HU186987B - Process for preparing hydroxy-ethyl-azetidinone derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of a compound of formula (I) by reacting a compound of formula (V) wherein R1 represents a phenyl group or a benzyl group substituted with one or more C1-4alkoxy groups, to form a novel thiol ester of formula (III). in the formula (III), R1 is as defined above, and R is phenyl, and the protecting group R1 of the resulting compound of formula (III) is removed by oxidation and the new compound of formula (II) wherein R is phenyl is reduced, and the product obtained is recovered, or the protecting group R1 of the novel compound of formula (III) is removed by oxidation, the new compound of formula (II) obtained in the formulas (II) and (III) is as defined in the process. is reduced and the product obtained is recovered, or GENERAL novel compound of formula - wherein R is phenyl - is reduced, and the product was recovered. The product is an intermediate of thienamycin and its related compounds. xj_Lch2co-s-r xJ COOH J - R1 xJl iLcochn? . -1-

Description

The present invention relates to a novel process for the preparation of 4- (2-hydroxyethyl) -2-azetidinone of the formula I. The compound is an intermediate of the manufacture of (±) -thienamycin and related compounds.

The compound of formula I and its preparation are described in German Patent Publication No. 2,751,597. This synthesis is extremely uneconomical because the first process step is carried out in less than 10% yield, and several further steps in less than 50% yield.

In our experiments, we have found that the compound of formula I can be prepared from the compounds of formula V in substantially better yields than known. In formula (V), R ^{1 is} phenyl or benzyl substituted with one or more alkoxy groups.

This invention relates to the preparation of compounds of formula (I) in such a way that the _one is a compound of formula (V): - wherein R ¹ are as defined above - is converted to (III) are new thiol esters of the formula - (III) wherein ^R1 is as defined above and R is phenyl - a compound of formula (III) the R ¹ protecting group is removed and the new (II) compound obtained - the (TT) R wherein is phenyl - is reduced, and the product was obtained, or the _two a new (III), the compound of formula protecting group ^R1 is removed to give a new compound (II) of formula - (II) and (III): wherein the substituents are as defined in the _L process, - reducing and recovering the resulting product, or ₃ reducing a new compound of formula (Π) and we get two of them.

The starting compounds are protected by our previous applications (2264/80 and 4012/81), but their preparation is also described in the examples of this application. The compounds of formula (II) and (III) are described first in this application.

According to the process of the invention, a compound of formula (V) is first converted to a thiol ester of formula (III).

The compound of formula (V) is subjected to a Wolff rearrangement known per se, wherein the α-diazo ketone side chain is first reacted with a thiol, preferably thiophenol ester (III), on the ketene side chain under nitrogen loss. develops.

Wolff rearrangement can be induced by catalyst, irradiation with ultraviolet light, thermal exposure, or a combination of the above. Of the possible solutions, irradiation with ultraviolet light has proven to be the most advantageous. The irradiation may be carried out, for example, in a photoreactor, preferably under an inert gas atmosphere, optionally in the presence of an inert organic solvent.

The resulting compound of formula (III) is then cleaved at the R ¹ -dimethoxybenzyl protecting group with an oxidizing agent, preferably a peroxydisulfate such as potassium or sodium peroxide sulfate. The reaction is carried out for about one hour. PH 7 buffer, water and organic solvent.

The compound of formula (II) thus obtained is then reduced. The reduction is carried out with a complex metal hydride, preferably an alkali metal borohydride, in a short chain alkanol. The product obtained is recovered by evaporation and / or extraction.

The procedure is illustrated by the following example:

Example 1

4- (2-Hydroxyethyl) -2-azetidinone

To a solution of phenyl (4-oxo-2-azetidinyl) thiolacetate (0.440 g, 2 mmol) in methanol (5 mL) was added sodium tetrahydroborate (III) (0.080 g, 2 mmol) and the solution was stirred at room temperature. After 2 hours, another portion (0.080 g) of sodium tetrahydroborate (III) Ιοί was added, and after stirring for a total of 4 hours at room temperature, the solution was acidified with acetic acid and evaporated to dryness. The filtrate was worked up by preparative thin layer chromatography (Adsorbent: Kieselgel ΡΓ ₂₅₄ - _3θβ , developing mixture: benzene-acetone 7: 3).

