LU85424A1 - HETEROCYCLIC ACETIC ACID ESTERS - Google Patents

Description

t i

V

The present invention relates to novel heterocyclic acetic acid esters and to a process for their preparation. The present invention relates more particularly to new diastereomers represented by the formula I below: S "3 ï î’ y®,

h3c -Îh -L

J-m v_y, and a method for preparing them.

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

Thienamycin is a broad spectrum antibiotic; the microbiological process allowing its preparation is described in US Patent No. 3,950,357 and the most recent synthesis of this antibiotic is described in European Patent No. 0,062,840.

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. the Applicant,

Ser. No. 4,014/81. These compounds correspond to the general formula III below: ”Γ ^ Η“ i y® v 1 l ^ c ^ c-0-αζ r; m. --r \ {Ô) H3C. - I \ - / 35 XN \, 0 y '1 s 5 2 / ~ in which R · * "represents a hydrogen atom or alternatively, as an amido-protective group, a phenyl or benzyl radical optionally substituted by a or several methoxy groups / The compound of general formula III is subjected to decetalization, the compound of general formula II below: 0 h H? (o)! \ J ^ CH ^ C-Ο ^ ζ a where HjC — C-1-KX (Ô) / V.

0 R * 15 thus obtained (where R ^ "is as indicated above) is reduced and the amido-protective group possibly present is eliminated. This gives the new pair of dia-stereomers of formula I, which can be separated into its components by chromatography, if desired.

The benzhydryl group of the diastereomers of formula I can be removed by catalytic hydrogenation, which gives the corresponding azetidinylacetic acid derivative. The latter derivative and its transformation into thienamycin are described in the description of European Patent No. 0 0 62 6240 ’.

% _

The present invention relates to a process for pre-. “Easter of new diastereomers of formula I, which includes the elimination of the ethylene ketal group from a compound of general formula III £ in which R ^ represents a hydrogen atom or, as a group amido-protector, a phenyl or benzyl radical optionally substituted by one or more methoxy groups / and the reduction of the new compound of general formula II thus obtained (or R1 is as defined above), then the iso-lemént of the product thus obtained - if desired after

V

fl fl 3 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 Applicant Nos. 4,013/81 and 4,014/81, the process for the preparation of these compounds also being indicated in the Examples which follow.

The ethylene ketal group can be removed from the compounds of general formula III using an acid. Incidentally, a sulfonic acid (e.g. p-toluene sulfonic acid), a sylyl halide (e.g. a sylyl halide formed from a mixture of sodium iodide and silicon tetrachloride or sodium iodide and trimethylsilicon chloride) or a mineral acid (preferably perchloric acid).

The decetalization reaction can be carried out in a suitable organic solvent, preferably in the mixture of a ketone (for example acetone) or a chlorinated hydrocarbon and acetonitrile.

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

* In accordance with another aspect of the present 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, as starting materials, i 4 are used compounds of general formula XII in which R 1 is a hydrogen atom, the pair of diastereomers of formula I is obtained directly, after reduction.

If compounds of general formula III are used as starting materials in which R ^ is a protective amido group, this is removed after reduction. This protective amido group can be removed using an oxidizing agent. Thus the dimethoxybenzyl group can be eliminated with an oxidizing group of the peroxy-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 diastereomer pair thus obtained can be separated into its components, if desired. This step is preferably carried out by chroma-tographic methods. Silica gel can be used as pre-ference adsorbent (Kieselgel PI> 254 + 366 ^ e * "A 7: 3 mixture of benzene acetone as eluent.

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

^ 25 The invention will be better understood with the help of the additional description which follows, which refers to 1 Examples of implementation of the process which is the subject of the present invention.

It should be understood, however, that these Examples of Implementation are given solely by way of illustration of the subject of the invention, of which they do not in any way constitute a limitation.

