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    • 专利摘要:
    The present invention relates to a process for the preparation of chiral succinic acid derivatives of the general formula (1) and novel intermediates used therein. In the above formula, R 1 is (C 1 -C 6 ) alkyl or benzyl.
    公开号:KR19990036858A
    申请号:KR1019980041660
    申请日:1998-10-02
    公开日:1999-05-25
    发明作者:한스 힐페르트
    申请人:프리돌린 클라우스너, 롤란드 비. 보레르；에프. 호프만-라 로슈 에이지；
    IPC主号:
    专利说明:

    Method for preparing chiral succinic acid derivative
    The present invention relates to a process for the preparation of a chiral succinic acid derivative of formula (I) comprising reacting a compound of formula (II) with a halohydantoin of formula (3) in the presence of a strong enolate-forming potassium base:
    Formula 1

    In the above formulas,
    R 1 is (C 1 -C 6 ) alkyl or benzyl,
    R 2 is halogen.
    There is a need for compounds that have valuable pharmacological properties and are useful as intermediates for the synthesis of compounds used in the treatment and prevention of diseases such as degenerative joint disease.
    The term halogen is hereafter understood as chlorine, bromine and iodine. (C 1 -C 6 ) alkyl represents a straight or branched alkyl group having 1 to 6 carbon atoms, for example methyl, ethyl, propyl, butyl, pentyl, hexyl or isopropyl, and tertiary butyl. R 1 is preferably (C 1 -C 4 ) alkyl. The term (C 1 -C 6 ) alkoxy refers to the bonding of oxygen to alkyl as defined above.
    Compounds of formula 1 are disclosed in European Patent Application Publication No. 0 816 341 A1. Compounds of formula 1 are valuable intermediates in the synthesis of the following pharmacologically active compounds of formula 10:
    The reaction of alkylating the compound of formula (2) with halomethyl-hydantoin of formula (3) is carried out in the presence of a strong base at a temperature of -100 to 22 ° C, preferably -60 ° C in a solvent such as ether, preferably THF.
    The stereoselectivity of the newly formed stereogenic center varies to a very large extent depending on the nature of the cation of the base. Lithium bases, for example LDA, produce syn-selectivity (ratio 90:10). On the one hand, sodium bases, for example NaN (TMS) 2 , are not specific (1: 1 mixture). Syn-selectivity according to LDA is generated when using succinic acid derivatives having ester groups and free acid groups, as already described in R. Becket et al., Synlett 137, February 1993. Unexpectedly, when the present invention uses acid amides and strong enolate-forming potassium bases such as KN (TMS) 2 or C 1 -C 6 -alkoxy potassium bases such as potassium tertiary butyrate It has been found that the anti-selectivity required for the preparation of the compound of formula 1 is obtained. Preferably KN (TMS) 2 is used in the preparation of the compound of formula (1). In this case a counter selectivity of 90:10 is achieved. The mixture of diastereomers can be separated by chromatography on silica gel using a suitable solvent such as hexane / ethyl acetate. As esters preferably tert-butyl esters of the formula (2) are used.
    Halohydantoin (3) used in the reaction with compound (2) can be obtained by halomethylation of 1,5,5-trimethyl-hydantoin. Thus, 1,5,5-trimethyl-hydantoin is conveniently reacted with hydrogen halide in acetic acid at a temperature of 20 to 100 ° C, preferably about 80 ° C. Trimethylhydantoin can be obtained according to a method known per se (see H. Heimgartner et al., Helv. Chim. Acta 75 , 1251 (1992)). Halogens associated with this are chlorine, bromine or iodine. Bromine is preferred.
    In connection with the preparation of the compound of formula (I) via the compound of the formula (2), the present invention also relates to a process of a) reacting a compound of formula (4) with (S) -4-benzyl-2-oxazolidinone (S) -3- ( 3-cyclopentyl-1-oxopropyl) -4- (phenylmethyl) -2-oxazolidinone (5) was obtained, and b) the obtained product (5) was reacted with a compound represented by the following formula (6) To a compound of formula (7), and c) cleaving the compound of formula (7) with (S) -4-benzyl-2-oxazolidone to obtain a compound of formula (8), d) a compound of formula (8) And a process for preparing a succinic acid derivative of formula (I) by reacting a compound of formula (II) with a halohydantoin of formula (III):
    Formula 2
    Formula 3


