CH631169A5 - Method for preparing amides of (2-pyrimidinylthio)-alkanoic acids, having an antilipemic activity - Google Patents

Description

The present invention relates to methods for preparing amides of alkanoic (2-pyrimidinylthio) acids having antilipemic activity and the products of these methods.

Alkanoic (2-pyrimidinylthio) acids, their esters, amides and hydrazides, are described in U.S.P. 3 814 761, with reference to an antilipemic effect. The replaced amides which are the subject of this application, structurally new, however, are clearly less toxic - with the same activity - than the compounds described in the cited patent. The amides of the present invention correspond to the general formula (I)

, /

IS

S-CH- (CHp) -CO-N 'i n \ 3

IS

(THE)

in which

Y represents halogen;

R represents hydrogen or CVC4 alkyl

4 5 E E

R1 represents halogen; a residue - N

IS

(where R4 = H or CrC4 alkyl, while R5 and R6, which can be the same or different, stand for H, halogen, methyl or methoxyl); a benzylamine residue; a residue

20

R1 represents a residue

(where is it

25 R5 and R6 have the meanings specified above), or a benzylamine residue;

n = 0;

R2 and R3, which can be the same or different, represent linear or branched alkyl or alkenyl CrC10;

30 c2-c5 hydroxyalkyl or mercaptoalkyl residues, linear or branched; while R2 can also represent hydrogen.

IS"

35

Non-limiting examples of R1 are residues

-HB ^ r

40 corresponding to the following amines, aniline, 2,3-xylidine, 4-chloroaniline, 4-methoxyaniline, 2,4,6-trimethylaniline, 3,4-di-chloroaniline, 4-fluoroaniline, 3-trifluoromethylaniline, 4-phenyl- aniline; the benzylamine residue; the groups -NH-CH2CH2OH and -N-CH2CH2OH; and similar.

45

CH,

According to the invention, the compounds (I) can be prepared by reacting the activated derivatives of the corresponding acids (II) with the amines of general formula (III), according to the scheme A:

Scheme A

55

60

ï Jl

V-S-CH- (CH „) -COX 1 i 2'n

+ H-H

/

\ 3

(D

(II)

(III)

where Y, R, R \ R2, R'en have the meanings specified above, while X represents halogen (preferably chlorine) or 65 the residue 0-C0-0C2H5. When (II) represents an acyl chloride (X = CI), the latter is obtained by treating the corresponding alkanoic acid (2-pyrimidinylthio) with SOCl2 or oxalyl chloride in benzene solution; not oc-

631169

4

it is necessary to isolate the compounds (II) thus obtained, which are directly treated with the amines (III), possibly in the presence of tertiary bases. When, on the other hand, the compounds (II) are mixed anhydrides (X = 0-C0-0C2H5), they are prepared by treating the corresponding alkanoic acids (2-pyrimi-dinylthio) with ethyl chlorocarbonate in the presence of a tertiary base (preferably triethylamine), in solvents such as tetrahydrofuran, chloroform or acetone; also in this case the compound (II) may not be isolated and be directly transformed into the final product (I) by reaction with the desired amine (III).

Alternatively, the compounds (I) can be prepared by directly treating the corresponding alkanoic (2-pyrimidinyl-thio) acids with two moles of amine (III), two moles of triethylamine and two moles of BF3-etherate, in benzene solution or toluene, reflux, anhydrifying the solvent on MgS04, according to the technique described by J. Tani, J. Dine and I. Inouf in Synthesis, 714,1975.

R2

In the particular case where the group -N ^ [, in the com-

R3

places of formula (I), represents a ß-hydroxyalkyl-amino residue, the preparation can be carried out by reacting the corresponding acids with aziridines of general formula (IV)

(IV)

R

10

wherein R9 and R10 represent hydrogen atoms or Cj-C3 alkyl groups, and R10 can also mean CH2CH2OH.

