MXPA00004425A - Process for the preparation of hydroxamic acids - Google Patents

Abstract

The present invention provides an improved process for preparing an hydroxycarbamoyl derivative of a carboxylic acid using a hydroxylammonium salt of a carboxylic acid as a reagent.

Description

PROCESS FOR THE PREPARATION OF HYDROXAMIC ACIDS.

Field of the Invention.

The present invention relates to an improved process for the preparation of a hydroxamic acid derivative from the corresponding carboxylic acid.

Background of the Invention The hydroxamic acid derivatives of certain carboxylic acids have been recognized as inhibitors of matrix metalloproteinases (MMPs) which are a family of proteases (enzymes) involved in the degradation and remodeling of connective tissues. Excessive degradation of the extracellular matrix by MMPs is implicated in the pathogenesis of many diseases, including rheumatoid arthritis, osteoarthritis, multiple sclerosis, bone reabsorbing diseases (such as osteoporosis), chronic obstructive pulmonary disease, restenosis, cerebral hemorrhage associated with infarction , periodontal disease, angiogenesis Ref: 119758 aberrant, invasion by tumors and metastasis, gastric and corneal ulceration, skin ulceration, aneurysm disease and complications of diabetes. The inhibition of MMP is therefore recognized as a good target for the therapeutic intervention of this type of diseases.

Current synthetic methods for the introduction of the hydroxylamine group into carboxylic acids and in particular such MMP inhibitors, employ the reaction with a hydroxyl ammonium salt derived from an inorganic acid such as HCl, H2SO4 or H3PO4, etc., such as sodium chloride. hydroxylammonium, hydroxylammonium sulfate or hydroxylammonium phosphate (see for example, EP 0 818 '442 A2 or WO 96/00214 for such inhibitors and methods for making them, especially with regard to the introduction of the hydroxylamine group). However, these reagents also have drawbacks with respect to side reactions, especially with sensitive or thermally hindered carboxylic acids, which reduce the yield of the obtained compound.

To overcome these problems, the reaction is then carried out by using hydroxylamine O-derivatives such as benzylhydroxy-lamonium chloride, O-tetrahydropyranyl-hydroxylamine or O-trimethylsilyl-hydroxylamine. All of these reagents are O-protected reagents which must be prepared separately and which require a subsequent deprotection to produce the hydroxylamine free group.

Accordingly, there is still a need to provide an improved process for the preparation of hydroxamic acid derivatives in general and for those suitable as inhibitors of particular enzymes. This problem has been solved by the present invention. Accordingly, the present invention provides a process for the manufacture of a hydroxamic acid derivative from the corresponding carboxylic acid, characterized in that the carboxyl group reacts with a hydroxylammonium salt of a carboxylic acid in an appropriate solvent. The corresponding carboxylic acid means the corresponding carboxylic acid precursor which becomes the hydroxamic acid derivative.

Description of the invention.

It has been unexpectedly found that the hydroxylamine group can also be introduced by using a hydroxylammonium salt of an organic acid as a reagent. These reagents can be advantageously used as effective reagents for making the hydroxamic acid from the corresponding carboxylic acid, especially when the corresponding carboxylic acid is hindered is either thermally or is very sensitive to basic conditions. Usually the carboxylic acid used in the hydroxylammonium salt reagent is different from the corresponding carboxylic acid with which it will react, especially if the corresponding carboxylic acid is difficult to obtain compared to acids useful in the reagent.

The following definitions are used in the description. Under "halogen", chlorine, bromine, iodine will be understood hereinafter. "I rent" means a straight or branched chain alkyl group with 1 to 8 C atoms, preferably 1-6 C atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and tert. butyl. "Alkoxy" means an alkyl-O-group wherein a hydrogen has been replaced by an oxygen atom. "Aryl", alone or in combination, means a bicyclic or a monocyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, for example, phenyl, 1-naphthyl, 2-naphthyl and the like. "Cycloalkyl" alone or in combination means a saturated monocyclic ring of 3 to 7 carbon atoms, for example, cyclopentyl, cyclohexyl or cycloheptyl.

