NL8401978A - HETEROCYCLIC ACETIC ACID ESTERS. - Google Patents

Description

NL 32176-Kp / Pf / ed - 1 - ^ 4

Heterocyclic acetic acid esters.

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The present invention relates to new heterocyclic acetic acid esters and to a process for their preparation. More particularly, the invention is directed to novel diastereomers of the formula I of the formula sheet, as well as a process for their preparation.

The new diastereomers of formula I are useful as intermediates in the preparation of thienamycin, a known antibiotic.

Thienamycin is a broad spectrum antibiotic, while the microbiological method for its preparation is described in US patent 3,950,357 and the most recent synthesis of this antibiotic is found in European patent 62,840.

It has been found that the compounds of formula I can be prepared by simple reaction steps, through new intermediates, and in high yields starting from compounds described in our earlier Hungarian patent application no. 4014/81. Said compounds correspond to the general formula III of the formula sheet, wherein R 1 represents a hydrogen atom or as an amide protecting group for a phenyl or benzyl group, which may be optionally substituted with one or more methoxy group (s). The compound of the general formula III is subjected to decetalization, the thus obtained compound of the general formula II of the formula-25, wherein R1 has the above meanings, is reduced, and if present the amide protecting group is removed. Thus, the new pair of diastereomers of the formula I are obtained, which, if desired, can be separated into its components by chromatography.

From the diastereomers of formula I, the benzhydryl group can be removed by catalytic hydrogenation to yield the corresponding azetidinylacetic acid derivative. The latter and its conversion to thienamycin are described in European patent application 62,840.

The present invention is directed to a process for the preparation of new diastereomers of the formula I, which process comprises the removal of the ethylene ketal group of a compound of the general formula III, wherein 8401978 "- 2 -1 S. ·. represents a hydrogen atom or as an amide protecting group for a phenyl or benzyl group, which may optionally be substituted with one or more methoxy group (s) and the reduction of the thus obtained new compound of the general formula II, wherein R1 has the same meanings and the isolation of the product thus obtained - optionally after removal of the amide protecting group - and, if desired, the separation of the pair of diastereomers thus obtained in its components.

According to the method of the present invention, a compound of the general formula III is used as the starting material.

The novel compounds of general formula III are described in Hungarian patent applications Nos. 4013 / 8L and 4014/81, while the process for their preparation is also mentioned in the examples of the present specification.

The ethylene ketal group can be removed from the compounds of the general formula III with an acid. For this purpose, a sulfonic acid (eg p-toluenesulfonic acid), a sylyl halide (eg a sylyl halide formed from a mixture of sodium iodide and silicon tetrachloride or sodium iodide and trimethyl silicon chloride) or a mineral acid (preferably perchloric acid) can be used. The dephelination reaction can take place in a suitable organic solvent, preferably in the mixture of a ketone (eg acetone) or a chlorinated hydrogen and acetonitrile

The reaction mixture is then neutralized and the new compound of the general formula II thus obtained is isolated if desired.

According to a further aspect of the present invention, new compounds of general formula II are provided, as well as a process for their preparation.

The compounds of the general formula II are reduced. The reduction can preferably be carried out with a complex metal hydride, in particular with an alkali tetrahydroborate (III).

When compounds of the general formula III are used as starting material in which R 1 is hydrogen, the pair of diastereomers of the formula I is obtained immediately after reduction.

8401978 • - - 3 -.

When compounds of general formula III are used as starting material, wherein Rx is an amide protecting group, this amide protecting group is removed after reduction.

The said protecting group can be removed using an oxidizing agent. For example, the dimethoxybenzyl group can be removed with an oxidizing agent of the peroxydisulfate type, the methoxyphenyl group by simultaneous use of a cerium (IV) salt and an acid, while the aminophenyl protecting group using a cerium (IV) salt and an acid or can be removed by using 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. As the adsorbent, silica gel (Kicker gel PF254 + 366) and a partial mixture of benzene and acetone can preferably be used.

