HU212104B - Process for producing 3 beta-/4(s)-aryl-oxazolidine-2-one-3-il/-azetidine-2-one derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of a compound of formula (I): wherein Ar is phenyl, phenyl substituted with C 1-4 alkyl, halogen or C 1-4 alkoxy, or naphthyl, R is phenyl, C 1-4 alkyl substituted, C 1-4 phenyl substituted with alkoxy or phenyl substituted with halo; Y is -CH = CH- or -CH 2 -CH 2 -; and R 'is phenyl, C 1-4 alkyl substituted phenyl, C 1-4 alkoxy substituted phenyl, halo substituted phenyl, furyl or naphthyl. The compounds of formula (1) are intermediates useful in the preparation of 1-carba (ldelta) -3-cefem-4-carboxylic acids. Ar R (0 EN 212 104 B Scope of the description: 12 pages (including 3 sheets))

Description

The present invention relates to a process for the preparation of valuable novel intermediates for the preparation of 1-carba- (1-detia) -3-cephem-4-carboxylic acids and their derivatives. More particularly, the present invention relates to a process for the preparation of 3P- [4 (S) -aryl-oxazolidin-2-one-3-yl] -azetidin-2-one intermediates of formula (I) wherein Ar is phenyl, C 1-4 alkyl, halo; phenyl substituted with C 1 -C 4 alkoxy, or naphthyl, R is phenyl, phenyl substituted with C 1 -C 4 alkyl, phenyl substituted with C 1 -C 4 alkoxy, or phenyl substituted with halo; Y is -CH = CH or -Ch ₂ -Ch ₂ -; and R 'is phenyl, C 1-4 alkyl substituted phenyl, C 1-4 alkoxy substituted phenyl, halo substituted phenyl, furyl or naphthyl. 1-Carba- (1-detia) -3-cephem-4-carboxylic acids, their antibiotic activity and the intermediates used in their preparation are described in detail in U.S. Pat. European Patent Specification.

Preferred are azetidinones wherein, in the formula (1), Ar and R are phenyl or substituted phenyl and R 'is phenyl, substituted phenyl or furyl. Preferred examples of such compounds are 1-0 € ηζί1-3β- [4 (5) -ίεηί1-οχ3ζο1ίόίη-2-οη-3-yl) -4P-styryl azetidin-2-one, 1-benzyl-3P- [4 (S). ) -phenyloxazolidin-2-one-3-yl] - (3-methoxy-styryl) -azetidin-2-one and 1-benzyl-4- [4 (S) -phenyl-oxazolidin-2-one-3-yl] yl) 4β- [2- (2-furyl) -etanil] azetidin-2-one.

The azetidinones of formula (I) are prepared by cycloadditioning the 4 (S) -aryloxazolidin-2-one-3-yl-acetyl halide with imine from benzylamine and 3-arylacrolein. The acid halide is converted in situ with the trialkylamine to the corresponding homochiral ketene. The cycloaddition of ketene and imine provides azetidinone. Alternatively, ketene may be prepared from a mixed anhydride of oxazolidinone acetic acid and trifluoroacetic acid, or phosphoryl chloride or phosphoryl bromide. The cycloaddition reaction is a key reaction of the process of the invention in the preparation of 1-carba- (1-detia) -cephalosporins.

The 4 (S) -aryloxazolidin-2-one-3-ylacetyl halide used in the ring closure is obtained from the laryl glycine of formula (Ia), wherein Ar has the same meaning as in the description of formula (I). The reaction scheme of the process is shown in Figure 1.

In the formulas of Figure 1, "alk" means a C 1-4 alkyl group such as methyl, ethyl, n-propyl and tert-butyl; X is halogen, preferably chlorine or bromine; X 'is chloro, bromo, trifluoroacetoxy or -OP (= O) X ₂ , wherein X is halogen; and Ar has the same definitions as above.

In the preparation of 4-aryloxazolidinone (4a), the L-arylglycine is first converted to the carbamate (2a). The arylglycine is dissolved in an aqueous base using slightly more bases than is required to dissolve it in the form of a salt. The solution is cooled to 0-10 ° C and haloformate is added in several portions with stirring in a non-stoichiometric amount. To redissolve the arylglycine, an additional base is added to the reaction mixture, and additional haloformate is added portionwise with stirring. This is repeated with cooling until the haloformate is already in excess and the carbamate formation is complete. Preferably, the reaction is carried out as quickly as possible. The base is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. 3 N sodium hydroxide is preferred. To recover the L-carbamate derivative (2a), the reaction mixture is acidified and the precipitated carbamate is extracted with a water immiscible solvent such as a chlorinated hydrocarbon such as dichloromethane.

