - 7 Hz, (CH3) 2CH], 2.26 [m, 1.25 (CH3) 2CH], 3.12 (m, l, ^ N- ( i: H-Ç-), and 5.15 ppm (s, ArCHzO).

O

IR (film) 1736 cm "1 (C = 0).

30 Example 13:

Each substituted arylamine listed in column XI was reacted with m-phenoxybenzyl 2-bromo-isovalerate, using the method of Example 4, to prepare the respective N-substituted compounds listed in column XII.

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Column XI

2,4-dichloroaniline

3-methoxyaniline

3.4-dimethylaniline

40 2,3,5,6-tetrachloroaniline 3-methylaniline

3.5-dichloroaniline 3-acetoaniline 2-acetoaniline

45 2-methylaniline

Column XII

M-Phenoxybenzyl esters of the following compounds: N- (2,4-dichlorophenyl) valine n / a 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 ss N- (3-acetophenyl) valine N- (2-acetophenyl) valine N- (2-methylphenyl) valine

Example 14:

"O According to the method of Example 1, each alcohol listed in column XIII was reacted with the acid chloride of α-bromo-isovaleric acid, in order to obtain the respective esters listed in column XIV .

65 Column XIII

3- (2,2-dichlorovinyloxy) benzyl alcohol 3- (o-fluorophenoxy) benzyl alcohol 4-phenyl-2-butenyl alcohol

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4- (4-methylphenoxy) -2-butynyl alcohol 4- (4-methylphenyl) -2-butenyl alcohol 3-phenylcarbonylbenzyl alcohol 1-ethynyl-2-methyl-2,5-hexadiene-1 -yl alcohol 1-ethynyl alcohol -2-methyl-2-pentene-1 -ylic alcohol 1 -ethyl ny l-2-methyl-3-phenyl-2-propene-1 -ylic alcohol l-ethynyl-3-phenyl-2-propene-l-ylique 2,4,6-trimethylbenzyl alcohol

Column XIV

3- (2,2-dichlorovinyloxy) benzyl a-bromo-isovalerate 3- (o-fluorophenoxy) benzyl a-bromo-isovalerate 4-phenyl-2-butenyl a-bromo-isovalerate 4 - 4- (4-methylphenyl) -2-butenyl a-bromo-iso-3-phenylcarbonylbenzyl a-bromo-isovalerate of 2-methyl-2-methylphenyl) -2-butynyl a-bromo-isovalerate -2,5-hexadienyl a-bromo-isovalerate of a-ethynyl-a-methyl-2-pentenylea-bromo-iso-valerate of a-ethynyl-2-methyl-3-phenyl-2-propenyl a-bromo- 2,4,6-trimethylbenzyl α-ethynyl-2-phenyl-2-propenyl isovalerate isovalerate

According to the above methods, such as in Example 5, p-methylaniline was reacted with each a-bromoester from column XIV, in order to obtain the respective esters of N- (p-methylphenyl) - valine from column XV.

Column XV

N- (p-methylphenyl) -valine 3- (2,2-dichlorovinyloxy) benzyl ester N- (p-methylphenyl) valine 3- (o-fluorophenoxy) benzyl ester 4-phenyl-2-butenyl ester 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-methyl-phenyl) valine ester a-ethynyl- N- (p-methylphenyl) -valine 2-methyl-2-pentenyl N- (p-methyl-phenyl) valine a-ethynyl ester a-ethynyl-2-methyl-3-phenyl-2-propenyl ester -3-phenyl-2-propenyl of N- (p-methylphenyl) -valine 2,4,6-trimethylbenzyl ester of N- (p-methylphenyl) valine Example 15:

Each α-haloester in column IX above was reacted with p-methylaniline to obtain the 3-phenoxy-benzyl esters of p-methylphenylamino acid from column XVI using the method of example 5.

3-phenoxybenzyl ester of N- (p-methylphenyl) isoleucine 3-phenoxybenzyl ester of N- (p-methylphenyl) leucine 3-phenoxybenzyl ester of 2- (p-methylphenylamino) -butanoic ester 3-phenoxybenzyl ester 2- (p-methylphenylamino) -hexanoic acid 3-phenoxybenzylic ester 2- (p-methylphenylamino-3-chloropropionic ester 3-phenoxybenzylic acid 2- (p-methylphenylamino) -5-chloropentanoic ester 2- (p-methylphenylamino) -4,4,4-trichlorobutanoic acid 3-phenoxybenzylic acid

Example 16:

Each α-bromoester listed in column IV was reacted with p-methylaniline using the method of Example 5, to respectively obtain the N- (p-methylphenyl) valine esters of column XVII.

Column 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 ester 4-allyl-2,6 -dimethylbenzyl of N- (p-methylphenyl) valine p-allylbenzyl ester of N- (p-methylphenyl) valine ester 2,6-dimethyl-4-propargylbenzyl of N- (p-methylphenyl) -

valine a-ethynyl-3-trifluoromethylbenzyl ester of N- (p-methyl-phenyl) valine ester 5-benzyl-3-furylmethyl of N- (p-methylphenyl) valine ester a-cyano-5-benzyl-3- N- (p-methylphenyl) -valine furylmethyl 5-propargylfurfuryl ester of N- (p-methylphenyl) valine 2-methyl-5-propargyl-3-furylmethyl ester of N- (p-methylphenyl) valine ester 5 -propargyl-a-ethynylfurfuryl of N- (p-methylphenyl) -valine ester 5-benzyl-2-methyl-3-furylmethyl of N- (p-methylphenyl) -valine ester 2-methyl-3-propargyl -oxo-2-cyclopentene-l-ylique of N- (p-methylphenyl) valine ester 3-allyl-2-methyl-4-oxo-2-cyclopentene-l-ylique of N- (p-methylphenyl) valine N- (p-methyl-phenyl) valine 3-benzyl-4-oxo-2-cyclopentene-l-yl ester 3,4,5,6-tetrahydrophthalipiidomethyl ester of N- (p-methyl-phenyl) 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 Np-methylphenyl) -valine ester 5-benzyl-2-thiophenemethyl of N- (p-methylphenyl) -valine ester 5-benzyl-3-thiophenemethyl of N- (p -methylphenyl) -valine

Example 17:

A. 2 g of α-bromo-isovaleric acid (0.011 mol) were titrated

dissolved in 10 ml of methanol with a 2N sodium hydroxide / methanol mixture at 0 ° C in the presence of phenolphthalein. The alcohol was then removed and 10 ml of dimethylformamide and 3.54 g (0.022 mol) of p-trifluoromethylaniline were added. The reaction mixture was heated to 100 ° C for 2 h and left at room temperature for 18 h. The reaction mixture was poured into 50 ml of 0.1 N sodium hydroxide, washed with ether and the aqueous phase was adjusted to pH 4 with concentrated HCl, then extracted 3 times with chloroform. The extracts were combined and washed with brine, dried, concentrated in a rotary evaporator and the solvent was removed in vacuo at around 50 ° C., in order to obtain the N- (p-trifluoromethylphenyl) valine.

B. A mixture of 1.84 g of acid A (0.0071 mol) and 1.95 g of potassium carbonate in 10 ml of dry dimethylformamide was stirred at room temperature under a nitrogen atmosphere, for 0.5 h, then 1.85 g (0.0071 mol) of m-phenoxybenzyl bromide was added at 0 ° C. The mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was poured into a water-ice mixture and extracted 3 times with ether. The ethereal extracts were combined and washed with water and brine, dried over calcium sulfate and evaporated in vacuo to obtain the m-phenoxybenzyl ester of N- (p-trifluoromethylphenyl) valine. Mass spectrum m / e 443 (M +, 5.9).

Example 18:

To a solution of 2 g (0.110 mol) of α-bromo-isovaleric acid and

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5 ml of methanol, one drop of phenolphthalein and enough sodium hydroxide in methanol was added to obtain a neutral pH. The solvent was distilled off and 7 g (0.055 mol) of p-chloroaniline was added. The mixture was melted in a water bath at 100 ° C and stirred at 100 ° C for 3 h. The mixture was cooled and taken up in ether, then adding a 10% aqueous sodium hydroxide solution. The aqueous phase was acidified to pH 4 and extracted with ether. The ethereal extracts were pooled and washed with brine, dried over sodium sulfate and distilled to obtain N- (p-chlorophenyl) valine.

According to the method of Example 1, part A, the N- (p-chlorophenyl) valine was converted to the acid chloride and it was reacted with m-phenoxybenzyl alcohol, in order to obtain 1 m-phenoxybenzyl ester of N- (p-chlorophenyl) valine.

Example 19:

According to the method of Example 17, 0.79 g of N- (2-fluoro-4-chlorophenyl) valine was reacted with 0.39 g of a-ethynyl-m-phenoxybenzyl bromide, in order to obtain the a-ethynyl-m-phenoxybenzyl ester of N- (2-fluoro-4-chlorophenyl) valine [mass spectrum m / e 451 (M +)]. N- (2-fluoro-4-chloro-phenyl) valine was prepared from 2- (fluoro-4-chloroaniline and α-bromo-isovaleric acid according to the method of Example 17.

Example 20:

According to the method of Example 5, the m-phenoxybenzyl α-bromo-isovalerate was reacted with each substituted phenylamine from column XVIII, in order to prepare the respective N-substituted valines from column XIX.

Column 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

Column XIX

M-Phenoxybenzyl esters of the following compounds: N- (4-chloro-3-methylphenyl) vaIine 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) saline N- (4-nitro-3-trifluoromethylphenyl) valine N- (3,5-ditrifluoromethylphenyl) valine

Example 21:

According to the process of Example 1, the m- (p-chlorophenoxy) benzyl, m- (p-methylphenoxy) benzyl and m- (m-trifluoromethylphenoxy) benzyl alcohols were reacted with the chloride of the acid a- bromo-isovalérique so as to obtain:

m- (p-chlorophenoxy) benzyl a-bromo-isovalerate, m- (p-methylphenoxy) benzyl a-bromo-isovalerate, and m- (m-trifluoromethylphenoxy) a-bromo-isovalerate benzyl.

Each of the above a-bromoesters was reacted with p-methylaniline to obtain:

the m- (p-chlorophenoxy) benzyl ester of N- (p-methylphenyl) valine,

the m- (p-methylphenoxy) benzyl ester of N- (p-methylphenyl) -valine, and the m- (m-trifluoromethylphenoxy) benzyl ester of N- (p-methyl-phenyl) valine.

Example 22:

To 2 g of m-phenoxybenzyl α-bromo-isovalerate (0.0055 mol) at 24 ° C., 3.33 g (0.0275 mol) of 2,6-dimethylaniline were added, followed by an analytical amount of '' potassium iodide (20 mg). The reaction mixture was heated to about 120 ° C for 48 h, then poured into 20 ml of water-ice mixture and 10 ml of 2N sulfuric acid before extracting with 3 times 30 ml of ether. The ethereal extracts were combined and washed with twice 20 ml of water until neutral and with 10 ml of brine, then dried over calcium sulphate. The reaction product was concentrated in vacuo and isolated by preparative thin layer chromatography to obtain the m-phenoxybenzyl ester of N- (2,6-dimethylphenyl) valine. Mass spectrum m / e 403.2 (M +, 7.5).

Example 23:

To 2 g (0.0055 mol) of m-phenoxybenzyl α-bromo-isovalerate, 2.95 g (0.0275 mol) of 2-methylaniline were added at 24 ° C., followed by an analytical amount of potassium iodide (20 mg). The reaction mixture was heated to 110-115 ° C for about 36 h, and poured into 30 ml of an ice-water mixture and 10 ml of 2N sulfuric acid before being extracted with 3 times 30 ml of ether. The ethereal extracts were combined and washed with twice 30 ml of water until neutral and with 10 ml of brine, then dried over calcium sulphate. The reaction product was concentrated in vacuo and isolated by preparative thin layer chromatography to obtain the 3-phenoxybenzyl ester of N- (2-methylphenyl) valine. Mass spectrum m / e 389.2 (M +).

Example 24:

To 1.2 g (0.00603 mol) of α-bromo-isovaleric acid in 2 ml of methanol at 5 ° C., sodium hydroxide in methanol was added dropwise until the phenolphthalein. The sodium salt of the acid was isolated in vacuo and added to it 3.65 g (0.03015 mol) of 2,6-dimethylaniline, then the suspension was heated in a pressure reactor to about 150 ° C for 12 h. After cooling, 20 ml of water was added to the reaction mixture and the excess 2,6-dimethylaniline was extracted 3 times with 20 ml of ether (3 times 20 ml). The aqueous basic layer was acidified with 2N sulfuric acid to about pH 4 and the N- (2,6-dimethylphenyl) valine was extracted with 3 times 20 ml of ether. The ethereal layers were combined, washed with water (2 times 20 ml) until neutral and 10 ml of brine and dried over calcium sulfate. N- (2,6-dimethylphenyl) valine was isolated by concentration in vacuo.