Further details of the present invention can be found in the following examples without limiting the scope to these examples.

Example I

Benzhydryl (2 RS, 3 SR) -3 / -1 (RS and SR) hydroxyethyl 25 -4-oxo-2-azetidinyl acetate}.

A mixture of 4.89 g (10.0 mmol) of benzhydryl- | (2 RS, 3 SR) -1- (2,4-dimethoxybenzyl) -3- / 1 (RS and SR) -hydroxyethyl7-4-- oxo-2-azetidinylacetate |, 10.81 g (40.0 mmol) potassium peroxydisulfate (K2S20g), 28.65 g (80.0 mmol) sodium hydrogen phosphate 30 (Na2HPO4 · 12 H2O), 56.0 ml acetonitrile and 21 .0 ml of water was heated to boiling for 3 hours with stirring. The reaction mixture was cooled, filtered and the filtrate separated. The aqueous layer of the filtrate was extracted three times with 50 ml of ethyl acetate each time. The organic layers were combined, extracted with a 10% aqueous sodium carbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The residual oil was worked up by chromatography (adsorbent: Kieselgel G, eluent: a 7: 1 mixture (40-chloromethane and acetone).

——— - —— - 8401978 ^ v - 4 -

Thus, 1.73 g of the desired mixture were obtained in a yield of 51%.

IR (KBr): 3400, 3250, 1755, 1735 cm -1.

1 H NMR (CDCl 3): S 1.18-1.32 dd (3H); 2.20-3.00 m (1H + 2H + 5 + 1H); 3.65-4.28 m (1H + 1H); 6.1 s (1H); 6.9 s (1H); 7.30 s (10H).

The starting material can be prepared as follows: a) To a suspension of 41.2 g (0.109 mol) trans-ethyl- / 1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolane) -2-10 -yl) -4-OXO-2- azetidinecarboxylate / (this compound is disclosed in Laid-Open Hungarian Patent Application No. 2263/80 and has the general formula VI of the formula sheet, wherein Z is ethyl and R represents dimethoxybenzyl) and 50 ml of ethanol a solution of 5.21 g (0.130 mol) of sodium hydroxide in 60 ml of water was added with stirring and external cooling with ice cold water and the mixture was stirred until a clear solution was formed (ca 20 min). 100 ml of water was added to the solution and the mixture was extracted with 100 ml of ether. The water phase was acidified with concentrated hydrochloric acid to pa = 1 and extracted quickly with 100 ml once and 50 ml of dichloromethane once. The dichloromethane solution was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residual oil was crystallized from a mixture of toluene and petroleum ether.

Thus, 35 g of trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine carboxylic acid in 92% yield were obtained . This compound has general formula VI (Z is hydrogen and R stands for dimethoxybenzyl). Melting point: 117-118 ° C (toluene).

Analysis: Calculated for the formula C 17 H 21 NO 7 (351.35): C% - 58.11; H% = 6.03; N% = 3.99; found: C% = 58.17; H% = 6.30; N% = 4.24.

IR (KBr): 35Qt2500, 2900, 1760, 1720 cm -1.

1 H NMR (CDCl 3): / 1.39 (s, 3H), 3.50 (d, 1H, J = 2.5 Hz), 3.77 35 (s, 3H), 3.79 (s, 3H ), 3.86 (d, 1H, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4.56 (d, 2H, JAB = 15Hz), 6.44 (m, 2H) + 7.15 (d, 1H, J = 10Hz), 7.58 (broad, s, 1H).

b) To a solution of 17.6 g (50 mmol) of trans-1- 40 - (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo- 2 - 8401978 - 5 -.

