CH661269A5 - HETEROCYCLIC ACETIC ACID ESTERS. - Google Patents

Description

The invention relates to new heterocyclic diastereomeric acetic acid esters of the formula I.

10th

OH H H

2. Process for the preparation of new diastereomers of the formula I.

H3C -CH-

H3C

OH H? ]

—CH — L

0

li y (pS

(I)

m <£>

0

s

• CH? - C - O — CH

X

<ö>

flH

<2>

(I)

characterized in that from a compound of general formula III

0

CH, -C-O-CH

and a method of manufacturing the same. The novel diastereomers according to the invention can be used in the therapeutic industry as intermediates in the production of the known effective thienamycin.

Thienamycin is a well-known antibiotic with a broad spectrum of activity, the microbiological production process of which was described in US Pat. No. 3,950,357 and the latest synthesis in European Pat. No. 62,840.

(III) It has now been found that the compounds of the form I from the compounds described in Hungarian Patent No. 18 5041 / so-called compounds with simple reaction steps,

can be produced by new intermediates and with good yield. The compounds mentioned correspond to the general formula III

35

r ^ b H ° ^ /

X—

40 H3C

0

H

0

-N,

CH ^ —C — 0 — CH

R

°)

(IH),

wherein R1 is a hydrogen atom or as an amide protecting group is a phenyl or benzyl group optionally substituted by one or more methoxy groups, the ethylene ketal group is split off and the compound of general formula II obtained

in which R1 has the meaning given above, and the amide protective group which may be present is removed from the product obtained and the product is isolated.

3. The method according to claim 2, characterized in that the resulting pair of diastereomers is separated into the individual optically active components.

4. The method according to claim 2 or 3, characterized in that the ethylene ketal group is split off with a mineral acid.

5. The method according to any one of claims 2 to 4, characterized in that one carries out the cleavage of the ethylene ketal group in the presence of a ketone.

6. The method according to any one of claims 2 to 4, characterized in that one carries out the reduction with a complex metal hydride.

7. The method according to claim 2, characterized in that the amide protecting group is removed with an oxidizing agent.

45

wherein R1 represents a hydrogen atom or, as an amide protecting group, a phenyl or benzyl group optionally substituted by one or more methoxy groups. By decetalation of the compound of the general formula III 50 and subsequent reduction or, if appropriate, removal of the protective group which may be present, the new diastereomer pair of the formula I is obtained, which, if desired, can be separated into the optically active components by chromatographic means. 55 The benzhydryl group can be removed from the diastereomers of the formula I by catalytic hydrogenation. This reaction leads to the corresponding azetidinyl acetic acid derivative, which was described in European Patent No. 62 840 together with its conversion into the Thienamy-60.

The invention relates to a process for the preparation of the new diastereomers of the formula I by, from a compound of the general formula III (in which R1 is a hydrogen atom or, as an amide protecting group, a phenyl or benzyl group optionally substituted by one or more methoxy group (s) means) the ethylene ketal group is split off and the new compound of general formula II obtained

3rd

661 269

0 H H

H3C

«L

O

/

■ CHZ-C-

fv y \ °)

° ~ c <^ m ,,

\

°>

in which R1 has the meaning given above, reduced and the product obtained - after removal of the amide protecting group which may be present - isolated and, if desired, the resulting pair of diastereomers separated into the individual components.

In the process according to the invention, compounds of the general formula III are used as starting material.

The new compounds of general formula III are protected in our Hungarian Patent Nos. 184 496 and 185 041, but their method of preparation is also disclosed in the examples of the present patent application.

The ethylene ketal group can be split off from the compounds of the general formula III using an acid. A sulfonic acid (e.g. p-toluenesulfonic acid), a sylyl halide (e.g. a sylyl halide formed from a mixture of sodium iodide and silicon tetrachloride or a mixture of sodium iodide and trimethyl silicon chloride) or a mineral acid (preferably perchloric acid) can be used as the acid. The decetalation can be carried out in a suitable organic solvent, advantageously in a mixture of a ketone (e.g. acetone) or chlorinated hydrocarbon and acetonitrile.

After neutralization of the reaction mixture, the new compound of general formula II thus obtained can, if desired, be isolated.

The new compounds of general formula II and the preparation process thereof are also the subject of the present invention.

The compound of general formula II obtained is reduced. The reduction can preferably be carried out with a complex metal hydride - in particular with an alkali metal [tetrahydridoborate (III)].

