MXPA98008000A - Process for preparing succinic acid derivatives qui - Google Patents

Abstract

The present invention relates to a process for the manufacture of chiral succinic acid derivatives of formula (I) wherein R 1 is alkyl of 1 to 6 carbon atoms or benzyl, and the new intermediate use of the same

Description

PROCESS FOR PREPARING QUIRAL SUCCINIC ACID DERIVATIVES The present invention relates to a process for the manufacture of chiral derivatives of succinic acid of formula (I) wherein R1 is alkyl of 1 to 6 carbon atoms or benzyl, the process comprises reacting a compound of formula (II) where R1 has the meaning previously stated, REF .: 28381 with a halohydantoin of formula (III) wherein R2 is halogen in the presence of a strong potassium base forming an enolate. By halogen is hereinafter understood to be chlorine, bromine and iodine. Alkyl of 1 to 6 carbon atoms means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl or isopropyl, and respectively, ter- butyl. R1 is preferably an alkyl of 1 to 4 carbon atoms. With respect to the alkoxy term of 1 to 6 carbon atoms, the above definitions are also applied with respect to the alkyl or oxygen-linked part. The compounds of the formula (I) are described in the publication of European Patent Application Number EP 0 816 341 Al. The compounds of formula I are valuable intermediates in the synthesis of the pharmacologically active compound (X).

