CH639370A5 - HALOGENATED MERCAPTOACYLAMINE ACIDS AND PROCESS FOR THEIR PREPARATION. - Google Patents

Description

The invention relates to the objects defined in the claims.

This invention, in its broadest aspects, relates to the halogenated derivatives of mercaptoacylproline and mercaptoacylpipecolic acids of formula I.

The preferred proline types (m = 1) are the compounds of general formula (I), having the following specific formulas:

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R /

r-

r— s - (ch) ^ - ch co— n

(ii) coor,

where R is hydrogen, lower alkanoyl, or of the formula:

R>

r-

30

-s-

(ch) ch n

CO

coor,

wherein Rj is hydrogen or lower alkyl; R2 and R5 are each hydrogen or fluorine; R3 and R4 are each hydrogen or trifluoromethyl, one being hydrogen, the other being trifluoromethyl; n is 1 or 0.

r4

r —s ~ • (ch)

not

R3

I 3

ch r,

co - n

(III)

coor-,

(V)

where R and R! are identical to those defined in formula II; R2 and 45 Rs are each hydrogen or halogen; R3 is hydrogen, lower alkyl or halogen, R3 being halogen when R2 and R5 are each hydrogen or R3 is different from halogen when R2 and R5 are each halogen; R4 is hydrogen; n is 0 or 1, in these cases, they are alkaline salts of the compounds 50 of formula II and III.

In the case of formula II: when n is equal to 0 and R2 and R5 are both hydrogen, R3 is trifluoromethyl. When n is equal to 1, one of the groups R3 and R4 is trifluoromethyl, the other being hydrogen. This means that there is a trifluoro-55 methyl group in the side acyl chain of the molecule. When n = 0, this group is located on the carbon a of the carbonyl group (R3 = CF3). This group is located either on the carbon a of the carbonyl group (R3 = CF3, R4 = H), or on the carbon ß of the carbonyl group (R3 or R4 is a trifluoromethyl, R2 and R5 are each a hydrogen 60 or a halogen.

In the case of formula III: one (or both) of the groups R2 and R5 is a halogen; R3 and R4 are each hydrogen, lower alkyl; or R2 and R5 are both hydrogen; R3 is a halogen, preferably chlorine or bromine; and R4 is a hydro-65 gene.

The preferred compounds are the compounds of formula II where R is hydrogen or lower alkanoyl, more specifically hydrogen or acetyl; R, is hydrogen or lower alkyl

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laughing, specifically hydrogen; R2 and R5 are each hydrogen or halogen, more specifically hydrogen or fluorine; R3 and R4 are each hydrogen or trifluoromethyl; one of these two groups is hydrogen, the other a trifluoromethyl, when R2, R5, Re are all hydrogen atoms; n is 0 or 1, more specifically 1.

The two halogen atoms can be located on the Pyrrolidine nucleus. Only one halogen can be on the carbon in position 3 or 4. The two halogen atoms can be on the carbon in position 4; it is preferable then that the two are identical. Fluorine is the preferred halogen, especially if one or two fluorine atoms are on the carbon in position 4.

The preferred pipecolic acids (m = 2) are the compounds of formula I, where R is hydrogen or lower alkanoyl, more specifically hydrogen or acetyl; R, is hydrogen or lower alkyl, more specifically hydrogen; R2 and R'2 are each hydrogen or halogen, more specifically hydrogen or fluorine; one of R3 and R4 is hydrogen, the other being trifluoromethyl (CF3); n is 0 or 1, more specifically 1; R2 and R'2 can each be hydrogen or halogen, more specifically fluorine. When R3 or R4 is a CF3, it is preferable that R2 and R'2 are both hydrogen.

The preferred form of prolines and pipecolic acids is the L configuration.

The various lower alkyl groups represented can be straight or branched chain hydrocarbon radicals, from methyl to heptyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, etc. The radicals from Ct to C4 are preferred, more specifically the radicals C2 and Cx.

The lower alkanoyl groups are acyl radicals of lower fatty acids (C2-C7): acetyl, propionyl, butyryl, etc. Preferred are lower alkanoyl groups having up to 4 carbon atoms, and more specifically acetyl.

The halogens used are the 4 common halogens; preferably chlorine, bromine and fluorine are used, the latter more specifically.

The compounds of formula I can be synthesized by different methods.

In general, the synthesis of these compounds is characterized in that an acid of formula:

R4

r4

Rs I

R-S - (CH) n - CH - COOH with the amino acid of formula:

(IV)

(V)

coor,

Any method capable of forming an amide bond can be used; see "Methoden der Organischen Chemie" (Houben-Weyl) part I, p. 376 et seq., Part III, p. 1 and seq. (1974).

The acids of formula IV are obtained (when n = 1) by addition of a thioacid R-SH to an adequately substituted acrylic acid. R may be a p-methoxybenzyl group in order to temporarily protect the mercapto group in the compounds of formula IV. This group is then removed with trifluoroacetic acid and mercuric acetate. The acids of formula IV (n = 0) are obtained by a displacement reaction with a thioacid or a 2-halogenic acid.

According to one of these methods, preferably used when n = 0, an acid of formula V is coupled with a haloalkanoic acid of formula:

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r3 I

X— (CH) n — CH — COOH (VI)

where X is a halogen, more specifically chlorine or bromine; 5 one of the known methods is followed in which an acid VI is activated before the reaction with acid V: this reaction is characterized by the formation of a mixed anhydride, a symmetrical anhydride, an acid chloride, an active ester or by the use of a reagent from Woodwark K, EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2,2-dihydro-10 quinoline), etc.

The product of this reaction is a compound of formula:

R,

r.

x— (ch) n ch

R,

h2c

(VII) b m

-CO

not

-coor,

This product is subjected to a displacement reaction with a thioacid anion of formula:

R4-CO-SH (VIII)

where R is lower alkyl;

25 a product of formula is obtained:

r, r'2

r,

R-

30

h2c

X

(IX) CHR6) m r? —Co-s - (ch) - ch-co— n lcoor1

which can be converted into the product of formula:

r,

40

hs-

R.

(ch)

r.

h2c

X

r '

2 (X)

n ch— co —n-

(chrc) 6 m coor,

by alkaline hydrolysis or ammoniolysis. When Rj is an ester group (i.e. Rj is lower alkyl, ester obtained from acid V), it can be removed by conventional techniques. If R, is a t-butoxy or a t-amyloxy, the corresponding free acid will be obtained by treating the ester of formula IX or X with trifluoroacetic acid and anisole. If other alkoxy groups are present, the corresponding acid will be obtained by alkaline hydrolysis. 50 If an acid V is used as starting material, or if the final product is in the form of a free carboxylic acid, this acid can be converted into its corresponding ester, by esterification with a diazoalkane, diazomethane for example, or a 1-alkyl-3-p-tolyltriazene, such as ln-butyl-3-p-tolyltriazene, etc. 55 According to another method, an ester V, preferably a methyl or t-butyl ester, is treated with an acylthioalkanoic acid of formula:

r4 r3

R7 - CO - S - (CH) n - CH - COOH

(XI)

in the presence of coupling agents such as dicyclohexylcarbodiimide, N, N'-carbonylbisimidazole, ethoxyacetylene, diphenylphosphorylazide, etc., at a temperature varying between 0 and 10 ° C; this reaction takes place in an anhydrous medium such as dichloro-65 methane, tetrahydrofuran, dioxane, etc. The ester group is then removed, by treatment with trifluoroacetic acid and anisole at room temperature; free acid is thus obtained (R, = H).

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Another method, used essentially when n = 1, R + = CF3 and R3 = H, is characterized in that a thioacid of formula VIII is reacted with an acrylic acid derivative of formula:

R4 R3 °

I I H

ch - ch— c

in place of the compound of formula VII; the rest of the procedure is identical to that described above. The compounds of formula XII are obtained from 3-trifluoromethylacrylic acid; ester V is obtained by the process described in Example 14 below. 15

The compounds of formula I, where R is:

-s (ch) - ch are obtained by iodic oxidation of the compound of formula I, where R 25 is hydrogen; a bisymmetric compound is obtained.

The halogenated compounds used as starting material can be obtained by usual methods: see “Biochemistry”, 4.2509 (1965), “Aust. J. Chem. ", 20,1493 (1967)," J. Bitter. Chem. Soc. ”, 86, 4709 (1964),“ J. Med. Chem. ”, 20, 1176 (1977). 30

The products of formula I have one or more asymmetric centers; the main center is indicated by an asterisk in formula I. These compounds exist in the form of stereoisomers or racemic mixture. The invention relates to all these different forms. The syntheses described above can use as starting material a racemate or one of the enantiomers. If a racemic mixture is used as starting material, the stereoisomers obtained can be separated by chromatography or fractional crystallization. The preferred isomeric form is the L isomer of the main asymmetric carbon. 40

The compounds of this invention form alkaline salts with various inorganic or organic bases; these salts are also objects of this invention. These are ammonium salts; alkali, sodium or potassium salts (preferred); alkaline earth metal salts, calcium or magnesium; salts of organic bases: dicyclohexylamine salts, benzathine, N-methyl-D-gluc-amine, hydrabamine; amino acid salts: arginine, lysine, etc. Non-toxic, physiologically acceptable salts are preferred, but the other salts can be used for isolation and purification of the product. 50

These salts are obtained by usual methods; by reacting the free acid with one or more molar equivalents of the appropriate base, the salt is obtained in ionic form in a solvent or a medium in which it is insoluble; if the medium is water, it must be removed by cold drying. Neutralization of the salt with an insoluble acid 55, such as a cation exchange resin in hydrogenated form (polystyrene sulfonic acid resin, such as Dowex 50)

or an aqueous acid, then extraction with an organic solvent,

ethyl acetate, dichloromethane, etc., produces the free acid from which another salt can be formed. Additional details 60 are described in the following examples; these examples illustrate the preferred forms of the invention, but they can also serve as models for other similar compounds.