    In the above formulas,
    R 1 is (C 1 -C 6 ) alkyl or benzyl,
    Hal and R 2 are halogen.
    In order to perform step e), reference is made to the description of the reaction of the compound of Formula 2 with the compound of Formula 3.
    (S) -4-benzyl-2-oxazolidinone (commercially available or obtained according to the method of M. Sudharshan, PG Hultin, Synlett, 171 (1997)) according to step a) The reaction to be acylated with cyclopentyl-propionyl chloride (4) (see Barret et al., J. Chemical Society 1065 (1935)) is -80 to 22 ° C, preferably according to a method known per se. At a temperature of −45 ° C. with a base such as NaH, LDA, LiN (TMS) 2 , or an alkyllithium compound, preferably BuLi, in a solvent such as THF. To prepare the alkylated compound (7), the remaining (S) -3- (3-cyclopentyl-1-oxopropyl) -4- (phenylmethyl) -2-oxazolidinone is used in isolated form or Or as a solution for convenience. The alkylation is halo-acetic acid esters, preferably in the above-mentioned solvents, preferably THF, at -80 to 22 ° C, preferably at -45 ° C in the presence of a base such as LiN (TMS) 2 or the preferred LDA. It is carried out using tert-butyl bromoacetate. The product 7 formed can be obtained in high optical purity (de> 99.9%) from the reaction medium by crystallization followed by addition of alkanes, preferably hexanes or by chromatography.
    Halo-acetic acid esters can be obtained commercially or by esterification of haloacetic acid derivatives according to methods known per se.
    The reaction of cleaving a chiral coagent from the compound of formula 7 according to step c) to give the acid (8) and (S) -4-benzyl-2-oxazolidinone is carried out by peroxidation in ether, for example tetrahydrofuran. Hydrogen and LiOH can be used according to methods known per se. THF peroxides produced by these present a number of safety risks. Surprisingly, it has now been found that the reaction proceeds quantitatively when using cheaper sodium hydroxide in a mixture of water and an alcohol, preferably isopropanol, at a temperature of -10 to 22 ° C, preferably 0 ° C. lost. The (S) -4-benzyl-2-oxazolidinone obtained by the above is almost quantitatively crystallized from the aqueous phase.
    The amide formation reaction of acid (8) with piperidine in step d) is carried out according to a coupling method known per se, for example acid chloride, mixed anhydride, mixed sulfonic anhydride or preferably active ester. This can be done via: In this process, ketones, for example methyl ethyl ketone, or ethers, for example tert-butyl methyl ether, or hydrocarbons, for example toluene, or halogenated, at temperatures from 0 to 80 ° C., preferably 22 ° C. Stoichiometric or catalytic amount of active ester-forming alcohol, for example N-hydroxysuccinimide, N-hydroxy, in a solvent such as a hydrocarbon, for example methylene chloride, or an ester, preferably isopropyl acetate In the presence of benzotriazole or preferably N-hydroxy-2-pyridone, a water-removing agent is used, for example carbodiimide, preferably dicyclohexylcarbodiimide.
    Compounds of formula (1) may be used in the preparation of compounds of formula (10):
    Formula 10
    In this process, a) a compound of formula 1 is obtained according to the description above, b) a compound of formula 9 is subsequently obtained by cleavage of the R 1 group, and c) subsequently a hydroxylamine group Is introduced into a compound of formula (9) to obtain a compound of formula (10), or d) benzylhydroxyl, in which a compound of formula ( 1 ) wherein R 1 represents a straight chain (C 1 -C 6 ) alkyl is activated using an alkylmagnesium halide The compound of formula 10 is likewise obtained by reacting with amine hydrochloride and subsequently cleaving the benzyl group by hydrogenolysis:
    Formula 1