The compounds (I) in which Y represents chlorine, while R1 has a different meaning from halogen, can be obtained according to the invention by treating the amides of alkanoic acids (4,6-di-chIoro-2-pyrimidinylthio) alkanoic (V) with two equivalents of an amine (VI), fusion, according to scheme B:

Scheme B

I

15

20

S — OH— (CH_) -CO-H

2'31

IS

\ 3

(V)

2 R'-H

(YOU)

CI JT

y Ys-? h- (cVi

-CO-IT

/

XR3

(THE)

where R, R2, R3 and n have the above specified meanings, while R1 has the above specified meanings except for the halogen one.

In turn, the alkanoic (4,6-dichloro-2-pyrimidinylthio) acids of general formula (VII) can be prepared by means of acid hydrolysis of the corresponding esters (VIII), ac-30 which can be dissolved for example according to the method described in USP 3 814 761 by condensation of sodium thiobarbiturate with bromoesters (IX) and subsequent reaction with POCl3, according to scheme C:

Scheme C

(VIII)

(VII)

where Ren have the meanings specified above, while Et represents an ethyl residue.

The compounds of this invention are all significantly less toxic than the corresponding free acid. For example 60 [4-chloro-6- (2,3-xylidino) -2-pyrimidinylthio] - (N-ß-hydroxyethyl) -acetamide administered as a single oral dose in the mouse does not result in the death of any animal or the appearance of toxic phenomena at the dose corresponding to DL100 in the case of the corresponding acetic [4-chloro-6- (2,3-xyl-65 dino) -2-pyrimidinylthio] acetic acid.

In particular, [4-chloro-6- (2,3-xylidino) -2-pyrimidinil-thio] - (N-ß-hydroxyethyl) acetamide at 5 g / Kg / os does not cause the death of any animal in the rat or in the mouse, male or

THE

female, while the [4-chloro-6- (2,3-xylidino) -2-pyrimidi-niltio] acetic acid administered orally presents in the male mouse a LD50 of 1600 mg / Kg (1260-2032) and in the female a DL50 of 1155 mg / Kg (970-1374), calculated according to Litchfield and Wilcoxon.

Likewise the compounds corresponding to the general formula

CI

NH

CH.

CH.

wherein X is: -N (CH2-CH2OH) 2; -NH (CH2CH2CH2OH); -NH (CH2CH2CH2CH2OH); -NHCH (CH3) CH2OH; -NH (CH2CH3); -NH (CH2CH2CH3); -NH (CH2CH2CH2CH3); -N (CH2CH3) 2 do not cause the death of any animal at 5 g / Kg / os. Medium-term toxicological research shows that [4-chloro-6- (2,3-xylidino) -2 - pyrimidinylthio] - (N-ß-hydroxyethyl) acetamide is less toxic than acid for the same dose. [4- chloro-6- (2,3-xylidino) -2-pyrimidinylthio] acetic, particularly in the liver. The considerable decrease in toxicity detected for the compounds of this invention, particularly those containing alkyl or hydroxy alkylic chains of up to 4 carbon atoms, is not followed by any decrease in activity, always with reference to free acid. These compounds reduce the concentration of triglycerides and cholesterol in the blood serum of normal rats or of rats treated with a hypercholesterolemic diet. In particular with the Buchanan test (the drug is administered in the normal rat for 4 days and the analysis of serum cholesterol is established on the fifth day) the compounds that lower the serum cholesterol by at least 20% at a dose of 400 are considered active mg / Kg; a standard drug, represented by Clofibrate, at a dose of 200 mg / Kg reduces the level of serum cholesterol by 20%. With this test, the following results were obtained when X was changed:

X

dose: mg / kg

% decrease in serum cholesterol levels oh

50

30,28

nhch2ch2oh

56

30,70

n (ch2ch2oh) 2

64

28,70

NHCH (CH3) CH2OH

59

31,20

nh (ch2) 3ch3

58

35,00

nhch2ch3

54

24,20

n (C2H5) 2

54

15,00

nhc3h,

56

21,00

nh (ch2) 2ch2oh

50

15,00

nh (ch2) 3ch2oh

50

19,00

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In the blood serum of normal rats or on a hypercholesterolemic diet treated with [4-chloro-6- (2,3-xylidino) -2-piri-midinylthio] - (N-ßhydroxyethyl) acetamide, there are no abnormal steroids possibly derived from the pathways of synthesis of cholesterol. 10 to 200 mg of active substance can be used as a single dose. Useful pharmaceutical forms can be:

- capsules: composition for 100 mg [4-chloro-6- (2,3-xylidino) -2-pyrimidinylthio] (N-ß-hydroxyethyl) acetamide mg 50 lactose mg 49 magnesium stearate mg 1

- tablets: composition per 100 mg [4-chloro-6- (2,3-xylidino) -2-pyrimidinylthio] (N-ß-hydroxyethyl)

acetamide mg

50

starch mg

27

lactose mg

18

talc mg

4

magnesium stearate mg

1

Example 1

[4-chloro-6- (2,3-xylidino) -2-pyrimidinylthio] - (N - & - hydroxyethyl) -acetamide

To the suspension of [4-chloro-6- (2,3-xylidino) -2 - pyrimidinylthio] acetic acid (60 g) in chloroform (1200 ml), ethylenymine (5.4) is added dropwise at room temperature ml) in chloroform (60 ml) and the resulting solution is heated to boiling for 4 hours. The mixture is cooled to room temperature, a further 2.7 ml of ethylenimine are added in chloroform (30 ml) and heated to reflux again for 4 hours.

After a further addition of 1.35 ml of ethylenimine in chloroform (15 ml) and re-heating to boiling for 4 hours, it is concentrated to a small volume (300 ml). The precipitated solid is filtered and subsequently crystallized from acetone. 40 g of [4-chloro-6- (2,3-xyl-dino) -2-pyrimidinylthio] - (N-ß-hydroxyethyl) acetamide are obtained.

Calculated for C16H19C1N402S: C 52.36 H 5.22 N 15.28 Found: C 52.43 H 5.20 N 15.31

mp = 150-151 ° C (acetone).

The following compounds were prepared with the same method:

Example 2

[4-chloro-6- (2,3-xylidino) -2-pirimidiniltio] - (N, N-bis - $ - hydroxy-ethyl) acetamide

Calculated for C18H23C1N403S: C 52.59 H 5.64 N 13.64 Found: C 52.37 H 5.48 N 13.53

mp = 166-167 ° C (acetone).

Example 3

[4-chloro-6- (2,3-xylidino) -2-pyrimidinylthio] -N- (ct-methyl-phi - hydroxyethyl) acetamide

Calculated for C17H21C1N402S: C 53.58 H 5.56 N 14.72 Found: C 53.39 H 5.42 N 14.69

mp = 170-172 ° C (acetone).

5

5

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there

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Example 4 -2-pyrimidinylthio] acetic, the correction is obtained with good yields

[4-chloro-6- (p-chloroaniline) -2-pyrimidinylthio] - (N - ^ - hydroxy ethyl) - N-ß-hydroxyethylamide coating.

acetamide Calculated for CnH17ClN403S: C 41.19 H 5.34 N 17.46

Calculated for C14H14C12N402S: C 45.03 H 3.78 N 15.02 5 Found: ^ c 41> 25 H 5> 40 N 17'40

Found: . C 44.95 H 3.80 N 15.07 pf "~~ 119" 121 ° c (ethyl acetate).

mp = 145-147 ° C (ethanol / water).

Example 5

Example 9

/ 4-chloro-6- (2,3-xylidino) -2-pirimidiniltio] - (N-ft-hydroxyethyl) - (5-chloro-6-benzylamino-2-pirimidiniltio) - (N - $ - hydroxyethyl) - acetamide acetamide

To the solution of [4-chloro-6- (2,3-xylidino) -2-piri-Calculated for C15H17C1N402S: C 51,04 H 4,86 N 15,89 midinylthio] acetic (85 g), triethylamine (45 ml), in chlorofor-Found: C 50.87 H 4.97 N 15.75 mj0 anhydrous (750 ml) cooled to -5 ° they drop, under