Yield: 0.156 g (68%) of the title compound

Elemental Analysis for C ₅ H ₉ NO ₂ (115.3): Calculated: N, 12.17; Found: N, 11.95.

IR (KBr): 3300, 2900, 1740, 1660 cm ^-1 .

Ή-ΝΜΚ: δ 1.75-1.95 m (2H), 2.25 s (1H, deuterable), 2.63 ddd (1H, J _gem = 14.8 Hz, J _Ti0 = 2.5 Hz, J _{Mon C. O NH} = 1.5 Hz), 3.11 ddd (1H, J _gem = 14.8 Hz, J = 5.0 Hz _vio, J _{Mon 0th 0th} = 2.0Hz _NH ), 3.70-3.90 m (3H), 6.48 s (1H deuterable).

The starting material of the example can be prepared as follows:

Ijl. 109.7 g (0.66 mole) of 2,4-dimethoxybenzaldehyde and 72 ml (0.66 mole) of benzylamine in 660 ml of methanol are stirred for 20 minutes at room temperature (initially as a suspension) and then under external ice-water cooling. Sodium tetrahydroborate (III) (13.2 g, 0.33 mol) was added in small portions.

After completion of the reaction, which was monitored by thin layer chromatography (layer: Kieselgel G, Stahl; developing mixture: benzene-acetone = 9: 1), the mixture was evaporated to dryness in vacuo, water (300 mL) was added and the residue was extracted with 500 mL ether. The aqueous phase was extracted with 2 x 200 mL ether. The combined ethereal phase was dried over magnesium sulfate, filtered and to the ethereal solution was added diethyl bromo malonate (122 mL, 0.66 mol) and triethylamine (93 mL, 0.66 mol). The reaction mixture was stirred for 2-3 days at room temperature. Activated triethylammonium bromide is filtered off and washed with ether. The mother liquor was evaporated and the residue was crystallized from 150 ml of ethanol. 210 g of crude product are obtained, which is recrystallized from 400 ml of ethanol.

Yield: 197 g (72%) of diethyl [(N-benzyl-N-) 2,4-dimethoxybenzyl) amino malonate.

Mp 62-63 ° C (ethanol)

IR (KBr): 1750/1725 cm ^-1 , d.

112. 61.7 g (0.149 mol), m.p. of diethyl [N-benzyl-N- (2,3-dimethoxybenzyl) amino] malonate] prepared in Example 1 in the presence of about 20 g of palladium on charcoal in 500 ml of ethanol at atmospheric pressure.

Hydrogenated at -24 to 186987. The catalyst was filtered off and the filtrate was evaporated.

Yield: 47.1 g (97%) of diethyl [(N- / 2,4-dimethoxybenzyl) amino malonate]; optionally converting it to the acid addition salt with hydrochloric acid.

HCl salt: mp 122-124 ° C (EtOAc).

Elemental analysis for C ₂₄ H _{e e} ClNO (361.82) Calcd: Calculated% C, 53.11; H, 6.69; Cl, 9.80; N, 3.87. Found: C, 52.51; H, 6.77; Cl, 10.30; N, 4.09.

IR (film): 3250, 2900, 2850, 1730, 1720 cm ^-1 .

1 H-NMR (CDCl ₃ ): δ 1.3 (t, 6H); 4.78 (s, 3H); 3.82 (s,

3H); 4.21 (q, 4H); 6.20 (s, 2H); 6.4-6.6 (m, 2H) + + 7.3-7.55 (m, 1H); 7.7 (s, s, 1H).

1/3. 47 g (0.144 mol), m.p. of diethyl [N - [(2,4-dimethoxybenzyl) amino-malonate] prepared in Example 4a in 200 ml of anhydrous benzene with 13.8 ml (19.6 g; 0.173 mol) of chloroacetyl chloride for 3.5 hours. boil over. The benzene is distilled off and the residual oil is distilled off for about 30 minutes. Recrystallize from 100 ml of ethanol.

Yield: 66% diethyl [N- (2,4-dimethoxybenzyl) -N- (chloro-aoethyl) -amino-malonate],

M.p. 83-84 ° C (ethanol).

Anal calcd for _{C] 8} H ₂₄ C1NO ₇ (401.94): Calculated% C, 53.80; H, 6.02; Cl, 8.82; N, 3.49; Found: C, 53.63; H, 6.26; Cl, 8.79; N, 3.56.