    Formula 10
    Compounds of formula 10 are known and are described, for example, in EP 684,240 A1. The compounds have valuable pharmacological properties and can therefore be used for the treatment and prevention of diseases such as degenerative joint disease.
    Hydrolysis of ester groups in compounds of formula (1) in which R 1 represents linear or branched (C 1 -C 6 ) alkyl other than tertiary butyl or similar sterically hindered alkyl groups according to step b) is carried out in a solvent, for example Alkali or alkaline earth metal hydroxides such as barium hydroxide, in alcohols such as i-propanol, or water and organic solvents such as ethers such as tert-butyl methyl ether, or preferably THF It is carried out at a temperature of 0 to 100 ° C., preferably 30 to 50 ° C. in the presence of calcium, sodium or potassium, preferably potassium hydroxide.
    The reaction for cleaving the tert-butyl group or similar sterically hindered alkyl group of the compound of formula 1 according to step b) to give the compound of formula 9 is carried out at inorganic acids at temperatures of 0 to 100 ° C., preferably 0 to 22 ° C. For example in the presence of aqueous phosphoric acid or sulfuric acid, preferably hydrochloric acid or hydrobromic acid and organic carboxylic acid, preferably acetic acid. The cleavage may also be carried out in carboxylic esters instead of carboxylic acids or in mixtures of carboxylic acids and carboxylic esters. Suitable carboxylic esters are methyl, ethyl or isopropyl acetate, preferably ethyl acetate. HBr in acetic acid is preferred for use in the cleavage method. Furthermore, cleavage with acids can be carried out in other suitable organic solvents. Methylene chloride or toluene are suitable organic solvents.
    The reaction to debenzylate the compound of formula 1 wherein R 1 is benzyl (Bz) in step b) to afford the compound of formula 9 is carried out in an organic solvent using hydrogen in the presence of a metal catalyst. Suitable solvents are (C 1 -C 6 ) alcohols, preferably methanol or ethanol. As the metal catalyst, platinum or palladium supported on a carrier material such as aluminum oxide, barium sulfate or charcoal can be used for convenience. Palladium on charcoal or barium sulphate is the preferred catalyst. Temperature and pressure are not critical and can vary widely. Preferably, the hydrogenation is carried out at room temperature and 1 to 10 bar.
    The introduction of the hydroxylamine group into compound 9 according to step c) is carried out at a temperature of 0 to 80 ° C., preferably 10 to 25 ° C. in a solvent, for example ether, for example tert-butyl methyl ether, or hydrocarbon Stoichiometric or catalytic amounts of active ester-forming alcohols, for example N-hydroxy succinimide, in toluene, or halogenated hydrocarbons, preferably methylene chloride, or esters, preferably ethyl acetate, Activators known per se in the presence of N-hydroxybenzotriazole or preferably N-hydroxy-2-pyridone, for example carbodiimide, for example dicyclohexylcarbodiimide, or iso O-trimethylsilylhydroxylamine is used with cyanide, for example tert-butyl isocyanide, or preferably with 2-morpholino-ethyl isocyanide W can be performed. Unexpectedly, during aqueous workup, it was found that the TMS protecting group was gently cleaved to obtain the desired product 10 in high yield and high purity without isolation of the TMS-protected intermediate.
    Hydroxylamine groups can be introduced using tetrahydropyranylhydroxylamine in a similar manner. Cleavage of the tetrahydropyranyl group is conveniently carried out at room temperature in the presence of a strong acid, such as an inorganic acid, preferably HCl, or a sulfonic acid, preferably methanesulfonic acid or paratoluenesulfonic acid, in alcohol, for example methanol or ethanol. Perform.