1.27 g was added to 1.07 g (0.00486 mol) of N- (2,6-dimethylphenyl) valine in THF (tetrahydrofuran) / HMPT (3 ml: 3 ml) at 24 ° C. 0.00486 mol) of m-phenoxybenzyl bromide and 0.670 g (0.00486 mol) of potassium carbonate, and the suspension was stirred at 24 ° C for 16 h. The product was isolated by pouring the reaction mixture into a water-ice mixture (20 ml) and extracted 3 times with 20 ml of ether. The ethereal extracts were combined, washed with water (2 times 20 ml), then with 10 ml of brine and dried over calcium sulfate. The reaction product was concentrated in vacuo and purified by preparative thin layer chromatography to obtain the m-phenoxybenzyl ester of N- (2,6-dimethylphenyl) valine. Mass spectrum m / e 403.2 (M +).

Example 25:

According to the method of Example 17 or 24, 3-fluoro-4-methylaniline was reacted with a-bromo-isovaleric acid, in order to prepare the N- (3-fluoro-4-methylphenyl) valine which then reacted with α-ethynyl-m-phenoxybenzyl bromide to obtain the α- ethynyl-m-phenoxybenzyl ester of N- (3-fluoro-4-methyl-phenyl) valine. Mass spectrum m / e 431 (M +).

N- (2-fluoro-4-methylphenyl) valine was prepared from α-bromo-isovaleric acid and 2-fluoro-4-methylaniline and reacted with α-ethynyl bromide -m-phenoxybenzyl, so

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to obtain the α-ethynyl-m-phenoxybenzyl ester of N- (2-fluoro-4-methylphenyl) valine. Mass spectrum m / e 431 (M +, 180).

Example 26:

To 1.57 g of m-phenoxybenzyl ester of N- (p-trifluoro-methylphenyl) valine in approximately 15 ml of benzene, with stirring and under nitrogen, 0.53 g of N-chlorosuccinimide was added. The reaction mixture was heated under reflux for about 2 h. The reaction was cooled and partitioned with ether and water. The aqueous layer was again extracted with ether. The ethereal extracts were pooled, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The reaction product was applied to thin layer chromatography plates and eluted with an ether / hexane mixture at 10% ether to obtain the m-phenoxybenzyl ester of N- (2-chloro-4 -trifluoromethylphenyl) -valine, mass spectrum m / e 477.1 (M +).

According to the above process, the m- phenoxy-a-cyanobenzyl ester of N- (2-chloro-4-trifluoromethylphenyl) valine, mass spectrum m / e 486.3 (M +), was prepared from of the m-phenoxy-a-cyanobenzyl ester of N- (p-trifluoromethylphenyl) valine.

Example 27:

To 0.1 mol of N-phenylvaline hydrochloride in an ether / THF mixture at 5 ° C., 0.06 mol of dimethylformamide was added, then, drop by drop, 0.15 mol of thionyl chloride. The reaction mixture was stirred at 24 ° C for 2.5 h. The hydrochloride of the acid chloride was isolated and then, in a THF / ether mixture at 5 ° C., 0.09 mol of "-cyano-3-phenoxybenzyl alcohol" was added and then slowly 0.3 mol of pyridine. The reaction mixture was stirred at 24 ° C for 17 h and the product was treated according to the method of Example 6 to obtain the 3-phenoxy-α-cyano-benzyl ester of N-phenylvaline.

Example 28:

Acid is bubbled through a mixture of 1.0 g of the m-phenoxybenzyl ester of N- (p-methylphenyl) valine and 10 ml of ether, stirred and cooled in an ice bath. gaseous hydrochloric acid for approximately 15 min. The reaction product was filtered, washed with ether and recrystallized from hot ethanol, in order to obtain the hydrochloric acid salt of the m-phenoxybenzyl ester of N- (p-methylphenyl ) valine, m .: 151-153 ° C.

According to the method of Example 6, 2-fluoro-4-trifluoromethylaniline was reacted with α-cyano-m-phenoxybenzyl α-bromo-isovalerate, in order to obtain the α-cyano- ester. N-(2-fluoro-4-trifluoromethylphenyl) valine m-phenoxybenzyl. Mass spectrum m / e 502.1 (M +).

Example 29:

To a solution of 15.8 g (0.1 mol) of ethyl 3,3-dimethyl-2-oxo-butyrate [Rabjohn et al., “J. Org. Chem. " 35.3726 (1970)], 12.7 g (0.1 mol) of p-chloroaniline and a catalytic amount (0.2 g) of p-toluenesulfonic acid were added. The solution was heated under reflux and the water was removed with a Dean-Stark trap. After 5 h of heating, the solution was poured into ether and this fraction was washed with solutions of saturated sodium bicarbonate and saturated brine, then dried over calcium sulfate. The solvent was removed by rotary evaporation in order to obtain the desired imine ester ^

To a solution of 13.4 g (0.05 mol) of imine ester in 100 ml of methanol at 10 ° C, an excess (2 g, 0.032 mol) of sodium cyanoborohydride was added in portions. The pH of the solution was maintained at around pH 6, during the course of the reduction, by adding concentrated sulfuric acid. After several hours, the reaction was stopped, most of the alcohol was removed by rotoevaporation and the residue poured into ether and water. The organic fraction was washed with saturated brine solution and dried over calcium sulfate. The solvent was removed by rotary evaporation to obtain ethyl 2- (p-chloro-phenylamino) -3,3-dimethylbutyrate.

Stirred at room temperature for 2 d of a solution of

2.7 g (0.01 mol) of the above ethyl amino ester and 0.4 g (0.01 mol) of sodium hydroxide in 17 ml of ethanol and 3 ml of water. The alcohol and water were removed by rotary evaporation under high vacuum and the sodium salt of 2- (p-chlorophenyl-amino) -3,3-dimethylbutyric acid was obtained. To the sodium salt, 50 ml of HMPT and 2.63 g (0.01 mol) of m-phenoxybenzyl bromide were added. After stirring overnight, the reaction mixture was poured into water and an ether / hexane mixture (1: 1). The organic phase was washed several times with water and dried over calcium sulfate. The solvent was removed by rotary evaporation, in order to obtain the 3-phenoxybenzylic ester of 2- (p-chlorophenylamino) -3,3-dimethylbutyric acid. Mass spectrum m / e 423 (M +).

The process of this example was repeated using 0.1 mol of ethyl 3,3,3-trifluoro-2-oxopropionate instead of ethyl 3,3-dimethyl-2-oxobutyrate, in order to obtain as final product 2- (p-chlorophenylamino) -3,3,3-trifluoropropionic acid 3-phenoxybenzyl ester.

Example 30:

N- (4-chlorophenyl) valine was reacted with m-phenoxy-a-methylbenzyl bromide in a THF / HMPT mixture and potassium carbonate to obtain the m-phenoxy-a-methyl ester -benzyl of N- (4-chlorophenyl) valine. Mass spectrum m / e 423 (M +). The m-phenoxy-a-methylbenzyl bromide was prepared from the m-phenoxybenzaldehyde by reaction with methyllithium, in order to obtain the secondary alcohol which was brominated by means of phosphorous tribromide.

Example 31:

A mixture of 10 g of 4-fluoronitrobenzene, 5 g of valine and 10 g of sodium bicarbonate was dissolved in 200 ml of ethanol and 100 ml of water. The reaction mixture was brought to reflux for 3 h, then cooled. The excess 4-fluoronitrobenzene was removed by ether extraction and the aqueous phase was acidified to pH 3-4 with hydrochloric acid. The oily precipitate was extracted with methylene chloride. After drying and removing the solvent, the residue was treated with 3 equivalents of sodium carbonate and 1 equivalent of m-phenoxybenzyl bromide in dimethylformamide as solvent. After stirring for 24 h, the mixture was diluted with water and extracted with ether. The organic phase was washed with water, dried and the solvent removed. The crude ester was purified by preparative thin layer chromatography to obtain 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 anhydrous dimethylformamide was added 2.76 g of anhydrous potassium carbonate and 1.04 g of 3,3-dimethyl-2-propenyl chloride. The mixture was stirred overnight at room temperature, then diluted with water and extracted with ether. The ethereal extracts were pooled, washed with water, dried over magnesium sulfate and the ether was evaporated to obtain 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, was 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 butyllithium) while maintaining the temperature at approximately - 60 ° C. The reaction was allowed to reach a temperature of - 30 ° C, then added at - 30 ° C

1.08 g of trimethylsilyl chloride in 5 ml of THF and stirred for 20 min. It was then cooled to -78 ° C and added again

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1.03 g of lithium diisopropylamide in THF. The reaction mixture was stirred at -60 ° C for 30 min and 1.08 g of trimethylsilyl chloride was added at -60 ° C. After 1 h at -60 ° C, the reaction mixture was allowed to return to room temperature and, 1 hour later, it was heated under reflux for 30 min. The reaction mixture was cooled and poured into 10 ml of 2N sodium hydroxide. The mixture was stirred for 20 min at room temperature and extracted with ether. The aqueous phase was acidified to pH 3 to 4 and again extracted with ether. After combining the ethereal extracts, they were washed with water, dried and evaporated, in order to obtain 2-phenylamino-3,3-dimethyl-4-pentenoic acid which was esterified using bromide. m-phenoxybenzyl, according to the above methods, to obtain 2-phenylamino-3,3-dimethyl-4-pentenoate of m-phenoxy-benzyl [2-phenylamino-2- (2-methyl-3-butene-2 -yl) m-phenoxybenzyl acetate].

Example 33:

A solution of 2 g of α-bromoisovaleric acid and 10 ml of methanol at 0 ° C., in the presence of phenolphthalein, was titrated with a solution of sodium hydroxide in methanol. The solvent was then removed and 6 ml of dimethylformamide and 2.97 g of p-acetyl-aniline were added. The clear reaction mixture thus obtained was heated at 100 ° C for 3 h, then stirred overnight at room temperature. The reaction mixture was poured into 50 ml of 0.1N sodium hydroxide and extracted with ether. The aqueous phase was acidified to pH4 with concentrated hydrochloric acid and extracted 3 times with chloroform. The chloroform extracts were dried and concentrated. The concentrate was taken up in 0.1N sodium hydroxide and washed with ether. The aqueous phase was washed and treated as above, in order to obtain 1.0 g of N- (p-acetylphenyl) valine which was reacted with 1.05 g of m-phenoxybenzyl bromide in dimethylformamide and potassium carbonate, according to the methods described above,

in order to obtain the m-phenoxybenzyl ester of N- (p-acetylphenyl) -valine. Mass spectrum m / e 417.1 (M +).

According to this process, N- (p-cyanophenyl) valine was prepared from 0.011 mol of α-bromo-isovaleric acid and 0.022 mol of p-cyanoaniline. 0.01 mol of N- (p-cyano-phenyl) valine was then esterified with 0.01 mol of m-phenoxybenzyl bromide and 0.020 mol of potassium carbonate in dimethylformamide, in order to prepare the m-phenoxybenzyl ester N- (p-cyano-phenyl) valine. Mass spectrum m / e 400.1 (M +).

Example 34:

The process of Example 29 was repeated using 0.1 mol of ethyl 3,3,3-trichloro-2-oxopropionate instead of ethyl 3,3-dimethyl-2-oxo-butyrate, in order to to obtain as final product the 3-phenoxybenzyl ester of 2- (p-chlorophenylamino) -3,3,3-trichloropropionic acid.

Example 35:

After passing a stream of nitrogen through a 100 ml flask, 25 ml of a 1M solution in THF of lithium N-isopropylcyclohexylamide (0.025 mol), then 5 ml of HMPT, were introduced into the flask. The flask was cooled to -78 ° C and 7.1 g (0.025 mol) of m-phenoxybenzyl 3-methyl-2-butenoate in 25 ml of THF were added dropwise over 5 min. After the addition, the mixture was stirred at -20 ° C for 1 h. To this cold solution was added dropwise 1.1 equivalent of bromine in THF at -78 ° C. It was left for 1 h at -78 ° C and 5 ml of concentrated hydrochloric acid were added, the mixture left return to room temperature and poured into ether and aqueous hydrochloric acid. The ethereal layer was washed with water and brine, and dried over calcium sulfate. After removing the solvent, m-phenoxybenzyl 2-bromo-3-methyl-3-butenoate was obtained, which was reacted with p-methyl-aniline by the method of Example 5, in order to obtain the 2- (p-methylphenylamino) -3-methyl-3-butenoate m-phenoxybenzyl ester.