P-f- = H7-119 ° C (ethanol / water). 15 stirring, 35 ml of ethyl chlorocarbonate and, subsequently, 22 ml of ethanolamine, keeping the temperature Example 6 aj below + 10 ° C. The reaction mixture is washed with

(4-chloro-6-aniline-2-pyrimidinylthio) - (N-ß-hydroxyethyl) - water (350 ml), dried on sodium sulphate and the solvent acetamide was removed under reduced pressure. The residue is washed with benzene

20 (500 ml) and subsequently crystallized from acetone. It is obtained by C14H15CIN402S: C 49.61 H 4.46 N 16.54 hold 55 g of [4-chloro-6- (2,3-xylidino) -2-pyrimidinylthio] -Founded: C 49,50 H 4.64 N 16.45 (NR-hydroxyethyl) acetamide, identical to the compound prepared pf - 136-138 ° C (ethanol / water). according to example 1.

Example 7 25 With the same method the following com- pounds were prepared

[4-chloro-6- (p-methoxyaniline) -2-pyrimidinylthio] - (N - $ - hydroxy- places.

ethyl) acetamide

Example 10

Calculated for C15H17C1N403S: C 48.82 H 4.65 N 15.20 ... -, ...,. , _. . ... 7 ,, T,

Found - C 48 95 H 4 64 N 15 12 30 l4-chloro-6- (2,3-xylidino) -2-pinmidinylthio] - (N-ethyl) acetamide m.p. = 119-121 ° C (ethanol / water). Calculated for C16H19C1N40S: C 54.75 H 5.46 N 15.98

Found: C 54.61 H 5.50 N 15.87

Example 8 m.p. = 191-192 ° C (acetone).

a) [4-chloro-6- (N-methyl-N-phi-hydroxyethylamino) -2-pyrimidinyl-

thio] ethyl acetate 35 ". ,,

Example 11

The mixture of (4,6-dichloro-2-pyrimidinylthio) ethyl acetate [4-chloro-6- (2,3-xylidino) -2-pyrimidinylthio] - (Nn-pwpil) - (g 16), carbonate of anhydrous sodium (3.7 g), N-methylaminoacetamide

ethanol (5.9 ml) of ethanol (100 ml) is heated to boiling, under stirring, for 16 hours. The mixture is filtered and 40 is calculated for C17H21ClN4OS: C 55.93 H 5.80 N 15.36 adds water until the precipitation is triggered (400 ml). Found: C 55.75 H 5.60 N 15.47

It is left to rest for 60 'at 0 ° C. The precipitated solid is filtered m.p. = 146-148 ° C (benzene).

which is recrystallized from ethanol / water. 13 g of [4-chloro-6- (N-methyl-N-ß-hydroxyethylamino) -2-pyrimidinylthio] are obtained -

ethyl acetate. 45 Example 12

Calculated for CnH16N3C103S: C 43.18 H 5.28 N 13.75 14-chloro-6f, 3-xylidino) -2-pyrìmidinylthio] - (N-i-propil) -

Found: C 43.20 H 5.38 N 13.68 acetamfnlde m.p. = 73-74 ° C (isopropyl ether). Calculated for C17H21ClN4OS: C 55.93 H 5.80 N 15.36

50 Found: C 56.06 H 5.96 N 15.24

b) Acid [4-chloro-6- (N-methyl-N - $ - hydroxyethylamino) -2- m.p. = 156-158 ° C (benzene).

-pyrimidinylthio] acetic

The 5.6 g solution of the ester described above in 30 ml Example 13

of ethanol, added with 0.7 g of NaOH in 8 ml of water,

it is boiled for two minutes, then diluted with 160 ml of water 55 [4-chloro-6- (2,3-xylidino) -2-pyrimidinylthio] - (N-n-butyl) -and extracted with ether. The aqueous phase is acidified with acetamide

17.6 ml of HCl IN and evaporated to dryness. By crystallization - Calculated for C18H23N4C10S: C 57.03 H 6.12 N 14.79 zation of the residue from about 60 ml of acetone are obtained Found - C 56 90 H 6 15 N 14.70

4 g of the desired acid. mp = 137-139 ° C (ethereal ether).