The alkylation of the compounds of formula II with the halomethylhydantoin (III) 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 ° C, preferably -60 ° C. The stereoselectivity of the new stereocenter formed depends to a high degree on the nature of the cation of the base. Lithium bases, such as for example LDA, give rise to a selectivity without (ratio of up to 90:10). On the other hand, sodium bases, such as for example NaN (TMS) 2, are not specific (1: 1 mixture). The selectivity without with the LDA has already been described by R. Becket et al. In Synlett 137, February 1993, when they used succinic acid derivatives having an ester group and a free acid. Unexpectedly, it has been found that in the case of an acid amide and the use of strong bases of potassium forming enolates, such as for example KN (TMS) 2 or potassium bases of alkoxy of 1 to 6 carbon atoms, such such as, for example, potassium tert-butylate, the anti-requerquer selectivity for the manufacture of compounds of formula (I) is achieved. Preferably, KN (TMS) 2 is used in the manufacture of the compounds of formula (I). This achieves an anti-selectivity in the 90:10 ratio. The mixture of diastereomers can be separated by chromatography on silica gel with suitable solvents, such as, for example, hexane / ethyl acetate. The tert-butyl ester of formula (II) is preferably used as the ester. The allohydantoin (I? I) ^ used for the reaction with a compound (II) can be obtained by halomethylation of 1,5,5-trimethylhydantoin. Thus, 1, 5, 5-trimethylhydantoin is conveniently reacted with a hydrogen halide in acetic acid at a temperature between 20 ° and 100 ° C, preferably at about 80 ° C. Terimethylhydantoin can be obtained according to methods known per se (H. Heimgartner et al., Helv. Chim. Acta 7_5, 1251 (1992)). Halogen in this connection means chlorine, bromine or iodine. The halogen is preferably bromine. In relation to the manufacture of the compounds of formula (I) via the compounds of formula (II), the present invention is also related to the manufacture of succinic acid derivatives of formula (I) by a process in which a) a compound of formula (IV) "" "is reacted with (S) -4-benzyl-2-oxazolidinone to give (S) -3- (3-cyclopentyl-1-oxopropyl) -4- (phenylmethyl) -2-oxazolidinone (V), b) the product (V) obtained is reacted with a compound of formula (VI) R ^ OCal (IV) wherein R1 means alkyl of 1 to 6 carbon atoms or benzyl, and Hal means halogen, to give a compound of formula (VII) (VII) c) a compound of formula (VIII) is obtained from the compound (VII) with the hydrolysis of (S) -4-benzyl-2-oxazolidone, d) a compound of the formula (II) R is obtained by reacting the compound (VIII) with piperidine, and e) the compound obtained in this way of the formula (II) is reacted with a halohydantoin of the formula (III) (III) wherein R2 is halogen. For carrying out step e), reference is made to the above description of the reaction of the compounds of formula (II) with those of formula (III). Acylation of (S) -4-benzyl-2-oxasolidinone (commercially available or producible according to M. Sudharshan, PG Huitin, Synlett, 171 (1997)) with cyclopentyl-propionyl chloride (IV) (Barrett 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 alkyllithium compound, preferably BuLi, in a solvent such as ether, preferably THF, at a temperature of -80 ° to 22 °, preferably -45 ° C. For the formation of the alkylated compounds (VII), the remaining (S) -3- (3-cyclopentyl-1-oxopropyl) -4- (phenylmethyl) -2-oxasolidinone can be used in isolation or, conveniently, in solution. The alkylation is carried out with a haloacetic acid ester, 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 ° C , preferably -45 ° C. The product (VII) that is formed can be obtained from the reaction medium in a high optical purity (of> 99.9%) by crystallization following the addition of an alkane, preferably hexane, or by chromatography. The haloacetic acid esters are commercially available, or are obtainable according to methods known per se by the esterification of haloacetic acid derivatives. The hydrolysis of the chiral auxiliary reagent of the compounds of formula (VII) to give the acid (VIII) and (S) -4-benzyl-2-oxazolidinone according to step c) can be carried out according to methods known per se. with hydrogen peroxide and LiOH in an ether, such as for example tetrahydrofuran. The THF peroxide that is produced with this represents a non-significant safety risk. Surprisingly, it has now discovered that the reaction proceeds quantitatively when sodium hydroxide is used more cheaply in a mixture of water and an alcohol, preferably isopropanol, at a temperature of -10 ° to 22 ° C, preferably 0 ° C. The (S) -4-benzyl-2-oxasolidinone obtained by this crystallizes almost quantitatively from the aqueous phase. The formation of the acid amide (VIII) with piperidine in step d) can be carried out according to coupling methods known per se, such as, for example, via the acid chloride, via a mixed anhydride, via a sulfonic acid anhydride mixed or, preferably, via an active ester. In doing so, water-entraining agents such as corbodiimides, preferably dicyclohexylcarbodiimide, are used in the presence of stoichiometric or catalytic amounts of alcohols that form active esters, such as, for example, N-hydroxysuccinimide, N-hydroxybenzotriazole or preferably N-hydroxy-2-pyridone. in a solvent such as a ketone, for example methyl ethyl ketone, or an ether, for example tert-butyl methyl ether, or a hydrocarbon, for example toluene, or a halogenated hydrocarbon, for example methylene chloride, or an ester, preferably isopropyl acetate , at a temperature of 0 to 80 ° C, preferably 22 ° C. The compounds of formula (I) can be used in a process for the manufacture of a compound of formula (X) In this process a) a compound of formula (I) wherein R 1 means alkyl of 1 to 6 carbon atoms or benzyl is obtained according to the preceding description, b) the compound of formula (IX) (IX) it is subsequently produced by hydrolysis of the R1 group, And c) the compound of formula (X) is obtained by subsequent introduction of the hydroxylamine group into the compound of formula (IX), or d) a compound of formula (I) in which R 1 means alkyl of 1 to 6 carbon atoms of straight chain is reacted with a benzylhydroxylate hydrochloride ina activated by means of an alkylmagnesium halide, and subsequently the benzyl group is hydrolyzed hydrogenolitically, and the compound (X) is likewise obtained. The compound (X) is known and described, for example, in EP 684 240 Al. The compound has valuable pharmacological properties, and can therefore be used for the treatment and prevention of diseases such as, for example, degenerative diseases of the joints The hydrolysis of an ester group in a compound of formula (I) in which R 1 means straight or branched chain alkyl of 1 to 6 carbon atoms, other than ter-butyl or a similar spherically hindered alkyl group, to the compound (IX) according to section b) is carried out in the presence of an alkali metal 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 i-propanol, or water with an organic solvent, such as an ether, for example tert-butyl methyl ether, or preferably THF, at a temperature of 0 to 100 ° C, preferably 30 to 50 ° C. hydrolysis of the tert-butyl group or a similar sterically hindered alkyl group in a compound of formula (I) to give the compound (IX) according to section b) is carried out in the presence of a mineral acid, such as for example acid phosphoric or aqueous sulfuric, preferably hydrochloric acid or hydrobromic acid and an organic carboxylic acid, preferably acetic acid at a temperature of 0 to 100 ° C, preferably 0-22 ° C. The hydrolysis can also be carried out in a carboxylic acid ester or a carboxylic acid mixture and carboxylic acid ester instead of a carboxylic acid. Suitable carboxylic acid esters are methyl, ethyl or isopropyl acetate, preferably ethyl acetate. HBr in acetic acid is the preferred hydrolysis method used. In addition, the average hydrolysis of an acid can be effected in an otherwise suitable organic solvent. Methylene chloride or toluene are a suitable organic solvent. The debenzylation of the compound (I) in which R1 is equal to benzyl (Bz) in section b) to give the compound (IX) is carried out in an organic solvent using hydrogen in the presence of a metal catalyst. Suitable solvents are alcohols having 1 to 6 carbon atoms, preferably methanol or ethanol. Palladium or platinum, which are suitably supported on a carrier material such as aluminum oxide, barium sulfate or carbon, can be used as metal catalysts. Palladium on carbon or barium sulfate is a preferred catalyst. The temperature and pressure are not critical, and can be varied over a wide range. Preferably, the hydrogenation is carried out at room temperature and at 1019-10.19 gk / cm2 (1.10 bar). The introduction of the hydroxymethylamine group into the compound (IX) according to section c) can be effected by means of O-trimethylsis-hydroxylamine with activating agents known per se, such as carbodiimides, for example, dicyclohexylcarbodiimide, or an isocyanide, example tert-butyl isocyanide, preferably 2-morpholino-ethyl isocyanide, in the presence of stoichiometric or catalytic amounts of alcohols forming active esters, such as for example N-hydroxy-succinimide, N-hydroxybenzotriazole or preferably N-hydroxy-2 -pyridone, in a solvent, such as an ether, for example tert-butyl methyl ether, or a hydrocarbon, for example toluene, a halogenated hydrocarbon, preferably methylene chloride, or an ester, preferably ethyl acetate, at a temperature of 0 to 80 ° C, preferably 10 to 25 ° C. Unexpectedly, it has been found that during the aqueous work the protective group of TMS is hydrolyzed gently, and the desired product (X) can be obtained in high yield and purity without the isolation of the intermediate protected with TMS. The hidoxylamine group can be introduced using tetrahydropyranyl hydroxylamine in an analogous manner. Hydrolysis of the tetrahydropyranyl group is conveniently carried out in an alcohol, such as methanol or ethanol, in the presence of a strong acid, such as a mineral acid, preferably HCl, or a sulfonic acid, preferably methanesulfonic acid or para-toluensunphonic acid, at a temperature ambient. Alternatively, the hydroxylamine group can be introduced into c) using benzylhydroxylazole hydrochloride and an activating agent in a manner previously described for the formation of amide from the acid and piperidine. Especially preferred activating agents are the carbodiimides for example dicyclohexylcarbodiimide, or an isocyanide, for example tert-butyl isocyanide, or preferably, 2-morpholino-ethyl isocyanide in the presence of stoichiometric or catalytic amounts of alcohols which form active esters, such as for example N-hydroxysuccinimide, N-hydroxybenzotriazole or preferably N-hydroxy-2-pyridone. The use and production of such isocyanides are described in EP 29 909 Bl.