The compounds of this invention are used as hypotensive agents. They inhibit the conversion of the decapeptide angiotensin I 65 to angiotensin II; they reduce or eliminate hypertension related to angiotensin. The renin enzyme acts on the angiotensinogen, plasma pseudoglobulin, to produce angiotensin I. Angiotensin I is converted by an angiotensin-converting enzyme (ACE) to angiotensin II. The latter is an active ten-sinogenic substance, which causes various forms of hypertension in several species of mammals: rats, dogs. The compounds of this invention are involved in the angiotensinogen sequence - ► (renin) - »angiotensin I -> (ACE) -» angiotensin II, by inhibiting the action of the angiotensin converter enzyme: they thus reduce or eliminate the formation of the tensinogen, angiotensin II. It is thus possible to alleviate the hypertension caused by angiotensin, from which certain mammals suffer, by administration of a composition based on one or a combination of the compounds of formula I, or their physiologically acceptable salt. A single dose (but rather 2 to 4 doses) daily is enough to reduce blood pressure, as shown, in experimental animal models, S.L. Engel, T.R. Schaeffer, M.H. Waugh and B. Rubin, “Proc. Soc. Exp. Biol. Med. ”, 143 (1973). The dose is calculated on the basis of 0.1 to 100 mg / kg / d, the optimal dose being 1 to 50 mg / kg / d. The substance is preferably administered orally, or optionally by parenteral routes: subcutaneous, intramuscular, intravenous, intraperitoneal.

The compounds of this invention, used to lower blood pressure, are incorporated into compositions such as pills, capsules, elixirs, for oral administration, or sterile solutions, suspensions, for administration by parenteral routes. About 10 to 500 mg of the compound, or of a mixture of the co-compounds of formula I, or of their physiologically acceptable salt, are incorporated into a physiologically acceptable support: excipient, binder, preservative, stabilizing agent, flavor, etc. These supports are suitable for current pharmaceutical practice. The amount of active substance in these preparations is determined by the dosage units defined above.

Examples of adjuvants: binder such as tragacanth, acacia, cornstarch, gelatin; excipient such as dicalcium phosphate, microcrystalline cellulose; disintegrating agent such as cornstarch, potato starch, alginic acid; lubricant such as magnesium stearate; sweetener such as sucrose, lactose, saccharin;

aroma such as mint, essence of gaultheria or cherry. When the preparation is in capsule form, it may contain, in addition to the adjuvants mentioned here, a liquid carrier such as an oil. Coatings, or any other product capable of modifying the appearance of the preparation, may be used. So the pills are coated with shellac, sugar; syrups and elixirs contain sucrose for sweetening, methyl and propyl parabens as preservatives, a color and an aroma of cherry or orange.

The sterile compositions are prepared for the injections, by dissolving or suspending the active substance in a support such as water, or in natural vegetable oils: sesame oil, coconut oil, peanut oil, cottonseed oil, etc.

The following examples are specific illustrations of this invention; the descriptions relate to the preferred compounds of this invention; all temperatures are expressed in degrees Celsius.

Example 1

3-acetylthio-2-trifluoromethylpropanoic acid

A mixture of thiolacetic acid (50 g) and 2- (trifluoromethyl) acrylic acid (66 g) is heated in a steam bath for 1 hour [M.W. Buxton, et al., "J. Chem. Soc. ”, 366 (1954)]. The mixture is stored for 18 h at room temperature. The reaction mixture is distilled in vacuo and 3-acetylthio-2-trifhioromethylpropanoic acid is obtained.

Example 2

Ester l- (3-acetylthio-2-trifluoromethypropanoyl) -L-proline-t-but-ylique

The L-proline-t-butyl ester (5.1 g) is dissolved in dichloromethane (40 mg); the solution is mixed and cooled in a bath

R2 2

^ (XII)

(chrfi) 2 | I 0 in

-n "coor,

r „r '2, 2

x "

-co - n '- coor h9c <chr,) "! j j 6' m

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of ice. First, dicyclohexylcarbodiimide (6.2 g) dissolved in 15 ml of dichloromethane is added thereto, then a solution of 3-acetylthio-2-trifluoromethylpropanoic acid (6.5 g) in dichloromethane (5 ml); the mixture is stirred for 15 min in an ice bath, then it is left to stand for 16 h at room temperature. The precipitate is filtered and then dried under vacuum. The residue is dissolved in ethyl acetate and washed until neutral. The organic phase is dried over magnesium sulfate, then concentrated in vacuo; we obtain the ester 1- (3-acetylthio-2-trifluoromethyl-propanoyl) -L-proline-t-butyl.

Example 3

1- (3-A cetylthio-2-trifluoromethylpropanoyl) -L-pr oline

The ester 1- (3-acetylthio-2-trifluoromethylpropanoyl) -L-proline-t-butyl (8 g) is dissolved in a mixture of anisole (55 ml) and trifluoroacetic acid (110 ml). It is left to stand for 1 h at room temperature; the solvent is removed in vacuo, the residue is precipitated several times from an ether / hexane solution; 1 - (3-acetylthio-2-trifluoromethylpropanoyl) -L-proline is obtained.

Example 4

l-l 3-Mercapto-2-trifluoromethylpropanoyl) -L-proline

The 1- (3-acetylthio-2-trifluoromethylpropanoyl) -L-proline (4 g) is dissolved in a mixture of water (8 ml) and concentrated ammonia (8 ml) under a nitrogen atmosphere. This mixture is stirred at room temperature for 25 min, then cooled, acidified and extracted with ethyl acetate. The organic layer is concentrated to dryness, under vacuum, and l- (3-mercapto-2-trifluoromethylpropanoyl) -L-proline is obtained.

Example 5

2-bromo-3,3,3-trifluoropropanoic acid

The 3,3,3-trifluoroalanine (88 g) is dissolved in a mixture of potassium bromide (250 g) and 2.5 N sulfuric acid (1,240 ml). This solution is cooled to 0 C in an ice and salt bath; 65.5 g of sodium nitrite are gradually added over 1 hour with continuous stirring. The reaction mixture is stirred for 1 hour in the cold bath, then extracted with ether. The organic layer is washed with water, dried over magnesium sulfate and concentrated to dryness under vacuum. 2-bromo-3,3,3-trifluoro-propanoic acid is obtained.

Example 6

2-bromo-3,3,3-trifluoropropanoic acid chloride

A solution of 2-bromo-3,3,3-trifluoropropanoic acid (5 g) in thionyl chloride (5 ml) is refluxed in a steam bath for 2 h. The excess thionyl chloride is removed in vacuo; the residue is distilled at reduced pressure; 2-bromo-3,3,3-trifluoropropanoic acid chloride is obtained.

Example 7

l- (2-A cetylthio-3,3,3-trifluoropropanoyl) -L-pr oline

2-bromo-3,3,3-trifluoropro-panoic acid chloride (12 g) is added to a solution of L-proline (5.75 g) in sodium hydroxide N (50 ml) , cooled in an ice bath; the mixture is vigorously stirred for 3 h at room temperature. A solution of thiolacetic acid (4 ml) and potassium carbonate (4.8 g) in water (50 ml) is added; the mixture is stirred for 16 h at room temperature; after extraction with ethyl acetate, the aqueous layer is acidified with concentrated hydrochloric acid, then reextracted with ethyl acetate. The last organic phase is dried over magnesium sulfate and concentrated to dryness under vacuum. The residue is subjected to column chromatography on Silicagel with a benzene / acetic acid mixture (7/2); 1 - (2-acetylthio-3,3,3-trifluoropropanoyl) -L-proline is obtained.

Example 8

1- (2-Mercapto-3,3,3-trifluoropropanoyl) -L-proline

1- (2-acetylthio-3,3,3-trifluoropropanoyl) -L-proline (4 g) is dissolved in a mixture of water (8 ml) and concentrated ammonia (8 ml) under an atmosphere of nitrogen. After 30 min at room temperature, the reactive mixture is acidified and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness under vacuum. We obtain l- (2-mercapto-3,3,3-trifluoropropanoyl) -L-proline.

Example 9

!,] '- [Dithiobis- (2-trifluoromethyl-3-propanoyl)] bis-L-proline

1- (3-Mercapto-2-trifluoromethylpropanoyl) -L-proline (1 g) is dissolved in water, the pH of which has been adjusted to 7, with N sodium hydroxide. drop an ethanolic solution of iodine while maintaining the pH between 6 and 7 with sodium hydroxide N. The addition of iodine is stopped at the appearance of a permanent yellow color, this color is removed by adding sodium thiosulfate. The reaction mixture is acidified and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated to dryness; the desired product is obtained.

Example 10

1- (3-acetylthio-2-trifluoromethylpropanoyl) -L-proline sodium salt

A suspension of 1- (3-acetylthio-2-trifluoromethylpropanoyl) -L-proline (1 g) in water (10 ml) is adjusted to pH 8 with sodium hydroxide N. The solution is lyophilized. The desired product is obtained.