    On the one hand, hydroxylamine groups can be introduced into step c) using benzylhydroxylamine hydrochloride and activator in the manner described for the formation of amides from the acid and piperidine. Particularly preferred activators are stoichiometric or catalytic amounts of active ester-forming alcohols such as N-hydroxysuccinimide, N-hydroxybenzotriazole or preferably N-hydroxy-2-pyridone Carbodiimide, for example dicyclohexylcarbodiimide or isocyanide, for example tert-butyl isocyanide or preferably 2-morpholino-ethyl isocyanide. The use and preparation of such isocyanides are disclosed in EP 29 909 B1.
    The benzyl group is then cleaved using a catalyst and hydrogen as described above for the debenzylation of the compound of formula 1 wherein R 1 is Bz.
    Furthermore, according to step d), the reaction for directly converting the ester of the compound of formula ( I ) in which R 1 is straight-chain (C 1 -C 6 ) alkyl, preferably methyl, is -70 to 50 ° C, preferably Is an alkylmagnesium halide of O-benzylhydroxylamine hydrochloride in the presence of ester (1) in a solvent such as ether, for example tert-butyl methyl ether or preferably THF at a temperature of -20 to 0 ° C. , Preferably with i-propylmagnesium chloride.
    The reaction in which the benzyl group is hydrolyzed to yield compound (10) can be carried out in a similar manner as described for the debenzylation of the compound of formula 1 wherein R 1 is Bz.
    In a preferred embodiment, the preparation of the compound of formula 10 from the compound of formula 1 is carried out without reacting through step d), followed by step b) wherein R 1 is tertiary butyl followed by reaction of compound (9) with trimethylsilylhydroxylamine .
    According to the process steps described above, the compound of formula 10 can be obtained in higher yield than according to the processes described in the art.
    New intermediates of formulas 7, 8 and 2 are also an object of the present invention. These are in particular tert-butyl (R) -4-[(S) -4-benzyl-2-oxo-oxazolidon-3-yl] -3-cyclopentylmethyl-4-oxo-butanoate, (R ) -2-cyclopentylmethyl-succinic acid 4-tert-butyl ester and tert-butyl (R) -3-cyclopentylmethyl-4-oxo-4-piperidin-1-yl-butanoate.
    Example
    Example 1
    A 53.1 g solution of (S) -4-benzyl-2-oxazolidinone in 420 mL of tetrahydrofuran was treated with 197 mL of 1.6 M butyllithium in hexane at −45 ° C. and cyclopentylpropionyl in 105 mL of tetrahydrofuran A 49.18 g solution of chloride was subsequently added and the solution was stirred at -45 ° C for 1 hour. (S) -3- (3-cyclopentyl-1-oxopropyl) -4- (phenylmethyl) -2-oxazolidinone produced as intermediate was 1.1 M lithium diisopropyl in tetrahydrofuran at -45 ° C. Treated with 286 ml of amide solution, stirred for 1.5 hours, and subsequently 64.38 g of tert-butyl bromoacetate in 60 ml of tetrahydrofuran were added. After 4 hours at −45 ° C., 600 ml of a semi-saturated ammonium chloride solution was added and the THF phase was washed with a semi-saturated sodium chloride solution, concentrated and crystallized by addition of hexane to give pure (de> 99.9%) Tert-butyl (R) -4-[(S) -4-benzyl-2-oxo-oxazolidin-3-yl] -3-cyclopentylmethyl-4-oxo-butanoate (melting point 113-119 C) 94.5 g (76%) was obtained. IR (KBr): 1768s, 1730s, and 1695s (C = O).