Example 36:

According to the method of Example 1, the m-phenoxybenzyl ester of α-bromo-isovaleric acid was reacted with 3 equivalents of 3,4-methylene-oxy-aniline at approximately 75 ° C. for approximately 14 h. , in order to obtain the m-phenoxybenzyl ester of N- (3,4-methylene-dioxyphenyl) valine. Mass spectrum m / e 419 (M +, 13.2), 192 (100).

According to the above process, the m- phenoxy-benzyl ester of N- (3-methoxyphenyl) valine was prepared, [mass spectrum m / e 405 (M +, 4.1), 178 (100)] , from m-anisidine.

Example 37:

A mixture of 1.17 mol of N-chlorosuccinimide, 1.23 mol of m-phenoxybenzyl ester of N- (p-methoxyphenyl) valine and 20 ml was heated under reflux, under nitrogen, for approximately 60 h. benzene. The reaction product was treated with water and ether. The ethereal layer was washed with water and brine, and dried over sodium sulfate. The crude product was purified by preparative thin layer chromatography eluting with a 15% ether / hexane mixture to give the m- phenoxybenzyl ester of N- (2-chloro-4-methoxyphenyl) valine. Mass spectrum m / e 439 (M +, 7.4), 212 (100).

Example 38:

A solution of 8.17 mmol of α-bromo-isovaleric acid in methanol was titrated with sodium methoxide in the presence of phenolphthalein. The solvent was removed by rotary evaporation, then 1.69 g of potassium carbonate, 16.38 mmol of 2-fluoro-4-methylaniline and 3 ml of HMPT were added. The reaction mixture was heated at 60 ° C for about 5 h and treated with 5% sodium hydroxide in ether and washed 3 times with water. The basic layer was acidified and extracted with ether, washed with water and brine, dried over sodium sulfate and evaporated in a rotary evaporator, in order to obtain the acid a- (2-fluoro- Isovaleric 4-methyl-phenylamino). (2-fluoro-4-methylaniline was prepared from 3-fluoro-4-nitrotoluene in a Parr flask with platinum oxide and hydrogen in ethanol.)

To a mixture of 5.15 mmol of a- (2-fluoro-4-methylphenyl-amino) isovaleric acid, 6.44 mmol of potassium carbonate, 4 ml of HMPT and 3 ml of THF, was added with stirring 5.13 mmol of m-phenoxybenzyl bromide. The reaction mixture was stirred overnight at room temperature. Then the mixture was poured into sodium hydroxide in 5% ether, extracted twice with water and then washed twice with water, dried over sodium sulfate and evaporated in an evaporator rotary vacuum. The crude product was purified by preparative thin layer chromatography eluting with a 10% ether / hexane mixture of ether to give the m- phenoxybenzyl ester of N- (2-fluoro-4-methyl- phenyl) valine.

NMR (CDC13) S 0.98 [d, 3, J - 7 Hz, CH (CH3) 2], 1.02 [d, 3,

5.13 ppm (s, 2, ArCH20). IR (such as) 1734 cm 1 (C = O).

According to the above process, the N- (4-tert.-butylphenyl) valine was reacted with the m-phenoxybenzyl bromide, to obtain the m-phenoxybenzyl ester of N- (4-tert.-butylphenyl). ) -valine.

NMR (CDCI3) 8 centered at 0.99 [d, 6, J = 7 Hz, (CH3) 2CH], 1.28 [s, 9, (CH3) 3C-Ar], 3.93 (m, 2, NH and HN-CH-C-),

O

and 5.11 ppm (s, 2, ArCH20). IR (film) 1743 cm-1 (C = 0).

The above process was used to prepare N- (3-chloro-4-fluorophenyl) valine and N- (3-fluoro-4-methylphenyl) valine, and each of these was reacted with bromide of m-phenoxy-

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benzyl, in order to obtain the m-phenoxybenzyl ester of N- (3-chloro-4-fluorophenyl) valine [mass spectrum m / e 427 (M +, 3.2), 200 (100)] and the m- phenoxybenzyl ester of N- (3-fluoro-4-methylphenyl) valine.

NMR (CDC13) 8 centered at 0.97 [d, 6, J = 7 Hz, CH (CH3) 2], 2.11 (d, 3, J = 2 Hz,> and 5'10 PPm <s'2 'ArCH20).

n ^ T ^ F

IR (such as) 1732 cm -1 (C = O).

Example 39:

A mixture of 5 g of p-trifluoromethylaniline, 2.25 g of α-bromo-isovaleric acid and 2.0 g of potassium carbonate was heated at 100 ° C for 1 h. After 1.5 h, 5 ml of HMPT was added and the mixture was heated at 100 ° C for 15 h. The reaction mixture was then poured into water and potassium carbonate was added to adjust the pH to about 11. The mixture was washed with ether and methylene chloride, and the aqueous phase was acidified to pH about 3, washed with ether and concentrated. The residue was recrystallized from hexane / ether, in order to obtain the N- (4-trifluoromethylphenyl) -valine which was reacted with m-phenoxybenzyl bromide, in order to obtain the m-phenoxybenzyl ester N- (4-trifluoromethyl-phenyl) valine. Mass spectrum m / e 443 (M +, 5.9).

The acidic N- (4-trifluoromethylphenyl) valine was reacted at room temperature in DMF / THF and potassium carbonate with m-phenoxy-a-ethynylbenzyl bromide to obtain the ester m -phenoxy-a-ethynylbenzyl of N- (4-trifluoromethylphenyl) valine. Mass spectrum m / e 467 (M +, 1.3), 216 (100).

The acidic N- (4-fluorophenyl) valine was prepared as above from 4-fluoroaniline and α-bromo-isovaleric acid and subsequently reacted with m-phenoxybenzyl bromide, in order to '' obtain the m-phenoxybenzyl ester of N- (4-fluorophenyl) -valine

NMR (cdci3) 8 centered at 0.90 [m, 6, (ÇH3) 2CH], 2.0 [m, 1, (CH3) 2CH], 3.80 (m, 2, NH and ^ N- ^ H

ethyl, N- (4-chlorophenyl) valine. Mass spectrum m / e 437 (M +, 3), 210 (100).

Example 41:

5 N- (4-fluoro-2-methylphenyl) valine was prepared from 4-fluoro-2-methylaniline and α-bromo-isovaleric acid, and reacted with bromide. m-phenoxybenzyl as in Example 38, in order to obtain the m-phenoxybenzyl ester of N- (4-fluoro-2-methylphenyl) valine. Mass spectrum m / e 407.2 (M +, 4.5), 10,180 (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 was added, with stirring, 0.82 g of m bromide - (3,4-dichlorophenoxy) benzyl. The reaction mixture was stirred overnight at room temperature and separated with water and ether. The aqueous phase was extracted twice with ether and, after combining the ethereal phases, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The concentrate was purified by preparative thin layer chromatography, eluting with a 10% ether / hexane mixture of ether, to obtain the m- (3,4-dichlorophenoxy) benzyl ester of N- (4 -methylphenyl) valine. Mass spectrum m / e 459.1 (M +, 2.4), 162.1 (100).

The m-phenoxybenzyl ester of N- (2-nitro-phenyl) valine was prepared [mass spectrum m / e 420.1 (M +, 2.7) 193 (100)], by reacting the bromide m-phenoxybenzyl and N- (2-nitrophenyl) valine as above.

N- (4-methylphenyl) valine was reacted with m-phenoxy-a-ethynylbenzyl bromide in DMF / THF and potassium carbonate at room temperature, as above, to obtain the ester m -phenoxy 2-ethynylbenzyl of N- (4-methylphenyl) -valine. Mass spectrum m / e 413.1 (M +, 3.8), 162.1 (100).

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-C—) and 5.15 ppm (s, 2,

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O

ArCH, Q). IR (film) 3400 cm "1 (NH).

N- (3-fluorophenyl) valine was reacted (prepared by reaction of α-bromo-isovaleric acid and 3-fluoroaniline at 140 ° C, under nitrogen, for 3.5 h) with bromide m-phenoxybenzyl in HMPT / THF and potassium carbonate, at room temperature, in order to obtain the m-phenoxybenzyl ester of N- (3-fluorophenyl) valine. Mass spectrum m / e 393 (M +, 2), 166 (100).

N- (2-chloro-4-methylphenyl) valine was prepared as above from α-bromo-isovaleric acid and 2-chloro-4-methylaniline and by subsequent reaction with m bromide -phenoxybenzyl, in order to obtain the m-phenoxybenzyl ester of N- (2-chloro-4-methylphenyl) valine. Mass spectrum m / e 423 (M +, 4), 196 (100).

Likewise, the m-phenoxybenzyl ester of N- (3-nitrophenyl) valine was prepared from N- (3-nitrophenyl) valine and m-phenoxybenzyl bromide. Mass spectrum m / e 420 (M +, 4), 193 (100).

Example 40:

To 1.21 mmol of triethyloxonium tetrafluoroborate in approximately 5 ml of methylene chloride, 1.05 mol of the m-phenoxybenzyl ester of N- (4-chlorophenyl) valine was added under nitrogen. The reaction product was stirred at room temperature overnight and poured into an ether / water mixture. The organic phase was washed with water and brine, dried over calcium sulfate and the solvent was removed. The product was purified by preparative thin layer chromatography eluting with a 20% ether / hexane mixture of ether to give the m-phenoxybenzyl ester of N-

ch3 ch3 \ /

h ch o

I I "

n-ch-c-o-ch-I

c = ch

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N- (3,4,5-trichlorophenyl) valine, made from 3,4,5-trichloroaniline and α-bromo-isovaleric acid, was reacted with m-phenoxybenzyl bromide in HMPT / THF and potassium carbonate at room temperature, in order to obtain the m-phenoxybenzyl ester of N- (3,4,5-trichlorophenyl) valine. Mass spectrum 477.1 (M +, 9.8), 250 (100).

Example 43:

A mixture of 2.1 g of 3,5-dimethoxyaniline, of 1.0 g of m-phenoxybenzyl ester of a-bromo-isovaleric acid, of 72, was heated overnight at 70-80 ° C. 9 mg potassium iodide and 5 ml HMPT. The reaction mixture was separated into two fractions by the addition of 100 ml of 2N sulfuric acid and 100 ml of ether. The aqueous phase was extracted with ether, then, after combining the ethereal phases, it was washed with 2N sulfuric acid, a saturated sodium bicarbonate solution and brine, dried over potassium carbonate, filtered and evaporated. The residue was purified by preparative thin layer chromatography eluting with ether / hexane to obtain the m- phenoxybenzyl ester of N- (3,5-dimethoxyphenyl) valine. Mass spectrum m / e 435.2 (M +, 11.7), 208.1 (100).

According to the above process, the 3,4,5-trimethoxy-aniline was reacted with the m-phenoxybenzyl α-bromo-isovalerate, in order to obtain the m- phenoxybenzyl ester of N- (3 , 4,5-trimethoxy-phenyl) valine. Mass spectrum m / e 465.2 (M +, 39.0), 182.9 (100).

According to the method of Example 42, the N- (4-chloro-phenyl) valine was reacted with m-benzylbenzyl bromide, in order to obtain

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the m-benzylbenzyl ester of N- (4-chlorophenyl) valine. Mass spectrum m / e 407.1 (M +, 6.2), 182 (100).

Example 44:

To 5.80 mmol of 3-methyl-2-butenoate of m-phenoxybenzyl and 30 ml of carbon tetrachloride, under nitrogen, 5.99 mmol of bromine in carbon tetrachloride was added slowly while keeping the reaction flask in an ice bath. After about 3 h, the reaction mixture was partitioned by adding water and ether. The aqueous phase was extracted with water and brine, dried over potassium carbonate, filtered and evaporated, in order to obtain m-phenoxybenzyl 2,3-dibromo-3-methylbutanoate.

A mixture of 4.1 mmol of the above dibrominated ester, 12.6 mmol of 4-methylaniline, 8.6 mmol of triethylamine, 20 ml of THF was heated to 50 ° C under nitrogen. and 2 ml of HMPT. 9 d later, the reaction mixture was partitioned by addition of ether and 2N HCl. The aqueous phase was extracted with ether and after combining the ethereal phases, they were washed with 2N HCl and brine, dried over potassium carbonate, filtered and evaporated. The residue was purified by preparative thin layer chromatography, eluting with a 10% ether / hexane mixture.

ether, to obtain the m-phenoxybenzylic ester of <x- (4-methylphenylamino) -3-methyl-3-butenoic acid. Mass spectrum m / e 387.2 (M +, 2.7), 160 (100).