Example 11

l- (3-A cetylthio-2-trifluoromethylpropanoyl) -4,4-difluoro-L-proline

3-acetylthio-2-trifluoromethylpropanoic acid chloride (12 g) is added (prepared from 3-acetylthio-2-trifluoromethylpropanoic acid and thionyl chloride, as described in Example 6), to a solution of 4,4-difluoro-2-proline (7.5 g) in sodium hydroxide N (50 ml), cooled in an ice bath; the mixture is vigorously stirred at room temperature for 2 h. After acidification with concentrated hydrochloric acid, the reactive mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, concentrated to dryness; the desired product is obtained.

Example 12

l- (3-Mercapto-2-trifiuoromethylpropanoyl) -4,4-difluoro-L-proline

The procedure is identical to that described in Example 4, but we replace l- (3-acetylthio-2-trifluoromethylpropanoyl) -L-proline by l- (3-acetylthio-2-trifluoromethylpropanoyl) -4,4- difluoro-L-proline. The desired product is obtained.

Example 13

l, l - - [Dithiobis- (2-trifluoromethyl-3-propanoyl)] bis-4,4-difluoro-L-proline

The procedure is identical to that described in Example 9, but the l- (3-mercapto-2-trifluoromethylpropanoyl) -L-proline is replaced by l- (3-mercapto-2-trifluoromethylpropanoyl) -4,4- difluoro-L-proline. The desired product is obtained.

Example 14

l- (4,4,4-trifluoro-2-buténoyl) -L-proline

This synthesis is characterized in that boric anhydride (7.0 g, 0.1 mol) is combined (prepared by melting boric acid in a platinum crucible, and grinding under a nitrogen atmosphere) with Ethyl 3-hydroxy-4,4,4-trifluorobutanoate (32.2 g, 0.173 mol);

this reaction takes place in a 50 ml flask equipped with a Dean-Stark condenser. The mixture is heated to 180 ° C. in

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a salt bath, until complete dissolution of the anhydride (about 6 h). The temperature is increased to 350 ° C: 23 ml of distillation product accumulates in the condensation trap; the distillation product is replaced in the reagent bottle and the whole process is restarted; it is repeated 4 times to ensure complete dehydration of the hydroxyester. The distillate is dissolved in petroleum ether dried over phosphorus pentoxide, then redistilled. 10 g of 4,4,4-trifluoro-2-butenoic acid ethyl ester are obtained: boiling point 115-120 ° C, and 650 mg of 4,4,4-trifluoro-2-butenoic acid : boiling point: 150 ° C, melting point: 53-55 ° C, recrystallization from pentane. This ester is combined with 10% aqueous sodium hydroxide (24 ml); the mixture is stirred at 25 ° C for 6 h. It is then diluted with water and extracted with methylene chloride to remove anything that has not reacted. The pH of the aqueous phase is adjusted to 3 with concentrated hydrochloric acid, which is extracted with methylene chloride (3 x 50 ml). The various organic phases are combined, dried over sodium sulfate, concentrated, distilled; 4,4,4-trifluoro-butenoic acid is obtained in crystalline form; after recrystallization from pentane, the acid has a melting point of 54-55 ° C; yield: 4.6 g.

A mixture of 4,4,4-trifluoro-2-butenoic acid (4.91 g, 35 mmol), hydroxybenzotriazole (4.73 g, 35 mmol), L-proline-t-butyl ester ( 6.00 g, 36 mmol) and dicyclohexylcarbodiimide (7.22 g, 35 mmol) in methylene chloride (200 ml) is stirred under nitrogen, overnight, at room temperature. The mixture is filtered; the filtrate is washed with 5% sodium bisulfate (2 x 50 ml), saturated with sodium bicarbonate (2 x 50 ml), dried over sodium sulfate, concentrated: an oil is obtained; it is dissolved in ether; the solution is cooled and filtered. The filtrate is concentrated until a solid is obtained. Melting point: 95-100 ° C, yield: 8.7 g; revelation of a single point by TLC (Silicagel EM 50/50, EtOAc / CH2Cl2, Rf = 0.85). The ester l- (4,4,4-trifluoro-2-butenoyl) -L-proline, thus obtained (4.0 g, 13.6 mmol), is mixed with trifluoroacetic acid (60 ml) and anisole (13 ml); this solution is stirred under a nitrogen atmosphere for 1 h. The solvents are removed in vacuo; the residue is dissolved in ether (10 ml), mixed with pentane (500 ml). This precipitation process is repeated; the residue is left to stand at 0 ° C for 72 h until complete crystallization. 1- (4,4,4-trifluor-2-butenoyl) -L-proline is recrystallized from ethyl acetate and hexane; 2.48 g of pure product are obtained; melting point: 119-120 ° C.

Example 15

l- (3-Mercapto-4,4A-trifluorobutanoyl) -L-proline

Thiolacetic acid (1.5 ml) is combined with 1- (4,4,4-trifluoro-2-butenoyl) -L-proline (720 mg, 3 mmol), under an atmosphere of argon. The mixture is stirred overnight at room temperature. The excess thiolacetic acid is removed in vacuo; the residual l- (3-acetylthio-4,4,4-trifluorobutanoyl) -L-proline is mixed with concentrated ammonia (15 ml) conc. NH3 + 15 ml of water), then stirred for 2 h at room temperature. The mixture is diluted with ice and acidified with concentrated hydrochloric acid. The acid mixture is extracted with methylene chloride (3 x 50 ml). The extracts are dried over sodium sulfate and concentrated; an oil is obtained. It is purified by dissolving it in double-distilled water, and by treating this solution with carbon, it is filtered through a millipore filter (0.4 m, followed by 0.08 m). After lyophilization of this product, 700 mg of l- (3-mercapto-4,4,4-trifluorobutanoyl) -L-proline are obtained in the form of a colorless crystal. Rf (benzene: acetic acid: 7/1) = 0.24.

Example 16

3-acetylthio-4,4,4-trifluorobutanoic acid chloride

The procedure is identical to that described in Example 1, but 2-trifluoromethyl acrylic acid is replaced by 4,4,4-trifiuoro-2-butenoic acid. 3-acetylthio-4,4,4- acid is obtained

trifluorobutanoic. The desired product is obtained by chlorination with thionyl chloride, as described in Example 6.

Example 17

1-f 3-Mercapto-4,4,4-trifluorobutanoyl) -4,4-difluoro-L-proline

The procedure is identical to that described in Example 11, but the 3-acetylthio-2-trifluoromethyl-propanoic acid chloride is replaced by the chloride of 1- (3-acetylthio-4,4,4,4-trifluoro acid). -butanoic; the product obtained is then subjected to the procedure described in Example 4; the desired product is obtained.

Example 18

1, l - [Dithiobis- (4,4,4-trifluoro-3-butanoyl)] bis-L-proline

The procedure is identical to that described in example 11, but the l- (3-mercapto-2-trifluoromethylpropanoyl) -L-proline is replaced by l- (3-mercapto-4,4,4-trifluorobutanoyl) - L-proline; the desired product is obtained.

Example 19

Cis-4-fluoro-L-proline hydrobromide a) N-carbobenzyloxy-4-hydroxy-L-proline methyl ester

The N-carbobenzyloxy-4-hydroxy-L-proline (12.4 g, 0.047 mol) is esterified with diazomethane in dioxane-ether (procedure described in "JACS", 79.191 (1957). dioxane freezes, the addition of diazomethane is started at 10 ° C and finished at 0-2 C. An almost colorless oil is obtained: 14.6 g (100%).

b) N-carbobenzyloxy-4-tosyloxy-L-proline methyl ester

11 g (0.058 mol) of tosyl chloride in 15 ml of pyridine are added dropwise to a solution of N-carbobenzyloxy-4-hydroxy-L-proline methyl ester (14.5 g, 0.052 mol) in 30 ml of pyridine, with continuous stirring. The temperature is maintained between -5 ° C and -8 ° C. This light yellow solution is left to stand in the cold for 3 d. 300 ml of cooled 2N hydrochloric acid are then added thereto. A gummy product precipitates, which is extracted with 200 ml of chloroform. The aqueous phase is reextracted with chloroform (3 x 100 ml). The various organic phases are combined, dried (on MgS04); the solvent is evaporated off and a light yellow viscous oil is obtained. This oil is dissolved in 100 ml of methanol, then diluted to 400 ml with water: the product first precipitates in the form of an oil which gradually crystallizes on initiation, friction and cooling; yield: 17.4 g (77%); melting point: 62-65 ° C. After recrystallization from 85 ml of isopropanol, 15.9 g (70%) of N-carbobenzyloxy-4-tosyloxy-L-proline methyl ester are obtained in the form of a colorless solid; melting point: 67-69 ° C; (a) ^ - 30 'C (c = 1; methanol).

c) Cis-N-carbobenzyloxy-4-fluoro-L-proline methyl ester

A homogeneous suspension of 19.1 g (0.044 mol) of N-carbobenzyloxy-4-tosyloxy-L-proline methyl ester in 100 ml of redistilled diethylene glycol is treated with 19.1 g (0.33 mol) of fluoride anhydrous potassium, at 42 ° C, under an argon atmosphere. The mixture is heated at 81-84 ° C for 20 h. After cooling and purification of the light yellow solution, 18.6 g (100%) of the desired product are obtained in the form of a light yellow oil.