The hydrolysis of the benzyl group is then carried out by means of hydrogen and a catalyst as previously described for the debenzylation of a compound of formula (I) in which R1 is equal to Bz. Additionally, according to section d) the direct conversion of an ester to a compound of formula (I) in which R 1 means alkyl of 1 to 6 carbon atoms of straight chain, preferably methyl, to benzylhydroxamate can be effected by the activation of O-benzylhydroxylamine hydrochloride with an alkylmagnesium halide, preferably i-propylmagnesium chloride, in the presence of the ester (I) in a solv such as an ester, for example t-butylmethyl ether or preferably THF, at a temperature from -70 ° to 50 ° C, preferably from -20 ° to 0 °. The hydrogenolytic hydrolysis of the benzyl group to give the compound (X) can then be carried out in a manner similar to that previously described for the debenzylation of the compound (I) in which R1 is equal to Bz. In a preferred embodim the manufacture of the compound (X) from the compounds of formula (I) is carried out not via section d), but via section b) with R1 equal to tert-butyl, followed by the subsequreaction of the compound (IX) with trimethylsilylhydroxylamine. According to the previously moned process steps, a compound of formula (X) can be obtained in a higher yield than according to the processes described in the currstate of the art. The novel intermediates of formula (VII), (VIII) and (II) are also objects of the presinvon. These are especially: (R) -4- [(S) -4-Benzyl-2-oxo-oxasolidin-3-yl] -3-cycloplmethyl-4-oxo-butanoate ^ of tert-butyl ester, 4-ter- (R) -2-cycloplmethyl-succinic acid butyl, and tert-butyl (R) -3-cycloplmethyl-4-oxo-4-piperidin-1-yl-butanoate.

