DE4032054A1 - Optically active 4-aryl-2-pyrrolidne derivs. prepn. - from new phthalimido-butanoic acid ester(s) and hydrazine hydrate - Google Patents

Abstract

Prepn. of (4S)- or (4R)-4-aryl-2-pyrrolidinone derivs. of formula (I) comprises reaction of optically active phthalimido-butanoic acid ester of formula (II) with hydrazine hydrate (III) and opt. removal of easily cleaved gps. and etherification of the resultant hydroxyl gps. In (I) and (II) R1= 1-7C hydrocarbyl opt. interrupted by oxygen; R2= 1-4C alkyl; R'1= R1 or an easily cleaved gp.; R3= 1-4C alkyl; Q= phthalimido. (II) are new cpds. USE/ADVANTAGE - (I) are useful as antiinflammatory agents, and treatment of neuroleptic and psychological disorders. The process is simple and gives high yields and high optical purity from accessible starting materials.

Description

The invention relates to the process for the production of optically active 4-aryl-2-pyrrolidinones and the process for the preparation of the optically active starting compounds which are used as intermediates for the preparation of 4S or 4R enantiomers of 4-aryl-2-pyrrolidinones are suitable.

It is known from US Patent 40 12 495 and WO 86/02 268 that 4- Aryl-2-pyrrolidinones are pharmacologically active compounds that are suitable for the treatment of neuroleptic and mental disorders and can also be used for the topical treatment of inflammation.

Of the 4-aryl-2-pyrrolidones, the 4- (3-cyclopentyloxy-4-methoxy phenyl) -2-pyrrolidinone examined in detail pharmacologically. By means of a very complex and not verifiable on a technical scale This connection was converted into its optical antipodes and found that both enantiomers are pharmacologically active compounds represent.

Since it is desirable that chiral drug ingredients only each used an antipode for the manufacture of pharmaceutical preparations the task was to develop a technically applicable process for Development of the optically active 4-aryl-2-pyrrolidones to develop.

According to the method of the invention are optically accessible from the active starting compounds in a simple synthesis the desired (4S) or (4R) -4-aryl-2-pyrrolidinones can be prepared and can be used in high optical purity and good yield without complex separation operations be isolated.

The invention relates to the process for producing (4S) -or (4R) -4-aryl-2-pyrrolidinones of the formula I.

wherein
R¹ is a hydrocarbon radical with up to 7 carbon atoms which may be interrupted by an oxygen atom and
R² is C _1-4 alkyl,
characterized in that an optically active compound of formula II

wherein
R¹ 'di has the meaning of R¹ or represents an easily removable group and
R² and R³ each denote C _1-4 alkyl, cyclized with hydrazine hydrate and optionally cleaving the easily removable group and etherifying the hydroxy group thus obtained.

As hydrocarbon radical R¹ are saturated or unsaturated, straight-chain or branched alkyl groups with 1-6 carbon atoms, preferably 1-4 carbon atoms, furthermore C _4-6 cycloalkylalkyl and cycloalkyl groups with 3-7 carbon atoms and the benzyl group.

Examples of saturated alkyl groups are, for example, methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, tert. Butyl, pentyl, 2,2-dimethyl propyl and hexyl are suitable, with methyl and ethyl being preferred for R³.  

The following may preferably be mentioned as alkenyl and alkynyl groups: 2-propenyl, 2-propynyl. If the hydrocarbon radical R¹ is a cycloalkyl group, so is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl ge means and for the cycloalkyl-alkyl group is cyclopropylmethyl, cyclo propylethyl and cyclopentylmethyl to be regarded as preferred.

If the hydrocarbon residue is interrupted by an oxygen atom, then is particularly meant the cycloalkyl radical in which a CH₂ group by an oxygen atom is replaced. As a cyclic ether radical are examples Wisely called 3-tetrahydrofuranyl and 3-tetrahyropyranyl.

If the molecule contains a cyclic ether residue, another can Center of asymmetry should be present, which in the usual way in the antipodes can be transferred.

Examples of easily removable hydroxy protective groups are in the frame This invention, for example, the methoxymethyl, methoxy ethoxymethyl and benzyl group, which, for example, with acids or can be split off hydrogenolytically.

The cyclization of 4-N-phthalimidobutanoic acid alkyl esters takes place with Hydrazine hydrate in protic solvents such as alcohols, for example Methanol, ethanol and n-butanol. The solution is generally 4 heated to reflux for 8 hours.