d) cis-N-Carbobenzyloxy-4-fluoro-L-proline

The cis-N-carbobenzyloxy-4-fluoro-L-proline methyl ester (18.4 g, about 0.044 mol) is dissolved in 140 ml of methanol; 33 ml (0.066 mol) of 2N sodium hydroxide are added dropwise thereto; the temperature is maintained between - 1 and 4 ° C, then at 0 ° C for 1 h, finally at room temperature overnight. About half of the solvent is removed with a rotary evaporator; the solution is diluted with 300 ml of water, washed with ether (washing product is eliminated), cooled and acidified with 12.5 ml of hydrochloric acid 1: 1 to pH 2, then extracted with ethyl acetate (4 x 150 ml). The extracts are combined, washed with 100 ml

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saturated sodium chloride solution, dried over magnesium sulfate; the solvent is evaporated in order to obtain 13.8 g of a light yellow viscous oil. It is dissolved in 60 ml of ethanol; the solution is treated with a solution of cyclohexylamine in 10 ml of ethanol and then diluted to 900 ml with ether. After initiation and friction, crystals of cis-N-carbo-benzyloxy-4-fluoro-L-proIine cyclohexylamine salt separate; after having allowed to cool overnight, 11.0 g are obtained; Fusion point; 180-183 ° C (s. 175 C). After recrystallization from ethanol (70 ml), 7.6 g of a colorless solid are obtained; melting point: 185-187 ° C, (a) 2D5 - 40 "C (c = 1; methanol).

The cyclohexylamine salt is suspended in 75 ml of ethyl acetate, which is treated with 45 ml of hydrochloric acid. The phases separate; the aqueous phase is extracted with ethyl acetate (2 x 75 ml); the combined organic phases are dried (MgS04), the solvent is removed by evaporation. The residual free acid, cis-N-carbobenzyloxy-4-fluoro-L-proline, crystallizes when it is dried at 0.2 mm and 45 ° C; yield: 5.7 g (49%); melting point: 116-118 ° C.

e) Cis-4-fluoro-L-proline hydrobromide

The cis-N-carbobenzyloxy-4-fluoro-L-proline (5.5 g, 0.021 mol) is treated with 28 ml of hydrogenated bromide in acetic acid (30-32%), in a stoppered bottle (not hermetic); the mixture is stirred for 1 h. Ether (300 ml) is added to this yellow mixture when the crystals appear, the etherolated liquor is decanted, and the crystals are rewashed with 300 ml of ether. The product is finally heated in a steam bath with 70 ml of methyl ethyl ketone, cooled for 2 h, washed with cold methyl ethyl ketone and ether, dried under vacuum. 3.8 g (86%) of cis-4-fluoro-L-proline hydrobromide are obtained, in the form of an almost colorless solid; melting point: 189-191 ° C (dec.), (a) ^ - 19 ° C (c = l, methanol).

Part of this crude hydrobromide salt is converted to free acid, by passing it through a column of Dowex 1-X8 ion exchange resin.

Example 20

cis-l- [D-3- (acetylthio) -2-methylpropanoyl] -4-fluoro-L-proline

Cis-4-fluoro-L-proline hydrobromide (4.5 g, 0.021 mol) and D-3-acetylthio-3-methylpro-panoic acid chloride (4.2 g, 0.023 mol) are reacted ) in 50 ml of water, in the presence of sodium carbonate; the latter serves as a buffer fixing the pH between 8 and 8.2 during the acylation process (approximately 20 min). After 1 h, the mixture is washed with ethyl acetate (2 x 50 ml), separated in phases with ethyl acetate, acidified to pH 2 with hydrochloric acid, saturated with chloride sodium. The aqueous phase is extracted with ethyl acetate; the organic phases are combined, dried, evaporated; the resulting solid is kneaded with ether; the latter is again evaporated; 5.4 g (93%) of a colorless product are obtained; melting point: 146-148 ° C (s. 133 ° C) (a) ^ —132 'C (c = 1; methanol).

The dicyclohexylamine salt is prepared by adding dicyclohexylamine to the solution of cis-1- (D-3-acetylthio-2-methyl-propanoyl-4-fluoro-L-proline in 70 ml of ethyl acetate). obtains 8.1 g of crystallized salt; melting point: 202-204 ° C (s. 187 ° C); (a) ^ - 72 'C (c = 1; methanol). After recrystallization from 90 ml of isopropanol, 7.0 g of solid is obtained; melting point: 205-207 ° C. (s, 190 ° C.), (a) 2β-74 ° C. A sample, recrystallized from ethanol, shows the same physico-chemical characteristics (melting point: (a) D).

The dicyclohexylamine salt (16.9 g) is reconverted into free acid, by distributive extraction with 10% potassium bisulfate and ethyl acetate (60 ml of 10% KHS04; 4 x 50 ml of acetate d 'ethyl). The organic phases are combined, evaporated to dryness; the free acid is obtained in the form of a colorless solid (4.1 g, 71%); melting point: 154-156 ° C (s. 140 ° C) (a) ^ - 142 ° C (c = 1, methanol).

Example 21

cis-4-Fluoro-l- (D-3-mercapto-2-methylpropanoyl) -L-proline

The cis-1- [D-3- (acetylthio) -2-methylpropanoyl] -4-fluoro-L-proline (3.9 g, 0.014 mol) is hydrolyzed in 22 ml of water containing 9 ml of hydroxide d concentrated ammonium. The reaction mixture is acidified with hydrochloric acid, then extracted with ethyl acetate. The organic layer is concentrated to dryness; 3.3 g of a solid having the appearance of glass are obtained; it gradually crystallizes when it dries to 0.2 mm and 50 ° C. This material is triturated with 20 ml of ethyl acetate (slight heating under an argon atmosphere); the product is diluted with 25 ml of hexane, stirred and cooled overnight; the desired product is obtained in the form of a colorless solid (2.8 g 85%); melting point: 135-137 ° C (s. 129 ° C), (a) 2Dc-116 ° C (c = l, methanol)

Example 22

l- [3- (Acetylthio) -2-chloropropanoyl] -L-proline (isomer A)

L-proline (1.44 g) and sodium carbonate (667 mg) are dissolved in 17 ml of water; the solution is stirred in an ice bath. First added sodium carbonate (2 g) in 8.5 ml of water, then 3-acetylthio-2-chloropro-panoic acid chloride (2.5 g); the ice bath is removed. After 30 min, the formation of a precipitate is observed, which dissolves with the addition of 17 ml of water. This mixture is left to stand for 1 h, in all, then it is extracted twice with ethyl acetate. The aqueous phase is cooled, acidified with concentrated hydrochloric acid, saturated with sodium chloride, then reextracted with ethyl acetate. The extract is dried over magnesium sulfate, concentrated to dryness under vacuum; 450 mg of the desired product are obtained; melting point: 111-113 ° C, (a) D — 170 ° C (c = 1; ethanol)

Example 23

l- [3- (Acetylthio) -2-chloropropanoyl] -L-proline (isomer B)

The aqueous mother liquor of Example 22 is lyophilized and run on chromatography on Silicagel with benzene / acetic acid 7: 1. The fractions which contain the absorbent material, the UVs, and which are homogeneous on the TLC examination, are collected; they are concentrated to dryness, crystallized from water; 800 mg of product are obtained; melting point: 90-109 ° C, (a) ^ - 4 ° C (c = 2, l; ethanol). The mother liquors are concentrated to dryness by lyophilization; the residue is crystallized from hexane / ether: 380 mg of 1- (3-acetylthio) -2-chloropropanoyl-L-proline (isomer B) are obtained; melting point: 108-110 ° C, (a) 2Ds + 17.6 ° C (c = 1.26; ethanol).

Example 24

l- [3- (A cetylthio) -2-bromopropanoyl] -L-pr oline

The procedure is identical to that described in Example 22, but the 3-acetylthio-2-chloropropanoic acid chloride is replaced by 3-acetylthio-2-bromopropanoic acid chloride. The desired product is obtained; melting point: 109-110 ° C, (a) D— 162 ° C (c = 1.39; ethanol).

Example 25

eis-4-Chloro-l- (D-3-mereapto-2-methylpropanoyl) -L-proline

The procedure is identical to that described in Example 20, but the cis-4-fluoro-L-proline hydrobromide is replaced by cis-4-chloro-L-proline ("Aust. J. Chem.", 20.1493 (1967)); the product obtained is subjected to the procedure described in Example 21; the desired product is obtained.

Example 26

trans-4-Bromo-1- (D-3-mercapto-2-methylpropanoyl) -L-proline

The procedure is identical to that described in Example 20, but the cis-4-fiuoro-L-proline hydrobromide is replaced by trans-4-bromo-L-proline ("Aust. J. Chem." 20 , 1493 (1967)); the product obtained is subjected to the procedure described in Example 21; we

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obtains trans-1 - (D-acetylthio) -2-methylpropanoyl) -4-bromo-L-proline and trans-4-bromo-1- (D-3-mercapto-2-methylpropanoyl) -L-proIine.

Example 27

cis-4-Iodo-l- (D-3-mercapto-2-methylpropanoyl) -L-proline

The procedure is identical to that described in Example 20, but the cis-4-fluoro-L-proline hydrobromide is replaced by cis-4-iodo-L-proline. The product obtained is subjected to the procedure described in Example 21; cis-1- [D-3- (acetylthio) -2-methyl-propanoyl] -4-iodo-L-proline and cis-4-iodo-l- (D-3-mercapto-2-methylpropanoyl) are obtained ) -L-proline.