Example 45:

To 0.57 g of N- (4-chlorophenyl) isoleucine in approximately 5 ml of HMPT was added 0.54 g of potassium carbonate, then 1.09 g of m-phenoxybenzyl bromide. The reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned by addition of water and ether. The aqueous phase was extracted with ether and, after combining the ethereal extracts, washed with water and brine, dried over potassium carbonate, filtered and evaporated. The residue was purified by preparative thin layer chromatography, eluting with an ether / hexane mixture at 10% ether, in order to obtain the m-phenoxybenzyl ester of N- (4-chlorophenyl) isoleucine. Mass spectrum m / e (M +, 3.7), 196 (100).

N- (4-chlorophenyl) isoleucine was prepared by reacting 4-chloroaniline at 100 ° C with the sodium salt of α-bromo-3-methylpentanoic acid as it was.

According to the above process, the m-phenoxybenzyl bromide was reacted with N- (4-methylphenyl) isoleucine, in order to prepare the m-phenoxybenzyl ester of N- (4-methylphenyl) isoleucine. Mass spectrum m / e 403.3 (M +, 3.3), 176.1 (100).

Example 46:

N- (4-methylphenyl) valine was reacted with m- (4-methoxyphenoxy) benzyl bromide in THF / HMPT and potassium carbonate at room temperature overnight to obtain the ester of m- (4-ethoxyphenoxy) benzyl of N- (4-methyl-phenyl) valine. IR (film) 3380 cm -1 (NH) and 1735 cm-1 (C = 0).

Example 47:

To 1.19 mmol of the m-phenoxybenzyl ester of N- (4-chloro-phenyl) valine in 4.5 ml of ether, under nitrogen, 4.25 mmol of cooled dimethylaminopyridine was added in a bath. ice then slowly 3.58 mmol of trichloroacetyl chloride in ether. The reaction mixture was heated at 40 ° C for 3 d. The mixture was partitioned by addition of ether and water. The aqueous phase was extracted with ether and then, after combining the ethereal phases, they were washed with water and brine and dried over sodium sulfate. The residue was purified by preparative thin layer chromatography, eluting with a 10% ether / hexane mixture of ether, to obtain the m-phenoxybenzyl ester of N-trichloroacetyl, N- (4-chloro- phenyl) valine. Mass spectrum 553 (M +, 1.8), 183 (100).

Example 48:

According to the method of Example 47, the m-phenoxy-benzyl ester of N-acetylformyl, N- (4-chlorophenyl) valine was prepared [mass spectrum m / e 479 (M +, 0.5), 183 (100)], by reacting the chloride of pyruvic acid with the m-phenoxybenzyl ester of N- (4-chlorophenyl) valine.

Example 49:

According to the method of Example 42, the N- (4-chloro-phenyl) valine was reacted with the m- (3,4-dichlorophenoxy) benzyl bromide, in order to obtain the ester m-3, 4-dichlorophenoxy) benzyl of N- (4-chlorophenyl) valine. Mass spectrum m / e 477 (M +, 2.1), 182 (100).

Example 50:

To 0.89 mmol of m-phenoxybenzyl ester of N- (4-methoxy-phenyl) valine in ether, 4.46 mmol of trifluoroacetic anhydride was added under nitrogen. The reaction mixture was stirred for 2.5 h, after which it was partitioned by addition of ether and water. After combining the ethereal layers, they were washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated to obtain the m-phenoxybenzyl ester of N-trifluoroacetyl, N - (4-methoxyphenyl) -valine. Mass spectrum m / e 501 (M +, 22.5) 183 (100).

Example 51:

A mixture of 1.22 mmol of m- phenoxybenzyl ester of N- (4-chlorophenyl) valine, of 23.8 mmol (2.1 g) was stirred overnight at room temperature and under nitrogen. acetic and formic anhydride in acetic acid and formic acid (1.5 ml). The reaction product was concentrated and purified by preparative thin layer chromatography, eluting with 20% ethyl acetate / hexane ethyl acetate to give the m-phenoxybenzyl ester. N-formyl, N- (4-chlorophenyl) -valine. Mass spectrum m / e 437 (M +, 8.1) 182 (100).

Example 52:

According to the method of Example 50, the trifiuoroacetic anhydride and the m-phenoxybenzyl ester of N- (4-chloro-phenyl) valine were reacted in order to obtain the m-phenoxybenzyl ester of N -trifluoroacetyl, N- (4-chlorophenyl) valine. Mass spectrum m / e 505 (M +, 14.9), 278 (100).

According to the method of Example 42, the α-ethynyl-m-phenoxybenzyl bromide and the N- (4-chlorophenyl) valine were reacted in order to obtain the α-ethynyl-m-phenoxybenzyl ester. N- (4-chloro-phenyl) valine. Mass spectrum m / e 433 (M +, 2.2), 182 (100).

Example 53:

To 1.2 mmol of the m-phenoxybenzyl ester of N-phenyl-valine was added 2.3 mmol of phosgene at 12.5% in benzene, cooled in an ice bath and then added 1.22 mmol of dimethylformamide. The reaction mixture was stirred at room temperature for 3 d. Then 1 ml of benzene, 0.15 g of dimethylaminopyridine and 2 ml of phosgene were added, and the reaction mixture was stirred at room temperature overnight. It was treated with chloroform and water and the chloroform layer was washed with dilute sulfuric acid, water and brine, dried over sodium sulfate and filtered. The solvent was removed by rotary evaporation, in order to obtain the m-phenoxybenzyl ester of N-chloroformyl, N-phenylvaline.

Stirred at room temperature for 4 d of a mixture of 0.89 mmol of the above ester, 1 ml of pyridine and 0.91 mmol of methanol. This mixture was treated with dilute HCl and ether. The ethereal layer was washed with aqueous HCl, with water and brine, dried over sodium sulfate and filtered. The solvent was removed and the residue was purified by preparative thin layer chromatography eluting with 8/20% ether / hexane mixtures of ether to obtain the m-phenoxybenzyl ester of N-methoxycarbonyl, N -phenylvaline. Mass spectrum m / e 433 (M +, 6.7), 206 (100).

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Example 54:

According to the method of Example 42, the N- (2-chloro-4-cyanophenyl) valine and the m-phenoxybenzyl bromide in THF / HMPT were reacted with potassium carbonate, in order to prepare the ester. m-phenoxybenzyl of N- (2-chloro-4-cyanophenyl) valine. Mass spectrum m / e 434 (M +, 3.7), 207 (100).

N- (2-chloro-4-cyanophenyl) valine was prepared from 2-chloro-4-cyanoaniline and α-bromo-isovaleric acid using the method of Example 18 among others.

Likewise, N- (2-4-difluorophenyl) valine was prepared from 2,4-difiuoroaniline and α-bromo-isovaleric acid. N- (2,4-difluorophenyl) valine was esterified with m-phenoxybenzyl bromide to obtain the m-phenoxybenzyl ester of N- (2,4-difluorophenyl) valine. Mass spectrum m / e 411 (M +, 3.5), 184 (100).

Example 55:

N- (2-fluoro-4-chlorophenyl) valine and m-phenoxybenzyl bromide were reacted according to the method of Example 42, in order to obtain the m-phenoxybenzyl ester of N- (2 -fluoro-4-chloro-phenyl) valine. Mass spectrum m / e 427.1 (M +, 4.1), 200 (100).

N- (2-fluoro-4-chlorophenyl) valine was prepared by heating the potassium salt of α-bromo-isovaleric acid and solvent-free 2-fluoro-4-chloroaniline at 130 ° C for approximately 2 h.

The N- (3-methyl-4-fluorophenyl) -valine was prepared in the same way which was esterified with m-phenoxybenzyl bromide to obtain the m-phenoxybenzyl ester of N- (3-methyl- 4-fluoro-phenyl) valine. Mass spectrum m / e 407.3 (M +, 0.3), 180 (100).

In the same way, N- (3-methyl-6-fluorophenyl) -valine and N- (3-fluoro-6-methylphenyl) valine were prepared, each esterified with m-phenoxybenzyl bromide, in order to to obtain the m-phenoxybenzyl ester of N- (3-methyl-6-fluorophenyl) valine [mass spectrum m / e 407.3 (M +, 4.3), 180 (100)] and the ester N-(3-fluoro-6-methylphenyl) valine m-phenoxybenzyl [mass spectrum m / e 407.3 (M +, 3.9), 180 (100)].

Example 56:

To a mixture of 0.79 g of α-cyano-m-phenoxybenzyl ester of N- (4-chlorophenyl) valine and approximately 20 ml of dry DMF, approximately 1 ml of triethanolamine was added at room temperature . H2S gas was slowly bubbled through the mixture for about 3 h. The reaction mixture was then stirred overnight, after which it was partitioned by addition of ether and water. The organic phase was washed 3 times with brine, dried over sodium sulfate, filtered and evaporated. The residue was applied to preparative thin layer chromatography plates, eluting with 20% ethyl acetate / hexane ethyl acetate to give the desired thioamide. Mass spectrum m / e 181.9 (100), IR (film) 3180 cm- '(NH) and 1740 cm-' (C = 0).

NH2

Example 57:

N- (2-cyano-4-chlorophenyl) valine was reacted with m-phenoxybenzyl bromide to obtain the m-phenoxy-benzyl ester of N- (2-cyano-4-chlorophenyl ) valine, applying the method of Example 42. Mass spectrum m / e 434.1 (M +, 3.5).

The a-cyano-m-phenoxy-benzyl ester of N- (2-methylphenyl) valine was prepared in the same way (mass spectrum m / e 414.1 (M +, 5.8)), starting from α-cyanophenoxybenzyl bromide and N- (2-methylphenyl) valine.

The m-phenoxy-benzyl ester of N- (2-methyl-4-chlorophenyl) valine was also prepared in the same way (mass spectrum m / e 423.1 (M +, 16.9)), at from m-phenoxybenzyl bromide and N- (2-methyl-4-chlorophenyl) valine.

According to the same procedure, the N- (pentafluorophenyl) valine was reacted with the m-phenoxybenzyl bromide, in order to obtain the m-phenoxybenzyl ester of the N- (pentafluorophenyl) valine. Mass spectrum m / e 465 (M +, 4.2).

Example 58:

The m-phenoxybenzyl bromide was reacted with N- (2,4-dimethoxyphenyl) valine and N- (2-methyl-6-chlorophenyl) valine, respectively, according to the method of Example 42, in order to d '' obtain the m-phenoxybenzyl ester of N- (2,4-dimethoxyphenyl) valine [mass spectrum m / e 435.2 (M +, 12.4)] and the p-phenoxy-benzyl ester of N - (2-methyl-6-chlorophenyl) valine [mass spectrum 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 was heated under reflux for 2 h. . The reaction mixture was diluted with hexane, washed twice with water and the solvent was separated to obtain the crude product. To the crude product was added 0.1 g of N-chlorosuccinimide and 3 ml of benzene. The mixture was heated under reflux for 30 min and allowed to stand overnight at room temperature. The reaction product was diluted with hexane, washed with water and the solvent was removed, to obtain the m-phenoxybenzyl ester of N- (2,6-dimethyl-4-chlorophenyl) valine. Mass spectrum m / e 437.1 (M +, 15.3).

Example 60:

N- (4-bromophenyl) valine was prepared from 4-bromo-aniline and a-bromo-isovaleric acid and was esterified with m-phenoxybenzyl bromide to obtain m-phenoxy-benzyl ester of N- (4-bromophenyl) valine. Mass spectrum m / e 454 (M +).

The sodium salt of α-bromo-isovaleric acid was reacted with p-ethylaminobenzoate, without solvent, at 140 ° C. for 3 h to obtain the N- (4-ethoxycarbonylphenyl) valine which was then made. react with m-phenoxybenzyl bromide to obtain the m-phenoxybenzyl ester of N- (4-ethoxycarbonylphenyl) valine. Mass spectrum m / e 447 (M +).

The m-phenoxybenzyl ester of N- (3-trifluoro-methylphenyl) valine (mass spectrum m / e 443 (M +)]) was prepared from N- (3-trifluoromethylphenyl) valine and bromide. m-phenoxybenzyl. The reaction of 3-trifluoromethylaniline with the sodium salt of α-bromo-isovaleric acid made it possible to obtain the starting material.

N- (3,4-dimethylphenyl) valine, N- (3-methyl-phenyl) valine, N- (2,4,6-trimethylphenyl) valine, N- (2-chloro-5) were esterified -trifluoromethylphenyl) valine and N- (2,6-difluoro-4-chlorophenyl) -valine with m-phenoxybenzyl bromide and potassium carbonate in THF / HMPT at room temperature, in order to obtain the respective esters listed below.