If a compound of the general formula III in which R1 is hydrogen is used as the starting material,

the diastereomer pair of formula I is obtained immediately after the reduction.

If a compound of the general formula III is used as the starting material, in which R1 represents an amide protective group, the protective group is removed after the reduction. The protective group can be removed using an oxidizing agent.

The dimethoxybenzyl group can be removed with a peroxydisulfate type oxidizing agent, the methoxyphenyl group using a cerium (IV) salt and an acid together, and the aminophenyl protecting group with a cerium (IV) salt and an acid or with glacial chromium trioxide.

If desired, the resulting pair of diastereomers can be separated into the components. The separation can be carried out particularly advantageously by chromatographic means. Silica gel / silica gel PF254 + 366 / can be used as the adsorbent and a 7: 3 mixture of benzene and acetone as the eluent.

Further details of the method according to the invention can be found in the examples below, without restricting the scope of protection to these examples.

example 1

Benzhydryl- | [2RS, 3 SR] -3 [1 (RS and SR) -hydroxy-ethyl] -4-oxo-2-azetidinyl-acetate)

A mixture of 4.89 g (10.0 millimoles) of benzhydryl-1 [2 5 RS, 3 SRI-1 - (2,4-dimethoxy-benzyl) -3-f 1 (RS and SR) -hydroxyethyl] -4-oxo-2-azetidinyl acetate), 10.81 g (40.0 millimoles) of potassium peroxydisulfate (K2S208), 28.65 g (80.0 millimoles) of disodium biphosphate (Na2HP04 ■ 12 H20), 56. 0 ml of acetonitrile and 21.0 ml of water are heated to boiling for 3 hours with stirring. The reaction mixture is cooled, filtered and the filtrate separated. The aqueous phase of the filtrate is extracted three times with 50 ml of ethyl acetate. The organic phases are combined, washed with a 10% aqueous sodium carbonate solution and a saturated aqueous i5 sodium chloride solution, dried over magnesium sulfate and concentrated. The remaining oil is worked up by column chromatography (adsorbent: silica gel G, eluent:

7: 1 dichloromethane-acetone mixture.

20 1.73 g of the mixture mentioned in the title are obtained, yield 51%.

IR (KBr): 3400, 3250, 1755, 1735 cm- '. 'H NMR (CDC13): 5 1.18-1.32 dd (3H); 2.20-3.00 m (IH + 2H + IH); 3.65-4.28 m (IH + IH); 6.1 s (IH); 6.9 s 25 (IH), 7.30 s (ÎOH).

The starting material can be prepared as follows: a) a suspension of 41.2 g (0.109 mol) of trans-ethyl - [l- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolane) -2-yl) -4-oxo-2-azetidine carboxylate] (this compound corresponds to the general formula VI

f

~ \

OH «

H

35

/

facci

X "

rt

') N,

COOZ

VI

\

R

40

in published Hungarian patent application No. 2263/80; Z = ethyl, R = dimethoxybenzyl) and 50 ml of ethanol, a solution of 5.21 g (0.130 mol) of sodium hydroxide in 60 45 ml of water is added with stirring and external cooling with ice water, after which the mixture is stirred until a clear Solution is created (about 20 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 to a pH of 1 with concentrated hydrochloric acid, and extracted rapidly once with 100 ml and twice with 50 ml dichloromethane. The dichloromethane solutions are dried over magnesium sulfate, filtered and the filtrate is evaporated. The remaining oil is recrystallized from a mixture of toluene and 55 petroleum ether. 35 g of trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylic acid are obtained. Yield 92%.

(This compound corresponds to the general formula VI; Z = hydrogen, R = dimethoxybenzyl). F .: 117-118 C 60 (toluene).

Analysis: for the formula Ci7H2 | N07 (351.35)

calculated: C% = 58.11; H% = 6.03; N% = 3.99; found: C% = 58.17; H% = 6.30; N% = 4.24.

IR (KBr): 3500-2500, 2900, 1760, 1720 cm "1, es' H NMR (CDC13): 5 1.39 (s, 3H), 3.50 (d, 1 H, J = 2, 5 Hz), 3.77 (s, 3H), 3.79 (s, 3H), 3.86 (d, 1H, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4.56 (d, 2H, J = 15 Hz), 6.44 (m, 2H) + 7.15 (d, lH, J = 10Hz), 7.58 (broad, s, 1H).