Example 28

cis-4-Fluoro-l- (3-mercapto-2-trifluoromethylpropanoyl) -L-proline

The procedure is identical to that described in Example 20, but the 3-acetylthio-2-methylpropanoic acid chloride is replaced by 3-acetylthio-2-trifluoromethylpropanoic acid chloride; the product obtained is subjected to the procedure described in Example 21; cis-1- (3-acetylthio-2-trifluoromethylpropanoyl) -4-fluoro-L-proline and cis-4-fluoro-1- (3-mercapto-2-trifluoromethyl-propanoyl) -L-proline are obtained.

Example 29

Cis-3-fluoro-DL-proline hydrobromide

The procedure is identical to that described in Example 19, but the N-carbobenzyloxy-4-hydroxy-L-proline is replaced by the N-carbobenzyloxy-3-hydroxy-DL-proline ("J. Am. Chem. Soc . ”, 85, 2824 (1963)). The desired product is obtained.

Example 30

cis-3-Fluoro-1- (D-3-mercapto-2-methylpropanoyl) -DL-proline

The procedure is identical to that described in Example 20, but the cis-4-fluoro-DL-proline is replaced by the hydrobromide of cis-3-fluoro-DL-proline; the product obtained is subjected to the procedure described in Example 21; cis-1- [D-3- (acetylthio) -2-methylpropanoyl] -3-fluoro-DL-proline and cis-3-fluoro-l- (D-mercapto-2-methylpropanoyl) -DL are obtained proline.

Example 31

cis-3-Chloro-l- (D-3-mercapto-2-methylpropanoyl) -L-proline

The procedure is identical to that described in Example 20, but the cis-4-fluoro-L-proline hydrobromide is replaced by cis-3-chloro-L-proline (obtained from 3-hydroxyproline, cf. "Aust. J. Chem.", 20.1493 (1967)). The product obtained is subjected to the procedure described in Example 21; we obtain cis-1- (D-3-acetylthio-2-methylpropanoyl) -3-chloro-L-proline and cis-3-chloro-1- (D-3-mercapto-2-methylpropanoyl) -L- proline.

Example 32

4,4-Dichloro-1- (D-3-mercapto-2-methylpropanoyl) -L-proline

The procedure is identical to that described in Example 20, but the cis-4-fluoro-L-proline hydrobromide is replaced by 4,4-dichloro-L-proline (prepared from 4-keto diketopiperazine -L-proline and phosphorus pentachloride, see "J. Med. Chem." 20, 1176 (1977)); the product obtained is subjected to the procedure described in Example 21; we obtain l- [D-3- (acetylthio) -2-methyl-propanoyl] -4,4-dichloro-L-proline and 4,4-dichloro-l- (D-3-mercapto-2-methylpropanoyl ) -L-proline.

Example 33

I, l - [Dithiobis- (2-D-methylpropanoyl) bis (cis-4-fluoro] -L-proline

The procedure is identical to that described in Example 9, but the l- (3-mercapto-2-trifluoromethylpropanoyl) -L-proline is replaced by cis-4-fluoro-l- (D-3-mercapto-2 -methylpropanoyl) -L-proline. The desired product is obtained.

Example 34

4,4-Difluoro-l- (3-mercaptobutanoyl) -L-proline

The procedure is identical to that described in Example 11, but the 3-acetylthio-2-trifluoromethyl-propanoic acid chloride is replaced by the 3-acetylthiobutanoic acid chloride; the product obtained is subjected to the procedure described in Example 12; we obtain l- (3-acetylthiobutanoyl) -4,4-difluoro-L-proline and 4,4-difluoro-1 - (3-mercaptobutanoyl) -L-proline.

Example 35

1- (3-propanoylthio-2-trifluoromethylpropanoyl) -L-proline

The procedure is identical to that described in Example 1, but the thioacetic acid is replaced by thiopropanoic acid; the product obtained is subjected to the procedure described in examples 2 and 3. The ester l- (3-propanoylthio-2-trifluoromethyl-propanoyl) -L-proline-t-butyl, 3-propanoylthio- is obtained 2-trifluoromethylpropanoic acid and 1- (3-propanoylthio-2-trifluoro-methylpropanoyl) -L-proline.

Example 36

3- (4-methoxybenzyl) thio-2-trifluoromethylpropanoic acid

A mixture of 1-trifluoromethylacrylic acid (3.9 g) and 4-methoxybenzylthiol (4.3 g) is stirred at 100-110 ° C for 1 h; the solution is left to stand at room temperature; the solid is crystallized from cyclohexane; melting point: 72-74 "C.

Example 37

Ester 1- [3- (4-methoxybenzyl) thio-2-trifluoromethylpropanoyl] -L-proline t-butyl

A solution of 3- (4-methoxybenzyl) thio-2-trifluoropropanoic acid (6.5 g) and t-butyl proline ester (3.76 g) in dichloromethane (500 ml) is stirred at 0 ° C; this mixture is treated with dicyclohexylcarbodiimide (4.53 g). It is left to stand at 0 ° C for 30 min and at room temperature overnight. The mixture is filtered; the filtrate is washed until neutral. The organic phase is dried, concentrated to dryness under vacuum. The TLC examination (Si-licagel, methylene chloride / ethyl acetate 95: 5) indicates two main points, Rf 0.46 and 0.51, corresponding to the two diastereoisomers.

Example 38

l- (3-Mercapto-2-trifluoromethylpropanoyl) -L-proline

A solution of 1- [3- (4-methoxybenzyl) thio-2-trifluoro-methylpropanoyl] -L-proline-t-butyl ester (4.47 g) and anisole (10 ml) is cooled to 0 ° VS; trifluoroacetic acid (100 ml) is added followed by mercuric acetate (3.18 g). The mixture is stirred at room temperature for 1 h. The solution is concentrated to dryness under vacuum, and the residue is triturated with ether / hexane. The insoluble material is suspended in water through which hydrogen sulfide is bubbled for 10 min. The precipitate is removed by filtration; the filtrate is lyophilized; the desired product is obtained in the form of an amorphous solid, Rf 0.29-0.31 (Silicagel, benzene / acetic acid 7: 1).

Example 39

The procedure is identical to that described in Example 1, but 2-trifluoromethylacrylic acid is replaced by 2-chloro-acrylic acid; reacting the product obtained with thionyl chloride; 3-acetylthio-2-chloropropanoic acid and 3-acetylthio-2-chloropropanoic acid chloride are obtained.

Example 40

D-3-acetylthio-2-methylpropanoic acid chloride

A suspension of 1- (D-3-mercapto-2-methylpropanoyl) -L-proline (150 g, 690 mmol) is refluxed under nitrogen for 8 h in 1274 ml of water and 426 ml of hydrochloric acid con5

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centered (5.526 mol), with continuous agitation. The solution is left to stand at room temperature overnight, then it is extracted with 400 ml of chloroform (10 ×). The various chloroformed extracts are combined, dried over magnesium sulfate, under a nitrogen atmosphere, then evaporated. To the residue (81.2 g) are added acetic anhydride (176 ml, 1.809 mol) and pyridine (180 ml), the mixture is left to stand at room temperature for 20 h. The mixture is evaporated and the oily residue is dissolved in 1000 ml of ethyl acetate; the solution is washed with: 200 ml of 5% hydrochloric acid / saturated sodium chloride (detergent at pH 2), 200 ml of saturated sodium chloride (2 x, the 2nd detergent at pH 7); solvents are removed; freshly distilled thionyl chloride (83 ml, 1.173) is added to the residue (in the form of a clear oil, 96.9 g, 86.5%, had (a) fec-61.8 ° C (CHCl3)) mol); the solution is stirred at room temperature for 18 h; the excess thionyl chloride is evaporated in vacuo in a bath at 50 ° C. The residue is distilled at reduced pressure; the desired product is obtained (56.9 g); boiling point: 40-44 ° C (0.17-0.2 mm Hg) (ct) ^ —42.5 = C (c = 2; methanol).

Example 41

3-acetylthio-2-bromopropanoic acid chloride

The procedure is identical to that described in Example 1, but 2-trifluoromethylacrylic acid is replaced by 2-bromo-acrylic acid; reacting the product obtained with thionyl chloride; the desired product is obtained.

Example 42

trans-l- [D-3- (acetylthio) -2-methyl-l-oxopropyl] -4-fluoro-L-proline a) trans-l-Carbobenzyloxy-4-fluoro-L-proline

A solution of 2N sodium hydroxide (11.5 ml) is poured dropwise into a solution of trans-1-carboxybenzyloxy-4-fluoro-L-proline methyl ester (6.2 g) in 50 ml of methanol; the temperature is maintained between 0 and 5 ° C; the solution is kept at 0 ° C. for 1 h, then it is left to stand at room temperature overnight; the reaction mixture is concentrated under reduced pressure to half the original volume, then diluted with 100 ml of water. The aqueous reaction mixture is extracted with ether (extracts removed). The solution is acidified with hydrochloric acid diluted to pH 2 (low temperature), then extracted with ethyl acetate (4 x 50 ml). The extracts are combined, dried over magnesium sulfate, concentrated under reduced pressure; the desired product is obtained. It is purified by conversion to the cyclohexylamine salt; melting point: 194-196 ° C, (a) | m — 44 ° C (c = 1%; methanol).