IR (KBr): 2920; 1755, 1680 cm ^-1 .

1 H NMR (CDCl 3): δ 1.2 t (6H); 3.72 s (6H); 4.08 q (4H); 4.17 s (2H); 4.56 s (2H); 4.95 s (1 H); 6.2-6.6 m (2H) + 6.95-7.25 m (1 H).

1/4. 35 g (0.087 mol), 1/3. of diethyl [N- (2,4-dimethoxybenzyl) -N- (chloroacetyl) -aminomalonate] prepared in Example 1 with 15.9 ml (11.4 g; 0.114 mol) of triethylamine in 200 ml of anhydrous benzene for 8 hours. boil over. The mixture was partitioned between water (100 ml), dilute hydrochloric acid (100 ml) and water (100 ml) again, the benzene layer was dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 28.4 g (89%) of diethyl [1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate].

Mp: 175-180 ° C (0.1 mm Hg).

Analysis for C _l8 H ₂₃ NO (375.38) Calcd: Calculated% C, 59.17; H, 6.34; N, 3.83; Found: C, 59.24; H, 6.24; N, 3.54.

IR (KBr): 2900, 1760-1720 cm -1 ¹ H-NMR-CDCl 3, δ: 1.15 t (3H); 1.25 t (3H); 3.25 s (2H); 3.7 s (6H); 3.8-4.25 m (4H); 4.50 s (2H); 6.3 m (2H) + 7.0 d (1H).

1/5. 66.2 g (0.18 mol), m.p. of diethyl [1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidinedicarboxylate] prepared in Example 1 in 70 ml of dimethyl sulfoxide was treated with 12.7 g (0.22 mol) of sodium chloride and , In the presence of 5 ml (0.36 mol) of water was stirred for 6 hours in an oil bath at 170-180 ° C. The mixture was poured into saturated aqueous sodium chloride solution (500 mL), extracted with ethyl acetate (5 x 100 mL), and the organic phase was dried over magnesium sulfate, filtered and the ethyl acetate was distilled off from the filtrate.

Yield: 47.6 g (90%) of ethyl [1- (2,4-dimethoxybenzyl) -4-oxo-2-azetidinecarboxylate].

Mp: 170-176 ° C / 0.15 mmHg

Analysis calculated for C ₂₅ H ₂₉ NO ₅ (293.32):% C, 61.42; H, 6.53; N, 4.77;

Found: C, 61.25; H, 6.87; N, 4.58.

IR (film): 2900; 1750-1725 cm ¹ .

1/6. 5.80 g (0.020 mol), 1/5. To a solution of the ethyl [1- (2,4-dimethoxybenzyl) -4-oxo-2-azetidinecarboxylate] prepared in Example 1 a in ethanol (25 mL) was added a solution of sodium hydroxide (0.88 g, 0.022 mol) in water (60 mL). The resulting solution was stirred for 2 hours and then extracted with ether (3 x 20 mL). The aqueous phase was acidified to pH = 10 = 2 with concentrated aqueous hydrochloric acid and extracted with dichloromethane (3 x 20 mL). The combined organic phases are dried over magnesium sulfate, filtered and the filtrate is distilled off with dichloromethane. The residue was triturated with ether and the filtered yellowish-white crystalline material was recrystallized from benzene.

Yield: 4.0 g (75.4%) of 1- (2,4-dimethoxybenzyl) -4-oxo-2-azetidine carboxylic acid.

124-125 ° C.

Elemental analysis for C ₁₃ H ₂₅ NO _S (265.26):

Found: C, 58.86; H, 5.70; N, 5.28;

Found: C, 58.83; H, 5.93; N, 5.49.

IR (KBr): 3500-2300, 1735, 1695 cm ^-1 .

