FR2549052A1 - DIASTEREOMERIC DERIVATIVES OF 4-OXO-2 AZETIDINYL-ACETIC ACID - Google Patents

Abstract

THE INVENTION RELATES TO NEW DIASTEREOMERS OF FORMULA I ACCORDING TO THE PATENT. THEY ARE PREPARED BY ELIMINATING THE ETHYLENE-CETAL GROUP FROM A COMPOUND OF GENERAL FORMULA III ACCORDING TO THE PATENT (OR R IS A HYDROGEN ATOM, OR AN AMIDO-PROTECTIVE GROUP CONSTITUTED BY A RADICAL PHENYLE OR BENZYLE WHICH MAY BE SUBSTITUTED BY OR METHOXY GROUPS), AND REDUCING THE NEW COMPOUND OF GENERAL FORMULA II THUS OBTAINED, THEN BY ISOLATING THE COMPOUND OF GENERAL FORMULA I OBTAINED, AND, IF DESIRED, BY SEPARATING THE PAIR OF DIASTEREOMERS OBTAINED FROM ITS COMPONENTS.

Description

The present invention relates to new acetic acid esters

  The present invention relates more particularly to new Séolwres diasteres represented by the formula I below: c-OC X i O CH ^ and a process for preparing them, The new diastereomers of formula I are useful as intermediaries in the preparation of the

  thienarqycin, which is a well-known antibiotic.

  Thienamycin is a broad spectrum antibiotic; the microbiological process allowing its preparation is described in US Pat. No. 3,950,357 and the most recent synthesis of this antibiotic is described

  in European Patent No. 062 840.

  It has been found that the compounds represented by formula I can be prepared according to simple reaction steps, by new intermediates and with high yields from the compounds described in an earlier Hungarian patent application by the Applicant, Ser Nl 4 014/81 These compounds correspond to the general formula III below 30 lo Il -C / XC Uz-C CH \ 111

NOT

  o 'C in which R 1 represents a hydrogen atom or alternatively, as an amido-protective group, a phenyl or benzyl radical optionally substituted by one or more methoxy groups / The compound of general formula III is subjected to decetalization, the compound of general formula II below:

O CR-C-O-CHU

  IQ Jfi-3 C -Lû O \ CD thus obtained (o R is as indicated above) is reduced and the protective amido group possibly present is eliminated We thus obtain the new pair of diastereomers of formula I, which can be separated into

  components by chromatography, if desired.

  The benzhydryl group of the diastereomers of formula I can be eliminated by catalytic hydrogenation,

  which gives the corresponding azetidinylacetic acid derivative This latter derivative as well as its transformation into thienamycin are described in the description of the patent

European No O 062 840.

  The present invention relates to a process for the preparation of new diastereomers of formula I, which comprises the elimination of the ethylene-ketal group from a compound of general formula III / in which R represents a hydrogen atom or, as of an amidoprotective group, a phenyl or benzyl radical optionally substituted by one or more methox groups Z 7 and the reduction of the new compound of general formula II thus obtained (o R 1 is as defined above), then also of the product thus obtained if desired after elimination of the group protecting the amide function and

  if desired, the separation of the pair of diastereomers thus obtained into its components.

  In accordance with the process of the present invention, a compound of general formula III is used as the starting material. The new compounds of general formula III are described in the Hungarian Patent Applications of De Nmanderesse N 4 013/81 and 4 01 l / 81, the preparation process roams the Co Rmposs being also indicated in the Examples.

which will follow.

  The ethyl ketal group can be removed from the compounds of general formula i IT using an acid. In this connection, a sulfonic acid (for example, 15 p-to-moon sulfonic acid), a halide of sylyl (for example, a sylyl halide formed from a mixture of sodium iodide and silicon tetrachloride or sodium iodide and trimethylsilicon chloride) or i a mineral acid (preferably perchloric acid ) o 20 The decetalization reaction can be carried out in a suitable organic solvent, preferably in the mixture of a ketone (for example acetone) or of a chlorinated hydrocarbon and of acetonitrile. The reaction mixture is then neutralized and the new compound of general formula II thus obtained is isolated

if that is desires.

  In accordance with another aspect of this

  invention, it provides new compounds represented by the general formula II and a process for preparing them.

  The compounds of general formula II are reduced.

  The reduction may preferably be carried out with a complex metal hydride, in particular with an alkaline tetrahydroborate (III).