The m-phenoxybenzyl esters of: N- (3,4-dimethylphenyl) valine [mass spectrum m / e 403.2 (M +)], N- (3-methylphenyl) valine [mass spectrum m / e 389 , 2 (M +)], N- (2,4,6-trimethylphenyl) valine [mass spectrum m / e 417.1 (M +)] N- (2-chloro-5-trifluoromethylphenyl) valine [spectrum of mass m / e 477 (M +)], and N- (2,6-difluoro-4-chlorophenyl) valine [mass spectrum m / e 445.1 (M +)].

The starting material was prepared by reacting the sodium salt of α-bromo-isovaleric acid with, respectively, 3,4-dimethylaniline, 3-methylaniline, 2,4,6-trimethylaniline, 3 -chloro-5-trifluoromethylaniline and 2,6-difluoro-4-chloroaniline, according to the method of Example 18.

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According to the method of Example 1, 4-n-butyl-aniline and 4-cyclopropylaniline were reacted with m-phenoxybenzyl α-bromo-isovalerate, in order to obtain, respectively, the ester m -phenoxy-benzyl of N- (4-n-butylphenyl) valine [mass spectrum m / e 431.2 (M +)], and the m-phenoxybenzyl ester of N- (4-cyclopropyl-phenyl) valine [mass spectrum m / e 415.1 (M +)].

The m-phenoxybenzyl esters of N- (4-chloro-phenyl) valine and N- (4-methylphenyl) valine were methylated, using the method of Example 2, in order to obtain the ester m -phenoxybenzyl of N-methyl, N- (4-chlorophenyl) valine [mass spectrum m / e 423 (M +)] and the m-phenoxybenzyl ester of N-methyl, N- (4-methyl-phenyl) valine [mass spectrum 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 ° C, 15 g of N-bromo-succinimide was added slowly. When the addition was complete, the reaction mixture was left at room temperature for 17 h with stirring. It was taken up in ether, washed with water and with a saturated solution of sodium sulfite, dried over magnesium sulfate and evaporated under reduced pressure to obtain ethyl 2-bromo-3-hydroxybutanoate.

To a mixture of 10 g of ethyl 2-bromo-3-hydroxybutanoate and 15 ml of HMPT, 13.2 g of aniline were added, then the reaction mixture was stirred at room temperature for 3 d, after which it was treated with ether and washed with dilute sulfuric acid, pH 3, and with water. The ether phase was dried over magnesium sulfate and evaporated to give ethyl 2-phenylamino-3-hydroxybutanoate which was saponified with 1.6 g of sodium hydroxide, 40 ml of methanol and 20 ml of water, stirring overnight at room temperature. 3.0 g of 2-phenyl-amino-3-hydroxybutanoic acid was reacted with 3.4 g of m-phenoxybenzyl bromide in 20 ml of HMPT and with 2.12 g of potassium carbonate at 35 ° C for a few hours, and treated with ether and water to obtain the m-phenoxybenzyl ester of 2-phenylamino-3-hydroxybutanoic acid.

To a solution of 1.24 g of N-chlorosuccinimide and 60 ml of dry THF was added slowly, with stirring at room temperature, 2.43 g of triphenylphosphine in 50 ml of THF. Then 3.5 g of the m-phenoxybenzyl ester of 2-phenyl-amino-3-hydroxybutanoate in 30 ml of THF was added slowly. The reaction mixture was stirred overnight and concentrated under reduced pressure. The oily residue was taken up in ether, washed with water, dried over magnesium sulfate and evaporated, in order to obtain the m-phenoxybenzyl ester of 2-phenylamino-3-chlorobutanoic acid. Mass spectrum m / e 395 (M +).

The ester prepared above was methylated, applying the method of Example 2, in order to obtain the 2- (methylphenylamino) -3-chloro-butanoate of m-phenoxybenzyl. Mass spectrum 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 was heated under reflux for about 5.5 h. -toluenesulfanylacetate and 10 ml of benzene. To remove the water, a Dean-Stark trap was used. The reaction mixture was poured into a solution of sodium bicarbonate and ether. The organic phase was washed with water and brine, dried over magnesium sulfate and evaporated. To the reaction product (0.79 g), 3 ml of methanol, 1 ml of THF and 0.19 g of NaCNBH3 were added. The reaction mixture was stirred at room temperature, then the pH was adjusted to 3-4 with concentrated sulfuric acid. Stirring was continued overnight and the reaction mixture was treated as above using ether and sodium bicarbonate solution, followed by thin layer chromatography eluting with an ether / hexane mixture at 20% ether, in order to obtain the m-phenoxybenzyl ester of N- (2,4,6-trichlorophenyl) valine. Mass spectrum m / e 477 (M +).

N- (2,4-dichlorophenyl) valine was prepared from 2,4-dichloroaniline and the sodium salt of α-bromo-isovaleric acid and reacted with m- bromide phenoxybenzyl, in order to obtain the m-phenoxybenzyl ester of N- (2,4-dichlorophenyl) -valine. Mass spectrum m / e 443 (M +).

According to the method of Example 6, the α-cyano-m-phenoxybenzyl α-bromo-iso-valerate was reacted with, respectively, 4-chloroaniline, 4-methoxyaniline and 4-methylaniline, in order to prepare the α-cyano-m-phenoxybenzyl ester of: N- (4-chlorophenyl) valine [mass spectrum m / e 434.1 (M +)], N- (4-methoxyphenyl) valine [spectrum mass m / e 430.1 (M +)], and N- (4-methylphenyl) valine [mass spectrum m / e 414.2 (M +)].

The α-cyano-m-phenoxybenzyl ester of N- (4-chlorophenyl) valine was reacted with methyl iodide, applying the method of Example 2, in order to obtain the ester a- cyano-m-phenoxy-benzyl of N-methyl, N- (4-chlorophenyl) valine. Mass spectrum m / e 448.1 (M +).

N- (2,3-dichlorophenyl) valine was prepared from 2,3-dichloroaniline and the sodium salt of α-bromo-isovaleric acid and reacted with m- bromide phenoxybenzyl, in order to obtain the m-phenoxybenzyl ester of N- (2,3-dichlorophenyl) -valine. Mass spectrum m / e 443 (M +).

Example 63:

According to the method of Example 1, the m-phenoxybenzyl α-bromo-iso-valerate was reacted with 4-ethyl-aniline and 4-isopropylaniline, respectively, in order to obtain the m- phenoxy-benzyl ester of N- (4-ethylphenyl) valine [mass spectrum m / e 403.2 (M +)] and m-phenoxybenzyl ester of N- (4-isopropylphenyl) -valine [spectrum mass m / e 417.2 (M +)].

According to the method of Example 18, the m-phenoxybenzyl bromide was reacted with N- (4-nitrophenyl) valine and N- (2,6-dichlorophenyl) valine, respectively, in order to obtaining the m-phenoxybenzyl ester of N- (4-nitrophenyl) valine [mass spectrum m / e 420.1 (M +)] and the m-phenoxybenzyl ester of N- (2,6-dichlorophenyl) valine [mass spectrum m / e 443 (M +)].

Example 64:

According to the method of Example 1, the m-phenoxybenzyl α-bromo-iso-valerate was reacted with 3-chloroaniline, so as to obtain the m-phenoxybenzyl ester of N- (3-chlorophenyl ) valine. Mass spectrum m / e 409.2 (M +).

According to the method of Example 18, the m-phenoxybenzyl bromide was reacted with, respectively, N- (3-trifluoromethyl-4-chlorophenyl) valine, N- (2-chlorophenyl) valine and N- ( 2,6-difluorophenyl) valine, in order to obtain the m - (- phenoxy-benzyl) esters of:

N- (3-trifluoromethyl-4-chlorophenyl) valine [mass spectrum m / e 477.1 (M +)],

N- (3-chlorophenyl) valine [mass spectrum m / e 409 (M +)], and N- (2,6-difluorophenyl) valine [mass spectrum 411.1 (M +)].

N- (4-t-butylphenyl) valine was reacted with benzyl bromide, using the method of Example 18, in order to obtain the benzyl ester of N- (4-t-butylphenyl) valine. Mass spectrum m / e 431 (M +).

According to the method of Example 24, the N- (4-chlorophenyl) valine was esterified, respectively, with 4-allyl-benzyl bromide, m- (3-trifluoromethylphenoxy) benzyl bromide, m bromide - (4-chlorophenoxy) benzyl, m- (4-methylphenoxy) benzyl bromide, m- (4-methoxyphenoxy) -benzyl bromide and m- (4-t-butylphenoxy) benzyl bromide, in order to obtain the respective esters below:

the 4-allylbenzyl ester of N- (4-chlorophenyl) valine [mass spectrum m / e 357.1 (M +)],

the m- (3-trifluoromethylphenoxy) benzyl ester of N- (4-chlorophenyl) valine [mass spectrum m / e 477 (M +],

the m- (4-chlorophenoxy) benzyl ester of N- (4-chlorophenyl) -valine [mass spectrum m / e 443 (M +)],

the m- (4-methylphenoxy) benzyl ester of N- (4-chlorophenyl) -valine [mass spectrum m / e 423 (M +)],

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the m- (4-methoxyphenoxy) benzyl ester of N- (4-chloro-phenyl) valine [mass spectrum m / e 439 (M +)], and the m- (4-t-butylphenoxy) benzyl ester N- (4-chlorophenyl) -valine [mass spectrum m / e 465.2 (M +)].

According to the method of Example 42, the N- (4-methyl-phenyl) valine was reacted with, respectively, 4-allylbenzyl bromide, m- (3-trifluoromethylphenoxy) benzyl bromide, m- (4-methylphenoxy) benzyl, m- (4-chlorophenoxy) -benzyl bromide and m- (4-t-butylphenoxy) benzyl bromide, in order to obtain the respective esters below:

the 4-allylbenzyl ester of N- (4-methylphenyl) valine [mass spectrum m / e 337.1 (M +)],

the m- (3-trifluoromethylphenoxy) benzyl ester of N- (4-methylphenyl) valine [mass spectrum m / e 457.1 (M +)],

the m- (4-methylphenoxy) benzyl ester of N- (4-methylphenyl) -valine [mass spectrum m / e 403.2 (M +)],

the m- (4-chlorophenoxy) benzyl ester of N- (4-methylphenyl) -valine [mass spectrum m / e 423 (M +)], and the m- (4-t-butylphenoxy) benzyl ester of N- (4-methylphenyl) -valine [mass spectrum m / e 445.2 (M +)].

Example 65:

To a mixture of 2.77 mmol of N- (4-methylphenyl) valine, 3.25 mmol of potassium carbonate and 3 ml of HMPT was added at room temperature, with stirring and under nitrogen, 2.77 mmol of 5-benzyl-3-furylmethyl bromide in THF. Stirring was continued at room temperature for 48 h, after which the reaction mixture was partitioned by addition of ether and water. The organic phase was washed with water and brine, dried over potassium carbonate, filtered and evaporated. The residue was applied to thin layer chromatography plates, eluting with a 10% ether / hexane mixture of ether, to obtain the 5- benzyl-3-furylmethyl ester of N- (4- methylphenyl) valine. Mass spectrum m / e 377.1 (M +).

According to the method of Example 17, N- (2-trifluoromethylphenyl) valine was reacted, prepared from 2-trifluoro-methylaniline and the sodium salt of α-bromo-isovaleric acid according to the method of Example 18, with m-phenoxybenzyl bromide, in order to obtain the m-phenoxybenzyl ester of N- (2-trifluoromethylphenyl) vaIine. Mass spectrum m / e 443 (M +).

By repeating the process of Example 1, 2-methoxyaniline and 4-ethoxyaniline were reacted respectively with m-phenoxybenzyl α-bromo-iso-valerate, in order to obtain the m-phenoxy- ester. benzyl of N- (2-methoxyphenyl) valine [mass spectrum m / e 405.2 (M +)] and the m-phenoxybenzyl ester of N- (4-ethoxy-phenyl) valine [mass spectrum m / e 419.1 (M +)].

According to the process of Example 42, the N- (3,4-dichlorophenyl) valine was reacted with m-phenoxybenzyl bromide, in order to obtain the m-phenoxybenzyl ester of N- (3,4 -dichlorophenyl) -valine. Mass spectrum m / e 443 (M +).

N- (3-cyanophenyl) valine and N- (3,4-dimethoxyphenyl) valine were reacted with m-phenoxy-benzyl bromide, respectively, using the method of Example 17, to '' obtain the m-phenoxybenzyl ester of N- (3-cyanophenyl) valine [mass spectrum m / e 400.1 (M +)] and the m-phenoxybenzyl ester of N- (3,4-dimethoxyphenyl) valine [mass spectrum 435 (M +)].