L-carbamate (2a) is reduced with excess borane dimethyl sulfide in tetrahydrofuran at 20-40 ° C to (3a) -alcohol. The borane dimethylsulfide reagent is added to a solution of the carbamate in tetrahydrofuran cooled to 0 ° C, and the reaction mixture is preferably stirred at room temperature for 10-20 hours. Excess borane is quenched by addition of water and the reaction mixture is evaporated to yield product (3a). If necessary, the residue is diluted with water and compound (3a) is extracted with a water immiscible solvent such as methylene chloride. The recovered alcohol (3a) is sufficiently pure to be used directly for ring closure, but may be further purified by recrystallization prior to use.

The L-alcohol (3a) is cyclized in an inert solvent to (S) -4-aryloxazolidin-2-one (4a) with n-butyllithium or an alkali metal alkoxide such as lithium or sodium ethoxide. A preferred base is n-butyllithium, which is generally used in small excess amounts.

The reaction is carried out at 25-65 ° C, preferably 55 ° C, for 2-8 hours. Suitable inert solvents include tetrahydrofuran, 1,2-dimethoxyethane and the like. After the ring closure is complete, acetic acid equivalent to the amount of base used is added to the reaction mixture and concentrated. Oxazolidin-2-one (4a) is extracted from the concentrated solution with a suitable organic solvent, such as methylene chloride, chloroform or tichloroethane.

(S) -4-Aryloxazolidin-2-one (4a) is N-alkylated with haloacetic acid, the ester group is removed and the acid is converted to the acid halide (5a).

Alkylation of compound (4a) with haloacetic acid ester is carried out in dimethylformamide or tetrahydrofuran in the presence of sodium hydride to give the corresponding (S) -4-aryloxazolidin-2-one-3-ylacetic acid ester. In the reaction sequence of Figure 1, the haloacetic acid ester is represented by the formula XCH ₂ -COC-alk where X is chloro or bromo, "alk" is C 1-4 alkyl. The alkyl group is preferably tert-butyl or ethyl. Examples of the haloacetic acid ester include tert-butyl bromoacetate, ethyl bromoacetate, methyl chloroacetate, tert-butylchloroacetate, methylbromoacetate, isopropylbromoacetate and the like. esters. Preferred esters are tert-butyl bromoacetate and ethyl bromoacetate.

HU 212 104 Β

Removal of the ester group of the oxazolidinone acetic ester is accomplished using conventional techniques. For example, the tert-butyl group may be removed by reaction with trifluoroacetic acid, while other lower ester groups, such as ethyl, may be removed by saponification.

The oxazolidinone acetic acid is converted into the acid halide (5a, where X '= halo), preferably acid chloride, or trifluoroacetic acid or phosphoryl halide, into the acid anhydride (X' = OCOCF ₃ and -OP (= O) X ₂ ). The acid halide, in particular the acid chloride, is the preferred ketene source for the next cycloaddition step. Acid chloride is obtained, for example, with oxalyl chloride in an inert solvent such as benzene, toluene or xylene. However, other suitable acid halide-forming reagents may also be used.

The (S) -4-aryloxazolidin-2-one-3-yl-acetyl halide or anhydride is the chiral unit in the functional form by which the β-lactam ring of the azetidinone intermediate of formula (I) can be formed. The acetyl halide (5a) can be reacted with an imine from benzylamine and 3aryl acrolein to give 1-benzyl-3 - [(S) -4-aryloxazolidin2-one-3-yl] - For (2-aryl-vinyl) -azetidinone (Formula 1 wherein Y = -CH = CH-). Small amounts of the isomer of the product of the cycloaddition reaction are also formed. The cycloaddition reaction is illustrated in Figure 2, wherein R, R 'and Ar are as defined in formula (1).

The reaction may be carried out at a temperature of from -78 ° C to 25 ° C in an inert solvent such as methylene chloride, chloroform, toluene, dichloroethane or trichloroethane in the presence of a trialkylamine having from 1 to 4 carbon atoms. The reaction is carried out by adding a solution of imine (6a) to a solution of compound (5a) in an inert solvent, which also contains an excess of the trialkylamine described above. The trialkylamine must be added to the solution of compound (5a) before the imine (6a) is added. The acid derivative (5a) and the amine are mixed in situ at temperatures between -80 ° C and -50 ° C to form ketene in situ. Imine (6a) must then be added to form azetidinone (1). Preferably, the solvent of the imine is the same as the solvent in which it is prepared as follows. Suitable solvents include benzene, toluene and xylene. After the imine is added, the reaction mixture is heated to 0 ° C and maintained at this temperature for 2 to 4 hours. The mixture of the main isomer (1) and the minor isomer can be recovered from the reaction mixture as follows. The reaction mixture is diluted with a water immiscible organic solvent, such as methylene chloride or chloroform, washed with a solution of a weak acid such as tartaric acid or citric acid, and then with a saturated aqueous solution of alkali metal bicarbonate. The dried organic extract is evaporated to dryness. In most cases, the main isomer (1) can be crystallized from the evaporation residue in ethyl acetate / hexane (30% by volume). Alternatively, the major isomer may be separated from the minor isomer by chromatography on silica gel using stepwise or gradient elution. In the step elution with ethyl acetate / methylene chloride, the main isomer (1) usually starts to elute from the mixture containing 20% by volume of ethyl acetate, while the by-product is more polar eluent (about 40-50% by volume of ethyl acetate). The product separated by chromatography (1) can be further purified by recrystallization.