  If compounds of general formula III are used as starting materials in which R is a hydrogen atom, the pair of

  diastereomers of formula I, after reduction.

  If compounds of general formula III are used as starting materials in which R 1 is a protective amido group, this is removed after reduction. This protective amido group can be removed using an agent. oxidant Thus the dimethoxybenzyl group can be eliminated with an oxidizing group of the peroxy10 disulfate type, the methoxyphenyl group can be removed by the simultaneous use of a cerium (IV) salt and an acid, while the protective aminophenyl group can be removed using a cerium (IV) salt and an acid

  or with chromium trioxide in glacial acetic acid.

  The pair of diastereomers thus obtained can

  be separated into its components, if desired. This step is preferably carried out by chromatographic methods. Silica gel (Kieselgel PF 254 + 366) and a 7: 3 mixture of benzene can be used as pre-ference adsorbent. -acetone as eluent.

  In addition to the foregoing provisions, the invention also comprises other provisions, which will emerge from

the description which follows.

  The invention will be better understood using the additional description which follows, which refers to

  Examples of implementation of the process which is the subject of the present invention. It should be understood, however, that these 0 Examples of implementation, are given only as

  illustrating the subject of the invention, of which they in no way constitute a limitation.

EXAMPLE 1

  (2 RS, 3 SR) -3- / 1 (RS and SR) -hydroxyethyl _ / - 435 benzhydryl oxo-2-azetidinylacetate.

  A mixture of 4.89 g (10.0 mmol) (2 RS, 3 SR) 1- (2,4-dimethoxy-benzyl) -3- / 1 (RS and SR) -hydroxyethyl 17 -4-oxo-2 -az 6 benzhydryl tidinyl acetate, 10.81 g (40.0 mmol) of potassium peroxy sulphate (K 25208), 28.65 g (80.0 mmol;) of sodium acid phosphate (Na 2 HPO 4 , 12:20 p.m.), 56.0 ml of acetonitrile and 21.0 ml of water

  is heated to boiling with stirring for 3 hours.

  The reaction mixture is cooled, filtered and the filtrate is separated. The aqueous layer of the filtrate is extracted three times with a portion of 50 ml of ethyl acetate.

  each time The organic layers are combined, extracted with a 10% aqueous solution of sodium carbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated.

  The residual oil is chromatographed (adsorbent: Kieselgel G, solvent eluent: 7: 1 mixture of dichloromethane

and acetone).

  1.73 g of the desired mixture are thus collected, yield: 51%.

  -1 IR (K Br): 3400, 3250, 1755, 1735 cm H-NMR (CDC 13) 1.18 1.32 dd (3 H); 2.20 3.00 m (1 H + + 2 H + 1 H); 3.65 4.28 (1H + 1H) 6.1S (1H); 6.9 S (1 H); 7.30 S (10 H). The starting material can be prepared as follows: a) A suspension of 41.2 g (0.109 mol) of trans / 1-i (2,4-dimethoxy-benzyl) -3- (2-methyl-1 , 3-dioxolane2-yl) -4-oxo-2azetidine-ethyl carboxylate / (this compound is described in the published Hungarian Patent Application N 2263/80 and corresponds to the general formula VI below: OI l COOZ in which Z is an ethyl group and R represents a dimethoxy-benzyl ra 10) and 50 ml of ethanol is added with a solution of 5.21 g (0.130 mole) of sodium hydroxide in 60 ml of water, with stirring and external cooling with ice water and the mixture is stirred until a clear solution has formed (about 20 mi15 minutes) The solution is added with 100 ml of water and the mixture is extracted with 100 ml of ether The aqueous phase is acidified with concentrated hydrochloric acid to p H 1 and quickly extracted once with 100 ml and twice with 50 ml portions of dichloromethane 20 La dichloromethane solution is dried over magnesium sulphate, filtered and the filtrate is evaporated The residual oil is recrystallized from a mixture of toluene and petroleum ether 35 g of trans-1- (2) acid is thus obtained , 4-dimethoxy-benzyl) - 3- (2-methyl-1 l, 325 dioxolane-2-yl) -4-oxo-2-azetidine-carboxylic, yield: 92% This compound corresponds to general formula VI (in

  which Z is a hydrogen atom and R represents a dimethoxybenzyl group) p f: 117 118 C (toluene).

  Analysis for Formula C 17 H 21 NO 7 (351.35) Calculated values: C% = 58.11; H% = 6.03; N% = 3.99;

  Values found: C% = 58.17; H% = 6.30; N% = 4.24.