661 269

b) a solution of 17.6 g (50 millimoles) of the trans -l- (2,4-dimethoxy-benzyl) -3- (2-methyl-l, 3-dioxolan-2-yl) prepared according to Example la) -4-oxo-2-azetidinecarboxylic acid in 150 ml of anhydrous tetrahydrofuran, 7.3 ml (52.5 millimoles) of triethylamine are added, followed by 5.0 ml (52.5 millimoles) of ethyl (chloroformate) with ice-cooling to the mixture. are fed. The reaction mixture is cooled to -15 ° C and stirred at this temperature for 20 minutes. The triethylamine salt formed at this temperature under argon is filtered off. A solution of 150 millimoles of diazomethane in 230 ml of cold diethyl ether is added to the filtrate. The solution is stirred, then allowed to warm to room temperature while standing and evaporated to dryness after 2 hours. The viscous brown mass obtained is dissolved in 20 ml of benzene and purified by column chromatography (adsorbent 150 g of silica gel 60, diameter: 0.063-0.200 mm; eluent: a 7: 2 benzene-acetone mixture). 12.0 g of trans -4- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -2-azetidinone are obtained, yield 64%. (This compound corresponds to the general formula V;

/ J § ^ C0CHNz H3C ^

f

0 ^

y ~ 'ki

V

R = dimethoxybenzyl).

Analysis: based on the formula CiSH2iN306 (375.37).

calculated: 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 millimoles) of the trans- (4-diazoacetyl) -1 - (2,4-dimethoxy-benzyl) -3- (2-methyl-l, 3- dioxolan-2-yl) -2-azetidinones, 100 ml of peroxide-free tetrahydrofuran and 50 ml of water are irradiated in a Pyrex apparatus provided with a submerged lamp under argon using a high-pressure mercury lamp (HPK 125) for about 4 hours. The solution is concentrated to 50 ml under reduced pressure and the residue is diluted to 130 ml with water. 2.4 ml of a 10% sodium hydroxide solution are added to the aqueous solution. The alkaline solution is extracted three times with 20 ml dichloromethane each time and the aqueous phase is acidified to pH 2 with concentrated hydrochloric acid. The acidic solution is extracted three times with 20 ml dichloromethane each time. The extract is dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The residue is crystallized using ether and filtered. 1.82 g of the ftrans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl] - Acetic acid obtained * yield 83%.

This compound corresponds to the general formula IV;

d) A solution of 5.48 g (15 millimoles) of the ftrans-l- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) prepared according to Example lc) -4-oxo-2-azetidinyl] acetic acid in 50 ml dichloromethane are added at room temperature with stirring 3.05 g (15.75 millimoles) of diphenyldiazomethane. After the nitrogen evolution has ceased, the remaining diphenyldiazomethane is decomposed with a few drops of acetic acid. The solution is evaporated to dryness and the residue (6.77 g) isolated.

io e) 5.31 g (10.0 millimoles) of the residue obtained according to Example ld) | Benzhydryl- (2RS, 3SR) -f 1 - (2,4-dimethoxy-benzyl) -3- (2-methyl-1 , 3-dioxolan-2-yl) -4-oxo-2-azetidinyl] acetate j are dissolved in 100 ml of anhydrous acetone and the solution is cooled to 0.degree. After addition of 2.0 ml of 15 (24.0 millimoles) of a 70% aqueous perchloric acid solution, the mixture is stirred for 45 minutes with ice cooling. 2.20 g (26.4 millimoles) of sodium hydrogen bicarbonate are added and the mixture is stirred for a further 10 minutes. The suspension is concentrated under reduced pressure without heating. The residue is dissolved in 60 ml of methanol, after which 0.370 g (10.0 millimoles) of sodium [tetrahydro-borate (III)] are added with stirring and ice-cooling. The implementation takes about an hour. The mixture is acidified to pH 7 with acetic acid and the methanol is removed. The residue is dissolved in 100 ml of dichloromethane and extracted twice with 25 ml of water and with 25 ml of a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and evaporated. hydroxyethyl] -4-oxo-2-azetidinyl-ace-tatj mixture obtained. Yield 61%.

IR (KBr): 3400.1725 cm- '.

35 'H NMR (CDC13), §): 1.06-1.24 dd (3H); 2.20-3.06 m (1H + 1H + 2H); 3.55-3.95 m (3H + 3H + IH + IH); 3.95-4.10 m (2H) 1 6.36-6.50 m (2H); 6.90 s (IH), 7.05-7.40 m (10H + IH).