Examples Example 1 A solution of 53.1 g of (S) -4-benzyl-2-oxasolidinone in 420 ml of tetrahydrofuran was treated -45 ° with 197 ml of 1.6 M butyl in hexane, a solution of 49.18 g of cycloplpropionyl chloride in 105 ml of tetrahydrofuran was subsequy added, and the solution was stirred at -45 ° for 1 hour. The resulting (S) -3- (3-cyclopl-1-oxopropyl) -4- (phenylmethyl) -2-oxasolidinone as an intermediate was treated with 286 ml of a solution of 1.1 M lithium diisopropylamide in tetrahydrofuran at -45 °. , was stirred for 1.5 hours, and 64.38 g of tert-butyl bromoacetate in 60 ml of tetrahydrofuran was subsequy added. After 4 hours at -45 °, 600 ml of semi-saturated ammonium chloride solution was added, the THF phase was washed with semi-saturated sodium chloride solution, concated and crystallized by the addition of hexane, obtaining 94.5 g (76%) of (R) -4- [(S) -4-benzyl-2-oxo-oxazolidin-3-yl] -3-cycloplmethyl-4-oxo-butanoate of pure tert-butyl (from > 99.9%), pf 113-119 ° C. IR (KBr): 1768s, 1730s and 1695s (C = 0).

Example 2 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 ° C to a suspension of 78.5 g of the oxazolidinone of example 1 in 550 ml of isopropanol, and the mezcal was stirred at 22 ° C for 1 h. The solution was concated, made basic with sodium hydroxide solution, and the precipitated (S) -4-benzyl-2-oxasolidinone was removed by filtration. The (S) -4-benzyl-2-oxazolidinone which was still preswas extracted with methylene chloride, whereby a total of 32.68 g (98%) of pure (S) -4-benzyl-2-oxazolidinone was recovered. , with melting point 86.5-88 ° C. The aqueous phase was adjusted to pH 3 with hydrochloric acid and extracted with isopropyl acetate. The organic extracts were washed, dried and evaporated, after which 47.79 g (99%) of enantiomerically pure (R) -2-cycloplmethyl-succinic acid-4-tert-butyl ester (ee > 99 %) as an oil. IR (film): 2700m, broad (COOH), 1733s and 1710s (C = O).

Example 3 A suspension of 34.48 g of the acid of example 2 and 5.98 g of N-hydroxy-2-pyridone in 170 ml of isopropyl acetate, treated at 0 ° C, with 12.03 g of piperidine, and subsequently with a solution of 30.53 g of dicyclohexylcarbodiimide in 92 ml of isopropyl acetate, and stirred 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 and filtered. The organic phase was washed with sodium carbonate and water, filtered and concentrated, after which 43.89 g (100%) of (R) -3-cyclopentylmethyl-4-oxo-4-piperidin-1-yl were obtained. pure tert-butyl butanoate (ee >99%), melting point 38-40 ° C, which crystallized from the oil. IR (film): 1729s and 1641s (C = 0).