Calculated for C9Hi2ClN303S: C 38.90 H 4.36 N 15.14 60

Found:. C39.05 H4.30 N 15.10 Example 14

mp = 188-190 ° C (acetone).

[4-chloro-6- (2,3-xylidino) -2-pyrìmidinylthio] - (N-n-hexyl) -

c) [4-chloro-6- (N-methyl-N-ß-hydroxyethylamino) -2-pyrimidinyl- acetamide thio] - (N - $ - hydroxyethyl) acetamide 65 Calculated for C20H27C1N4OS: C 59.00 H 6.69 N 13.77

Operating according to Example 1, by reaction of ethylene. Found: C 59.15 H 6.52 N 13.80

imine with t4-chloro-6- acid (N-methyl-N- | ß-hydroxyethylamino) - m.p. = 116-118 ° C (benzene-hexane).

7

631169

Example 15

[4-chloro-6- (2,3-xylidino) -2-pirimidiniltio] - (N-n-octyl) acetamide

Calculated for C22H31C1N40S: C 60.71 H 7.23 N 12.89

Found: C 60.85 H 7.35 N 12.78

mp = 144-146 ° C (benzene).

Example 16

[4-chloro-6- (2,3-xylidino) -2-pirìmidiniltio] - (N-allyl) acetarnmide

Calculated for C1TH19C1N40S: C 56.24 H 5.28 N 15.45 Found: C 56.35 H 5.25 N 15.47

mp = 143-145 ° C (benzene / hexane).

Example 17

[4-chloro-6- (2,3-xylidino) -2-pirimidiniltio] - (N-cyclohexyl) acetamide

Calculated for C20H25C1N4OS: C 59.30 H 6.23 N 13.84 Found: C 59.43 H 6.35 N 13.72

mp = 156-158 ° C (acetone).

Example 18

[4-chloro-6- (2,3-xylidino) -2-pyrimidinylthio] - (N, N-diethyl) -acetamide

Calculated for C18H23ClN4OS: C 57.03 H 6.12 N 14.79 Found: C 57.29 H 6.07 N 14.68

mp = 104-106 ° C (ethyl acetate / hexane).

Example 19

l4-chloro-6- (2,3-xylidino) -2-pirimidiniltio] - (N ~ $ -tioletil) acetamide

Calculated for C16H19ClN4OS2: C 50.16 H 5.00 N 14.64 Found: C 50.25 H 5.05 N 14.51

mp = 117-119 ° C (ethyl acetate / hexane).

Example 20

[4-chloro-6- (2,3-xylidino) -2-pirimidiniltio] - (N-morpholino) acetamide

Calculated for C18H21N4C102S: C 55.00 H 5.39 N 14.27 Found: C 55.05 H 5.48 N 14.13

mp = 106-108 ° C (ethyl acetate / hexane).

Example 21

14-chloro-6- (2,3-xylidino) -2-pirimidiniltio] - (N-piperidino) -acetamide

Calculated for C19H23N4C10S: C 58.35 H 5.93 N 14.34 Found: C 58.20 H 5.83 N 14.27

mp = 113-115 ° C (methylene chloride / hexane).

Example 22

[4-chloro-6- (2,3-xylidino) -2-pìrimidiniltio] - (N-3-hydroxypropyl) -acetamide

Calculated for CnH21ClN402S: C 53.58 H 5.56 N 14.72 Found: C 53.48 H 5.45 N 14.70

mp = 122-124 ° C (ethyl acetate).

Example 23

[4-chloro-6- (2,3-xylidino) -2-pirimidiniltio] - (N-4-hydroxybutyl) acetamide

Calculated for C18H23CIN402S: C 54.72 H 5.87 N 14.19

Found: C 54.68 H 5.75 N 14.25

mp = 84-86 ° C (ethyl acetate).

Still according to the method described in Example 9, the compounds of Examples 2-7 were also prepared.