The free acid is obtained by suspending the cyclohexylamine salt in 25 ml of ethyl acetate and 25 ml of N hydrochloric acid; the aqueous phase is extracted with 4 x 35 ml of ethyl acetate; the combined extracts are dried over anhydrous magnesium sulfate, concentrated under reduced pressure; the desired product is obtained: trans-1 -carbobenzyloxy-4-fiuoro-L-proline.

b) Trans-4-fluoro-L-proline hydrobromide

A mixture of trans-1-carbobenzyloxy-4-fluoro-L-proline (3 g) and hydrogenobromide (15 ml) in acetic acid (30-32%) is stirred for 1 h; 150 ml of anhydrous ether are added thereto. The solvent is decanted from the precipitate, which is triturated with ether and methyl ethyl ketone. The desired product is obtained; melting point: 162-164 C (dec), (<x) ks-30 ° C (c = 1%; methanol).

c) Trans-1- [D-3- (acetylthio) -2-methyl-l-oxopropyl] -4-fluoro-L-proline

1 g of sodium carbonate is added to a solution of trans-4-fluoro-L-proline hydrobromide (1.9 g) in 25 ml of cold water to adjust the pH to 8.2. D-3-acetylthio-2-methyl-propionyl chloride (1.8 g) in 2.5 ml of ether is added dropwise, while maintaining the temperature at around 5: C; the pH is maintained between 8.2 and 8.3 by addition of sodium carbonate. Continue to stir and cool the solution for 1 h. The reaction mixture is extracted with ethyl acetate (2 x 25 ml) (the extracts are eliminated). The aqueous phase is acidified to pH 2, with concentrated hydrochloric acid, extracted with ethyl acetate; it is saturated with sodium carbonate, the ethyl acetate phase separates. The aqueous phase is reextracted with ethyl acetate (3 x 25 ml); the combined extracts are dried over magnesium sulfate, concentrated under reduced pressure, in order to obtain the desired product. The dicyclohexylamine salt is prepared by dissolving the product in 25 ml of ethyl acetate and adding to it a solution of 1.8 g of dicyclohexylamine in 35 ml of ethyl acetate. The salt which precipitates is filtered, recrystallized from isopropanol; the dicyclohexylamine salt of trans-1 - (D-3-acetylthio-2-methyl-1-oxopropyl) -L-proline is obtained; melting point: 209-211 ° C, (a) 2D5-85 ° C (c = 1% in methanol).

The free acid is obtained by dissolving the dicyclohexylamine salt in 5% acid potassium sulfate, followed by extraction with ethyl acetate; the ethyl acetate solution is dried over magnesium sulfate, concentrated under reduced pressure; the desired product is obtained.

Example 43

trans-4-Fluoro-l- (D-3-mercapto-2-methyl-l-oxopropyl) -L-proline

A stream of argon is circulated in a cold solution of concentrated ammonium hydroxide (4.2 ml) in 16 ml of water. To this solution is added 1.8 g of trans-1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -4-fluoro-L-proline while stirring under an argon atmosphere. The mixture is stirred for 2 h, then extracted with ethyl acetate (extracts removed). The aqueous phase is acidified with concentrated hydrochloric acid; 30 ml of ethyl acetate are added thereto. The aqueous phase is saturated with sodium carbonate, so that the ethyl acetate phase separates. The aqueous phase is reextracted with ethyl acetate (3 x 30 ml); the combined extracts are dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The desired product is obtained; (a) ^ | - 112 ° C (c = 1%

in methanol).

Example 44

l- [D-3- (acetylthio) -2-methyl-l-oxopropyl-] 4,4-difluoro-L-proline a) L-carbobenzyloxy-4,4-difluoro-L-proline methyl ester

3.3 ml of diethylaminosulfurtri-fluoride are added dropwise to a solution of 3.3 g of 1-carbobenzyl-oxy-4-keto-L-proline methyl ester in 80 ml of methylene dichloride. The mixture is allowed to stand at room temperature overnight. The solution is cooled by adding 100 g of crushed ice to it, while stirring for 45 min. The organic phase separates and the aqueous phase is extracted with methylene chloride (2 x 40 ml). The combined extracts are dried over anhydrous magnesium sulfate, concentrated under reduced pressure; the desired product is obtained.

b) l-Carbobenzyloxy-4,4-difluoro-L-proline

A solution of 2N sodium hydroxide (11.5 ml) in a solution of 5.6 g of 1-carbobenzyloxy-4,4-difluoro-L-proline methyl ester in 50 ml of methanol is added dropwise , while maintaining the temperature between 0-5 ° C. The mixture is left to stand for 1 hour at 0 ° C., then overnight at room temperature. The reaction mixture is concentrated under reduced pressure to half its initial volume, then diluted with 100 ml of water. The aqueous reaction mixture is extracted with ether (extracts removed). The aqueous solution is acidified with hydrochloric acid diluted to pH 2, then extracted with ethyl acetate (3 x 50 ml). The combined extracts are washed with a saturated sodium chloride solution, dried over magnesium sulfate, concentrated; the desired product is obtained. It is purified by conversion to the cyclohexylamine salt. Melting point: 180-185 ° C (a) ^ - 24 ° C (c = 1% in methanol). The free acid is obtained by treatment of the aqueous solution of cyclohexylamine salt with hydrochloric acid, then by extraction with ethyl acetate

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(4 x 30 ml). The extracts are dried over magnesium sulphate, concentrated under reduced pressure in order to obtain the desired product.

c) 4,4-difluoro-L-proline hydrobromide

A solution of 2.4 g of l-carbobenzyloxy-4,4-difluoro-L-proline and 12 ml of hydrogenobromide in acetic acid (30-32%) is stirred for 30 min at room temperature. ; anhydrous ether (300 ml) is added thereto. The mixture is cooled, the solid which precipitates is filtered, dried under reduced pressure. The desired product is obtained. Fusion point; 163-165 ° C (dec), (a) mp - 14 ° C (c = 1% in methanol).

d) l- (D-2-acetylthio) -2-methyloxopropyl-4,4-difluoro-L-proline

The pH of a solution of 2.7 g of 4,4-difluoro-L-proline hydrobromide in 30 ml of water is adjusted to 8.4 with solid sodium carbonate; the temperature is maintained at 5 ° C. 2.4 g of D-3-acetylthio-2-methylpropionyl chloride in 3 ml of anhydrous ether are added dropwise while stirring. the pH is maintained between 8.1 and 8.3 by addition of 2% aqueous sodium carbonate. The mixture is stirred for 1 h. The mixture is extracted with ethyl acetate (2 x 25 ml) (extracts removed). Ethyl acetate (50 ml) is added to the aqueous phase which is acidified to pH 2 with concentrated hydrochloric acid. This aqueous phase is saturated with sodium chloride, the ethyl acetate phase separates. The aqueous phase is extracted with ethyl acetate (3 x 25 ml). The extracts are combined, dried over magnesium sulfate, concentrated at reduced pressure; the desired product is obtained. The dicyclohexylamine salt is prepared by dissolving the product obtained in 40 ml of ethyl acetate and adding thereto 2.3 g of dicyclohexylamine in 5 ml of ethyl acetate; the salt which precipitates is filtered and recrystallized from ethanol. The dicyclohexylamine salt of 1- (D-2-acetylthio) -2-methyl-1-oxopropyl-4,4-difluoro-L-proline has a melting point of 225-227 ° C, (a) ^ j— 70 ° C (c = 0.5% in methanol).

The free acid is obtained by dissolving the dicyclohexylamine salt in 5% acid potassium sulphate, then extracting with ethyl acetate. The ethyl acetate solution is dried over magnesium sulfate, concentrated under reduced pressure; the desired product is obtained.

Example 45

4,4-difluoro-l- (D-3-mercapto-2-methyl-l-oxopropyl) -L-proline

A stream of argon is circulated through a cold solution of 4.6 ml of concentrated ammonium hydroxide in 11 ml of water. 2.1 g of l- [D-3- (acetylthio) -2-methyl-l-oxopropyl] -4,4-difiuoro-L-proline are added to this solution, still under an argon atmosphere. The reaction mixture is stirred for 2 h, then extracted with ethyl acetate (extracts eliminated). 30 ml of ethyl acetate are added to the aqueous phase, then it is acidified with concentrated hydrochloric acid. It is saturated with sodium chloride, the ethyl acetate layer separates. The aqueous phase is extracted with ethyl acetate (3 x 25 ml). The combined extracts are dried over anhydrous magnesium sulfate, concentrated under reduced pressure; the desired product is obtained.

Example 46

1- [D-3- (acetylthio) -2-methyl-l-oxopropyl] -5-fluoro-2-pipecolic acid a) L-carbobenzyloxy-5-hydroxy-L-pipecolic acid methyl ester

A solution of 5 g of 1-carbobenzyloxy-5-hydroxy-L-pipecolic acid in 60 ml of dioxane is treated with an etherolated solution of diazomethane, until a permanent yellow color is obtained. The temperature is maintained at around 5 C. The excess diazomethane is destroyed with glacial acetic acid; the solution is dried over magnesium sulfate, concentrated under reduced pressure; the desired product is obtained in the form of a light yellow viscous oil.