The imine (6a) used in the cycloaddition reaction is prepared by reacting 3aryl acrolein with benzylamine or substituted benzylamine in a suitable solvent. The water resulting from the reaction is removed by dehydration or azeotropic distillation. It is preferable to use slightly more acrolein than the stoichiometric amount. Magnesium sulfate or molecular sieves may be used as the dehydrating agent. Organic solvents include diethyl ether or aromatic hydrocarbons such as benzene or toluene.

Condensation to imine occurs rapidly at 25-65 ° C in the presence of a dehydrating agent or azeotropic removal of water.

For example, 3-aryl acrolein of the formula OCH-CH = CH-R 'wherein R' is phenyl, alkylphenyl, wherein alkyl is

C 1 -C 4 alkoxyphenyl, wherein the alkoxy group is C 1 -C 4 halogenated phenyl, furyl, or maubiphenyl.

Examples of such aldehydes include cinnamaldehyde, 4-methylcinnamaldehyde, 3-ethylcinnamaldehyde, 4-ethoxycinnamaldehyde, 3-methoxycinnamaldehyde, 3-bromocinnamaldehyde, 2- (2-furyl) acrolein,

2- (2-naphthyl) acrolein and the like.

Examples of benzylamine for imine formation include benzylamines unsubstituted, C 1-4 alkyl, C 1-4 alkoxy, or halo, such as 4-methylbenzylamine, 3-chlorobenzylamine. , 3,4-dichlorobenzylamine, 4-methoxybenzylamine, 2-bromobenzylamine, 3-ethylbenzylamine, 3,4-dimethylbenzylamine, 2,4-dimethylbenzylamine , 4-chloro-3-methylbenzylamine, 4-isopropylbenzylamine, 4-tert-butylbenzylamine, and the like.

The imine (6a) can be used in the cycloaddition reaction without prior separation. The reaction mixture in which the imine was prepared can be used directly in the preparation of compound (1) for the cycloaddition reaction.

The azetidinone of formula (I), wherein Y is -CH = CH- and R 'is m-alkoxyphenyl, is a valuable intermediate in the asymmetric production process of 1-carbacephalosporins of this invention. The process is particularly suitable for the preparation of 1-carba-3-hydroxy-4-carboxylic acid esters.

According to the process, (S) -4-aryloxazolidin-2-one-3-ylacetyl halide (5a) is reacted with imine (6a) from a benzylamine and an m-alkoxycinnamaldehyde in the above-mentioned cycloaddition reaction. produced. The reaction results in the azetidinone of formula (1) wherein Y is -CH = CH- and R 'is - m-alkoxyphenyl, wherein the alkoxy is 1-4 carbon atoms. Azetidinone (1) is the corresponding 4β- [2- (τη-3 ^ οχί-ίεηίΙ) -εύ1] ^ 6ύύίηοηηύ hid3

The reaction mixture is hydrogenated and reduced with lithium in ammonia in the presence of tert-butyl alcohol. The reduction reduces the phenyl ring, cleaves the chiral auxiliary and 1-benzyl to give 3β-3-hydroxy-4β [2- (5-alkoxy-cyclohexa-1,4-dienyl) -ethyl] -azetidinone. The 3-amino group of the azetidinone is protected with one of the commonly used amino groups and this protected 3-amino azetidinone is subjected to ozonolysis with 5- [3β- (νέύεΚ amino) azetidin-2-one esterified with C 1-4 alkyl group. 4β-yl] -3-oxopentanoic acid.

The β-keto ester product of ozonolysis is converted to the α-diazo derivative and the diazo derivative can be cyclized with rhodium (II) to the corresponding 3-hydroxy-1-carbacephalosporin ester.