  -1 IR (K Br): 3500 2500, 2900, 1760, 1720 cm 1 1 H-NMR (CDC 1: 6 1.39 (s, 3 H); 3.50 (d, 1 H, J = 2, 5 Hz); 3.77 (s, 3 H); 3.79 (s, 3 H); 3.86 (d, 35 1 H, J = 2.5 Hz); 3.96 (m, 4 H ); 4.21 + 4.56 (d, 2 g, J = 15 Hz); 6 c 44 (m, 2 H); JAB 5 H); 64 + 7.15 (d, 1 H, 3 = 10 Hz); 7.58 (large s, 1 H). b) A solution of 17.6 g (50 min) of trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolane2-yl) -4-oxo-2- acid azetidine-carboxylic acid (prepared according to the procedure of Example 1a) in 150 ml of anhydrous tetrahydrofuran, 7.3 ml (52.5 mmol) of triethylamine is added, then 5.0 ml is added to the mixture ( 52.5 ml) of ethyl chloroformate under ice-cooling The reaction mixture is cooled to -15 ° C. and stirred at this temperature for 20 minutes, after which the triethylanine salt which has precipitated at this temperature under argon, is separated by filtration A solution of 150 mmol of diazomethane and 230 ml of cold diethyl ether is added to the filtrate. The solution is stirred and allowed to warm to ambient temperature, then after a period of 2 hours, the mixture is evaporated to dryness The brown viscous mass is dissolved in 20 ml of benzene and subjected to column chromatography (adsorbent: 1 50 g of Kieselgel 60 diameter: 0.063 0.200 mm; eluent: a 7-2 mixture of benzene and acetone) o 12.0 g of trans-4- (diazo-acetyl) -l- (2,4 dimethoxy-benzy) -3 (2-methyl) are thus obtained 1, 3-dioxolane-2-yl) -2-azetri25 dinone, yield 64% This compound corresponds to general formula V below:

2549 C 52

  wherein R is a dimethoxybenzyl group.

  Analysis: for Formula C 18 H 21 N 306 (375.37) Calculated values: C% = 57.59; H% = 5.64%

  Values found: C% = 57.78; H% = 5.39.

  -1 IR (K Br): 2900, 2110, 1760 cm c) A mixture of 2.25 g (6 mmol) of trans-4 (diazo-acetyl) -1- (2,4-dimethoxybenzyl) -3- ( 2-methyl-1,3dioxolane2-yl) -2-azetidinone, 100 ml of tetrahydrofuran devoid of peroxide and 50 ml of water, is irradiated in a Pyrex apparatus equipped with an immersion lamp, under argon, for approximately 4 hours with a mercury vapor lamp under high pressure (HPK 125) The solution is evaporated to 50 ml under vacuum and the residue is diluted with water to 130 ml The aqueous solution is added with 2.4 ml of a 10% aqueous solution of sodium hydroxide The alkaline solution is extracted three times with 20 ml portions of dichloromethane and the aqueous layer is acidified with concentrated hydrochloric acid to p H = 2 The solution acid is extracted three times dosed with 20-20 ml portions of dichloromethane The extract is dried over sulfate

  of magnesium, filtered and the filtrate is evaporated to dryness.

  The residue is recrystallized from ether and filtered.

  1.82 g of / -trans-1- (2,4-dimethoxy-benzyl) -3 (2-methyl-1,3-dioxolan-2-yl) -4-oxo-225 azetidinyl / -acetic acid were thus obtained. yield: 83%.

  This compound corresponds to the general formula IV below:

H

 \ / L CI # COOH 1 C

/ d "30 e o R Pl

2,549 '52

  (R is a dimethoxybenzyl group).

  mp: 124 C (ether) Analysis: for Formula C 18 H 23 N 07 (365.37)

  Calculated values: C% = 59.17; H% = 6.34; N% = 3.83; 5 Values found: C% = 59.22; H% = 6.49; N% = 4.07.