EXAMPLE 1 (2 RS, 3 SR) -3 ~ / ~ 1 (RS and SR) —hydroxyethyl / -4-35 oxo-2-azetidinyl — benzhydryl acetate.

i s 5

A mixture of 4/89 g (1Q70 mmol) · ί'2 RS, 3. SR) - 1— (2,4-dimethoxy-henzyl) -3- / 1, (RS and SR) —hydroxyethyl? -4-oxo-2-azetidinyl-benzhydryl acetate, 1Q / 81 g (4Q / Q mmoles) potassium peroxy disulfate (K2 ^ 2 ° 8 ^ / 5 28.65 g (80, Q mmoles) acid phosphate sodium, 12 Η · 2 °), 56/0 king dracetonitrile 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 50 ml portion 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: Kie-selgel G, eluting solvent: 7: 1 mixture of dichloromethane and acetone).

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

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

1H-NMR (CDCl3): fi 1.18 - 1.32 dd (3H); 2.20 - 3.00 m (1H + + 2H + 1H); 3.65 - 4.28 (1H + 1H); 6.1 s (1H); 6.9 s (1H); 7.30 s (10H).

The starting material can be prepared as follows: a) A suspension of 41.2 g (Q, 109 mole) of trans- / 1- (2,4-dimethoxy-benzyl) -3- (2- methyl 1-1.3-dioxolane-2- yl) -4-ethyl oxo-2-azetidine carboxylate / (this compound is described in the published Hungarian Patent Application \ 30 No. 2263/80 and corresponds to the general formula VI below: 6 r \ h = / \ 'F cooz.

5 Xe — H "

H3c U

0 R

in which Z is an ethyl group and R represents a dimethoxy-benzyl radical) 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 mi-15 minutes). 100 ml of water are added to the solution and the mixture is extracted with 100 ml of ether. The aqueous phase is acidified with concentrated hydrochloric acid to pH 1 and rapidly extracted once with 100 ml and twice with 50 ml portions of dichloromethane. The dichlorornethane solution is dried over magnesium sulfate, filtered and the filtrate is evaporated. The residual oil is recrystallized from a mixture of toluene and petroleum ether. 35 g of trans-1- (2,4-dimethoxy-behzyl) -3- (2-methyl-1,3-25 dioxolane-2-yl) -4-oxo-2-azetidine-carboxylic acid are thus obtained. , yield: 92%. This compound corresponds to the general formula VI (in which Z is a hydrogen atom and R represents a dimethoxybenzyl group) m.p. : 117-118 ° C (toluene).

Analysis for Formula C] _7H21 ^ 7 (351.35) 30 Calculated values: C% = 58.11; H% = 6.03; N% = 3.99;

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

IR (KBr): 350Q - 2500, 290Q, 1760, 172Q cm “1.

1H-NMR (CDCl3): δ 1.39 (s, 3H); 3.5Q (d, 1K, J = 2.5 Hz); 3.77 (s, 3H); 3.79 (s, 3H); 3.86 (d, 35 1H, J = 2.5 Hz); 3.96 (m, 4H); 4.21 + i * 7 4.56 (d, 2H, J = 15 Hz); 6.44 (m, 2H);

he d

+ 7.15 (d, 1H, J = 1Q Hz); 7.58 (large s, 1H).

b) A solution of 17.6 g (5Q iranoles) of trans-1- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolane-2-yl) -4 acid —Oxo-2-azetidine-carboxylic acid (prepared in accordance with the procedure of Example la) in 150 ml of anhydrous tetrahydro-furan, 7.3 ml (52.5 mmol) of triethylamine are added, then the mixture is supplemented with 5.0 ml 10 (52.5 mmol) 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 triethylamine 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 room 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: 150 g of Kieselgel 60, diameter: 0.063 -0.200 mm; eluent: a 7: 2 mixture of benzene and acetone). 12.0 g of trans-4- (diazo-acetyl) -1- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolane-2-yl) -2- are thus obtained. azéti-25 dinone, yield 64 *%. This compound corresponds to the general formula V below: 30 Oj_jUoo ^ I i v / wv O R.

(\ 8 wherein R is a dimethoxybenzyl group.