In the hydroxylammonium salt of the carboxylic acid, the anion is derived from an organic carboxylic acid of the general formula R-C (0) OH. R may be any organic residue such as H, alkyl, cycloalkyl or an aryl and the like, residues which (except H) may further be optionally substituted by halogen, nitro, carboxy and the like. Accordingly, dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, Maleic acid or phthalic acid can also be used. Monocarboxylic acids are preferred. Preferred carboxylic acid salts are hydroxylammonium acetate, hydroxylammonium propionate, hydroxylammonium benzoate and the like. Such salts have a higher solubility in organic solvents and therefore, a better reactivity than salts of inorganic acids. Moreover, the carboxylate is a weak base which, based on its reaction with the free protons in the reaction mixture, provides a better reactivity of the non-protonated reagents and causes less side reactions. More preferably, hydroxylammonium acetate is used.

The hydroxylammonium carboxylates can be prepared by treating a 50% solution of hydroxylamine in water with the corresponding carboxylic acid in an alcohol such as methanol, ethanol or propanol, at temperatures from -10 to 30 ° C. After cooling to temperatures below -10 ° C, the salt can crystallize and wash and dry later. Alternatively, DE 3601216 Al also describes a process for the preparation of hydroxylammonium salts of fatty acids with 1 to 4 carbon atoms, especially acetate and propionate, by reacting hydroxylammonium sulfate and alkaline salts of fatty acids in an appropriate solvent. The preparation of the salts of organic acids has also been described in US Patent No. 2,483,252 and in EP 0 108 294 A2 wherein salts of oxalate, acetate, benzoate and formate are described.

For the introduction of the hydroxylamine group into the carboxylic acid, the carboxyl group is preferably activated. This can be effected with activating agents known per se, such as carbodiimides, for example, dicyclohexyl carbodiimide, or an isocyanide, for example, tert-butyl isocyanide, or preferably, isocyanide of 2-morpholino-etiol in the presence of amounts stoichiometric esters of ester-forming alcohols such as, for example, N-hydroxy-succinimide, N-hydrobenzotriazole or preferably N-hydroxy-2-pyridone, in a solvent, such as an ether, for example, methyl tert-butyl ether, tetrahydrofuran or dioxane, or a hydrocarbon, for example, toluene or a halogenated hydrocarbon, for example, CH2C12, CC14, preferably methylene chloride, or a nitrile, for example, CH3CN or an ester, for example, methyl or ethyl acetate, preferably ethyl acetate or an alcohol, for example methanol or ethanol, a temperature of 0 to 80 °, preferably 10 to 25 °.

The reaction can be carried out without the addition of a base in order to neutralize the acid generated from the hydroxylammonium salt. In a preferred embodiment a base is added. Such an organic base may be an amine, preferably a tertiary amine, for example, triethylamine or N-methylmorpholine.

The preparation of the reaction mixture can be carried out in a usual manner by extracting and washing the organic layer with water and / or aqueous buffer solutions to remove the reagents. Further purification can be carried out by chromatography and / or crystallization to obtain the final hydroxycarbamoyl derivative. The derivative is. can crystallize in the form of free hydroxamic acid or as a salt using the appropriate base. Alternatively, when the hydroxamic acid derivative is further substituted with a basic portion, addition salts can be formed or, when the derivative is substituted with an acidic portion, the base addition salts can be formed by known methods.

In a particular embodiment of the process of the present invention, 1 - [3-cyclopentyl-2 (R) - [1 (R) - (hydroxycarbamoyl) -2- (3, 4, 4 -trimethyl-2, 5 -dioxo-1-imidazolinyl) ethyl] propionyl] piperidine (I) is prepared.

This process comprises the reaction of a compound of formula II with a hydroxylammonium salt of a carboxylic acid in a suitable solvent as described above. This means that a compound of formula (II) is the "preferred carboxylic acid" referred to in various embodiments of the process of the present invention as described above.