-azetidine carboxylic acid (prepared according to Example 1a) in 150 ml anhydrous tetrahydrofuran 7.3 ml (52.5 mmol) of triethylamine was added and 5.0 ml (52.5 mmol) of ethyl chloroformate was added to the mixture under ice-cooling. The reaction mixture was cooled to -15 ° C and stirred at this temperature for 20 min, after which the triethylamine salt precipitated at this temperature was filtered off under argon. A solution of 150 mmol of diazomethane and 230 ml of cold diethyl ether was added to the filtrate. The solution was stirred and warmed to room temperature, after which the mixture was evaporated to dryness after 2 h. The brown viscous mass was dissolved in 20 ml of benzene and subjected to column chromatography (adsorbent: 150 g Kieselgel 60, diameter: 0.063-0.200 mm: eluent: a 7: 2 mixture of benzene and acetone). Thus, 12.0 g of trans-4- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxo Lan-2-yl> -2-azetidinone were obtained in yield 64% This compound has the general formula V of the formula sheet wherein R is dimethoxybenzyl.

Analysis: Calculated for the formula C18H21N3 <::> 6 (375.37): C% = 57.59; H% = 5.64; found: C% = 57.78; H% = 5.39.

IR (KBr): 2900, 2110, 1760 cm-1.

c) A mixture of 2.25 g (6 mmol) trans-4- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -25 -2-azetidinone, 100 ml of peroxide-free tetrahydrofuran and 50 ml of water were irradiated under a argon atmosphere under a argon atmosphere using a high-pressure mercury vapor lamp (HPK 125) in a pyrex set-up for approx. 4 h. The solution was evaporated to 50 ml under vacuum and the residue was diluted with water to 130 ml. 2.4 ml of a 10% aqueous sodium hydroxide solution was added to the aqueous solution. The alkaline solution was extracted three times with 20 ml of dichloromethane each time and the aqueous layer was acidified with concentrated hydrochloric acid to a pH-2. The acidic solution was extracted three times with 20 ml of dichloromethane each time. The extract was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was crystallized from ether and filtered.

For example, 1.82 g of trans-1- (2,4-dimethoxybenzyl) -3- (2- 40 -methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl-7 ”acetic acid was added 84 U 1 9 7 8 * - 6 - in a yield of 83%.

This compound has the general formula IV of the formula sheet, wherein R is dimethoxybenzyl.

M.p .: 124 ° C (ether).

5 Analysis: for the. formula CHNO (365.37): IE 23 7 calculated; C% = 59.17; H% = 6.34; N% = 3.83; found: C% = 59.22; H% = 6.49; N% = 4.07.

IR (KBr): 3500-2300, 2900, 1730, 1700 cm -1.

d) To a solution of 5.48 g (15mmol) (, tr.ans-1-10 - (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4 oxo-2-azetidinyl-7'-acetic acid, prepared according to Example 1c, in 50 ml of dichloromethane, 3.05 g (15.75 mmol) of diphenyldiazo-methane was added with stirring. the remaining diphenyldiazomethane decomposed by adding a few drops of acetic acid, the solution was evaporated to dryness and the residue (6.77 g) was isolated.

e) Of the residue obtained according to Example 1d, which consisted of benzhydryl- (2 'RS, 3' SR) - / - 1- (2,4-dimethoxybenzyl) - 20-3 ('2-methyl-1,3) -dioxolan-2-yl) -4-oxo-2-azetidinyl-7 ”acetate, 5.31 g (10.0 mmol) were dissolved in 100 ml anhydrous acetone and the solution was cooled to 0 ° C, after which 2.0 ml (24.0 mmol) 70% perchloric acid was added. The reaction mixture was stirred under ice-cooling for 45 min, then 2.20 g (2.64 mmol) of sodium hydrogen carbonate was added and the mixture was stirred for an additional 10 min. The suspension was evaporated in vacuo without heating, the residue was dissolved in 60 ml of methanol, and 0.370 g (10.0 mmol) of sodium 1-tetrahydridoborate (III) _7 was added under ice-cooling and stirring. The reaction took about 1 hour. The mixture was acidified with acetic acid to a pH of 7 and the methanol was distilled off. The residue was dissolved in 100 ml of dichloromethane and extracted twice with 25 ml of water each and with 25 ml of a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and evaporated to dryness. So. 3.00 g of benzhydryl (2 'RS, 3' SR) -1- (2,4-dimethoxybenzyl) -3 - / “1- (RS and ... SR) -hydroxyethyl 7-4-oxo- 2 - azetidinyl acetate as a mixture obtained in a yield of 61%.