Analysis: for Formula ^ jg ^ 21 ^ 3 ^ 6 (375.37)

Calculated values: C% = 57.59; H% = 5.64%

Values found: C% - 57.78; H% = 5.39-5 IR (KBr): 29OQ, 2110, 1760 cm “1.

c) A mixture of 2.25 g (6 mmol) of trans-4- (diazo-acetyl) —1— (2,4-dimethoxybenzyl) -3— (2-methyl-1,3-dioxolane-2-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. 2.4 ml of a 10% aqueous sodium hydroxide solution are added to the aqueous solution. The alkaline solution is ex treated three times with 20 ml portions of dichloromethane and the aqueous layer is acidified with concentrated hydrochloric acid to pH = 2. The acid solution is extracted three times with portions of 20 20 ml of dichloromethane. The extract is dried over magnesium sulfate, filtered and the filtrate is evaporated to dryness.

The residue is recrystallized from ether and filtered.

There was thus obtained 1.82 g of acid / trans-1- (2,4-dimethoxy-benzyl) - 3- (2-methyl 1-1, 3-dioxolan-2-yl) -4-oxo-2 -25 azetidinyl / -acetic, yield: 83%.

This compound corresponds to the general formula IV below: *

30 / ^ HH

° \ / '\ f ^ CHzC00H IV

35 Xr I

\ 9 (R is a dimethoxybenzyl group). m.p. : 124 ° C (ether)

Analysis: for Formula C18H23NQ7 (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.

XR (KBr): 35QQ - 23ÜQ, 29QQ, 1730, 1700 cm “1.

d) A solution of 5.48 g (15 mmol) of acid "/ trans-1- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) - 4-oxo-2-azetidinyl / acetic acid prepared according to the hard procedure of Example le) in 50 ml of dichloromethane, 3.05 g (15.75 mmol) of diphenyldiazomethane is added at room temperature and under agitation. After stopping the evolution of nitrogen, the residual diphenyldiazomethane is broken down by adding a few drops of acetic acid. 15T 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 according to the procedure of Example 1d) are dissolved (consisting of (2 RS, 3 SR) - / 1- (2,4-dimethoxy-benzyl) - 3- (2-methyl-1,3-20 dioxolane-2-yl) -4-oxo-2-azetidinyl / -benzhydryl acetate in 100 ml of aqueous acetone and the solution is cooled to Q ° C, then 2.0 ml (24.0 mmol) of 70% perchlo-ric acid are added The reaction mixture is stirred for 45 minutes under cooling with ice, then 2.20 g (2.64 mmol) sodium hydrogen carbonate are added and the mixture is stirred for an additional 10 minutes.

The suspensiôn ~ is evaporated under vacuum without heating, the residue is dissolved in 60 ml of methanol, then 0.370 g (10.0 mmol) of sodium tetrahydroborate (III) is added while the system is stirred and cooled by ice. The reaction takes about an hour. The mixture is acidified with acetic acid to pH = 7 and the methanol is distilled off. The residue is dissolved in 100 ml of dichloromethane and extracted with. twice with 35 servings of 25 ml of water and with 25 ml of a solution

v IQ

saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate and evaporated. 3 QQ g of a mixture of (2 RS, 3 SR) —1— (27 4-dimethoxy-benzyl) -3 - ^ / 1- (RS and SR) -hydroxyeth.yl7-4-oxo are thus obtained -2-5 benzhydryl azetidinyl acetate, yield 61%.

IR (KBr): 34QQ 7 1725 cm “1.

1H-NMR (CDC13 7 δ): 17G6 - 1724 dd (3H)? 2720 - 3706 m (1H + 1H + 2H); 3.55 - 3795 m (3H + 3H + 1H + III); 3.95 - 4.10 m (2H); 1Q 6.36 - 6.5Q m (2H); 6.90 s (1H); 7.05 - 7.40 m (10H + 1H).

EXAMPLE 2 (2 RS, 3 SR) -3- / 1- (RS and SR) -hydroxy-ethyl / -4-oxo-2-azë-tidinyl-benzhydryl acetate.