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b) L-carbobenzyloxy-5-tosyloxy-L-pipecolic acid methyl ester

A solution of 4 g of tosyl chloride in 6 ml of pyridine is added dropwise to a solution of 5.7 g of 1-carbobenzyloxy-5-hydroxy-L-pipecolic acid methyl ester in 12 ml of pyridine; the temperature is maintained between 5 and 8 ° C. The solution is left to stand at 5 ° C for 72 h, which is then treated with 200 ml of cold 2N hydrochloric acid. The precipitate is dissolved in chloroform; the aqueous phase is extracted with chloroform (3 x 75 ml). The combined extracts are dried over magnesium sulfate and concentrated under reduced pressure. The desired product is obtained having a melting point of 74-76 ° C; after crystallization from isopropanol, (a) mp - 5 ° C (c = 1% in methanol); (a) ^ - ll 'C (c = 1% in chloroform).

c) L-carbobenzyloxy-5-fluoro-L-pipecolic acid methyl ester

A suspension of 5.2 g of 1-carbobenzyloxy-5-tosyloxy-L-pipecolic acid methyl ester in 50 ml of diethylene glycol is treated with 5.2 g of anhydrous potassium fluoride at a temperature of 80 °. C, with continuous stirring for 14 h. The cold solution is then diluted with 50 ml of water and extracted with ethyl acetate (3 x 100 ml). The combined extracts are washed with a saturated solution of sodium chloride, dried over magnesium sulfate, concentrated under reduced pressure. The desired product is obtained in the form of a yellow oil.

d) L-carbobenzyloxy-5-fluoro-L-pipecolic acid

A solution of 7.3 ml of 2N sodium hydroxide is added to a cold (0: C) solution of 1-carbobenzyl-oxy-5-fluoro-L-pipecolic acid methyl ester in 32 ml of methanol. The reaction mixture is left to stand between 0 and 5 ° C for 1 h, then at room temperature overnight. The solution is concentrated under reduced pressure to half its initial volume, then diluted with 20 ml of water. The solution is extracted with ether (extracts removed). The aqueous solution is cooled, acidified with hydrochloric acid, extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulfate, concentrated under reduced pressure; the desired product is obtained. It is purified by conversion to the cyclohexylamine salt having a melting point of 158-161 ° C, (ü) 2 ^ - 11C (c = 1% in methanol).

The free acid is obtained by treating the aqueous solution of the salt with hydrochloric acid, then extracting the mixture with ethyl acetate (4 x 25 ml) and concentrating the dried extracts under reduced pressure.

e) 5-Fluoro-L-pipecolic acid hydrobromide

A solution of 2.2 g of l-carbobenzyloxy-5-fluoro-L-pipecolic acid, 12 ml of hydrogenobromide, in acetic acid (30-32%) is stirred for 30 min at room temperature. ). 300 ml of anhydrous ether are added thereto. The cold mixture is filtered; the solid precipitate is dried under reduced pressure, in order to obtain the desired product.

f) Acid l- [D-3- (acetylthio) -2-methyl-l-oxopropyl-] fluoro-L-pipëco-lique

10 g of N-methylmorpholine are added to a suspension of 5.1 g of 5-fluoro-L-pipecolic acid hydrobromide. 5.4 g of D-3-acetyl-2-methylpropionyl chloride are added little by little, with continuous stirring, to this mixture; the mixture is heated at 90 ° C for 3 h. The reaction mixture is filtered and concentrated under reduced pressure. The residue is treated with dilute hydrochloric acid and then extracted with ethyl acetate (3 x 150 ml). The combined extracts are dried and concentrated under reduced pressure; the desired product is obtained. The acid is purified by conversion to the dicyclohexylamine salt, followed by crystallization from acetonitrile.

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40

45

50

55

60

65

639,370

12

Example 47

5-fluoro-l- f D-3-mercapto-2-methyl-l-oxopropyl) -L-pipëcolic acid

Nitrogen is bubbled through a cold solution (5 ° C) of concentrated ammonium hydroxide (11 ml) in 25 ml of water for 30 min. 1.6 g of 1- (D-3-acetylthio-2-methyl-1-oxopropyl) -5-fluoro-L-pipecolic acid are added to this solution. This solution is stirred for 15 min at 5 ° C, then for 4 h at room temperature. The solution is cooled, acidified with concentrated hydrochloric acid, extracted with ethyl acetate (3 x 50 ml); the combined extracts are dried over anhydrous magnesium sulfate, concentrated under reduced pressure, in order to obtain the desired product.

Example 48

A cide 1-f 3-mercapto-2-trifluoromethylpropanoyl) -L-pipecolic

The procedure is identical to that described in Example 2, but the t-butyl ester of L-proline is replaced by the t-butyl ester of L-pipecolic acid; the product obtained is subjected to the procedure of Examples 3 and 4; the desired product is obtained.

Example 49

1-f 2-mercapto-3,3,3-trifluoropropanoyl) -L-pipecolic acid

The procedure is identical to that described in Example 7, but the L-proline is replaced by L-pipecolic acid. The product obtained is subjected to the procedure described in Example 8; the desired product is obtained.

Example 50

A cide l- <3-mercapto-2-trifluoromethylpropanoyl) -5,5-difluoro-DL-pi-pécolic

The procedure is identical to that described in Example 11, but replacing 4,4-difluoro-L-proline with 5,5-difluoro-DL-pipecolic acid (obtained from 5-keto acid -DL-pipecolic, cf. "J. Med. Chem.", 20, 1176 (1977) The product obtained is subjected to the procedure of Example 12, the desired product is obtained.

Example 51

1dithiobis- (2-trifluoromethyl-3-propanoyl) J-bis-5,5-difluoro-DL-pipecolic acid

The procedure is identical to that described in Example 9, but l- (3-mercapto-2-trifluoromethyl-propanoyl) -proline is replaced by l- (3-mercapto-2-trifluoro-methylpropanoyl) - 5,5-difluoro-DL-pipecolic; the product obtained is subjected to the procedure of Example 9; the desired product is obtained.

Example 52

1- (3-Mercapto-4,4,4-trifluoromethylbutanoyl) -L-pipecolic acid

The procedure is identical to that described in Example 14, but the t-butyl ester of L-proline is replaced by the t-butyl ester of L-pipecolic acid; the product obtained is then subjected to the procedure described in Example 15; the desired product is obtained.

Example 53

A cide 1- f 3-mercapto-2-trifluoromethylpropanoyl) -5,5-dichloropipe-colic

The procedure is identical to that described in Example 11, but the 4,4-difluoro-L-proline is replaced by 5,5-dichloro-DL-pipecolic acid (prepared from 5-keto acid -DL-pipecolic and phosphorus pentachloride, according to a process identical to that described in "J. Med. Chem." 20, 1176 (1977); the product obtained is subjected to the procedure of Example 12; desired product.

Example 54

1-f3-mercapto-2-methylpropanoyl) -5,5-difluoro-DL-pipêcolic acid

The procedure is identical to that described in Example 11, but the 3-acetylthio-2-trifluoromethylpro- acid chloride is replaced.

panoic with 3-acetylthio-2-methylpropanoic acid chloride; the product obtained is subjected to the procedure of Example 12; the desired product is obtained.

5 Example 55

1- (3-mercapto-2-methylpropanoyl) -5-fluoro-DL-pipecolic acid

The procedure is identical to that described in Example 11, but the 4,4-difluoro-L-proline is replaced by 5-fluoro-DL-pipecolic acid (prepared from 5-hydroxypipecolic acid, cf. 10 "Biochemistry", 4, 2507 (1965)), and 3-acetylthio-2-trifluoromethylpropanoic acid chloride by 3-acetylthio-2-methylpropanoic acid chloride. The product obtained is subjected to the procedure of Example 12; 1- (3-acetylthio-2-methylpropanoyl) -5-fluoro-DL-pipecolic acid and 1- (3-mercapto-2-methylpropanoyl) -5-fluoro-DL-pipecolic acid are obtained.

Example 56

1-f 3-mercaptopropanoyl) -5-bromo-DL-pipêcolic acid

The procedure is identical to that followed in Example 11, but the 3-acetylthio-2-trifluoromethyl-propanoic acid chloride is replaced by 3-acetylthiopropanoyl chloride, and the 4,4-difluoro-L-proline by 5-bromo-DL-pipecolic acid (prepared from 5-hydroxypipecolic acid, cf. "Aust. J. Chem.", 20, 25 1493 (1967). The product obtained is subjected to the procedure described in Example 12; l- (3-acetylpropanoyl) -5-bromo-DL-pipecolic acid and l- (3-acetylpropanoyl) -5-bromo-DL-pipecolic acid and l acid are obtained - (3-mercaptopropanoyl) -5-bromo-DL-pipecolic.

30

Example 57

L- (3-acetylthio-2-trifluoromethylpropanoyl) -D L-pipecolic acid methyl ester

The procedure is identical to that described in Example 2, but the t-butyl ester of L-proline is replaced by the methyl ester of DL-pipecolic acid. The desired product is obtained.

Example 58

L- (3-Mercapto-2-trifluoromethylpropanoyl) -40 DL-pipecolic acid methyl ester

The procedure is identical to that followed in Example 2, but the t-butyl ester of L-proline is replaced by the methyl ester of DL-pipecolic acid, and the 3-acetylthio-2-methylpropanoic acid 45 with 3-mercapto-2-trifluoromethylpropanoic acid. The desired product is obtained.

Example 59

1- (3-propanoylthio-2-trifluoromethylpropanoyl) -5-fluoro-DL-50 pipecolic acid

The procedure is identical to that followed in Example 1, but the thiolacetic acid is replaced by thiolpropanoic acid; the product obtained is subjected to the procedure of Example 26; the desired product is obtained.