The compound (I) is known and described for example, in EP 684 240 Al. The compound has valuable pharmacological properties and can be used in accordance for the treatment and presentation of conditions such as, for example, degenerative diseases of the joints. The compound can be prepared as described in EP 0 684 240 Al or as described in EP 0 816 341 Al.

The compound (I) can be prepared from the acid according to the description of the reaction conditions given above. In this connection, the carboxylic acid used in the reagent of the hydroxylammonium salt must be different from the carboxylic acid precursor with which it is going to process. The hydroxylammonium salt of this spherically hindered carboxylic acid would react not specifically with the activation with oxygen and the active nitrogen center of the hydroxylamine. More preferably, the hydroxylammonium acetate is used which unexpectedly provides the smallest amount of dimers of the compounds of formula (II) linked via the hydroxy lamino group. With respect to the other reaction conditions, the reaction is preferably carried out in halogenated hydrocarbons, preferably CH2C12 or a nitrile, preferably CH3CN using hydroxylammonium acetate. The activated ester is preferably made with N-hydroxy-2-pyridone as the alcohol component. The preferred activator is the 2-morpholino-yl isocyanide. The preparation of the reaction mixture is done by washing the organic layer with water or an aqueous buffer solution. Further purification can be carried out by subsequent chromatography on silica gel using CH2Cl2 / MeOH. Alternatively, the crystallization can be done in an organic solvent such as wet methyl tert-butyl ether, or in water to obtain the compound (I). Preferably, an organic acid, especially acetic acid, is added before concentrating the final organic layer, for example, for crystallization, it is made in particular if a large scale synthesis of compound (I) is carried out.

In connection with the manufacture of the compound of formula (I) by means of compound (II), compound (II) can be prepared as described in EP 0 684 240 Al or as described in EP 0 816 341 Al. , the compound (II) can be prepared by the reaction of a compound of formula (III with (S) - -benzyl-2-oxazolidone to give (S) -3- (3-cyclopentyl-1-oxopropyl) -4- (phenyl) -2-oxazolidinone (IV), b) the product obtained reacts with a compound of formula (V) wherein R1 means alkyl or benzyl (C? -C6) and Hal means chlorine, bromine or iodine, to give a compound of formula (VI) c) separating (S) -4-benzyl-2-oxa zolidinone to obtain a compound of formula (VII) d) by reacting a compound of formula (VII) with piperidine to obtain a compound of formula (VIII) e) the compound thus obtained of formula (VIII) reacts with a halohydantoin of formula (IX) O R (IX) where R is chlorine, bromine or iodine, in the presence of a strong enolate-forming base, to give a compound of formula (X) wherein R 1 means alkyl or (C 1 -C 6) benzyl and f) obtaining a compound of formula (II) (II) by separating the group R The compound (II) then further reacts with a hydroxylammonium salt as described above to produce the compound (I).

Acylation of (S) -benzyl-2-oxa zolidinone (commercially available or producible according to M. Sudharshan, PG Hultin, Synlett, 171 (1997)) with cyclopentyl-propionyl chloride (III) (Barren et al. , J. Chemical Society 1065 (1935)) according to step a) is carried out according to methods known per se with a base, for example, NaH, LDA, LiN (TMS) 2, or an alkyl lithium compound, preferably BuLi, in a solvent such as an ether, preferably THF, at a temperature of -80 ° to 22 °, preferably -45 °. For the formation of the alkylated compounds (VI) in step b), the (S) -3- (3-cyclopentyl-l-oxopropyl) -4- (phenylmethoxy) -2-oxa zolidinone which remains It can be used alone or conveniently in solution. The alkylation is carried out with an ester of haloacetic acid, preferably tert-butyl bromoacetate in the presence of a base, for example, LiN (TMS) 2 or preferably LDA in a solvent mentioned above, preferably THF, at -80 ° to 22 °, preferably -45 °. The product (IV) which is formed can be obtained from the reaction medium in a high optical purity (of> 99.9%) by crystallization followed by the addition of an alkane, preferably hexane or by chromatography.