15 0.381 g (1.0 mmol) of (2 RS, 3 SR) - / 3- (2-methyl- 1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7 - benzhydryl acetate est dissolved in 10 ml of acetone and to this solution is added 0.2 ml (2.3 mmol) of 70% aqueous perchloric acid, under cooling with ice and then, after a period of 45 minutes, of 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) of borosodium hydride (NaBH4) while the dull 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 magnesium sul-30ate and purified by chromatography (Kieselgel PF 254 adsorber; eluent: 7: 1 mixture dichloromethane and acetone). Q, 25 g of the desired product are thus collected, yield 74%. the physical constants of the product thus obtained are identical to those of the pre-prepared compound according to Example 1., \ 11

The starting material can be prepared as follows:

A solution of 5.48 g (15 immoles) of acid / trans- 1- (2,4-dimethoxy-benzyl) —3- (2-methyl-1,3-dioxolan-2-yl) -5 4- oxo-2-azetidinyl / acetic acid prepared in accordance with the procedure of Example 1c) and 50 ml of dichloromethane, 3.05 g (15.75 mmol) of diphenyl diazome-thane are added, with stirring at room temperature . When the evolution of nitrogen has stopped, the residual diphenyl diazomethane 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. To this solution are added 16.20 g (60 mmol) of potassium peroxy disulfate (K2S20g), 21.60 g (120 mmol) of disodium acid phosphate monohydrate (Na2HP0 ^, H2O) and 54 ml of water, the mixture is intensively stirred for 4 hours, heated to a boil and cooled. The cold reaction mixture is filtered and the layers of the filtrate are separated. 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-1,3-dioxolan-2-yl ·) -4-oxo-2-azetidinyl / -benzhydryl acetate are thus obtained, yield : 47%. mp: 130 ° C (ethanol).

30 Analysis: for Formula C22H23N05 (387.41)

Calculated values: C% = 69.27; H% = 6.08; N% = 3.67; Values found: C% = 69.15; H% = 6.20; N% = 3.55.

IR (KBr): 3250, 29Q0, 176Q, 1740 cm-1.

1H-NMR (CDCl3): 6 1.39 s (3H); 2.63 dd (2H, j = 4.4 Hz) 35 and 2.89 dd (2H, J = 9.1 Hz); 3.97 m (5H); 12 6.12 ε (1Η); 6.9 ε (1Η); 7.28 ε (10Η).

The product prepared according to the procedure of Example 1 or 2, can be converted into the acid (2 RS, 3 SR) -3- / 1- (SR) -h-ydroxy-ethyl7'-4-oxo- 2-azetidinyl-acéti-5 as follows. (The latter compound is an intermediate of thienamycin and it is described in the specification of European Patent No. 0 062 840).

'Stirred under hydrogen, a mixture of 0.339 g (1.0 mmol) of (2 RS, 3 SR) -3- / 1- (RS and SR) -hydroxyethyl / 10 -2-azetidinyl-benzhydryl acetate, 0 , 03 g of catalyst consisting of 10% palladium on charcoal and 15 ml of anhydrous ethanol, until the consumption of hydrogen 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 t is dried. 0.121 g of acid (2 RS, 3 SR) - 3- / 1 (SR) -hydroxyethyl / -4-oxo-2-azetidinyl acetic is thus obtained, yield: 70%.

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

1H-NMR (CDCl3 + DMSO): δ 1.25 d (3H, J = 6 Hz); 2.58 d (2H, J = 6 Hz), - 2.9 dd (1H, J * = 5.3 Hz and J = 2.3 Hz); 3.7 - 4.2 m (1H + 1H).

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 technician in the matter, without departing from the framework, or the scope, of the present invention.

Claims (5)

0 R1 / in which R1 is a hydrogen atom or alternatively, as a protective amido group, a phenyl or benzyl radical optionally substituted by one or more # 14 methoxy groups / then in that the new is reduced compound t represented by the general formula IX below: K 0 HH? (o) ï] l ^ CNz-CO-CH ^^ U h5c — c ——K x (o) j <0 1Q thus obtained (where is as defined above h.aut) and in that we isolate the resulting product - if desired after removal of the protective amido group - and, if desired, the pair of diastereomers thus obtained are separated into its components. 3.- Method according to claim 2, characterized in that the ethylene-ketal group is detached using a mineral acid. 4. A process according to any one of claims 2 or 3, characterized in that the ethylene ketal group is detached 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 Q "R" is as defined in claim 2. Y