The following are examples to illustrate what has been said. The examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

Example 1

Preparation of (S) -4-phenyloxazolidin-2-one:

To a solution of 25.3 g (167.4 mmol) of L-phenylglycine in 60 ml of 3N aqueous sodium hydroxide solution is added 8 ml of ethyl chloroformate in portions, with stirring. To dissolve the condensed phenylglycine, an additional 35 mL of 3N aqueous sodium hydroxide solution was added, followed by the addition of 4 mL of ethyl chloroformate. This was repeated with 65 mL of 3N aqueous sodium hydroxide solution and 8 mL of ethyl chloroformate (20 mL total, 209 mmol). Within 10 minutes. After stirring for 1 hour at 0 ° C, the solution was acidified with 6 M sulfuric acid and the precipitated carbamate was extracted with 2 x 300 ml of dichloromethane containing 8% isopropanol. The combined organic extracts were dried over sodium sulfate and evaporated to give 37.3 g of N-ethoxycarbonyl-L-phenylglycine as a white solid. The carbamate was dissolved in 170 mL of tetrahydrofuran, cooled to 0 ° C, and 33.5 mL of 10M borane dimethylsulfide solution was added and stirred at room temperature for 17 hours. The excess borane was quenched by careful addition of 100 mL of water and the bulk of tetrahydrofuran was evaporated under reduced pressure. The white paste was diluted with 350 mL of water and extracted with dichloromethane (2 x 500 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (100 mL), dried over sodium sulfate and evaporated to give (S) -2-ethoxycarbonylamino-2-phenylethanol (27.4 g) as a white solid. The crude alcohol was dissolved in 200 ml of tetrahydrofuran, cooled to 0 ° C, and 6 ml of a 2 M solution of n-butyllithium in hexane was added. After 6 hours at 55 ° C, 1 ml of acetic acid was added and evaporated. The residue was dissolved in dichloromethane (300 mL), washed with brine (100 mL), dried over sodium sulfate and evaporated to a white solid. Recrystallization from toluene gave (S) -4-phenyloxazolidin-2-one (17.14 g, 63%).

Mp .: 132-133 'C.

[α] D = + 49.5 ° (c = 2.1, CHCl 3).

IR (CHCl3): 3460, 3020, 1760, 1500, 1480, 1460,

1400, Í230cm- '.

1 H-NMR, δ: 7.45-7.30 (m, 5H, ArH), 6.42 (bs,

1H, NH), 4.96 (br t, 1H, J = 7.8 Hz, _OCH2 CH);

4.72 (t, 1H, J = 8.6 Hz, one of OCH ₂ ), 4.17 (dd,

1H, J = 6.7 Hz, 8.7 Hz, one of the OCH ₂ CH).

Analysis calculated for C ₉ H ₉ NO ₂ : C, 66.24; H, 5.56%;

Found: C, 66.16%; H, 5.62%.

Example 2

Preparation of (S) -4-phenyloxazolidin-2-one-3-yl-acetic acid:

To a solution of (S) -4-phenyloxazolidin-2-one (1.07 g, 6.54 mmol) in tetrahydrofuran (15 mL) was added a solution of sodium hydride (60% in oil, 0.32 g, 60%) with stirring. 8.0 mmol). When gas evolution is approx. After 10 minutes, 0.87 mL (7.8 mmol) of ethyl bromoacetate was added to the reaction mixture. After stirring for 2 hours at 0 ° C, 50 ml of 2N aqueous sodium hydroxide solution were added, stirred vigorously at room temperature for 1 hour, and the reaction mixture was partitioned between 50 ml of hexane and 50 ml of water. The aqueous phase was separated, acidified with 6M aqueous sulfuric acid and extracted with dichloromethane (2 x 200 mL). The combined organic extracts were dried over sodium sulfate and evaporated to a thick oil which was dissolved in 4 mL of warm toluene, seeded with crystals and allowed to crystallize overnight. Filtration gave (S) -4-phenyloxazolidin-2-one-3-yl-acetic acid (1.33 g, 92%).

Mp .: 106-108 'C.

[?] g = + 173 '(c = 2.0, CHCl 3).

IR (CHC1 _3): 3500-2500 (very broad), 1760 (broad),

1480, 1460, 1430, 1230 cm ^-1 .

1 H-NMR, δ: 11.2 (bs, 1H, COOH), 7.47-7.25 (m,

5H, ArH), 5.05 (t, 1H, J = 8.4 Hz, OCH ₂ CH), 4.72 (t, 1H, J = 8.8 Hz, one of OCH ₂ CH), 4.32 (d,

1H, J = 18.4 Hz, one of _NCH2), 4.17 (t, lH, J =

8.4 Hz, one of _OCH2 CH), 3.41 (d, 1H, J = 18.4

Hz, one of NCH ₂ ).