40 JK (KBr) 1 3400, 1725 to -1.

8401978-7-1'H-NMR (CDCl 3 / /): 1.06-1.24 dd (3H); 2.20-3.06 m (1H + 1H + 2H); 3.55-3.95 m (3H + 3H + 1H + 1H); 3.95-4.10 m (2H); 6.36-6.50m (2H); 6.90 s (1H)? 7.05-7.40 m (10H + 5 1H).

Example II

Benzhydryl - (2 RS, 3 SR) ~ 3 - ^ (RS and SR) -hydroxyethyl7 -4-oxo-2-azetidinylacetate £ 10 0.381 g (1.0 mmol) of benzhydryl- ** f in 10 ml of acetone (2 3 SR) - / 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetiri-dinyl-7-acetate and dissolved in the solution under ice-cooling with 0.2 ml ( 2.3 mmol) 70% aqueous perchloric acid to which was added 0.20 g (2.4 mmol) sodium hydrogen carbonate 15 after 25 min. The mixture was stirred for 5 min and evaporated to dryness under vacuum at low temperature. The residue was suspended in 10 ml anhydrous methanol and 0.038 g (1.0 mmol) of sodium borohydride (NaBH4) was added under ice-cooling and stirring, the mixture was stirred for 3 h, cooled, neutralized with cold acetic acid and evaporated to dryness . The residue was suspended in dichloromethane, extracted with water, while the dichloromethane solution was dried over magnesium sulfate and purified by chromatography (adsorbent: Kieselgel PF 254; eluent: a 7: 1 mixture of dichloromethane and acetone). Thus, 0.25 g of the desired product were obtained in a yield of 74%.

The physical constants of the product thus obtained are identical to those of the compound prepared according to Example I.

30 The starting material can be prepared as follows:

To a solution of 5.48 (15 mmol) (_ trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2- aze-tidinyl-7-acetic acid prepared according to Example 1c, in 50 ml of dichloromethane, 3.05 g (15.75 mmol) of diphenyldiazo-35-methane was added with stirring at room temperature. Diphenyldiazomethane decomposed by adding a few drops of acetic acid The solution was evaporated to dryness and the residue (6.77 g) was dissolved in 84 ml of acetonitrile To the solution were added 40.20 g (60 mmol) potassium peroxysulfate (E ES9090), 21.60 g (120 8401978 - - 8 - mmol) disodium hydrogen phosphate monohydrate (1 ^ 2 ^ 0 ^ · H2 O) and 54 ml of water were added, the mixture was stirred vigorously for 4 h, heated to boiling and cooled. mixture was filtered and the layers of the filtrate separated 5. The aqueous phase was extracted three times with 30 ml each of ethyl acetate. dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was dissolved in benzene and the solution was worked up by chromatographic methods (adsorbent: Kieselgel 60; diameter: 0.050-0.200 mm; eluent: a 7: 2 mixture of benzene and acetone). Thus, 2.68 g of benzhydryl- (2 RS, 3 SR) - / 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl-7-acetate were obtained in a yield of 47% .

Mp: 130 ° C (ethanol).

Analysis: Recalculated for the formula C22H23N05 (387.41): C% = 69.27; H% = 6.08; N% = 3.67; found: -: C% = 69.15; H% = 6.20; N% = 3.55.