CH, COOH

R = dimethoxybenzyl). F .: 124 ° C (ether). Analysis: on the formula CI8H23N07 (365.37)

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- '.

40

45

IV

Example 2

Benzhydryl- {(RS, 3 SR) -3- [l- (RS and SR) -hydroxy-ethyl] -4-oxo-2-azetidinyl acetate |

0.381 g (1.0 millimole) of benzhydryl-1 (2 RS, 3 SR H3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl] acetate are in 10 ml The solution is added while cooling with ice 0.2 ml (2.3 millimoles) of a 70% aqueous perchloric acid solution and after 45 minutes 0.20 g (2.4 millimoles) of sodium bicarbonate are added The residue is suspended in 10 ml of anhydrous methanol. 0.038 g (1.0 millimole) of sodium borohydride is added to this suspension with stirring and ice-cooling. The mixture is stirred for 3 hours , cooled and neutralized in the cold with acetic acid and concentrated to dryness The residue is suspended in dichloromethane, shaken with water, the dichloromethane solution is dried over magnesium sulfate and purified chromatographically (adsorbent: silica gel PF 254; eluent: a 7: 1 Dichloromethane-acetone mixture).

0.25 g of the compound mentioned in the title are obtained. Yield 74%. The physical constants of this compound are identical to those of the product obtained according to Example 1.

The starting material can be produced as follows:

A solution of 5.48 g (15 millimoles) of the [trans-l- (2,4-dimethoxybenzyl) -3- (2-methyl-l, 3-dioxolan-2-yl) prepared according to example lc) ) -4-oxo-2-azetidinyl] acetic acid in 50

60

65

5

661 269

ml of dichloromethane are added at room temperature with stirring 3.05 g (15.75 millimoles) of diphenyldiazomethane. After the nitrogen evolution has ceased, the remaining diphenyldiazomethane is decomposed with 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 millimoles) of potassium peroxydisulfate (K2S208), 21.60 g (120 millimoles) of disodium biphosphate monohydrate (Na2HPÒ4 • H20) and 54 ml of water are added to the solution, and the mixture is then stirred for 4 hours with vigorous stirring Boiling is heated and cooled. The cold reaction mixture is filtered and the filtrate is separated into two phases. The aqueous layer is extracted three times with 30 ml 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 worked up by column chromatography. (Adsorbenti Kieselgel 60, diameter 0.050-0.200 mm; eluent: a 7: 2 benzene-acetone mixture).

2.68 g of the benzhydryl-1 (2RS, 3 SR) - [3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2-azetidinyl] -acetate are obtained. F .: 130 ° C (ethanol).

Analysis: on the formula C22H23NO 5 (387.41)

calculated: C% = 69.27; H% = 6.08; N% = 3.67; found: C% = 69.15; H% = 6.20; N% = 3.55.

IR (KBr): 3250, 2900, 1760, 1740 cm- '.

'H NMR (CDCL3): 5 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 (IH), 6.9 s (IH), 7.28 s (ÎOH).

s The product prepared according to Example 1 or 2 can be converted into (2 RS, 3 SR) -3 - [- l (SR) -hydroxyethyl] -4-oxo-2-azet-idinyl-acetic acid as follows (the above compound is described in European Patent No. 62 840 as a thienamycin intermediate): io A mixture of 0.339 g (1.0 millimoles) of benzhydryl- (2 RS, 3 SR) - | 3-fl- (RS and SR) -hydroxyethyl ] -2-azetidi-nyl | acetate, 0.03 g of a 10% palladium / carbon catalyst and 15 ml of anhydrous ethanol are stirred under hydrogen until the hydrogen uptake ceases 15 (about 6 hours). The catalyst is filtered off and the filtrate is concentrated in the cold under reduced pressure. The residue is triturated with ether, decanted and the residue dried.

0.121 g of (2 RS, 3 SR) -3- [l- (SR) -hydroxy-2oethyl] -4-oxo-2-azetidinyl-acetic acid are obtained, yield 70%.

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

'H NMR (CDCL3 + DMSO): 5 1.25 d (3H, J = 6Hz); 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).

C.

Claims (2)

661 269 PATENT CLAIMS 1. Diastereomers of Formula I HiC OH L H H ii G- ■ 0-Cr <f <£> 8. A compound of formula II, wherein R1 has the meaning given in claim 2, as an intermediate in the process according to claim 2. 0 -WH <5) (I):