Haloacetic acid esters are commercially available or obtainable according to the per se methods by the esterification of the haloacetic acid derivatives.

The separation of the chiral auxiliary reagent from the compounds of formula (VI) to give the acid (VII) and (S) -4-benzyl-2-oxazolidinone according to step c) can be carried out according to the methods known per se with hydrogen peroxide and LiOH in an ether, such as, for example, tetrahydrofuran. Alternatively, the reaction also proceeds quantitatively when the sodium hydroxide and the hydrogen peroxide in a mixture of water and an alcohol, preferably isopropanol, is used at a temperature of -10 ° to 22 °, preferably 0 °. The (S-) -4 -benzyl-2- oxazolidinone, which is obtained with which, crystallizes almost quantitatively from the aqueous phase.

The formation of the acid amide (VII) with piperidine in step d) can be carried out according to the coupling methods known per se, such as, for example, by means of the acid chloride, by means of a mixed anhydride, by means of a mixed sulfonic acid anhydride or, preferably by means of an active ester. In so doing, water scavengers such as carbodiimides, preferably di-cyclohexyl carbodiimide, are used in the presence of catalytic or tequiometic amounts of ester-forming active alcohols, such as, for example, N-hydroxysuccinimide, N-hydroxyben zot riazole or preferably N-hydroxy-2-pyridone in a solvent such as a ketone, for example methyl ethyl ketone or an ether, for example, methyl tert -butyl ether, or a hydrocarbon eg toluene, or a hydrocarbon halogenated, for example, methylene chloride or an ester, preferably isopropyl acetate, at a temperature of 0 to 80 °, preferably 22 °.

The alkylation of the compounds of formula VIII with the halometyl-hydantoin (IX) in step e) is carried out in the presence of a strong base in a solvent such as an ether, preferably THF, at a temperature of -100 ° to 22. °, preferably -60 ° C. With strong enolate-forming bases, such as KN (TMS) 2 or Cl-C6-alkoxy potassium bases, such as for example potassium tert-butyl, KH, or KNH2, the ant i-selectivity required for the manufacture of the compounds of formula (X) is reached. The mixture of diastereomers can be separated by chromatography on silica gel with suitable solvents such as, for example, ethyl acetate / hexane.

The halohydrin oin (IX) used for the reaction with a compound (VIII) can be obtained by the halomethylation of 1, 5, 5-t rimet il-hydantoin. Thus, 1, 5, 5-trimethyl-hydantoin reacts conveniently with a hydrogen halide in acetic acid at a temperature between 20 ° and 100 °, preferably at about 80 °. Trimethylhydantoin can be obtained according to methods known per se (H. Heimgartner et al., Helv. Chim. Acta 75, 1251. (1992)).

The hydrolysis of an ester group in a compound of formula (X) in which R 1 signifies a branched or straight chain alkyl (C 6 -C 6), other than tert-butyl or a spherically similar hindered alkyl group, to the compound (II ) according to section f), is carried out in the presence of an alkaline or alkaline earth metal hydroxide, such as barium, calcium, sodium or potassium hydroxide, preferably potassium hydroxide, in a solvent such as an alcohol, for example, -propanol, or water with an organic solvent, such as an ether, for example, methyl tert-butyl ether, or preferably THF, at a temperature of 0 to 100 °, preferably 30 to 50 °.

The separation of the tert-butyl group or a spherically hindered alkyl group such as isopropyl or sec-butyl, which is not easily accessible to the separation of the base, in a compound of formula (X) to give the compound (II) according to the section f) is carried out in the presence of a mineral acid, such as aqueous phosphoric or sulfuric acid, preferably hydrochloric acid or hydrobromic acid and an organic carboxylic acid, preferably acid acetic acid at a temperature of 0 to 100 °, preferably 0-22 °. The separation can also be carried out in a carboxylic acid ester or a mixture of carboxylic acid and carboxylic acid ester instead of a carboxylic acid. Suitable esters of carboxylic acids are methyl, ethyl or isopropyl acetate, preferably ethyl acetate. Preferably, the separation in section f) is carried out with a mineral acid in a carboxylic acid, preferably with HBr / acetic acid. In addition, the separation by means of an acid can be carried out in an otherwise appropriate organic solvent. Methylene chloride or toluene is a suitable organic solvent.