55

Example 60

1- (3-Mercapto-2-methylpropanoyl) -5-fluoro-DL-pipecolic acid sodium salt

An aqueous solution of 1- (3-mercapto-2-methyl-propanoyl) -5-fluoro-DL-pipecolic acid is mixed with an equimolar amount of aqueous N sodium hydroxide; the solution is lyophilized.

Example 61

65

1- (3-mercaptopropanoyl) -5,5-dichloro-DL-pipecolic acid

The procedure is identical to that described in Example 53, but the 3-acetylthio-2-trifluoromethyl- acid chloride is replaced.

20

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propanoic with 2-acetylthiopropanoic acid chlorine; the desired product is obtained.

The racemic forms of the final products, in the preceding examples, are produced using the D form of the amino acid

instead of the L shape. 5

1000 pills, each containing 100 mg of l- (D-3-mercapto-propanoyl) -cis-4-fluoro-L-proline, are produced from the following ingredients:

l- (3-mercaptopropanoyl) -cis-4-fluoro-L-proline 100 g cornstarch 50 g i °

gelatin 7.5 g avicel (microcrystalline cellulose) 25 g magnesium stearate 2.5 g

The 1- (D-3-mercaptopropanoyl) -cis-4-fluoro-L-proline and the cornstarch are mixed with an aqueous gelatin solution. The mixture is dried and ground into a fine powder. Avicel and magnesium stearate are incorporated into the granules; the whole is compressed in the form of pills: 1000 pills are produced, each containing 100 mg of active ingredient.

1000 pills each containing 200 mg of 1- [D-3- (acetylthio) -2-20 methylpropanoyl] -cis-4-fluoro-L-proline are produced from the following:

l- [D-3- (acetylthio) -2-methylIpropanoyl] -cis-4-fluoro-

L-proline

200 g lactose

100 g avicel

150 g cornstarch

50 g magnesium stearate

5g

The 1- [D-3- (acetylthio) -2-methylpropanoyl] -cis-4-fluoro-L-proline is mixed with lactose and poultry and finally with cornstarch. The dry mixture is compressed in a pill press; 1000 pills of 505 mg are obtained, each containing 200 mg of active substance. The pills are coated with a solution of methocel E 15 (methyl cellulose) and a coloring based on * 6.

2 gelatin capsules * 1, each containing 250 mg l- (3-mer-capto-4,4,4-trifiuorobutanoyl) -L-proline, are filled with a preparation based on the following substances:

l- (3-mercapto-4,4,4-trifluorobutanoyl) -L-proline 250 mg magnesium stearate 7 mg lactose USP 193 mg

A solution for injection is produced with the following substances: eis-1 - (D-3-mercapto-2-methylpropanoyl) -cis-4-fluoro-

L-proline 500 g methyl paraben 5 g propyl paraben 1 g sodium chloride 25 g water for injection qs 5 1

The active substance, the preservatives and the sodium chloride are dissolved in 3 liters of water for injection; the volume is made up to 5 1. The solution is filtered through a sterile filter; we fill, aseptically, pre-sterilized vials; these are sealed with pre-sterilized elastics. Each vial contains 5 ml of the solution at a concentration of 100 mg of active substance / ml of solution.

The products of each example can be incorporated into compositions of the type described above.

R

Claims (22)

639 370 CLAIMS 1. Compounds of general formula: R, r. -s- - (CH) —CH - CO- n - coor, (I) "çhr6) m ch-coor in which R is hydrogen, lower alkanoyl, or of formula: in which R: is hydrogen or a lower alkyl; R2 and Rs are each hydrogen or fluorine; R3 and R4 are each a drogen hy-io or a trifluoromethyl; one of these groups being a hydro-1 gene, the other being a trifluoromethyl; n is 0 or 1, as well as its alkaline salts. 1 i - (ch) —c r— s - (ch) ^ - ch — co — n r. coor, r — s " R / "(ch) ch — co n II 2.m ch-coor, in which R is hydrogen, lower alkanoyl, or of formula: where R is hydrogen, lower alkanoyl, or of formula :. 2. Compound according to claim 1 of formula: r-> r 'o R, r-s - (ch) not R3 i ■ ch .x. co n ■ coor, in which R is hydrogen, a lower alkanoyl group, or of formula: r. • s— (ch) —ch- Rr R, -CO- not R, coor, wherein Rt is hydrogen or lower alkyl; R2, R'2 and R6 are each hydrogen, or halogen; R4 is hydrogen, lower alkyl, trifluoromethyl; n is 0 or 1; with the condition that at least one of the groups R2, R3, R5 and R6 is a halogen, only R2 and R'2 can be simultaneously halogens, as well as its alkali salts. 3 639,370 R2 \ / R 2 VS R, r. H2C <ch2> m -s- (ch) —ch-co-n ch-coor, where m is 2; n is 0 or 1; Rj is hydrogen or lower alkyl; R2 and R'2 are each hydrogen or halogen; R3 and R4 are each hydrogen, lower alkyl or trifluoromethyl, there can be no more than one trifluoromethyl; and in which at least one of the groups R2, R'2, R3 is a halogen, as well as its alkaline salts. 3. Compound according to claim 1 of formula: in which R and R! have the same meaning as in claim 2; R2 and R5 are each hydrogen or fluorine; R3 is hydrogen, halogen or lower alkyl; R3 is halogen when R2 and R5 are both hydrogen; if R2 and R5 are halogen, R3 cannot be halogen; R4 is hydrogen; n is 0 or 1, as well as its alkaline salts. 4. Compound according to claim 1 of formula: R, r. (chrfi) o m ch-coor, 5. A compound according to claims 1 and 2, wherein R is a hydrogen gene or a lower alkanoyl; Rj is hydrogen or lower alkyl; R2 and R'2 are hydrogen or halogen or lower alkanoyl; Rx is hydrogen or lower alkyl; R2 and R'2 are hydrogen or halogen; R3 is hydrogen or lower alkyl; R4 is hydrogen or lower alkyl; n is 35 equal to 0 or 1. 6. A compound according to claims 1 and 2, where n is 0 or 1; R is hydrogen or lower alkanoyl; R! is hydrogen or lower alkyl; R2 and R'2 are each hydrogen or fluorine; R3 is hydrogen or lower alkyl; R4 is a 40 hydrogen or lower alkyl. 7. A compound according to claims 1 and 2, wherein R is hydrogen; R2 and R'2 are each fluorine. 8. A compound according to claims 1 and 2, wherein R and Ri are each hydrogen; R2 and R'2 are each fluorine; R3 and R4 are 45 each hydrogen or lower alkyl. 9. A compound according to claim 4, wherein R2 is hydrogen or fluorine; Rs is fluorine; R is hydrogen; Rt and R3 are each hydrogen or lower alkyl; R4 is hydrogen. 10. The compound of claim 4, wherein R2 is hydrogen; so Rs is fluorine; R is hydrogen; R1; R3 and R4 are each hydrogen; R3 is methyl. 11. A compound according to claims 9 and 10, wherein Ri and R4 are each hydrogen; R3 is methyl. 12. Compound according to claim 1 of formula: 55 R, r. 13. A compound according to claim 12, wherein R, R2, R'2 and R4 are all hydrogen atoms; R3 is trifluoromethyl. 14. A compound according to claim 12, wherein R2 is halogen; R'2 is hydrogen. 15. A compound according to claim 14, wherein the halogen is a fluorine. 16. The compound of claim 12, wherein R is hydrogen; R2 and R'2 are each a halogen. 17. The compound of claim 16, wherein the halogen is a fluorine. 18. A compound according to claim 12, where R and R! are hydrogen; R2 is hydrogen or fluorine; R'2 is fluorine; R3 is methyl; R4 is hydrogen; n is equal to 1. 19. Process for the preparation of compounds of formula (I) as defined in claim 1, characterized in that an acid of formula: R * R3 R — S— (CH) n — CH — COOH in which R, R3, R4 and n are defined, as indicated for formula (I), with an amino acid of formula: (IV) coor, wherein R is hydrogen or lower alkanoyl, or a protective group, p-methoxybenzyl, which is removed along the way; the other groups are similar to those defined above; this reaction results in the formation of a product where R is hydrogen or lower alkanoyl. 20. Process for the preparation of a compound of formula (I), according to claim 1, in which R is: R4 r3 -S - (CH) —CH — CO n characterized in that a compound of formula (I) is prepared in which R is hydrogen according to the process of claim 19 and that the product thus obtained is then oxidized with medium iodine. 20 r-s - (ch) ^ - ch- co — n coor, s ~ (CH) —CH — co where m is 1 or 2; n is 0 or 1; R! is hydrogen or lower alkyl; R2 and R'2 are each hydrogen or halogen; R3 is hydrogen, lower alkyl or CF3, or also halogen, when n is 1; R4 is hydrogen, lower alkyl or trifluoromethyl; Rs is hydrogen, or halogen when m is 1; at least one of the groups R2, R'2, R3 and Re being a halogen or CF3, only R2 and R'2 can be simultaneously halogens, as well as their alkaline salts. 21. Process for the preparation of a compound of formula (I), according to claim 1, in which R is a hydrogen, characterized in that a compound of formula (I) in which R is a lower alkanoyl according to is prepared the process of claim 19 and that the product thus obtained is then hydrolyzed. 22. Method according to claim 21, characterized in that the hydrolysis is carried out in an alkaline or ammoniacal medium.