The etherification of the hydroxy compound can be carried out according to the methods described in the US patent 40 12 495 described methods are performed. For example etherification is carried out by reaction with an appropriate tosylate, Mesylate or halide in the presence of a base such as alkali hydroxides and carbonates and tetrabutylammonium hydrogen sulfate in inert solvents such as dimethyl sulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, Methylene chloride or alcohols at room temperature to the boiling point of the Solvent.  

The invention further relates to the compounds of formula II, which are optical are active starting compounds, from which the Compounds of formula I obtained with very high optical purity will.

The invention also relates to the process for the preparation of the compounds of formula II, characterized in that a compound of formula III

wherein R¹, R² and R³ have the above meaning, ozonolyzed and so Compound of the formula IV obtained

oxidized to carboxylic acid and esterified to a compound of formula II.

Ozonolysis is carried out according to known methods, such as, for example, in low temperature in a mixture of methylene chloride and methanol.

The oxidation of the compounds of formula IV to the carboxylic acid takes place with known oxidizing agents such as pyridinium dichromate, Pyridinium chlorochromate, CrO₃ in polar solvents such as dimethyl form amide, for example, according to E. J. Corey, G. Schmidt Tetrahedron Letters 1979, 399.  

After the solvent has been stripped off, the esterification can be carried out in a conventional manner take place, for example, with methanolic hydrochloric acid or with diazomethane in ethers.

Conveniently, all the reactions described here are under Protective gas atmosphere such as under nitrogen or argon.

The preparation of the starting compounds of the formula III is known or is carried out stereoselectively in analogy to the preparation of known compounds. Depending on whether as the starting product (4S) - or (4R) -4- (benzyl) -2-oxazolidine is used, the antipode is obtained after the addition of the olefin.

The following examples are intended to illustrate the process according to the invention explain:

Preparation of the starting compounds 1. 3-benzyloxy-4-methoxy-benzyl cyanide (15)

90 g (0.34 mol) of 3-benzyloxy-4-methoxy-benzyl chloride are dissolved in 300 ml absolute dimethylformamide dissolved with 23 g (0.47 mol) sodium cyanide and 2.3 g (15 mmol) of sodium iodide were added. It will take about 45 minutes Refluxed, the progress of the reaction thin-layer chrome is tracked graphically. After the reaction is allowed to cool, the solid is filtered off and the solvent is removed. The raw product can be recrystallized from ethyl acetate / hexane. There are 81 g (94%) yellow, flaky crystals with a melting point of 78 ° C.

2. 3-benzyloxy-4-methoxy-phenylacetic acid (16)

18 g (71 mmol) of the cyanide (15) are dissolved in 180 ml of ethanol and with 50 ml of 25% potassium hydroxide solution are added and the mixture is refluxed for 24 hours heated. After cooling, the batch is freed of ethanol in vacuo and diluted with 100 ml of water. After the aqueous phase twice with each 100 ml of ether were washed and brought to pH = 1 with 6N hydrochloric acid is, the accumulated, thick-flocculent precipitate with methylene chloride be shaken out. The organic phase is over sodium sulfate dried and distilled off in vacuo. The backlog can be in Ethyl acetate / hexane are recrystallized. 15.6 g (81%) of one are obtained fine crystalline product with a melting point of 121 ° C.

3. (2S) -2-amino-3-phenylpropanol (17)

Under an argon atmosphere, 100 g (605 mmol) of L-phenylalanine in 700 ml absolute tetrahydrofuran and within 30 minutes with 86 g (74.5 ml, 605 mmol) boron trifluoride diethyl ether complex added. After 1 Hour of reflux becomes the now clear, colorless solution, the has cooled slightly below the boiling point within 2 hours 50.5 g (10 M, 66.5 ml, 665 mmol) of borane-dimethyl sulfide complex were added dropwise, a strong hydrogen evolution can be observed. That arise de Dimethyl sulfide is distilled off. The colorless solution becomes more  Heated under reflux for 6 hours. After cooling to room temperature the excess borane carefully by dropping 75 ml of a 1: 1 Tetrahydrofuran-water mixture hydrolyzed. Be under ice bath cooling 450 ml of 5M KOH solution was added dropwise. After 8 hours of reflux, it will Mixture cooled to room temperature, concentrated in vacuo, five times each 200 ml of methylene chloride extracted, dried over sodium sulfate and in Crystallized ethyl acetate / hexane. 80.3 g (88%) of colorless are obtained Crystals with a melting point of 91 ° C.