The debenzylation of the compound (X) in which R1 is equal to benzyl (Bz) in section e) to give the compound (II), is carried out in an organic solvent using hydrogen in the presence of a metal catalyst. Suitable solvents are Ci-Ce alcohols, preferably methanol or ethanol. As metal catalysts platinum or palladium can be used, which are suitably supported in a carrier material such as a aluminum, barium sulfate or mineral coal. Palladium in mineral coal or barium sulfate is a preferred catalyst. The temperature and pressure are not critical and can vary over a wide range. Preferably the hydrogenation is carried out at room temperature and 1-10 bars.

The invention is now further described by way of examples which are not intended to be limiting in the scope of the claims.

Eg emplos In the Examples and the description, the following abbreviations are used: The enantomeric excess CG gas chromatography (in molten silica) to determine the amount of product obtained MS (ISP, El) Mass Spectroscopy p.f. melting point All temperatures are given in degrees Celsius.

Example 1 Preparation of the hydroxylammonium acetate salt 100 g of a hydroxylamine solution (50% in water) are placed in a 500 ml flask and cooled in an ice bath (0-5 °) with a magnetic stirrer. 93 g of glacial acid is added slowly with stirring for 30 minutes and cooled. The mixture is cooled to -20 ° C and the suspension is filtered. The crystals are washed with tert-butyl methyl ether and dried under vacuum in the rotavap at 35 ° C yielding 131 g (91%) of white crystals of hydroxylammonium acetate. p.f. 87 °.

Example 2 Dissolve 30 g of 1- [2 (R) - [1 (R) -carboxy-2- (3,4,4-trimethyl-2, 5-dioxo-l-imidazolidinyl) -ethyl] -3-cyclopentylpropioni 1] piperidine and 8.71 g of N-hydroxy-pyridone in 120 ml of CH2C12 in a 250 ml round bottom flask. The mixture was treated at room temperature with 10.73 g of morphol inoe t i 1 socianide. After 10-20 minutes, the mixture became clear and agitation continued to Room temperature during the night. The solution was added slowly to a stirred suspension of 9.94 g of hydroxylammonium acetate and 7.2 g of triethylamine in 180 ml of CH2C12 and the mixture was stirred for an additional 4 hours. The reaction mixture contained about 97% of the product and about 3% of starting material. This mixture was extracted with 95 ml of water. The aqueous layer was extracted with 60 ml of CH2C12 and the combined organic layers were extracted twice with 95 ml (total 190 ml) of a 5% NaHCO3 solution and once with a 95 ml solution of 2% H2SO4. The organic layer was evaporated at 35-40 °. The oily residue was treated with 300 ml of wet tert-butyl methyl ether and evaporated to a volume of 200 ml and stirred for 10 hours. The solid was completely filtered, washed twice with 20 ml of tert-butyl methyl ether and dried under reduced pressure at room temperature affording 25.6 g (82%) of 1 - [3-cyclopentyl-2 (R) - [1 ( R) - (hydroxy carbamoyl) -2- (3,4-trimethyl-2,5-dioxo-l-imidazolidinyl) ethyl] propionyl] piperidine MS (El): 436, m.p. 120 ° dec.