    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 to a suspension of 78.5 g of oxazolidinone from Example 1 in 550 mL of isopropanol at 0 ° C. and the mixture was stirred at 22 ° C. for 1 hour. . The solution was concentrated, made basic with sodium hydroxide solution, and the precipitated (S) -4-benzyl-2-oxazolidinone was filtered off. (S) -4-benzyl-2-oxazolidinone still present is extracted with methylene chloride, followed by a total of 32.68 g of pure (S) -4-benzyl-2-oxazolidinone (melting point 86.5 to 88 ° C.) 98%) was recovered. The aqueous phase was adjusted to pH 3 with hydrochloric acid and extracted with isopropyl acetate. After washing, drying and evaporating the organic extract, 47.79 g (99%) of ethanethiomerically pure (ee> 99%) (R) -2-cyclopentylmethyl-succinic acid 4-tert-butyl ester as oil Obtained. IR (film): 2700 m, br. (COOH), 1733 s and 1710 s (C = O).
    Example 3
    A suspension of 34.48 g of acid from Example 2 and 5.98 g of N-hydroxy-2-pyridone in 170 ml of isopropyl acetate was treated with 12.03 g of piperidine at 0 ° C. and subsequently in 92 ml of isopropyl acetate. Treated with 30.53 g solution of dicyclohexylcarbodiimide and stirred at 22 ° C. for 16 h. 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 is washed with sodium carbonate and water, filtered and concentrated and then crystallized from oil to give pure (ee> 99%) tert-butyl (R) -3-cyclopentylmethyl-4-oxo-4-piperidine- 43.89 g (100%) of 1-yl-butanoate (melting point 38-40 ° C.) were obtained. IR (film): 1729s and 1641s (C = O).
    Example 4
    A solution of 10.7 g of the ester from Example 3 in 50 mL of tetrahydrofuran was added dropwise to a solution of 8.76 g of potassium bistrimethylsilylamide in 80 mL of tetrahydrofuran at -60 ° C, and the mixture was stirred at -60 ° C for 30 minutes. Subsequently, a 7.76 g solution of 3-bromomethyl-1,5,5-trimethylhydantoin in 40 ml of tetrahydrofuran was added at -60 ° C and the mixture was stirred at -60 ° C for 30 minutes. The reaction mixture was washed with semi-saturated sodium chloride solution and dilute hydrochloric acid, dried, filtered and concentrated to give 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-1-imidazolidinyl) ethyl] -3-cyclopentylpropionyl] piperidine 15.11 g (78% yield of pure counter-compound) of a 9: 1 mixture were obtained, which were 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 15.11 g solution of a 9: 1 mixture from Example 4 in 15 mL of acetic acid was treated with 15 mL of 33% hydrogen bromide in acetic acid at 0 ° C. and stirred at 0 ° C. for 4 h. The solution was diluted with methylene chloride, washed with water, the organic phase was dried, filtered and evaporated. The residue was crystallized from 26 ml tertiary butyl methyl ether and 26 ml hexane and then diastereomer-pure (de> 98%) 1- [2 (R)-[1 (R) -carboxy-2- (3,4 , 4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -3-cyclopentylpropionyl] piperidine (9) (melting point 111-114 ° C.) yields 6.90 g (70%) It was. IR (KBr): 1770 m and 1715 s (C = O).
    Example 6
    1- [2 (R)-[1 (R)-(methoxycarbonyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) in 3 ml of THF) Ethyl] -3-cyclopentylpropionyl] piperidine (see European Patent Application No. 97110942.6 (July 2, 1997)) 1.78 g solution was treated with a 0.69 g solution of KOH in 6.1 mL of water and at 0 ° C. Stir vigorously for 5 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 was pure up to about 95% 1- [2 (R)-[1 (R) -carboxy-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] 1.86 g of 3-cyclopentylpropionyl] piperidine (9) were contained. IR (KBr): 1769 m and 1714 s (C = O).
    Example 7
    0.78 g of 2-morpholino-ethyl isocyanide was added to 1- [2 (R)-[1 (R) -carboxy-2- (3,4) from Example 5 or 6 in 21 ml of methylene chloride at 22 ° C. 2.11 g of, 4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -3-cyclopentylpropionyl] piperidine (9) and 0.61 g of N-hydroxy-2-pyridone To the suspension was added and the mixture was stirred for 3 hours. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hours. The reaction mixture was washed with saturated NaHCO 3 solution and water and evaporated. The residue was dissolved in 20 ml tertiary butyl methyl ether and 0.23 ml of water and stirred at 22 ° C. for 1 hour 30 minutes, the suspension was diluted with 10 ml of hexane, filtered and the residue dried at 22 ° C./11 mbar to give pure 1 -[3-cyclopentyl-2 (R)-[1 (R)-(hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) 1.82 g (83%) of ethyl] propionyl] piperidine (10) were obtained. MS (EI): 436 (40%).