Analysis calculated for the C _{11 H] 1} NO ₄ Calculated: C, 59.72%; H, 5.01%;

Found: C, 59.83%; H, 5.00%.

Example 3

Preparation of (S) -4-phenyloxazolidin-2-one-3-yl-acetyl chloride:

A 250 mL round bottom flask equipped with a reflux condenser and a calcium sulfate drying tube was charged with 5.3 g (23.96 mmol) of (S) -4-phenyloxazolidin-2-one-3-ylacetic acid and 60 mL of toluene. To the suspension was added 3.2 mL (36.7 mmol) of oxalic chloride and stirred at 60 ° C for 3 hours. By this time gas evolution ceased and the reaction mixture was homogeneous. Removal of the solvent under reduced pressure gave the desired acid chloride as a thick oil.

Example 4

Preparation of imine from benzylamine and 3-methoxycinnamaldehyde:

To a solution of 3-methoxycinnamaldehyde (4.27 g, 26.33 mmol) in toluene (40 mL) was added benzylamine (2.73 mL, 25.9 mmol). The solution was briefly 40 ° C

The mixture is heated to a temperature of B and becomes turbid from the precipitated water during cooling. Argon-purged 18 g of freshly activated 4 A molecular sieve is added to the reaction mixture and allowed to stand at room temperature for 16 hours. The imine solution is used directly for the subsequent cyclization step.

Example 5

Preparation of] benzyl-3 - [(S) -4-phenyloxazolidin-2-one-3-yl] 4β- (3-methoxystyryl) azetidin-2-one:

Oxalidinone acid chloride was dissolved in dichloromethane (70 mL), cooled to -78 ° C, and triethylamine (5.0 mL, 35.9 mmol) was added. A fine sediment will form over the next 15 minutes. A toluene solution of the above-prepared imine is added via cannula to the reaction mixture. The screen filtered from the imine solution was washed with dichloromethane (2 x 10 mL) and the washings were added to the reaction mixture. The cooling bath was removed and the mixture was allowed to warm to 0 ° C and maintained at this temperature for 2 hours. The reaction mixture was poured into 200 ml of dichloromethane, washed with 50 ml of 0.5 M tartaric acid solution and 50 ml of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated to a reddish oily residue. Crystallization from about 150 ml of 30% hexane in ethyl acetate gave 6.87 g of the desired compound as white needle crystals. The mother liquor was chromatographed on 170 g of silica gel with 20% ethyl acetate in dichloromethane to give an additional 1.9 g of azetidinone (8.77 g, 80% total). Further elution with 40% ethyl acetate in dichloromethane gives the minor isomer which is further purified by chromatography on silica gel using 30% hexane in ethyl acetate as eluent.

Details of the main isomer:

M.p. 142-143 ° C.

[α] D = + 46.4 ° (c = 1.0, CHCl 3).

IR (CHCl 3): 3020, 1760, 1600, 1410 cm ^-1 .

1 H-NMR, δ: 7.45-6.75 (m, 14H, ArH), 6.45 (d, 1H, J =

Hz, ArCH = CH), 5.81 (dd, 1H, J = 16 Hz, 8.9 Hz,

ArCH = CH), 4.88 (dd, 1H, J = 8.9 and 7.4 Hz,

OCH ₂ CH), 4.61 (t, 1H, J = 8.9 Hz, one of OCH ₂ CH), 4.55 (d, 1H, J = 25 Hz, C-3 H), 4.53 ( d, 1H, J = 14.7 Hz, one of ArCH ₂ ), 4.23-4.12 (m, 3H, one of ArCH _2, one of OCH ₂ CH and C-4 H), 3.82 (s, 3H, OCH,).

Analysis calculated for C ₂₈ H ₂₆ N ₂ O ₄ : C, 73.99; H, 5.77;

Found: C, 74.06%; H, 5.74%.

Example 6

From the imine from benzylamine and cinnamaldehyde and 4 (S) -phenyloxazolidin-2-one-3-yl-acetyl chloride as in Example 5, 1-benzyl-3β- [4 (S) -phenyloxazolidine 2-one-3-yl] -4β-styryl-azetidin-2-one is prepared.

M.p. 186.5-187.5 ° C.

[α] D = + 56.9 ° (c = 1.7, CHCl ₃ ).