Example 3 a) In accordance with the procedure described in Example 2 but reacting 10 g of 1- [2 (R) - [1 (R) -carboxy-2- (3,4, 4-trimeti 1-2, 5-dioxo -1-imidazolidinyl) ethyl] -3-cyclopentyl-propionyl] piperidine with 2.9 g of N-hydroxy-pyridone and 3.66 g of morpholinoethyl isocyanide and a subsequent reaction with 2.47 g of hydroxylammonium chloride and 6 g of triethylamine were obtained. % of the dimer. This dimer was further reacted for the product and the starting material. The final reaction mixture contained 55% of the product, 25% of the starting material and 18% of the dimer. b) Reacted 1- [2 (R) - [1 (R) -carboxy-2- (3,4,4-trimethyl-2,5-dioxo-l-imide zol idini 1) ethyl] -3- cyclopentyl-propionyl] piperidine with hydroxylammonium sulfate in a manner analogous to that described in a), the same reaction mixture composition was obtained. c) Reacted 1- [2 (R) - [1 (R) -carboxy-2-. { 3,4,4-trimethyl-2,5-dioxo-l- imidazolidinyl) ethyl] -3-cyclopentyl-propionyl] piperidine with hydroxylammonium phosphate giving the same reaction mixture as in a). d) In accordance with the procedure described in a), but reacting 2.5 g of l- [2 (R) - [l (R) -carboxy-2- (3,4, 4 -trimeti 1-2, 5- dioxo-1-imide zol idini 1) ethyl] -3-cyclopentyl-propionyl] piperidine with 0.73 g of N-hydroxy-pyridone and 0.92 g of isocyanide of morpholinoe ti 1 and a subsequent reaction with 0.94 g of hydroxylamine (50% in water) dissolved in methanol (2.25 ml) and water (0.3 ml) gave a reaction mixture containing 80% of the product and 16% of the corresponding ammonium (reaction in the O-terminal of hydroxylamine).