    Example 8
    0.74 g of N-ethylmorpholine, 0.60 g of N-hydroxybenzotriazole hydrate and 0.75 g of N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide were continuously run in 13 ml of methylene chloride at 0 ° C. 1- [2 (R)-[1 (R) -carboxy-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] from Example 5 or 6]- To a solution of 1.38 g of 3-cyclopentylpropionyl] piperidine (9) was added and the mixture was stirred at 0 ° C. for 20 minutes. 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 and washed with sodium bicarbonate solution and dilute hydrochloric acid, dried and concentrated. The residue was crystallized from ethyl acetate / hexanes and the crystallized product was dried to give pure 1- [2 (R)-[1 (R)-(benzyloxycarbamoyl) -2- (3,4,4-trimethyl-2, 5-dioxo-1-imidazolidinyl) ethyl] -3-cyclopentylpropionyl] piperidine (melting point 138-140 ° C.) was obtained 1.26 g (73%).
    On the other hand, 3.86 g of 2-morpholino-ethyl isocyanide was added to a suspension of 10.54 g of compound (9) and 3.06 g of N-hydroxy-2-pyridone from Example 5 in 110 ml of methylene chloride at 22 ° C. Was added and the mixture 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. 11.19 g (85%) of pure benzylhydroxyxamate (melting point 140-142 ° C.) was obtained after the residue was recrystallized from methylene chloride / hexane.
    Example 9
    1- [2 (R)-[1 (R)-(methoxycarbonyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) in 7 mL of THF) A solution of 1.10 g of ethyl] -3-cyclopentylpropionyl] piperidine and 568 mg of O-benzylhydroxylamine hydrochloride was treated with 3.5 mL of a 2M i-PrMgCl solution in THF at -20 ° C and 1 at -20 ° C. After time again it was treated with 1.7 ml of Grignard reagent again. After an additional 2 h 30 min at -20 ° C, the mixture was treated with ammonium chloride solution and extracted with methylene chloride. The extract was dried and concentrated. The residue was crystallized from tert butyl methyl ether / hexane and the crystallized product was dried to obtain 1- [2 (R)-[1 (R)-(benzyloxycarbamoyl) -2- (3,4,4-trimethyl- 2,5-dioxo-1-imidazolidinyl) ethyl] -3-cyclopentylpropionyl] piperidine (melting point 135-137 ° C.) was obtained.
    Example 10
    For debenzylation, 1- [2 (R)-[1 (R)-(benzyloxycarbamoyl) -2- (3,4,4-trimethyl-2) from Example 8 or 9 in 40 ml of ethanol. Hydrogenation of 5.5 g suspension of 5-5-oxo-1-imidazolidinyl) ethyl] -3-cyclopentylpropionyl] piperidine and 1.7 g of Pd / C (5%) at 22 ° C./1 bar for 4 hours I was. The suspension was filtered, the filtrate was fully concentrated and the residue was crystallized from water to give pure 1- [3-cyclopentyl-2 (R)-[1 (R)-(hydroxycarbamoyl) -2- (3,4 3.9 g (85%) of, 4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl] piperidine (10) were obtained. MS (EI): 436 (40%).
    By the present invention, compounds having valuable pharmacological properties are obtained which are useful as intermediates for the synthesis of compounds used for the treatment and prevention of diseases such as degenerative joint diseases.
    权利要求:
    Claims (16)
    [1" claim-type="Currently amended] A process for preparing a chiral succinic acid derivative of Formula 1 comprising reacting a compound of Formula 2 with a halohydantoin of Formula 3 in the presence of a strong enolate-forming potassium base:
    Formula 1