1/7. 13.2 g (50 mmol), 1/6. 1- (2,4-Dimethoxybenzyl) -4-oxo-2-azetidinecarboxylic acid (Example 25) was dissolved in anhydrous tetrahydrofuran (150 mL) and triethylamine (7.3 mL, 52.5 mmol) was added, followed by ice-cooling and stirring. 5.0 mL (52.5 mmol) of ethyl chloroformate was added. The mixture was cooled to -15 ° C, stirred at this temperature for 20 to 30 minutes, and then the resulting triethylamine salt was filtered off at this temperature under argon. To the filtrate was added a solution of 22.5 g (150 mmol) of diazomethane in 230 ml of cold diethyl ether. The solution was stirred, allowed to warm to room temperature and after 35 hours, the mixture was evaporated to dryness. The residue was dissolved in benzene (20 ml) and subjected to column chromatography (Adsorbent: 150 g Kieselgel 60, 0.063-0.2000 mm; eluent: benzene-acetone = 7: 2). The product crystallizes on trituration with ether.

Yield: 10.5 g (73%) of d- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -2-azetidinone.

90-91 ° C.

Analysis ₃ 0 ₄ (289.28) calcd for C ₄ H ₁₅ N: Calculated% C, 58.12; H, 5.23;

Found: 0, 58.24; H, 5.45.

IR (KBr): 2100, 1740, 1625 cm ^-1 .

1/8. 3.0 g (10.4 mmol), 1/7. A solution of 4- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -2-azetidinone prepared in Example 1 and 50 1.3 ml (12.6 mmol) of thiophenol in 300 ml of dichloromethane under argon atmosphere under high pressure mercury vapor lamp (HPK 125) until the starting material is consumed (about 3.5 hours). The solution was evaporated and the residual benzene solution 55 was purified by column chromatography. (Adsorbent: 100 g Kieselgel 60, 0.063-0.2000 mm, eluent: benzene-acetone - 7: 2).

Yield: 3.0 g (78%) of phenyl [1- (2,4-dimethoxybenzyl) -4-oxo-2-azetidinyl] thiolacetate.

Elemental Analysis for: C ₂₀ H ₂₁ NO ₄ S (371.35): Calculated: N, 3.77; Found: N, 4.01.

IR (KBr): 2900, 1760, 1710 cm ^-1 .

I) 9th 2.09 g (5.6 mmol) of Example 18 are obtained. Phenyl [1- (2,4-dimethoxybenzyl) -4-oxo-2-azetidinyl] thiolacetate prepared according to Example 1 in a mixture of 30 ml of acetonitrile and 20 ml of water was treated with 3.05 g (11.2 mmol) of potassium Peroxydisulphate (K ₂ S ₂ O ₈ ) and 4.01 g (22.4 mmol) of disodium hydrogen phosphate dihydrate (Na ₂ HPO ₄ X ₂ H ₂ O) are refluxed for 4 hours. A further 3.05 g of potassium peroxydisulfate and 4.01 g of disodium hydrogen phosphate dihydrate are added and the mixture is refluxed for 2 hours.

After cooling, the inorganic salts are filtered off, the organic phase is separated off, the aqueous phase is extracted with ethyl acetate (2 x 15 ml), the combined organic phases are evaporated and the resulting oil is subjected to column chromatography (adsorbent: Kieselgel 60, 0.063-0.200 mm; = 9: 1 7: 3).

Yield: 0.66 g (53%) of phenyl [(4-oxo-2-azetidinyl) thiolacetate]

IR (KBr): 3230, 2930, 1750, 1710 cm ^-1 .

Claims (3)

1. A process for preparing a compound of formula (I), - wherein ^the i a (Y) a compound of formula - wherein R ¹ is phenyl substituted by one or more C1-4 alkoxy, benzyl, - of formula (III) are new forming thiolester - (III) wherein ^R1 is as defined above and R is phenyl - a compound of formula (III) the R ¹ protecting group eltávolít5 Juk oxidation, followed by (II) of formula new compounds - where R is phenyl means - is reduced, and the product is recovered, or a ₂ (III) are novel compounds of formula ^I R deprotection by oxidation, the new (II) is obtained The compound of formula (11) - in the formulas (II) and (III) - is replaced by the substituents as defined in process ( ₄₎ , and the resulting product is recovered, or _{3 is} a new compound of formula (II) wherein Reduce the phenyl group to R and recover the product. Process ₄ according to claim 1, characterized in that the compound of formula (V) is reacted with thiophenol under conditions of Wolff rearrangement 20. Process ₄ or ₂ according to claim 1, characterized in that the oxidation of the compound of formula (III) is carried out with a peroxydisulfate-type oxidant. 25 4 according to claim 1 in the _"2 or method _3, characterized in that the compound of formula (II) is reduced with a complex metal hydride.