According to the method of Example 6, the 6,4-trifluoro-methylaniline was reacted with α-cyano-m-phenoxy-benzyl α-bromo-isovalerate, in order to obtain the ester a- cyano-m-phenoxybenzyl of N- (4-trifluoromethylphenyl) valine. Mass spectrum m / e 468.2 (M +).

Example 66:

To 14.1 g of p-nitrothiophenol suspended in 100 ml of water, 52 ml of 2N sodium hydroxide were added at room temperature. The mixture was stirred for 15 min and 9.4 ml of methyl iodide was added slowly at 10 ° C. The reaction mixture was warmed to room temperature and stirred for 2 h. It was extracted with 3 times 80 ml of ether, washed with water and brine, dried over calcium sulphate and evaporated to obtain p-nitro-phenyl methyl sulphide (12.2 g).

In 10.5 g of p-nitrophenyl methyl sulfide in 120 ml of chloroform, cooled to 10-17 ° C, under a nitrogen atmosphere, chlorine was bubbled by lighting with a 150 W lamp. trace of 2,2'-azobis- (2-methylpropionitrile) and, after passing the chlorine stream for approximately 3 h, the reaction being completed, a stream of nitrogen was passed for 0.5 h. The solution was concentrated and recrystallized from hot acetone to obtain p-nitrophenyl trichloromethylsulfide. M: 94-96 ° C.

1.5 g of p-nitrophenyl trichloromethylsulfide and 1.96 g of purified SbF3 were stirred together under nitrogen in a Claisen flask and heated to 110-120 ° C. About 0.5 h later, distilled at 85-90 ° C under reduced pressure (5 mm). The distillate was taken up in 50 ml of ether and the ethereal layer was washed with 10% HCl until the addition of water no longer caused cloudiness. The ethereal layer was washed with water until neutral and with brine, dried over calcium sulfate and evaporated, to obtain the p-nitrophenyl trifluoromethylsulfide.

To 3.0 g of p-nitrophenyl trifluoromethylsulfide in 30 ml of absolute ethanol, Adams catalyst (Pt02.0.026 g) was added. The mixture was hydrogenated in a Parr container at 3.5 kg / cm2 for about 15 min. Then filtered through Celite and evaporated to obtain p-aminophenyl trifluoromethylsulfide.

According to the process of Example 43, p-aminophenyl trifluoromethylsulfide was reacted with m-phenoxybenzyl α-bromo-isovalerate, in order to obtain the m- phenoxybenzyl ester of N- (4-trifluoromethylthiophenyl ) valine. Mass spectrum m / e 475 (M +).

Alternatively, by applying the method of Example 38, the p-aminophenyl trifluoromethylsulfide was reacted with the sodium salt of α-bromo-isovaleric acid, in order to obtain the N- (4-trifluoromethylthiophenyl) valine which has been esterified to obtain the m-phenoxybenzyl ester of N- (4-trifluoromethyl) thiophenyl) -valine.

Example 67:

10.08 g (65 mmol) of 2-fluoro-4 was charged into a 100 ml three-necked flask, equipped with a dropping funnel and a reflux condenser, to which a water / gas trap was attached. -nitrotoluene. 7.0 ml (22.3 g, 138 mmol) of bromine were added to the ampoule and the flask was heated. When the temperature of the oil bath reached approximately 100 ° C., the bromine was slowly introduced by lighting the flask with a 150 W bulb. The bromination started quickly when the temperature was raised to 160-170 ° C. and a moderate release of HBr was observed. 4 h later, the heating was stopped, the cooled mixture was poured onto ice and a saturated solution of sodium bisulfite and extracted 3 times with ether. The organic layers were pooled and washed again with saturated NaHSO3 and once with brine, and dried over sodium sulfate. After filtration and evaporation of the solvent, 17.0 g of a mixture of benzal bromide and benzyl bromide (1.7: 1 by NMR analysis) were obtained. The raw material was suspended in a hypobromite solution prepared by combining 60 g of sodium hydroxide and 20 ml of bromine in 600 ml of water. The mixture was stirred for 6 d at room temperature, then filtered to obtain 2-fluoro, 4-nitro-a-, a, a-tribromotoluene which can be crystallized from methanol.

A mixture of 8.5 g of 2-fluoro-4-nitro-a, a, a-tribromo-toluene (22 mmol) and 4.7 g was introduced into a small flask equipped with a condenser for distillation. (26 mmol) of antimony trifluoride. The flask was heated slowly and the mixture was allowed to distill at atmospheric pressure, then under reduced pressure until the end of the distillation. The distillate was partitioned between 6N hydrochloric acid and ether. The organic layer was then washed 1 time with 6N sodium hydroxide and 1 time with brine and dried over sodium sulfate. After filtration and evaporation, 2-fluoro-4-nitrobenzotrifluoride was obtained.

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To a solution of 20 ml of concentrated hydrochloric acid and 15 ml of 95% ethanol, 5.0 g (24 mmol) of 2-fluoro-4-nitrobenzotrifluoride was added. The mixture was stirred and 20 g (88 mmol) of stannous chloride dihydrate was added gradually over 30 min. The reaction was exothermic and, during the addition, the temperature was maintained at 60 ° C. When the addition was complete, the mixture was stirred at 60 ° C for a further 30 min. The reaction mixture was cooled and then poured into a mixture of ice and 36% sodium hydroxide before being extracted 3 times with ether. The ethereal layers were combined, washed once with brine and dried over sodium sulfate. After filtration and evaporation of the solvent, 4-amino-2-fluorobenzotrifluoride (3-fluoro-4-tri-fluoromethylaniline) was obtained.

According to the method of Example 38, 3-fluoro-4-trifluoromethylaniline was reacted with the sodium salt of x-bromoiso-valeric acid, in order to obtain N- (3-fluoro-4- trifluoromethylphenyl) -valine which has been esterified to obtain the m-phenoxybenzyl ester of laN- (3-fluoro-4-trifluoromethylphenyl) valine.

The N- (2,4-dinitrophenyl) valine was reacted with the m-phenoxybenzyl bromide according to the method of Example 38, in order to obtain the m-phenoxybenzyl ester of N- (2,4- dinitrophenyl) valine.

This process was repeated, replacing 2-fluoro-4-nitrotoluene with 3-fluoro-4-nitrotoluene to prepare 2-fluoro-4-trifluoro-methylaniline which was converted to N- (2-fluoro-4 -trifluoromethyl-phenyl) valine and which has been esterified, in order to obtain the m-phenoxy-benzyl ester of N- (2-fluoro-4-trifluoromethylphenyl) valine. Mass spectrum m / e 461.1 (M +).

Example 68:

A mixture of 25.05 g of 2-fluoro-4-chlorotoluene, 55.04 g of KMnO4 and 400 ml of water was heated under reflux for 5 h. The reaction product was filtered hot on celite and the filtrate was acidified with 2N HCl. White crystals were separated by filtration, dissolved in ether, then washed with water and brine, dried over sodium sulfate, filtered and evaporated to obtain acid 2 -fluoro-4-chlorobenzoic acid.

A mixture of 6.05 g of 2-fluoro-4-chlorobenzoic acid, 62.51 g of polyphosphoric acid and 5.1 g of CH 3 NO 2 was heated to 130 ° C. After about 2.5 h, the reaction mixture was poured onto ice and made basic by adding dilute sodium hydroxide, then extracted with ether. The ethereal extracts were pooled, washed with water and brine, dried over sodium sulfate, filtered and evaporated to obtain 2-fluoro-4-chloroaniline.

Example 69:

In a flask fitted with a short distillation head, under nitrogen, a mixture of 0.6 g of N- (4-chlorophenyl) valine was heated to 150 ° C. with stirring for 7 h and under vacuum (about 50 mm). , 0.57 g of m-phenoxybenzyl sulfide and 0.9 g of tetra (t-butoxy) titanate. The reaction mixture was allowed to cool and was kept standing for several hours. Ether and 2N sulfuric acid were added and extracted with ether. The ethereal extracts were collected, washed with water, with a 10% bicarbonate solution, then again with water and brine, dried over calcium sulfate and rotoevaporated. The concentrate was chromatographed in a thin shower, eluting with an ether / hexane mixture at 10% ether, and the main band consisting of the thiolester-m-phenoxybenzyl of N- (4-chlorophenyl) valine was collected. M.p .: 103.5-105 ° C.

The above process was repeated using N- (4-methyl-phenyl) valine, in order to obtain the m-phenoxybenzyl thiolester of N- (4-methylphenyl) valine. Mass spectrum m / e 405 (M +).

Example 70:

To a solution of 3.9 g of o-fluoroaniline in 50 ml of methylene chloride, cooled to -20 ° C. under nitrogen, a 35 mmol solution of 2,4,4,6-tetrabromocyclohexadienone was added in methylene chloride. After several hours, the reaction mixture was poured into 15% NaOH solution. The layers were separated and the organic fraction was again stirred with 15% NaOH solution. The methylene chloride fraction was washed with saturated NaCl solution, dried over calcium sulfate and evaporated to obtain 4-bromo-2-fluoroaniline.

s A1.42 g of the potassium salt of α-bromo-isovaleric acid, 1.9 g of 4-bromo-2-fluoroaniline were added. The mixture was heated to 125 ° C under nitrogen for 3.5 h, then cooled to room temperature. The reaction product was then poured into 2M NaOH and an ether / chloroform mixture. The basic phase was separated and acidified with concentrated HCl, then extracted with ether, washed with saturated NaCl solution, dried over calcium sulfate and evaporated to obtain N- (4- bromo-2-fluorophenyl) valine.

A mixture of 0.45 g of N- (4-bromo-2-fluorophenyl) valine, 0.25 g of potassium carbonate, 4 ml of THF, 4 ml of DMF was stirred for about 60 h. and 0.43 g of m-phenoxy-a-cyanobenzyl mesylate, then poured into water and a hexane / ether mixture (9: 1). The organic phase was washed with water and with a saturated sodium chloride solution, dried over calcium sulfate and evaporated. The residue was chromatographed in a thin layer 20, eluting with a methylene chloride / hexane mixture containing 25% methylene chloride, then with a methylene chloride / hexane mixture containing 30% chloride, and the main strip was collected for obtaining the m-phenoxy-a-cyanobenzyl ester of N- (4-bromo-2-fluorophenyl) valine. Mass spectrum m / e 496 (M +).

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Example 71:

In 4.9 g of N- (4-chlorophenyl) valine (0.0215 mol) in 50 ml of 1,4-dioxane, a stream of phosgene gas was slowly passed by stirring the solution and cooling to maintain the 30 solution at room temperature. When the solution was saturated with phosgene, the passage of phosgene was stopped and the mixture was continued to stir under nitrogen at room temperature. After 45 h, two-thirds of the dioxane was removed by distillation under reduced pressure. The residue was diluted with hexane, then allowed to crystallize overnight at room temperature. The solid was collected by filtration and washed with hexane, taking care to avoid contact with air as much as possible. The solid was dried in vacuo to obtain 3- (4-chlorophenyl) -4-isopropyloxazolidine-2,5-dione. M: 137-138 ° C.

40 To a mixture of 0.43 g of m-naphthoxybenzaldehyde, 0.5 g of 3- (4-chlorophenyl) -4-isopropyloxazolidine-2,5-dione and 0.23 g of potassium cyanide in about 10 ml of benzene, about 0.1 g of benzyltriethylammonium chloride was added with stirring. The reaction mixture was stirred for about 50 h, then the mixture was treated with ether, washed with water and brine, dried over sodium sulfate and evaporated. The concentrate was chromatographed in a thin layer, eluting with an ether / hexane mixture at 20% ether, in order to obtain the m- naphthoxy-a-cyanobenzyl ester of N- (4-chloro-phenyl) valine. .

50 NMR (CDClj) S concentrated 1.0 [m, 6, (CH3) 2CH], 2.10 [m, 1,

(CH3) 2CH], and 4.0 ppm (m, 2, NH and .N-Ìh).

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The process of Example 69 was repeated, using N- (2-chloro-4-trifluoromethylphenyl) valine, N- (4-chloro-2-fluoro-phenyl) valine, N- (2-fluoro -4-trifluoromethylphenyl) valine, and N- (4-bromo-2-fluorophenyl) valine as starting material, in order to obtain the m-phenoxybenzyl thiolesters of: N- (2-chloro-4-trifluoromethylphenyl) valine, N- (4-chloro-2-fluorophenyl) valine, N- (2-fiuoro-4-trifluoromethylphenyl) valine, and N- (4-bromo-2-fluorophenyl) valine.