IR (CHCl 3): 3010, 1760, 1500, 1460, 1410 cm ^-1 . 1 H-NMR, δ: 7.45-7.10 (m, 15H, ArH), 6.48 (d, 1H, J =

Hz, CH = CH-Ar), 5.87 (dd, 1H, J = 9 and 16 Hz,

CH = CH-Ar), 4.88 (dd, 1H, J = 7.4 and 8.9 Hz,

OCH ₂ CH), 4.61 (t, 1H, J = 28.9 Hz, one of OCH ₂ CH), 4.55 (d, 1H, J = 16 Hz, one of ArCH ₂ ),

4.54 (d, 1H, J = 24.7 Hz, C-3 H, overlapping 4.55), 4.21 (dd, 1H, J = 24.7 and 9.0 Hz, C-4 H) , 4.17 (dd, J = 7.4 and 8.9 Hz, one of OCH ₂ CH), 4.14 (dd, J = 16 Hz, one of ArCH ₂ ). Elemental analysis according to the formula C ₂₇ H ₂₄ N ₂ O ₃ :

Calculated: C, 76.39; H, 5.70%;

Found: C, 76.53%; H, 5.69%.

Example 7

According to the procedure of Example 5, the imine prepared from benzylamine and 3- (2-furyl) acrolein and 4 (S) -phenyloxazolidin-2-one-3-ylacetyl chloride are condensed with 1-benzyl-3β- [4 ( S) -phenyl-oxazolidin-2-on-3-yl] -4- [i- [2- (2-furyl) ethenyl] azetidine-2-one.

M.p .: 181-182'C.

[α] D = + 13.6 ° (c = 1.6, CHCl ₃ ).

IR (CHCl 3): 3020, 1760, 166, 1500, 1460, 1410 cm -1. 1 H-NMR, δ: 7.45-7.07 (m, UH, ArH), 6.39 (dd, 1H, J = 1.8 and 3.3 Hz, OCH = CH), 6.27 (d , 1H, J = 16 Hz,

N-CH-CH = CH), 6.25 (d, 1H, J = 3.3 Hz, OC = CH), 5.75 (dd, 1H, J = 16 and 8.9 Hz, N-CHCH = CH), 4.91 (dd, 1H, J = 8.8 and 7.4 Hz,

OCH ₂ CH), 4.65 (t, 1H, J = 8.9 Hz, one of OCH ₂ CH), 4.61 (d, 1H, J = 15 Hz, one of ArCH ₂ ),

4.55 (d, 1H, J = 4.8 Hz, C-3H), 4.20 (dd, 1H, J =

7.4 and 8.8 Hz, one of _OCH2 CH), 4.11 (dd, J =

4.8 and 8.9 Hz, C-4 H), 4.02 (d, J = 15 Hz, one of ArCH ₂ ).

Analysis for C ₂₅ H ₂₂ N ₂ O _4: Calcd; C: 72.44%; H: 5.35%;

Found: C, 72.44%; H, 5.41%.

Example 8

Preparation of 1-benzyl-3 - [(S) -4-phenyloxazolidin-2-one-3-yl] -4β- [2- (3-methoxyphenyl) ethyl] azetidin-2-one: 0.552 g (1.22 mmol) of the 3-methoxy-styryl-substituted azetidinone prepared in Example 5 is hydrogenated in 20 mL of dichloromethane at room temperature under balloon pressure over 0.052 g of 5% Pd / carbon for 3 hours. The reaction mixture was filtered through celite and the solvent removed under reduced pressure to give the title compound 43- [2- (3-methoxyphenyl) ethyl] azetidinone (compound 8) as a white solid (0.555 g, 100%). Recrystallization from hexane / ethyl acetate gave long needle crystals.

134-135 ° C.

[α] D = + 38.6 ° (c = 2.2, CHCl 3).

IR (CHCl?): 3010, 1755, 1605, 1590, 1410 cm ^- '. 1 H-NMR, δ: 7.44-6.42 (m, 14H, ArH), 4.97-4.78 (broad t, 1H, OCH ₂ CH), 4.68 (t, 1H, J = 9 Hz, one of _OCH2), 4.64-4.59 (br d, lH, C-3 H), 4.32 (s, 2H, _ArCH2), 4.77 (dd, IH, J = 6 , 4 and 9.0 Hz, one of OCH ₂ ), 3.77 (s, 3H, OCH ₃ ), 3.57 (dt, 1H, J = 6.6 and 4.9 Hz, C-4 H) 2.36 (br t, 1H, J = 8 Hz, _{ArCH2 CH2),} 1.56-1.44 (br q, IH, _{ArCH2 CH2).}

HU 212 104 B

Example 9

Preparation of methyl 5- [3β- (tert-butyloxycarbonylamino) azetidin-2-on-4-yl] -3-oxopentanoate:

Lithium wire (0.548 g, 79 mmol) was added to 55 mL of ammonia at -78 ° C and the mixture was briefly heated to melt the metal and then cooled to -78 ° C under positive argon pressure. To the dark blue solution, first 12 ml of tert-butanol, followed by cannulation over 24 minutes with 24 ml of tetrahydrofuran / tert-butanol 3: 1 in 2.36 g (5.17 mmol) of 1-benzyl-3p - [(S 4-Phenyloxazolidin-2-one-3-yl] -4- [2- (3-methoxyphenyl) ethyl] azetidin-2-one is added. After stirring for exactly 30 minutes, 2 ml of dry benzene are added to the solution. After about 1 minute the blue color disappears. Ammonium acetate (6.08 g, 79 mmol) was added to the reaction mixture, the cooling bath was removed and most of the ammonia was distilled through a mercury bubbler. The solvent and the residual ammonia were removed under reduced pressure at 40 ° C. The remaining white solid was suspended in 50 mL of 1: 1 tetrahydrofuran / water, adjusted to pH 8 with 3N hydrochloric acid, and di-tert-butyl dicarbonate (1.8 mL, 7.8 mmol) was added. The biphasic mixture was stirred vigorously for 12 hours and then partitioned between dichloromethane (200 mL) and water (50 mL). The aqueous phase is extracted with another 50 ml of dichloromethane and the combined organic phases are washed with 50 ml of a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel (110 g) with ethyl acetate (40% hexane). 1.23 g of partially purified dihydroaromatic 3β-tert-butyloxycarbonylamino-4β- [2- (5-methoxycyclohex-1,4-diene) ethyl] azetidin-2-one are obtained in the form of a waxy material. form.

The diene product was dissolved in 25 mL of methanol / dichloromethane 1: 1, a drop of pyridine and ca. 1 mg Sudan III dye (Aldrich Chemical Co.) and ozonize at -78 ° C until the red color disappears. Dimethyl sulfide (3 mL) was added, the cooling bath removed and stirred at room temperature for 5 hours. The pale orange solution was poured into brine (100 mL) and extracted with dichloromethane (200 mL, then 50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was chromatographed on 65 g of silica gel with 7% isopropanol in dichloromethane to give 0.97 g (60% of 8) of methyl 5- [3 P- (tert-butyloxycarbonylamino) azetidin-2]. -on-4P-yl] -3-oxopentanoate as an off-white solid. Recrystallization from toluene gave colorless needle crystals.

122-123 'C.

[a] § = +48.6 (c = 1.4, _CHCl3).

IR (CHCl ₃ ): 3430, 3420, 3340 (broad), 3020, 2990,

1770, 1720, 1510, 1370, 1250, 1160 cm -1.

1 H-NMR, δ: 6.51 (bs, 1H, NH of β-lactam), 5.50 (bd, 1H, butyloxycarbonyl-NH), 5.05-4.98 (m , 1H, C-3H), 3.83-3.71 (m, 1H, C-4H), (s, 3H,

OCH ₃ ), 3.48 (s, 2H, COCH ₂ CO), 2.74-2.56 (m,

2H, CH ₂ CH ₂ CO), 1.93-1.74 (m, 2H, CH ₂ CH ₂ CO),

1.45 (s, 9H, tert-butyl).

Analysis for C ₁₄ H ₂₂ N ₂ O ₆ based O: Calculated: C, 53.49%; H, 7.06%;

Found: C, 53.56%; H, 7.11%.

The 3-tert-butyloxycarbonylamino-azetidinyl-β-keto ester prepared as described above is then converted to the 3-hydroxy-1-carba (indetia) -3-cephem ester according to the procedure described in Example 10. .

Example 10 (Reference)

1-Benzyl-7β- (tert-butyloxycarbonylamino) -3-hydroxy-1-carba (1-detia) -3-cephem-4-carboxylate is prepared by the following reaction step:

A) Diazo Transfer: To a solution of β-keto ester (1.13 g, 3.6 mmol) in acetonitrile (10 mL) cooled to 0 ° C was added 3.6 mL of a 1.5 M solution of p-toluenesulfonyl azide in dichloromethane and 0.13 mL (0.75 mmol) of diisopropylethylamine. The reaction mixture was covered with foil, stirred at room temperature for 2 hours, then partitioned between 100 mL of dichloromethane and 50 mL of brine containing 10 mL of 0.5 M tartaric acid. The aqueous phase was re-extracted with dichloromethane (50 mL), and the combined organic layers were dried over sodium sulfate and evaporated. The residue was chromatographed on 100 mg of silica gel with 5% isopropanol in dichloromethane to give 1.15 g (94%) of the diazoketo ester as a white solid. Recrystallization from ethyl acetate / hexane gave small needle crystals.

136-137 'C (dec.).

[?] g = +65.8 '(c = 0.6, CHCl3).