4. (4S) -4- (phenylmethyl) -2-oxazolidinone (18)

80 g (526 mmol) (S) -phenylalaninol (17), 7.3 g (53 mmol) potassium carbonate and 126.8 g (130 ml, 1.07 mol) of diethyl carbonate are placed under a protective gasate submitted to the atmosphere and warmed carefully to 135-140 ° C. That at the The reaction released ethanol is distilled off. After 2 hours it will Cooled reaction mixture to room temperature with 500 ml of methylene chloride slurried and the remaining residue filtered off. The filtrate is washed with sodium bicarbonate solution, dried over sodium sulfate net and concentrated in vacuo. After recrystallization in ethyl acetate / hexane can 75.4 g (81%) of the title compound as colorless crystals with a Melting point of 88 ° C can be obtained.

5. (4S) -3- [2- (3-Benzyloxy-4-methoxyphenyl) acetyl] -4- (phenylmethyl) - 2-oxazolidinone (19)

To a solution of 12.2 g (44.8 mmol) carboxylic acid cooled to -78 ° C (16), and 5.2 g (7.1 ml, 51.4 mmol, 1.15 eq) triethylamine in absolute Tetrahydrofuran slowly become 5.9 g (6.0 ml, 48.9 mmol) 1.1 eq) pivaline acid chloride added dropwise. The resulting suspension is 10 minutes stirred at -78 ° C and 30 minutes at 0 ° C. After cooling again at -78 ° C, the strongly stirred solution is opened via a cannula -78 ° C cooled lithiated oxazolidinone solution (made from 8 g (45.1 mmol) Oxazolidinone (18) and 28.2 ml (45.1 mmol, 1.6M in hexane) n-butyllithium at -78 ° C) and another 30 minutes at 0 ° C touched. The reaction mixture is mixed with 200 ml of saturated ammonium chloride solution added and concentrated in a water jet vacuum. The backlog will  extracted with methylene chloride, the combined organic phases over Dried sodium sulfate, concentrated in vacuo and column chromatography cleaned (ethyl acetate / hexane 1: 3). 16.8 g (87%) of colorless are obtained Crystals with a melting point of 102 ° C.

6. (4S, 2′S) -3- (2 ′ - (3-benzyloxy-4-methoxyphenyl) -4′-pentenoic acid) - 2-oxazolidinone (20)

To a clear, colorless solution, prepared at -78 ° C from 1.56 g (2 ml, 9.67 mmol, 1.04 eq) hexamethyldisilazane and 6 ml (9.6 mmol, 1.04 eq, 1.6M) in hexane) n-butyllithium in 30 ml of absolute tetrahydrofuran, 4 g (9.27, 1.0 eq) of oxazolidinone (19), dissolved in 10 ml of absolute tetrahydrofuran, are slowly added dropwise and the mixture is stirred at -78 ° C. for 30 minutes. 1.43 g (1 ml, 11.8 mmol), 1.3 eq) of allyl bromide are injected through a septum within 5 minutes and the mixture is stirred at -78 ° C. for a further 6 hours. After thawing, the reaction is saturated with 20 ml. Ammonium chloride solution interrupted and concentrated in vacuo. The aqueous residue is extracted several times with ethyl acetate and the combined fractions are dried over sodium sulfate. The solvent is drawn off and the remaining yellow, viscous oil can be purified by preparative column chromatography (eluent: ethyl acetate / hexane 1: 3). 2.5 g (57%) of a light yellow, viscous oil which has the purity required for further processing are obtained.
= + 87.6 (c = 2.5 chloroform).

7. (2S) -2 - (- 3-benzyloxy-4-methoxyphenyl) -4-pentenol (21)

1.83 g (4.24 mmol) of the educt (20) are dissolved in 10 ml of absolute tetrahydro furan and to a suspension of 200 mg (5.27 mmol, 1.25 eq) of lithium aluminum hydride in 50 ml, cooled to 0 ° C. Section. Tetrahydrofuran slowly added dropwise. After 30 minutes, the cooling can be removed and 1 ml of dilute sodium hydroxide solution is injected. The aluminum sludge obtained can be solidified and filtered off by adding sodium sulfate. The filtrate is dried over sodium sulfate and purified by column chromatography tographically (eluent: ethyl acetate / hexane 1: 1). The combined fractions give 1.1 g (87%) of a colorless, mobile oil.
[α] = + 13.5 (c = 2.8 chloroform).