Example 4 The starting material used in Example 2 was prepared as follows: a) A solution of 53.1 g of (S) -benzyl-2-oxazolidinine in 240 ml of tetrahydrofuran was treated at 45 ° with 197 ml of butyllithium 1.6M in hexane, a solution of 49.18 g of cyclopentylpropyl chloride in 105 ml of tetrahydrofuran was subsequently added, and the solution was stirred at -45 ° for 1 hour. The resulting (S) -3- (3-cyclopentyl-1-1-oxopropyl) -4- (phenylmethyl) -2 -oxa zolidinone as an intermediate was treated with 286 ml of a solution of lithium diisopropylamide 1. IM in tetrahydrofuran at -45 °, stirred for 1.5 hours and 64.38 g of tert-butyl bromoacetate in 60 ml of tetrahydrofuran was subsequently added. After 4 hours at -45 °, 600 ml of semi-saturated ammonium chloride was added, the THF phase was washed with a semi-saturated sodium chloride solution, concentrated and crystallized by the addition of hexane, with 94.5 g (76%) of tert-butyl (R) -4- [(S) -4-benzyl-2-oxo-oxa-zollinin-3-yl] -3-cyclopentylmethyl-oxo-butanoate pure (ee > 99.9%), mp 113-119 °, being obtained. IR (KBr): 1768s, 1730s and 1695s (C = O). b) A solution consisting of 36.7 g of 35% hydrogen peroxide and 8.31 g of sodium hydroxide in 78 ml of water was added at 0 ° to a suspension of 78.5 g of the oxazolidinone of a) in 550 ml of isopropanol and the mixture was stirred at 22 ° for 1 hour. The solution was concentrated, made basic with a sodium hydroxide solution and the precipitated (S) -4-benzyl-2-oxazolidinone was completely filtered. Still present the (S) -4-benzyl-2-oxazolidinone was extracted with methylene chloride, giving a total of 32.68 g (98%) of the pure (S) -4-benzyl-2-oxa zolidinone, m.p. 86.5-88 °, recovered. The aqueous phase was adjusted to a pH of 3 with hydrochloric acid and extracted with isopropyl acetate. The organic extracts were washed, dried and evaporated, after which 47.79 g (99%) of the 4-tert-butyl ester of (R) -2-cyclopentyl acid was obtained. enantiomerically pure il-succinic met (ee > 99%) as an oil. IR (film): 2700m, br. (COOH), 1733s and 1710s (C = O). c) A suspension of 34.48 g of the acid of b) and 5.98 g of N-hydroxy-2-pyridone in 170 ml of isopropyl acetate, was treated at 0 ° with 12.03 g of piperidine and subsequently with a solution of 30.53 g of ducyclohexyl-cabodiimide in 92 ml of isopropyl acetate and stirring at 22 ° for 16 hours. The suspension was treated with 82 g of 10% acetic acid in water and the mixture was stirred for 4 hours. hours and it leaked. The organic phase was washed with sodium carbonate and water, filtered and co-concentrated, after which 43.89 g was obtained. (100%) of the (R) -3-cyclopentylmethyl-4-oxo-4-piperidin-1-yl-butanoate of tert-butyl (ee> 99%), m.p. 38-40 °, crystallized from the oil. GO (film): 1729s and 1641s (C = O). -d) A solution of 10.7 g of the ester of c) in 50 ml of tetrahydrofuran was added dropwise at -60 ° to a solution of 8.76 g of potassium bis-trimethylsilylamide in 80 ml of tetrahydrofuran and the mixture was stirred at -60 ° for 30 minutes. Subsequently, a solution of 1 was added. 1 6 g of 3-bromomet-1, 5, 5-trimethylhydantoin in 40 ml of tetrahydrofuran at -60 ° and the mixture was stirred at -60 ° C for 30 minutes, the reaction mixture was washed with a chloride solution of sodium semi-saturated and with dilute hydrochloric acid, dried, filtered and concentrated, obtaining 15.11 g of a 9: 1 mixture of l- [2 (R) - [l (R) - (tert-butoxycarbonyl) - 2- (3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl) ethyl] -3-cyclopentyl-propionyl] piperidine and 1- [2 (R) - [1 (S) - (tert-butoxycarbonyl ) -2- (3, 4, 4-trimethyl-2, 5-dioxo- 1-imidazolidinyl) ethyl] -3-cyclopentyl-propionyl] piperidine, which was used in the next step without further purification. The mixture can be separated by chromatography on silica gel with hexane / ethyl acetate (1: 1). e) A solution of 15.11 g of a 9: 1 mixture of d) in 15 ml of acetic acid was treated at 0 ° with 15 ml of 33% hydrogen bromide in acetic acid at 0 ° for 4 hours. The solution was diluted with methylene chloride, washed with water and the organic phase was dried, filtered and evaporated. The residue was crystallized from 26 ml of tert-butyl methyl ether and 26 ml of hexane, after which 6.90 g (70%) of pure diastereomer was obtained (ee> 98%) 1 - [2 (R ) - [1 (R) -carboxy'-2- (3, 4, 4 - 1 rime t il-2, 5-di oxo-1-imide zol idini 1) ethyl] -3-cyclopentyl-propionyl] piperidine, pf 111-114 °. IR (KBr): 1770m and 1715s (C = O).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (9)

Claims

1. A process for the manufacture of a hydroxamic acid derivative from the corresponding carboxylic acid, characterized in that the carboxyl group is reacted with a hydroxylammonium salt of a carboxylic acid in an appropriate solvent.

2. The process according to claim 1, characterized in that the hydroxylammonium salt is hydroxylammonium acetate, hydroxylammonium propionate, or hydroxylammonium benzoate.

3. The process according to claim 2, characterized in that the hydroxylammonium salt is hydroxylammonium acetate.

4. The process according to any one of claims 1-3, characterized in that a base is added.

5. The process according to claim 4, characterized in that the base is triethylamine.

6. The process according to any one of claims 1-5, can be etherified because the solvent is a halogenated hydrocarbon.

7. The process according to any one of claims 1-6, characterized in that the corresponding carboxylic acid is 1- [2 (R) - [1 (R) -carboxy-2- (3,4, -trimethyl-2, 5 -dioxo-l-imidazolidinyl) ethyl] -3-cyclopentyl-propionyl] piperidine.

8. The use of the hydroxylammonium salt of a carboxylic acid in the preparation of the hydroxamic acid derivative of the corresponding carboxylic acid.

9. The invention is substantially as described herein, especially with reference to the new processes and uses.