Example 4 A solution of 10.7 g of the ester of Example 3 in 50 ml of tetrahydrofuran was added dropwise at -60 ° C to a solution of 8.76 g of potassium bis-trimethylsilylamide in 80 ml of tetrahydrofuran, and the mixture was stirred at - 60 ° C for 30 tes. Subsequently, a solution of 7.76 g of 3-bromomethyl-1,5,5-trimethylhydantoin in 40 ml of tetrahydrofuran was added at -60 °, and the mixture was stirred at -60 ° C for 30 tes. The reaction mixture was washed with half-saturated sodium chloride solution with dilute hydrochloric acid, dried, filtered and concentrated to obtain 15.11 g of a 9: 1 mixture of 1- [2 (R) - [1 (R) - (tert-butoxycarbonyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -3-cyclopentylpropionyl] piperidine and 1- [2 (R) - [1 (S) - (tert-butoxycarbonyl) -2- (3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl) ethyl] -3-cyclopentylpropionyl] piperidine (78% yield of the antipyret compound), 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).

Example 5 A solution of 15.11 g of the 9: 1 mixture of Example 4 in 15 ml of acetic acid was treated at 0 ° C with 15 ml of 33% hydrogen bromide in acetic acid, and stirred 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 ether and 26 ml of hexane, after which 6.90 g (70%) of 1- [2 (R) - [1 (R) -carboxy-2- ( 3, 4, 4-trimethyl-2, 5-dioxo-l-imidazolidinyl) ethyl] -3-cyclopentylpropionyl] piperidine (IX) diastereorically pure (from> 98%), with melting point 111-114 ° C. IR (KBr): 1770m and 1715s (C = 0).

Example 6 A solution of 1.78 g of 1- [2 (R) - [1 (R) - (methoxycarbonyl) -2- (3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl) ethyl] -3- Cyclopentylpropionyl] piperidine (see European Patent Application Number 97110942.6 (July 2, 1997)) in 3 ml of THF was treated with a solution of 0.69 g of KOH in 6.1 ml of water and stirred vigorously at 0 ° C for 5 hours. hours, and at 40 ° C for 10 hours. The mixture was adjusted to pH 2 with dilute hydrochloric acid, and treated with 8 ml of THF and 6 ml of saturated sodium chloride solution. The THF phase was washed with semi-saturated sodium chloride solution dried and concentrated. The residue contained 1.86 g of 1- [2 (R) - [1 (R) -carboxy-2- (3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl) ethyl] -3-cyclopentylpropionyl] Piperidine (IX) up to 95% pure. IR (KBr): 1769m and 1714s (C = 0).

Example 7 0. 78 g of 2-morpholino-ethyl isocyanide were added to a suspension of 2.11 g of 1- [2 (R) - [1 (R) -carboxy-2- (3,4,4-trimethyl-2, 5- dioxo-l-imidazolidinyl) -ethyl] -3-cyclopentylpropionyl] piperidine (IX) of example 5 or 6 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride at 22 ° C, and the mixture was stirred for 3 hours. The solution was treated with 0.58 g of 0-trimethylsilylhydroxyla, and stirred for 2 hours. The reaction mixture was washed with saturated NaHCO 3 solution and with water and evaporated. The residue was dissolved in 20 ml of tert-butyl methyl ether and 0.23 ml of water, stirred at 22 ° C for 1 hour, the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 22 ° C. 11.21x10-3 kg / cm2 (11 mbar), obtaining 1.82 g of (83%) of 1- [3-cyclopentyl-2 (R) - [1 (R) - (hydroxycarbamoyl) -2- (3, 4, Pure 4-trimethyl-2, 5-dioxo-l-imidazolidinyl) ethyl] propionyl] piperidine (X), MS (El): 436 (40%).

Example 8 • »0.74 g of N-ethylmorpholine, 0.60 g of hydrate N-hydroxybenzotriazole and 0.75 g of N-ethyl-Nt- (3-dimethylapropyl) -carbodiimide were added at 0 ° C in succession to a solution of 1.38 g of 1- [2 (R) - [1 (R) -carboxy -2- (3,4-, 4-trimethyl-2, 5-dioxo-l-imidazolidinyl) -ethyl] -3-cyclopentylpropionyl] piperidine (IX) from example 5 or 6 in 13 ml of methylene chloride, and the mixture it was stirred at 0 ° C for 20 tes. The reaction mixture was treated with 0.45 g of N-ethylmorpholine and 0. 63 ° g of O-benzylhydroxylamine hydrochloride, and then stirred at 0 ° C for 30 minutes and at 22 ° C for 17 hours. The solution was diluted with 13 ml of methylene chloride, washed with sodium bicarbonate solution and dilute hydrochloric acid, dried and concentrated.