8. (2S) -N- (2- (3-benzyloxy-4-methoxyphenyl) -4-pentene) phthalimide- (22)

To a solution of 5 g (16.8 mmol) of the alcohol (21), 2.71 g (18.4 mmol), 1.1 eq) phthalide and 4.83 g (18.4 mmol, 1.1 eq) triphenylphosphine in 100 ml absolute tetrahydrofuran, 3.08 g (2.75 ml, 17.7 mmol) at 0 ° C., 1.05 eq) Diethyl diazodicarboxylic acid slowly added dropwise. The cooling is removed after 2 hours and the solution for a further 12 hours at room temperature stirred. After removing the solvent in vacuo, this will return permanent viscous oil of a chromatographic purification (ethyl acetate / Hexane 1: 2) subjected. The combined product fractions contain 6.6 g (92%) of the title compounds with a melting point of 91 ° C.

9. (3S) -3- (Benzyloxy-4-methoxyphenyl) -4-N-phthalimido-butanal (23)

2 g (4.68 mmol) of the olefin (22) are extracted from 150 ml of a 1: 1 mixture absolute and absolute methylene chloride dissolved and at -78 ° C ozonoly siert. The reaction is discolored when the Sudan III (1- (4- Benzolazo) -benzolazo) -2-naphtol) canceled. The solution is 5 minutes flushed with oxygen, mixed with 1.5 g (5.71 mmol) triphenylphosphine and thawed within 2 hours. After stirring for 3 hours in the room temperature, the organic solvents are removed in vacuo and the Residue in ether / hexane added to the resulting triphenylphosphine separated by crystallization. The concentrated filtrate is through Column chromatography (eluent: ethyl acetate / hexane 1: 1) purified. It will 1.4 g (70%) as a colorless, finely crystalline product with a melt point of 154-156 ° C isolated.

10. (3S) -3 - (- 3-Benzyloxy-4-methoxyphenyl) -4-N-phthalimidobutanoic acid methyl ester (24)

410 mg (0.95 mmol) of the aldehyde (23) are dissolved in 3 ml of dimethylformamide dissolved and mixed with 1.3 g (3.5 mmol, 3.5 eq) pyridinium dichromate and 6 Stirred for hours at room temperature. The dark brown, viscous mixture is filtered through a short frit with silica gel for 60 minutes. That almost colorless filtrate is concentrated on a rotary evaporator, with little Methylene chloride added and with freshly made ethereal  Diazomethane solution added. The clear, colorless solution is 15 minutes stirred and freed from the solvent and column chromatography (eluent: Ethyl acetate / hexane 1: 2) cleaned. There can be 192 mg (445) of a colorless Substance with a melting point of 124 ° C can be isolated.  

Example 1 (4S) -4- (3-benzyloxy-4-methoxyphenyl) -2-pyrrolidinone (14)

112 mg (0.24 mmol) of the methyl ester (3S) -3 - (- 3-benzyloxy-4-methoxy phenyl) -4-N-phthalimido-butanoic acid methyl ester in 50 ml of ethanol dissolved and mixed with 2 ml of hydrazine hydrate (80%) and under 6 hours Reflux cooked. After cooling, the solvent is removed and the residue by column chromatography (eluent: methylene chloride / acetone 7: 3) cleaned. 49 mg (69%) of a colorless solid with a Melting point of 118 ° C can be obtained. The enantiomeric ratio be according to analytical HPLC (ethanol + 4% water, flow 0.3 ml / min, CTA, 4 * 250, UV detection (254 nm) (4R) -pyrrolidinone (RT .: 14.25 min: (4S) -pyrrolidinone (RT: 22.27 min) = 4.8: 95.2 (ee = 90%).

Claims (3)

1. Process for the preparation of (4S) - or (4R) -4-aryl-2-pyrrolidinones of the formula I. wherein
R¹ is a hydrocarbon radical with up to 7 carbon atoms which may be interrupted by an oxygen atom and
R² is C _1-4 alkyl,
characterized in that an optically active compound of formula II wherein
R¹ 'has the meaning of R¹ or represents an easily removable group and
R² and R³ each denote C _1-4 alkyl, cyclized with hydrazine hydrate and optionally cleaving the easily removable group and etherifying the hydroxy group thus obtained. 2. Optically active compounds of the formula II wherein
R¹ 'has the meaning of R¹ or represents an easily removable group and
R² and R³ each represent C _1-4 alkyl. 3. A process for the preparation of the compounds of formula II, characterized in that a compound of formula III wherein R¹ ', R² and R³ have the above meaning, ozonolysed and the compound of formula IV thus obtained oxidized to carboxylic acid and esterified to a compound of formula II.