  -1 IR (K Br): 3500 2300, 2900, 1730, 1700 cm d) A solution of 5.48 g (15 mmol) of acid / trans-l- (2,4-dimethoxy-benzyl) -3- (2-methyl-l, 3dioxolan2-yl) -4-oxo-2-azetidinyl 7 acetic prepared according to the hard procedure of Exen-mple lc) in 50 ml of dichloromethane is added 3.05 g (15, 75 mmol) of diphenyldiazomethane, at ambient temperature and with stirring After stopping the evolution of nitrogen, the residual diphenyldiazomethane is decomposed by the addition of a few drops of acetic acid. 15 The solution is evaporated to dryness and the residue (6.77 g)

is isolated.

  e) 5.31 g (10.0 mmol) of the residue obtained is dissolved according to the procedure of Example ld) (consisting of (2 RS, 3 SR) - / l- (2,4-dimethioxy-benzyl) - 3- (2-methyl-1,320 dioxolane-2-tl) -4-oxo-2-azetidinyl 7-benzhydryl acetate in 100 ml of aqueous acetone and the solution is cooled to OC, then 2 0.0 ml (24.0 mmol) of 70% perchloric acid The reaction mixture is stirred for 45 minutes under ice cooling, then 2.20 g (2.64 mmol) of sodium hydrogen carbonate are added and

  the mixture is stirred for an additional 10 minutes.

  The suspension is evaporated in vacuo without heating, the residue is dissolved in 60 ml of methanol, then 0.370 g

  (10.0 Imanoles) of sodium tetrahydroborate (III) is added while the system is stirred and cooled with ice.

  The reaction takes about one hour, The mixture is acidified with acetic acid to pl H = 7 and the methanol is distilled off The residue is dissolved in ml of dichloromethane and extracted twice with 35 portions of 25 ml of water and with 25 ml of a solution

2549 052

the

  saturated aqueous sodium chloride The organic layer is dried over magnesium sulfate and evaporated. 3.00 g of a mixture of (2 RS, 3 SR) -1- (2,4dimethoxy-benzyl) -3- are thus obtained. / 1- (RS and SR) -hydroxyethyl 74-oxo-25-azetidinyl-benzhydryl acetate, yield 61%.

  -1 IR (K Br): 3400, 1725 cm 1 H-NMR (CDC 13, 6): 1.06 1.24 dd (3 H); 2.20 3.06 m (1H + 1H + 2H); 3.55 3.95 m (3 H + 3 H + 1 H + 1 H); 3.95 4.10 m (2 H); 10 6.36 6.50 m (2 H); 6.90 S (1 H);

7.05 7.40 m (10 H + 1 H).

EXAMPLE 2

  (2 RS, 3 SR) -3- / -1- (RS and SR) -hydroxy-ethyl 7-4-oxo-2-azetidinylacetate of benzhydryl.

  0.381 g (1.0 mmol) of (2 RS, 3 SR) - / - 3- (2-methyl1,3-dioxolan-2-yl) -4oxo-2-azetidinyl 7- ben zhydrvle acetate is dissolved in 10 0.2 ml of acetone and 0.2 ml (2.3 mmol) of 70% aqueous perchloric acid is added to this solution, under cooling with ice and then, after a period of 45 minutes, 0.20 g (2.4 mmol) of sodium hydrogen carbonate The mixture is stirred for 5 minutes and evaporated to dryness under cold vacuum The residue is suspended in 10 ml of anhydrous methanol, then added with 0.038 g (1.0 mmol) d borosodium hydride (Na BH 4) while the system is stirred and cooled by ice; the mixture is stirred for 3 hours, cooled, neutralized with cold acetic acid and evaporated to dryness The residue is suspended in dichloromethane, extracted with water, then the dichloromethane solution is dried over sul30 fate of magnesium and purified by chromatography (Kieselgel PF 254 adsorbent; eluent: 7: 1 mixture of dichloromethane and acetone) 0.25 g of the product is thus collected

  desired, Yield 74% the physical constants of the product thus obtained are identical to those of the prepared compound 35 according to Example 1.

  The starting material can be prepared as follows: A solution of 5.48 g (15 mmol) of acid / trans1- (2,4-dimethoxy benzyl) - 3 (2-methyl-1,3-dioxolan- 2-yl) 5 4-oxo-2-azetidinyl 7 acetic acid prepared according to the procedure of Example 1c) and 50 ml of dichloromethane is added 3.05 g (15.75 mmol) of diphenyl diazomethane, under agitation at room temperature When the nitrogen evolution has stopped, the residual diphenyl 10 diazometrethane is decomposed by adding a few drops of acetic acid The solution is evaporated to dryness and the residue (6.77 g) is dissolved in 84 ml of acetonitrile 16.20 g (60 mmol) of potassium peroxydisulfate (K 25208), 21.60 g (120 mmol) 15 of disodium phosphate monohydrate (Na 2 HPO 4 E 20) are added to this solution ) and 54 ml of water, the mixture is intensively stirred for 4 hours, heated to boiling and cooled. The cold reaction mixture is filtered and the layers of the filtrate are dried. trimmed The aqueous phase is extracted three times with 30 ml portions of ethyl acetate The combined organic phases are dried over magnesium sulfate, filtered and the filtrate is evaporated The residue is dissolved in benzene and the solution is subjected to chromatography (adsorbent: Kieselgel 60, diameter: 0.050

  0.200 mm; eluent: a 7: 2 mixture of benzene and acetone).