IRJtKBr): 3250, 2900, 1760, 1740 cm 1.

1 H NMR (CDCl 3); ƒ 1.39 s (3H), 2.63 dd (2H, J * 4.4 Hz) and 2.89 dd (2H, J = 9.1 Hz), 3.97; m (5H), 6.12 s (1H), 6.9 s (1H), 7.28 s (10H).

The product prepared according to Example I or II can be converted to the (2 RS, 3 SR) -3- / -1- (SR) -hydroxyethyl 7 ~ 25 -4-oxo-2-azetidinylacetic acid as follows. compound is an intermediate for thienamycin and is mentioned in European patent 62,840).

A mixture of 0.339 g (1.0 mmol) benzhydryl- (2 RS, 3 SR) ”{3- / 1 (RS and SR) -hydroxyethyl 7 ~ 2-azetidinyl] acetate, 0.03 g 10% palladium / charcoal catalyst and 15 ml of anhydrous ethanol were stirred under hydrogen until the consumption of hydrogen was stopped (ca 6 h). The catalyst was filtered off, the filtrate was evaporated under low temperature vacuum. The residue was treated with ether, decanted and the residue was dried. Thus, 0.121 g (2 RS, 3 SR) -3-fl (SR) -hydroxyethyl 7 -4-oxo-2-azetidinylacetic acid was obtained in a yield of 70%.

IR (KBr): 3400, 3250, 1740-1660 cm -1.

1 H NMR (CDCl 3 + DMSO): S 1.25 d (3H, J = 6Hz); 2.58 d (2H, 40J = 6Hz); 2.9 dd (1H, J = 5.3 Hz 84 0 1 9 7 & - / and J = 2.3 Hz); 3.7-4.2 m (1H + 1H).

8401978

Claims (7)

1. New diastereoras with formula I from the formula sheet. 2. A process for the preparation of new diastereomers of the formula I of the formula sheet, comprising 5. that the ethylene ketal group is removed from a compound of the general formula III of the formula sheet wherein R 1 represents a hydrogen atom or as an amide protecting group for a phenyl or benzyl group, which may optionally be substituted with one or more methoxy group (s), and the new formula II of the formula sheet thus obtained, in which R1 can have the same meanings, is reduced, and the product thus obtained - if desired after removal of the amide protecting group - is isolated and, if desired, the pair of diastereomers thus obtained is converted into its components divorced. 3. Process according to claim 2, characterized in that the ethylene ketal group is split off with the aid of a mineral acid. 4. Process according to claim 2 or 3, characterized in that the ethylene ketal group is split off in the presence of a ketone. Process according to claim 2, characterized in that the reduction is carried out with a complex metal hydride. 6. Process according to claim 2, characterized in that the amide protecting group is removed with an oxidizing agent. New compounds of the general formula II of the formula sheet, wherein R has the meanings set out in claim 2. 30 8401978 ^ NL 32,176-Pf / ed Belongs to patent application Attn. Richter Gedeon Vegyëszeti Gyar R.T. and Biogal Gyóqyszergyar_ OH H hl 0> - i i! fi AS) H3C —CH —'_ f ^ CH2-C-0-CH (^ 0J — 4jh (°) o Η H} / ¾ 1% cS-4_Pc "-c-0-ch ^ ö> Λν. MHH 0 / T \ ° \ / 1 f II A £ / y ~ -1_i ^ CHr-CO-CH Hic ZL \ £> VN \ o V 8401978 -EN 32.176-Pf / ed Belongs to patent application in the name of Richter Gedeon Vegyészeti Gyar RT and Biogal Gyogyszergyar_ o \ μ y ΊΣ \ t 1 f ^ CHzCOOH "f '' Li / \ D 0 R Γ \ H» 2: ° \ / i ^ cocm ^ I / ~ w \ o> / 'bhy 2E V /] f / COOZ u / ^ 1 1 3> —N \ 0 R 8401978