    Formula 2

    Formula 3

    In the above formulas,
    R 1 represents (C 1 -C 6 ) alkyl or benzyl,
    R 2 is chlorine, bromine or iodine.
    [2" claim-type="Currently amended] The method of claim 1,
    Process using KN (TMS) 2 as potassium base.
    [3" claim-type="Currently amended] The method according to claim 1 or 2,
    R 1 is tertiary butyl.
    [4" claim-type="Currently amended] The method according to claim 1 or 2,
    R 2 is bromine.
    [5" claim-type="Currently amended] The method according to claim 1 or 2,
    a) Reacting the compound of formula 4 with (S) -4-benzyl-2-oxazolidone to give Obtained oxazolidinone (5),
    b) reacting the product obtained with a compound of formula 6 to give a compound of formula
    c) cleaving (S) -4-benzyl-2-oxazolidinone from the compound of Formula 7 to obtain a compound of Formula 8
    d) reacting the compound of Formula 8 with piperidine to obtain a compound of Formula 2
    e) a process for preparing a succinic acid derivative, wherein the obtained compound of formula 2 is reacted with halohydantoin of formula 3 according to the method of claim 1 or
    Formula 2

    Formula 3

    Formula 4

    Formula 6

    Formula 7

    Formula 8

    In the above formulas,
    R 1 represents (C 1 -C 6 ) alkyl or benzyl,
    Hal and R 2 represent chlorine, bromine or iodine.
    [6" claim-type="Currently amended] The method of claim 5,
    The process of step b) wherein R 1 of compound (6) is tertiary butyl.
    [7" claim-type="Currently amended] The method of claim 5,
    R 2 is bromine.
    [8" claim-type="Currently amended] The method of claim 5,
    The cleavage of (S) -4-benzyl-2-oxazolidinone in step c) is carried out with H 2 O 2 and NaOH in a mixture of water and alcohol.
    [9" claim-type="Currently amended] a) obtaining a compound of formula 1 according to the method of claim 1 or 2,
    b) subsequently cleaving the R 1 group to obtain a compound of formula
    c) subsequently introducing a hydroxylamine group into the compound of formula 9 to yield a compound of formula 10, or
    d) reacting a compound of formula 1 wherein R 1 represents a straight chain (C 1 -C 6 ) alkyl with benzylhydroxylamine hydrochloride activated with an alkylmagnesium halide and subsequently cleaving the benzyl group by hydrogenolysis To obtain a compound of formula 10:
    Formula 1

    Formula 9

    Formula 10

    In the above formulas,
    R 1 has the meaning indicated in claim 1.
    [10" claim-type="Currently amended] The method of claim 9,
    If R 1 is tert-butyl, the cleavage of step b) is carried out using an inorganic acid in the carboxylic acid, preferably HBr / acetic acid.
    [11" claim-type="Currently amended] The method of claim 9,
    If R 1 is (C 1 -C 6 ) alkyl other than tert-butyl or similar sterically hindered alkyl groups, the cleavage of step b) is carried out using alkali or alkaline earth metal hydroxides.
    [12" claim-type="Currently amended] The method of claim 9,
    If R 1 is Bz, the cleavage of step b) is carried out by hydrogenolysis.
    [13" claim-type="Currently amended] The method of claim 9,
    In step c) for the compound of formula (9) the reaction of introduction of hydroxylamine groups is carried out.
    a) using trimethylsilyl-hydroxylamine or tetrahydropyranyl-hydroxylamine and cleaving said trimethylsilyl or tetrahydropyranyl group, or
    b) by using benzylhydroxylamine hydrochloride and cleaving said benzyl group by hydrogenolysis.
    [14" claim-type="Currently amended] A compound of formula 7, in particular tert-butyl (R) -4-[(S) -4-benzyl-2-oxo-oxazolidon-3-yl] -3-cyclopentylmethyl-4-oxo-buta No-Eight:
    Formula 7

    In the above formula,
    R 1 is (C 1 -C 6 ) alkyl or benzyl.
    [15" claim-type="Currently amended] A compound of formula 8, in particular (R) -2-cyclopentylmethyl-succinic acid-4-tert-butyl ester:
    Formula 8

    In the above formula,
    R 1 is (C 1 -C 6 ) alkyl or benzyl.
    [16" claim-type="Currently amended] A compound of formula 2, in particular tert-butyl (R) -3-cyclopentylmethyl-4-oxo-4-piperidin-1-yl butanoate:
    Formula 2

    In the above formula,
    R 1 is (C 1 -C 6 ) alkyl or benzyl.
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    CN1515561A|2004-07-28|
    US5952507A|1999-09-14|
    JP2986464B2|1999-12-06|
    CN1213663A|1999-04-14|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1997-10-03|Priority to EP97117191.3
    1997-10-03|Priority to EP97117191
    1998-10-02|Application filed by 프리돌린 클라우스너, 롤란드 비. 보레르, 에프. 호프만-라 로슈 에이지
    1999-05-25|Publication of KR19990036858A
    2002-07-18|Application granted
    2002-07-18|Publication of KR100303376B1
    优先权:
    申请号 | 申请日 | 专利标题
    EP97117191.3|1997-10-03|
    EP97117191|1997-10-03|
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