  2.68 g of (2 RS, 3 SR) - / 3- (2-methyl-1,3dioxolan-2-yl 4oxo-2-azetidinyl / -benzhydryl acetate are thus obtained,

yield: 47%.

mp: 130 C (ethanol).

  Analysis: for Fo-arule C 22 H 23 N 05 (387.41) Calculated values C% = 69.27; H% = 6.08; M% = 3.67; Values found: C% = 69.15; H% = 6.20; N% = 3.55 -1 IR (K Br): 3250, 2900, 1760, 1740 cm H-NMR (CD C 13): 1.39 S (3 H); 2.63 dd (2 H, 3 = 4.4 Hz) and 2.89 dd (2 H, J = 9.1 Hz); 3.97 m (5 H) 6.12 S (1 H); 6.9 S (1 H); 7.28 S (10 H). The product prepared according to the procedure of Example 1 or 2, can be converted into the acid (2 RS, 3 SR) -3- / l 1- (SR) -hydroxy-ethy 17-4-oxo-2azetidinyl -acéti5 as in the following way (The latter compound is an intermediate of thienamycin and it is described in

  specification of European Patent N O 062 840).

  The mixture is stirred under hydrogen, a mixture of 0.339 g (1.0 mmol) of (2 RS, 3 SR) -3- / (RS and SR) -hydroxyethyl 17 10 -2 -benzhydryl azetidinyl acetate, 0.03 g of catalyst consisting of 10% palladium on charcoal and 15 ml of anhydrous ethanol, until the hydrogen consumption stops (about 6 hours) The catalyst is separated by filtration, the filtrate is evaporated under vacuum , Cold. The residue is treated with ether, decanted and the residue is dried. This gives 0.121 g of acid (2 RS, 3 SR) 3 - / - l (SR) -hydroxyethyl 7-4-oxo-2- azetidinyl acetic,

yield: 70%.

  -1 IR (K Br): 3400, 3250, 1740 1660 cm-i H-NMR (CD C 13 + DMSO): 6 1.25 d (3 H, J = 6 Hz); 2.58 d

  (2 H, J = 6 Hz); 2.9 dd (1 H, J = 5.3 Hz and J = 2.3 Hz); 3.7 4.2 m (1 H + 1 H).

  As is apparent from the above, the invention is in no way limited to those of its modes of implementation, embodiment and application which have just been described more explicitly; on the contrary it embraces all the variants which may come to

  the mind of the person skilled in the art, without departing from the scope or the scope of the present invention.

7 5 _ 9 W

Claims (7)

  l. New diastereomers, characterized by formula I below: H: C__ O CH X /   (O 2. Process for the preparation of new diastereomers of formula 1 below: o H 08 Y characterized in that a compound represented Cz C_ OCH o I eliminates the ethylene-ketal group by the general formula III below: I ", ' -i oe i 1 o O XY 2 \ CH \   i c_ ox Ill / -in which R is a hydrogen atom or alternatively, as a protective amido group, a phenyl or benzyl radical optionally substituted by one or more methoxy groups 7 then in that the new compound is reduced represented by the general formula II below: HOC o / H 3 C C L GOLD.   thus obtained (where R is as defined above) and in that the resulting product is isolated if desired   after removal of the protective amido group and, if desired, the pair of diastereomers thus obtained is separated into its components.   3. Method according to claim 2, characterized in that the ethylene ketal group is detached using of a mineral acid.   4 Method according to any one of claims 2 or 3, characterized in that the group is detached   ethylene ketal in the presence of a ketone.   5. Method according to claim 2, characterized   in that the reduction is carried out with a complex metal hydride.   6. Method according to claim 2, characterized in that the group protecting the amide function is eliminated. with an oxidizing agent.   7. New compounds of general formula II in which P1 is as defined in claim 2.