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Example 73:

N- (2-fluorophenyl) valine was prepared from 2-fluoro-aniline and α-bromo-isovaleric acid and reacted with

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m-phenoxybenzyl bromide, as in Example 17, in order to obtain the m-phenoxybenzyl ester of N- (2-fluorophenyl) -valine. Mass spectrum m / e 493.2 (M +).

According to the method of Example 28, the hydrochloric acid salt of the m-phenoxybenzyl ester of N- (4-chloro-phenyl) valine was prepared. M: 126-130 ° C.

Example 74:

According to the method of Example 6, the 2-fluoro-4-chloroaniline was reacted with the a-bromo-isovalerate of m-phenoxya-cyano-benzyl, in order to obtain the ester m-phenoxy-a -Cyanobenzyl of N- (2-fluoro-4-chlorophenyl) valine. Mass spectrum m / e 452 (M +). Alternatively, the 2-fluoro-4-chloroaniline was reacted with the sodium salt of a-bromo-isovaleric acid, in order to obtain the N- (2-fluoro-4-chlorophenyl) valine which was esterified with bromide or m-phenoxy-a-cyanobenzyl mesylate.

The N- (4-chlorophenyl) valine was reacted with the bromide or • m-phenylcarbonylbenzyl mesylate according to the method of Example 24, in order to obtain the m- phenylcarbonylbenzyl ester of N- (4- chlorophenyl) valine. Mass spectrum m / e 421 (M +).

Example 75:

N- (2-chloro-4-fluorophenyl) -valine, N- (4-methylthiophenyl) valine, N- (4-chloro-3-fluoro-phenyl) valine, N- ( 4-cyano-2-fluorophenyl) valine, N- (4-bromo-2-fluorophenyl) valine and N- (4-trifluoromethoxyphenyl) valine with m-phenoxybenzyl bromide, according to the method of Example 24, in order to obtain the m-phenoxybenzyl esters of: N- (2-chloro-4-fluorophenyl) valine [mass spectrum m / e 427 (M +)],

N- (4-methylthiophenyl) valine [mass spectrum m / e 421 (M +)], N- (4-chloro-3-fluorophenyl) valine [mass spectrum m / e 427 (M +, 200)],

N- (4-cyano-2-fluorophenyl) valine [mass spectrum m / e 418 (M +)],

N- (4-bromo-2-fluorophenyl) valine [mass spectrum m / e 471, (M +)], and N- (4-trifluoromethoxyphenyl) valine [mass spectrum m / e 459 (M +)].

According to the method of Example 70, the m- phenoxy-a-cyanobenzyl ester of N- (4-chloro-3-fluorophenyl) valine was prepared [mass spectrum m / e 452 (M +)] and l m-phenoxy-a-cyanobenzyl ester of N- (2-fluoro-4-methylphenyl) valine [mass spectrum m / e 432 (M +)], respectively from N- (4-chloro-3- fluorophenyl) -valine and N- (2-fluoro-4-methylphenyl) valine and mesylate or m-phenoxy-a-cyanobenzyl bromide. The starting materials were prepared by reacting 4-chloro-3-fluoroaniline or 2-fluoro-4-methylaniline with the potassium salt of α-bromo-isovaleric acid.

0.984 g of 3- (trifluoroacetyl) diphenyl ether was dissolved in 5 ml of methanol and reduced with 0.25 g of sodium borohydride to obtain the corresponding alcohol. To 0.27 g of this alcohol (1.0 mol) were added 2 ml of pyridine and 0.5 g (1.97 mol) of 3- (4-chlorophenyl) -4-isopropyloxazolidine-2,5- dione. The solution was heated at 80 ° C for 15 h under nitrogen. The reaction mixture was diluted with ether / hexane and washed with dilute hydrochloric acid, then with an aqueous solution of sodium bicarbonate. The organic phase was separated and chromatographed on a 1 m silica column, eluting with an ether / hexane mixture at 10% ether, to obtain the 3-phenoxy-a- ester. trifluoromethylbenzyl of N- (4-chlorophenyl) valine. Mass spectrum m / e 477.1 (M +), 182 (100).

Example 76:

According to the method of Example 65, the N- (4-chloro-phenyl) valine was reacted with, respectively, 5-benzyl-3-furyl-methyl bromide, m-allyloxybenzyl bromide and bromide of m-propargyloxybenzyl, in order to obtain the 5-benzyl-3-furyl- ester

N- (4-chlorophenyl) valine methyl [mass spectrum m / e 397 (M +)], m- allyloxybenzyl ester of N- (4-chlorophenyl) valine [mass spectrum m / e 373 (M + )] and the m-propargyloxybenzyl ester of N- (4-chlorophenyl) valine [mass spectrum m / e 371 (M +)].

The 4-chloroaniline was reacted with the m-phenoxybenzyl 2-bromobutanoate according to the method of Example 4, in order to obtain the 2- (4-chlorophenylaminobutanoate m-phenoxybenzyl [mass spectrum m / e 395 ( M +)].

By applying the method of Example 6, 4-chloroaniline was reacted with p-benzyl-benzyl a-bromo-isovalerate and m-benzyl-a-cyanobenzyl a-bromo-isovalerate, respectively. in order to obtain the p-benzylbenzyl ester of N- (4-chlorophenyl) valine [mass spectrum m / e 407 (M +)] and the m-benzyl-a-cyano-benzyl ester of N- ( 4-chlorophenyl) valine [mass spectrum m / e 432 (M +)].

According to the method of Example 60, N- (4-iso-propoxycarbonylphenyl) valine was prepared and reacted with m-phenoxybenzyl bromide, in order to obtain the m-phenoxybenzyl ester of N- (4-isopropoxycarbonylphenyl) valine. Mass spectrum m / e 461 (M +).

Example 77:

To a suspension of 0.50 g of sodium hydride in 25 ml of dioxane under argon, 2.80 g of 2- (2-fluoro-4-trifluoromethylphenylamino) -3-methylbutanoic acid was gradually added. When the evolution of hydrogen ceased, the mixture was cooled in an ice bath and a stream of phosgene was passed over the surface of the stirred mixture. There was naturally a reaction with dissolution of the sodium salt and release of more hydrogen. When the evolution of hydrogen seemed to have stopped, the ice bath was removed and the addition of phosgene continued until the solution appeared almost saturated, the reaction mixture was then filtered through sintered glass, in order to remove the insoluble salts and the filtrate was distilled under 15 to 20 mm of pressure to remove the phosgene and about 15 ml of the solvent dioxane. The residue was then diluted with hexane and allowed to stand at room temperature until crystallization was complete. The anhydride was collected by filtration, washed with hexane and dried under vacuum, taking care to reduce exposure to humidity as much as possible, in order to obtain 3- (2-fluoro-4-trifluoromethylphenyl ) -4-isopropyloxazoIidine-2,5-dione.

3- (2-fluoro-4-trifluoromethylphenyl) -4-isopropyloxazolidine-2,5-dione was reacted with phenol by applying the method of Example 75, in order to obtain the phenyl ester of N - (2-fiuoro-4-trifiuoromethylphenyl) vaIine which was then reacted with NaHS by applying the method of Hirakayashi et al., "Bull. Chem. Soc. Japan ”38.320 (1965) to obtain the sodium salt of the thio-acid:

The thioacid was reacted with the m-phenoxy-a-cyanobenzyl bromide or mesylate, using the method of Example 70, in order to obtain the N- (2-m-phenoxy-a-cyanobenzyl thiolester). -fluoro-4-trifluoromethylphenyl) valine.

Example 78:

According to the method of Example 38, the N- (4-trifluoromethylphenyl) valine was reacted with p-benzoylbenzyl bromide, in order to obtain the p-benzoylbenzyl ester of N- (4-trifluoromethyl-phenyl ) valine.

By applying the method of Example 77, 3- (2-fluoro-4-trifluoromethylphenyl) -4-isopropyl-oxazolidine-2,5-dione and 3- (4-trifluoromethylphenyl) -4- were prepared respectively. isopropyl-oxazolidine-2,5-dione and they were reacted with m-benzoylbenzal-dehyde and potassium cyanide, by applying the method of example 71, in order to obtain the ester m-benzoyl-a -cyanobenzyl of

5

10

15

20

25

30

35

40

45

50

55

60

65

632232

20

N- (2-fluoro-4-trifluoromethylphenyl) valine and the m-benzoyl-a-cyanobenzyl ester of N- (4-trifluoromethylphenyl) valine.

Example 79:

According to the method of Example 42, m- (o-fluorophenoxy) benzyl bromide was used to esterify, respectively, the N- (2-fluoro-4-trifluoromethylphenyl) valine, the N- (2-chloro- 4-trifluoro-methylphenyl) valine, N- (4-chloro-2-fluorophenyl) valine and N- (4-bromo-2-fluorophenyl) valine, in order to obtain the benzyl esters m- (o-fluorophenoxy) of: N- (2-fluoro-4-trifluoromethylphenyl) valine, la- (2-chloro-4-trifluoromethylphenyl) valine, N- (4-chloro-2-fluorophenyl) valine, and la- (4-bromo -2-fluorophenyl) valine.

By repeating the above process with m- (p-fluoro-phenoxy) benzyl bromide as the esterifying agent, the respective m- (p-fluorophenoxy) benzyl esters of the amino acids listed above were prepared.

Example 80:

According to the method of Example 38, N- (2-fluoro-4-methoxyphenyl) valine was prepared and reacted with m-phenoxybenzyl bromide and m-phenoxy-a- bromide, respectively. cyano-benzyl, in order to obtain the m-phenoxybenzyl ester of N- (2-fluoro-4-methoxyphenyl) valine and the m-phenoxy-a-cyanobenzyl ester of N- (2-fluoro-4- methoxyphenyl) vaIine.

By applying the method of Example 42, the N- (2-fluoro-4-methoxyphenyl) valine and the N- (2-fluoro-4-trifluoromethylphenyl) valine were reacted with the bromide of m- ( p-fluorophenoxy) benzyl, in order to obtain 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-trifluoromethyl-phenyl) valine.

Example 81:

According to the method of Example 17 or of Example 42, the N- (2-fluoro-4-trifluoromethylphenyl) valine was esterified, respectively with 2,6-dimethyl-4-allylbenzyl bromide, the bromide of 2,6-dimethyl-4-propargylbenzyle, 4-propargylbenzyl bromide, 4-phenyl-3-chloro-2-butene-1-yl bromide, 3,4-dichloro-a-ethynylbenzyl bromide 3-trifluoromethoxybenzyl bromide, 3-trifluoromethyl-a-ethynylbenzyl bromide, 4- (p-fluorophenyl) -3-chloro-2-butene-1-yl chloride, 4- (o-fluoro- chloride phenyl) -3-chloro-2-butene-1-yl and 3- (2,2-dichloro-vinyloxy) benzyl bromide, in order to obtain the 2,6-dimethyl-4-allylbenzyl ester of N - (2-fluoro-4-trifluoro-methylphenyl) valine,

the 2,6-dimethyl-4-propargylbenzyl ester of N- (2-fluoro-4-trifluoromethylphenyl) valine,

the 4-propargylbenzyl ester of N- (2-fluoro-4-trifluoromethyl-phenyl) valine,

the 4-phenyl-3-chloro-2-butene-1-ester of N- (2-fluoro-4-trifluoromethylphenyl) valine,

the 3,4-dichloro-a-ethynylbenzyl ester of N- (2-fluoro-4-trifluoromethylphenyl) valine,

the 3-trifluoromethoxybenzyl ester of N- (2-fluoro-4-trifluoro-methylphenyl) valine,

the 3-trifluoromethyl-a-ethynylbenzyl ester of N- (2-fluoro-4-tri-fluoromethylphenyl) valine,

the 4- (p-fluorophenyl) -3-chloro-2-butene-1-yl ester of N- (2-fluoro-4-trifluoromethylphenyl) valine,

the 4- (o-fluorophenyl) -3-chloro-2-butene-1-yl ester of N- (2-fluoro-4-trifiuoromethylphenyl) valine, and the 3- (2,2-dichlorovinyloxy) ester benzyl of N- (2-fluoro-4-tri-fluoromethylphenyl) valine.

By applying the method described in US Patent No. 3,979,519, the 3-trifluoromethoxy-a-cyanobenzyl ester of N- (2-

30

fluoro-4-trifluoromethylphenyl) valine, by reacting the acid chloride of N- (2-fluoro-4-trifluoromethylphenyl) valine and the cyanohydrin of 3-trifluoromethoxybenzaldehyde. Alternatively, the 3-trifluoromethoxybenzaldehyde was reacted with 3- (2-fluoro-4-5 trifluoromethylphenyl) -4-isopropyloxazolidine-2,5-dione and potassium cyanide, by applying the method of Example 71, in order to obtain the 3-trifluoromethoxy-a-cyanobenzyl ester of N- (2-fluoro-4-trifluoromethylphenyl) valine.