Example 24

[4-chloro-6- (2,3-xylidino) -2-pyrimidinylthio] - (N-n-bu til) -acetamide

The mixture of [4-chloro-6- (2,3-xylidino) -2-pyrimidinyl-thio] acetic acid (1.6 g), triethylamine (1.4 ml), n-butylamine (730 mg), trifluoride of 47% boron etherate (2.68 ml), in anhydrous benzene (70 ml), is heated to boiling for 24 hours. The reaction solvent is dehydrated by passing it in a Soxlet extractor containing magnesium sulfate. The reaction mixture was washed with 10% NaOH, then with hydrochloric acid and finally with water until neutral. The mixture is dried over sodium sulphate and the solvent is evaporated under vacuum. The compound obtained is identical to that of Example 13.

Example 25

a) Acetic acid (4,6-dichloro-2-pyrimidinylthio)

The solution of the ethyl ester of the acetic acid (4,6-dichloro-2-pyrimidinylthio) (4 g) in a mixture of glacial acetic acid (40 ml) and 37% HCl (8 ml) is heated to boiling for three hours. After cooling to 0 ° C, water and ice are added and the precipitated solid is filtered. The latter is purified by extracting the aqueous solution of its sodium salt with ether which is then acidified to filter again the acid which is washed with water in neutral and dried under vacuum on P205. By crystallization from chloroform 2.5 g of acetic acid (4,6-dichloro-2-pyrimidi-nylthio) are obtained.

Calculated for C6H4C12N2S02: C 30.12 H 1.68 N 11.72 Found: ■ C 30.20 H 1.69 N 11.61

mp = 120-122 ° C (chloroform).

b) (4,6-dichloro ~ 2-pyrimidinylthio) - (N-phi-hydroxyethyl) acetamide

To the suspension of (4,6-dichloro-2-pyrimidinylthio) -acetic acid (2,390 g) in anhydrous benzene (24 ml), 1.27 ml of oxalyl chloride in anhydrous benzene (6 ml) are added dropwise at room temperature ). The reaction mixture is heated under stirring at 40 ° C for 30 ', then it is kept at 60 ° C for another 10'. The solvent is evaporated under vacuum to obtain an oily residue which is taken up with anhydrous chloroform (50 ml); the chloroform solution is added drop by drop to an ethanolamine solution (1.1 ml) in anhydrous chloroform (40 ml), keeping the temperature at about 15 ° C. It is left to rest at room temperature for 60 ',

then the separated solid is filtered. The filtrate is evaporated under vacuum to obtain a residue which is crystallized from ethyl acetate / hexane (1.5 g).

Calculated for C8H9N3C12S02: C 34.03 H 3.19 N 14.90 Found: C 34.12 H 3.22 N 14.85

mp = 95-96 ° C (ethyl acetate / hexane).

With the same method were prepared:

Example 26

(4,6-dichloro-2-pirimidiniltio) - (N-.beta.-tioletil) acetamide

Calculated for C8H9C12N3S20: C 32.20 H 3.02 N 14.10 Found: C 32.30 H 3.06 N 14.20

mp = 88-90 ° C (ethyl acetate / hexane).

5

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I *

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Example 27 (4,6-dichloro-2 ~ pyrìmidìniltio) - (N-butyl) acetamide

Calculated for C10H13C12N3SO: C 40.80 H 4.46 N 14.29 Found: C 40.91 H 4.42 N 14.29

mp = 109-111 ° C (ethyl acetate / hexane).

Example 28

[4-chloro-6- (2,3-xylidino) -2-pyrimidinylthio] - (N - $ - hydroxyethyl) -acetamide

A mixture of (4,6-dichloro-2-pyrimidinylthio) - (N-ß-hydroxy-ethyl) acetamide, obtained according to example 25, (0.490 g) and 2.3-dimethylaniline (0.434 ml) is heated to melting by immersing it in an oil bath (T = 110 ° C) for 10 '. The solid residue 5 thus obtained is cooled and crystallized from acetone to obtain 0.400 g of [4-chloro-6- (2,3-xylidino) -2-pyrimidiniI-thio] - (N- | ß-hydroxyethyl) acetamide, identical to the one prepared according to example 1.