The residue was crystallized from ethyl acetate / hexane and the crystallized material was dried to obtain 1.26 g. (73%) of l- [2 (R) - [l (R) - (benzyloxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl) ethyl] -3-cyclopentylpropionyl ] pure piperidine, with pf 138-140 ° C.

Alternatively, 3.86 g of 2-morpholinyl isocyanide was added to a suspension of 10.54 g of compound (IX) of example 5 and 3.06 g of N-hydroxy-2-pyridone in 110 ml of methylene chloride at 22 ° C, and the mezcal was stirred for 2 hours. The solution was treated with 3.39 g of O-benzylhydroxylamine, and stirred for 5 hours. The reaction mixture was washed with dilute hydrochloric acid, NaHCO 3 solution and water, dried and concentrated. After recrystallization from methylene chloride / hexane, the residue yielded 11.19 g (85%) pure benzylhydroxamate, melting point 140-142 ° C.

Example 9 A solution of 1.10 g of 1- [2 (R) - [1 (R) - (methoxycarbonyl) -2- (3,4, 4-trimethyl-2, 5-dioxo-l-imidazolidinyl) ethyl] -3- cyclopentylpropionyl] piperidine and 568 ml of O-benzylhydroxylamine hydrochloride in 7 ml of THF was treated at -20 ° with 3.7 ml of a solution of 2M i-PrMgCl in THF and, after 1 h at -20 °, again with 1.7 ml of Grignard reagent. After an additional 2 hours at -20 °, the mixture was treated with ammonium chloride solution, and extracted with methylene chloride. The extracts were dried and concentrated. The residue was crystallized from tert-butylmethyl ether / hexane, and the crystallized material was dried, thereby obtaining 1- [2 (R) - [1 (R) - (benzyloxycarbamoyl) -2- (3, 4, 4-tr : Lmethyl-2, 5-dioxo-l-imidazolidinyl) ethyl] -3-cyclopentylpropionyl] piperidine, with a melting point of 135-137 ° C.

Example 10 For debenzylation, a suspension of 1- [2 (R) - [1 (R) - (benzyloxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -3 -cyclopentylpropionyl] piperidine, of example 8 or 9 in 40 ml of ethanol and 1.7 g of Pd / C (5%) was hydrogenated at 22 ° / 1.019 kg / cm2 (1 bar) for 4 h. The suspension was filtered, the filtrate was completely concentrated and the residue was crystallized from water, 3.9 g (85%) of l- [3-cyclopentyl-2 (R) - [1 (R) - (hydroxycarbamoyl) -2 were obtained. - (3, 4, 4-trimethyl-2, 5-dioxo-l-imidazolidinyl) ethyl] propionyl] piperidine (X) pure, MS (El): 436 (40%). It is noted that in relation to this date, the best method known by the applicant to carry out the present invention, is the conventional one for the manufacture of the objects to which it refers. Having described the invention as above, the content of the following is claimed as property:.

Claims (19)

1. A process for the manufacture of chiral succinic acid derivatives according to formula (I) wherein R "means alkyl of 1 to 6 carbon atoms or benzyl, which process is characterized in that it comprises reacting a compound of the formula (II) (II) wherein R1 has the meaning previously set forth in the claim, with a halohydonline of formula (III) wherein R2 is chloro, bromo or iodo, in the presence of a strong potassium base forming an enolate.