Young Lima bean leaves (in water) infested with about 50 adult Tetranychus urticae, the following compound, were sprayed until runoff: the N- m-phenoxy-a-cyanobenzyl ester phenylvaline diluted according to 3 different concentrations in an aqueous support containing 0.025% of the product known under the trade name Tween 20 and 0.1% of wetting agent. The leaves thus treated were kept at 24 ° C., with 16 h of lighting for 2 d. Live adult mites were then counted and subtracted from the original total to obtain the affected number which is expressed as a percentage of the total. A correction was made to account for witness mortality using Abbott's Formula 20. The compound had an LC50 (mean lethal concentration) of less than 0.1%.

Individual bean leaves were immersed in the following compound: the m-phenoxybenzyl ester of N-phenyl-N-methylvaline diluted at 3 different concentrations in acetone with 0.025% Tween 20 and 0.1% wetting agent. The leaves were allowed to dry for 2 h, then infested with 10 adult Aphis fabae trapped on the upper surface of the leaves. The leaves thus treated were kept for 48 h at 24 ° C. with a lighting period of 16 h. The effect obtained was determined by the number of deaths calculated as a percentage of total aphids. Corrections were made to witness mortality, if applicable, by applying Abbott's formula. The compound had an LC50 of less than 0.05%.

35 Musca domestica L. adult females, 72 h old, were anesthetized with ether vapor. Then they were treated with 1 μl of the m-phenoxybenzyl ester of N- (p-methylphenyl) valine diluted at 3 different concentrations in acetone, applied to the dorsal surface of the prothorax. They were kept in a test container 40 with cotton saturated with milk at 25 ° C for 24 h, with a lighting period of 16 h. The effect obtained by the number of deaths as a percentage of the total, corrected for control mortality, was determined using Abbott's formula. The compound had a CLS0 of less than 0.01%.

45 In 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 ester N-(p-chlorophenyl) -valine m-phenoxybenzylic at 3 different concentrations, 15 nymphs of fed ticks (Ornithodoros nymph I) were immersed. The 50 treated nymphs were kept on a filter paper for 7 d at 28 ° C. and 64% humidity, with 16 h of lighting period, then they were observed. A correction was made for witness mortality by applying Abbott's formula. The LC50 of the compound was less than 0.01%.

55 Two groups were each treated with 10 larvae of Heliothis virescens instar III from 0 to 24 h with 1 μl of the m-phenoxybenzyl ester of N- (p-methoxyphenyl) valine in acetone at 3 different concentrations, applying the compound to the back of the chest. Two groups of 10 larvae were treated in the same way with 60 l (3 μl of acetone as controls. The larvae were kept individually in 30 ml plastic cups, filled with an artificial medium, for 72 h to 25 ° C with a lighting period of 4 pm After 72 hours, the percentage of deaths was calculated in relation to the total number originally treated, then corrected for mortality, 65 in the control groups, by applying the formula of Abbott The LC50 of the compound was less than 0.5%.

Adult aphids (Aphis fabae adults) were treated with each of the compounds listed below, using the method

21

632232

described above. Each compound had a CLS0 of less than 15 pj (parts per million):

m-phenoxy-a-cyanobenzyl ester of N- (2-chloro-4-trifluoro-methylphenyl) valine,

m-phenoxy-a-cyanobenzyl ester of N- (2-fluoro-4-trifluoro-methylphenyl) valine,

m-phenoxybenzyl ester of N- (2-fluoro-4-trifluoromethyl-phenyl) valine, and m-phenoxybenzyl ester of N- (4-trifluoromethylphenyl) valine.

An emulsion concentrate 4E was prepared using the m-phenoxybenzyl ester of N- (4-trifluoromethylphenyl) valine (51.3%) and the products known under the trade names: Atlox 3404 F (3%), Atlox 3403 F (3%) and Tenneco 500-100 (42.7%) were diluted with water and applied to Tetranychus urticae as described above. The LC50 value was less than 10 ppm.

The compounds listed below have been used to treat tick nymphs (Ornithodoros nymph I), using the method described above. The LC50 was less than 15 ppm:

m- phenoxy-a-cyanobenzyl ester of N- (2-chloro-4-trifluoro-methylphenyl) valine,

m-phenoxy-a-cyanobenzyl ester of N- (2-fluoro-4-trifluoro-methylphenyl) 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-methyl-phenyl) valine,

m- phenoxy-a-ethynylbenzyl ester of N- (2-fluoro-4-methyl-phenyl) valine,

s m- phenoxy-a-cyanobenzyl ester of N- (2-fluoro-4-methyl-phenyl) valine, and m-phenoxy-a-cyanobenzyl ester of N- (4-chloro-2-fluoro-pheayl) valine.

Each of the compounds listed below was applied to Heliothis virescens larvae, using the method described above, and an LC50 of less than 0.1% was obtained:

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-trifluoromethyl-phenyl) valine,

m- phenoxy-a-cyanobenzyl ester of N- (4-bromo-2-fluoro-phenyl) valine, m-phenoxybenzyl ester of N- (2-chloro-4-20 trifluoromethylphenyl) valine,

m-phenoxy-a-cyanobenzyl ester of N- (2-fluoro-4-trifluoro-methylphenyl) valine,

m- phenoxy-α-cyanobenzyl ester of N- (2-chloro-4-trifluoro-methylphenyl) valine, and m-phenoxybenzyl ester of N- (2-fluoro-4-methylphenyl) valine.

Claims (27)

632232 2 1. Compounds which correspond to formula (A) R 'R3 o \ I II , N-C-C-WR5 / I R / R4 (at) in which W is oxygen or sulfur; R1 is a cycloalkyl, cycloalkenyl, cycloalkenyl group substituted by halogen or lower alkyl, or the group % R12 and R13 together form a lower alkylene or a lower alkenylene bridge; R14 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or arylalkyl; R15 is hydrogen or lower alkyl; R16 is hydrogen, or a chloro, fluoro or methyl group; R17 is hydrogen, chloro, fluoro, methyl or, together with Rlfi, can form a carbon-carbon bond; R18 is a phenyl or phenyloxy group; io R19 is hydrogen, halogen, methyl or ethyl; R20 is an allyl, propargyl, 3-butenyl, 3-butynyl, phenyl or benzyl group; and their mineral acid salts into strong organic. 2. Compound according to claim 1, characterized in that it corresponds to the formula: in which t is equal to 0,1,2,3 or 4; Y is independently selected from hydrogen, lower alkyl, lower haloalkyl, lower alkoxy, lower alkylthio, lower alkylcarbonyl, lower alkoxycarbonyl, lower acyloxy, halo, cyano, nitro and lower haloalkylthio; and Z is independently selected from the meanings of Y, a cycloalkyl and lower haloalkoxy group; or Y and Z form a methylenedioxy group; R2 is hydrogen, lower alkyl, haloalkyl-lower carbonyl or formyl; R3 is a lower alkyl group having 2 to 5 carbon atoms, lower alkenyl having 2 to 5 carbon atoms, lower haloalkyl having 1 to 4 carbon atoms, halogeno lower alkenyl having 2 to 4 carbon atoms, or cycloalkyl 3 or 4 carbon atoms lower; R4 is hydrogen or a fluoro group, and Rs is a group chosen from: & R3 O ^ n-ch-c-w-çh— rp R8 R ' wherein R3 is an isopropyl, isopropenyl or trifluoromethyl group. 3. Compound according to claim 1, characterized in that it corresponds to the formula ch3 ch3 \ / ch o S v RIO Rll -CHR «-J ^ jÌj R19 I —CH — C = CH — R20 C = CH -chr "—r8 -VR, J CH2 Ve * '3 w -CH2-C = C-CH2-R18 I I R16R17 or p is 0.1,2 or 3; R6 is hydrogen, cyano, methyl, trifluoromethyl, ethynyl or —C = S; I NH2 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 an alkylenedioxy bridge between two adjacent cyclic carbon atoms; R9 is hydrogen, lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower haloalkynyl, lower alkylcarbonyl, arylcarbonyl, substituted arylcarbonyl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylalkyl, substituted arylalkyl, cycloalkyl, cycloalkyl, cycloalkyl aryloxy-carbonyl, lower alkoxycarbonyl or lower haloalkenyloxy; R10 is hydrogen or a lower alkyl group; R11 is hydrogen, lower alkenyl, lower alkynyl or arylalkyl; -n-ch-c-o-ch- r2 r® in which: Z is hydrogen, a trifluoromethyl, fluoro, chloro, bromo, cyclopropyl or lower alkyl group having from 1 to 4 carbon atoms, R2 is hydrogen, methyl or ethyl; R6 is hydrogen, cyano, ethynyl or S II -vs- ■ NH, R9 is a phenoxy or p-fluorophenoxy group. 4. Compound according to claim 3, characterized in that R2 and R6 are each hydrogen and R9 is a phenoxy group. 5. Compound according to claim 1, characterized in that it corresponds to the formula: in which R2 is hydrogen, methyl or ethyl; R6 is hydrogen, cyano, ethynyl or —C — NH2; R9 is a phenoxy or p-fluorophenoxy group; ") Y is hydrogen, a trifluoromethyl group, fluoro, chloro, bromo, lower alkyl having from 1 to 4 carbon atoms, lower alkoxy having from 1 to 4 carbon atoms, or lower alkylthio having from 1 to 3 atoms carbon; Z is independently selected from the values of Y and the group 65 cyclopropyl, and t is equal to 0.1 or 2. 6. Compound according to claim 5, characterized in that t is equal to 0 and Z is in meta position or in ortho position. 3 632232 7. Compound according to claim 5, characterized in that t is equal to O, Y is in the ortho position and Z is in the para position. 8. Compound according to claim 5, characterized in that t is equal to 1, Y is in the meta position and Z is in the para position. 9. Compound according to one of claims 7 or 8, characterized in that Y is the fluoro group. 10. Compound according to claim 5, characterized in that Z is a lower alkyl group having from 1 to 4 carbon atoms, a chloro, fluoro, bromo, trifluoromethyl or cyclopropyl group; Z is in the para position; Y is in ortho position and t is equal to 1. 11. Compound according to claim 10, characterized in that Y is the fluoro group. 12. Compound according to claim 11, characterized in that Z is a lower alkyl group having from 1 to 4 carbon atoms. 13. Compound according to one of claims 11 or 12, characterized in that R2 and R6 are each hydrogen. 14. Compound according to one of claims 11 or 12, characterized in that R9 is the phenoxy group. 15. Compound according to claim 1, characterized in that it corresponds to the formula: ✓ \ L-L: ' r2 r4 wherein R3 is an isopropyl, isopropenyl or trifluoromethyl group. 16. Compound according to claim 15, characterized in that R2 is hydrogen, R3 is isopropyl group, R® is hydrogen or cyano group, R9 is phenoxy group, W is oxygen, and Y is the: bromo, chloro or fluoro group. 17. Compound according to claim 1, characterized in that it corresponds to the formula: ch3 ch3 y \ / A A / CH o v-nh-ch-c-o-ch-l ij — o! L jj \ = / R6 v in which R6 is hydrogen or the cyano group. 18. Compound according to claim 17, characterized in that Y is the fluoro group, and Z is the chloro, bromo, fluoro, trifluoromethyl group or a lower alkyl group having from 1 to 4 carbon atoms. 19. Compound according to claim 17, characterized in that Y is fluoro and Z is the trifluoromethyl group. 20. Compound according to claim 17, characterized in that Y is fluoro and Z is chloro. 21. Compound according to claim 17, characterized in that Y is the chloro group and Z is the trifluoromethyl group. 22. Compound according to claim 1, in the form of a salt of a strong inorganic or organic acid. 23. Compound according to claim 22, characterized in that it is formed from an acid chosen from hydrochloric, sulfuric, phosphoric acids, p-toluenesulfonic, p-benzenesulfonic and methanesulfonic. 24. Use of the compounds according to claim in the fight against insects and mites, characterized in that it consists in treating said insects or mites with an effective amount, as regards its pesticidal effect, of a composition containing the compound of <formula A or a salt thereof. 25. Use according to claim 24, characterized in that the insect is an insect of the order Lepidoptera, Orthoptera, Heteroptera, Homoptera, Diptera, Beetles or Hymenoptera. 26. Use according to claim 24, characterized in that 1 the insect is a mite or a tick of the order mites. 27. Use according to claim 26, characterized in that the mite is from the family of tetranychids or tarsonemids.