The 10 compounds of Examples 2 to 7 and 10 to 23 were also prepared with the same method.

v

Claims (3)

631169 2. Process for the preparation of amides of alkanoic acids (2-pyrimidinylthio) of general formula (IX) S-CH- (CH0) -C0-ÏÏ J l "N, 3 (X) 65 where R, R1, R2, R3 and n have the meanings specified above, except that of halogen for R1; characterized in that the aforementioned amides are treated by fusion with two equivalents of an amine of formal R1 - !!, according to the scheme: 3 631169 oi ^ H J | ^ p S- ^ H- (CH2) n-C0-M X3 + E -H ■ Cl R XR3 where R, R1, R2, R3 and n have the meanings specified above, except that of halogen for R1. 4. Amides of alkanoic acids (2-pyrimidinylthio) of general formula (I). R7 R8 I i - N - CH - CH2OH (where R7 and R8, which can be the same or different, stand for H or for alkyl Cj-C ^; 5 n represents 0, 1 or 2; R2 and R3, which can be the same or different, represent linear or branched alkyl or alkenyl Cj-C ^ residues; cycloalkyl residues; C2-C5 hydroxyalkyl or mercapto-alkyl residues, linear or branched; or, together with I N, form a saturated heterocyclic ring with 5 or 6 members, optionally containing another heteroatom; while R2 can also mean hydrogen. Particularly preferred, according to the invention, are the compounds of formula (I) in which: 15 Y represents chlorine; R represents hydrogen; S-CH- (CH) -C0-N UT k 2n * 2 CLAIMS 1. Process for the preparation of amides of alkanoic acids (2-pyrimidinylthio) of general formula (I) S-CH- (CH2) n-C0-N R XR3 in which Y represents halogen; R represents hydrogen or Cj-C4 alkyl (THE) S-ÇlH- (CH2) n-C0-Nx r H "10 CH-CHgOH (IX) io in which Y, R, R1 en have the meanings specified above, while R9 and R10 represent H or alkyl groups Ct-C3, and R10 can also represent CH2-CH2OH, according to claim 1, characterized in that 15 are reacted the corresponding alkanoic (2-pyrimidinylthio) acids with aziridines of general formula (IV) according to the scheme: R- R1 represents halogen; a residue R 20 l-CH- (CH-) —COOH The 2 n E + R -H / ÇHa .10 I CH-R 25 (IV) (where R4 = H or C, -C4 alkyl) while R5 and R6, which can be the same or different, stand for H, halogen, methyl or methoxyl); a benzylamine residue; a residue R7 R8 - N - CH - CH2OH (where R7 and R8, which can be the same or different, stand for H or for Cx-C4 alkyl); n represents 0, 1 or 2; R2 and R3, which can be the same or different, represent straight or branched chain alkyl or alkenyl residues C ^ C ^; cycloalkyl residues; C2-C5 hydroxyalkyl or mercaptoalkyl residues, linear or branched chain; or, together with N, they form a saturated heterocyclic ring with 5 or 6 members, possibly containing another heteroatom, while R2 can also represent hydrogen, characterized in that compounds of general formula (II) are reacted with amines of general formula ( III), according to the scheme: H N-j- "S-CH- (CHg) n-C0X S? IS ♦ H "- / (II) (III) 30 CH- (GH2) n- C0 ÷ "10 0H-CH20H (IX) 35 in which Y, R, R1, n, R9 and R10 have the meanings specified above. 3. Use of the amides of formula (I) 40 s-tp-Ccs ^ -co-: R ■ R (D 50 (where R, R2, R3 and n have the above specified meanings) obtained according to claim 1, to obtain amides of alkanoic acids (4-chloro-2-pyrimidinylthio) of general formula (X) XR3 (THE) 55 where Y, R, R1, R2, R3 en have the meanings specified above, while X represents halogen, preferably chlorine, or OH, or the residue 0-C0-0C2H5, and R10 represents hydrogen, in aprotic solvents and in the presence of tertiary bases. 3 CD wherein Y, R, R1, R2, R3 and n have the meanings specified above, produced by means of the process according to claim 1.