2. A process according to claim 1, characterized in that KN (TMS) 2 is used as the potassium base.

3. A process according to claim 1 or 2, characterized in that R1 is terbutyl.

4. A process according to any of claim 1 or 3, characterized in that R2 is bromide.

5. A process for the manufacture of succinic acid derivatives according to any of claims 1-3, characterized because a) a compound of formula (IV) ~~~ is reacted with (S) -4-benzyl-2-oxasolidone to give (S) -3- (3-cyclopentyl-1-oxopropyl) -4- (phenyl) -2-oxazolidinone (V), b) the product obtained is reacted with a compound of formula (VI) RaOOC Hal (VI) 20 wherein R1 means alkyl of 1 to 6 carbon atoms or benzyl and Hal means chlorine, bromine or iodine, to give a compound of formula (VII) 25 (VII) c) a compound of formula (VIII) (VIII) is obtained from compound VII with the hydrolysis of (S) 4-benzyl-2-oxaz-olidinone, d) a compound of formula (II) is obtained by reacting the compound (VIII) with piperidine, and e) the thus obtained compound of the formula (II) is reacted with a halohydantoin of the formula (III) wherein R2 is chloro, bromo or iodo, according to any of claims 1 to 4.

6. A process according to claim 5, characterized in that in step b) R1 in the compound (VI) is tert-butyl.

7. A process according to claim 5 or 6, characterized in that R2 is bromine.

8. A process according to any of claims 5 to 7, characterized in that in step c) the hydrolysis of (S) -4-benzyl-2-oxazolidinone is effected by means of H202 and NaOH in a mixture of water and a alcohol.

9. A process for the manufacture of a compound of the formula (X) characterized in that a) a compound of formula (I) wherein R has the meaning given in claim 1, is obtained according to any of claims 1-8, b) the compound of formula (IX) (IX) it is produced by hydrolysis subsequently of the group R1 c) the compound of formula (X) are obtained by subsequent introduction of the hydroxylamine group into the compound of formula (IX), or d) a compound of formula (I) in which R means alkyl of 1 to 6 carbon atoms of straight chain is reacted with a hydrochloride of benzylhydroxylamine activated by means of an alkylmagnesium halide, and subsequently the benzyl group is hydrolyzed hydrogenolitically, and the compound (X) is likewise obtained.

10. A process according to claim 9, characterized in that when R1 is terbutyl, the hydrolysis in section b) is carried out with a mineral acid in a carboxylic acid, preferably with HBr / acetic acid.

11. A process according to claim 9, characterized in that when R1 is ~~~ alkyl of 1 to 6 carbon atoms other than terbutyl or a similar spherically hindered alkyl group, the hydrolysis in section b) is carried out 15 with an alkali metal or alkaline earth metal hydroxide.

12. A process according to claim 9, characterized in that R1 is Bz, the . Hydrolysis in section b) is carried out 20 * hydrogenolitically.

13. A process according to any of claims 9 to 12, characterized in that in section c) the introduction of the hydroxylamine group 25 is carried out in the case of compound (IX). a) by means of the triraethylsilyl-hydroxylamine or tetrahydropyranyl-hydroxylamine and the hydrolysis of the tri-ethylsilyl or the tetrahydropyranyl group, or ... b) by means of the benzylhydroxylamine hydrochloride and the hydrogenolytically hydrolysis of the benzyl group.

14 The compounds of formula (VII) wherein R1 means alkyl of 1 to 6 carbon atoms or benzyl, especially (R) -4- [(S) -4-benzyl-2-oxo-o-azolidon-3-yl] -3-cyclopentylmethyl-4- tert-butyl oxo-butanoate. fifteen .

Compounds of formula (VIII) (VIII) wherein R 1 means alkyl of 1 to 6 carbon atoms or benzyl, especially 4-tert-butyl ester of (R) -2-cyclopentylmethyl-succinic acid.

16. Compound of the formula (II) characterized in that R 1 means alkyl of 1 to 6 carbon atoms or benzyl, especially (R) -3-cyclopentylmethyl-4-oxo-4-piperidir-1-yl-butanoate of tert-butyl.

17. The use of a process according to any of claims 1 to 8, for the manufacture of compound of formula (I) (I) wherein R 1 means alkyl of 1 to 6 carbon atoms or benzyl,

18. The use of a process according to any of claims 1 to 13, for the manufacture of the compound of formula (X)

19. The compounds manufactured according to any of claims 1-13.