IR (CHCl ₃ ): 3440, 3420, 3360 (broad), 3020, 2990,

2150, 1770, 1720, 1650, 1510, 1440, 1370, 1320,

1160 cm ^-1 .

1 H-NMR, δ: 6.49 (broad s, 1H, NH of β-lactam), 5.46 (d, 1H, J = 8.6, benzyloxycarbonyl-NH), 5.06 (dd,

1H, J = 4.8 Hz and 8.1 Hz, C-3 H), 3.85 (s, 3H,

OCH ₃ ), 3.85-3.78 (m, 1H, C-4H), 3.06-2.82 (m,

2H, CH ₂ CH ₂ CO), 2.0-1.75 (m, 2H, CH ₂ CH ₂ CO),

1.45 (s, 9H, tert-butyl).

Analysis calculated for C ₁₄ H ₂₀ N ₄ O ₆ : C, 49.40; H: 5.92%;

Found: C, 49.47; H, 5.93%.

B) Transesterification: A mixture of 20 mL (193 mmol) benzyl alcohol and 0.78 mL (2.62 mmol) titanium isopropoxide was stirred at 1 mm Hg for 45 min to remove isopropanol. The vessel was covered with foil, rinsed with argon, and diazo-β-ketomethyl ester (0.953 g) was added. The solution was maintained at 36 ° C for 42 hours, diluted with diethyl ether (60 mL), and saturated aqueous sodium sulfate (3 mL) was added. The mixture was stirred vigorously overnight and then filtered through a pad of celite. After removal of the ether in a rotary evaporator, the benzyl alcohol is distilled off in a "kugelrohr" oven at a pressure of 15 millitorr and 50 ° C. The residue was chromatographed on 100 g of silica gel to give 0.837 g (72%) of the diazo-P-keto-benzyl ester as a white solid.

152-153 ° C (dec.).

[?] g = +55.6 '(c = 0.7, CHCl3).

HU 212 104 B

IR (CHC1 _3): 3450, 3420, 3350 (broad), 3020, 2990, 2150, 1770, 1715, 1655, 1510, 1370, 1305, 1165 cm ^- '.

1 H-NMR, δ: 7.45-7.3 (m, 5H, ArH), 6.4 (bs, 1H, NH of β-lactam), 5.40 (d, 1H, J = 4 5 Hz, 8.5 Hz, C-3 H), 3.79 (dt, J = 4.5 and 8.5 Hz, C-4 H), 3,052,82 (m, 2H, CH ₂ CH ₂ CO), 2.0-1.73 (m, 2H, CH ₂ CH ₂ CO), 1.45 (s, 9H, tert-butyl).

Elemental analysis according to the formula C ₂₀ H ₂₄ N ₄ O ₆ :

Calculated: C, 57.68; H: 5.81%;

Found: C, 57.57%; H, 5.74%.

C) Ring closure: A solution of 0.12 g (0.29 mmol) of diazo-ketobenzyl ester in 6 mL of chloroform filtered through alumina was refluxed and 1.5 mg (0.0034 mmol) of rhodium (II) was added. -acetate with a dimer. After heating for 20 minutes, benzyl 73- (tert-butyloxycarbonylamino) -3-hydroxy-1-carba (1-dethia) -3-cephem-4-carboxylate is obtained.

Example 11

Preparation of 1-benzyl-3- [4- (4) S-phenyloxazolidin-2-one-3-yl] -4-hydroxymethyl azetidin-2-one:

3.0 g (7.06 mmol) of 1-benzyl-33- [4 (S) -phenyloxazolidin-2-one-3-yl] -4-styryl-azetidin-2-one in 80 ml of methanol / dichloromethane , 1: 1, containing 2 drops of pyridine and a few milligrams of Sudan III dye (Aldrich Chemical Co.), was reacted with oxygen-mixed ozone at -78 ° C. When the red color of the dye disappears, the ozone supply is discontinued and 8 ml of dimethylsulfide are added. The solution was stirred for 3 hours at room temperature and then concentrated under reduced pressure. The oily residue was dissolved in ethanol (35 mL), cooled to 0 ° C, and treated with sodium borohydride (0.40 g, 10.6 mmol). After 15 minutes, a precipitate formed. Water (35 mL) was added and the mixture was stirred for an additional 30 minutes at room temperature. Most of the ethanol was evaporated under reduced pressure and the resulting slurry was partitioned between dichloromethane (200 mL) and water (200 mL). The organic layer was dried over sodium sulfate and evaporated to a white solid. This was recrystallized from ethyl acetate / dichloromethane (first generation, 1.887 g) and ethyl acetate / hexane (second generation, 0.501 g) to give 2,388 g (96%) of 1-benzyl- [4 (S) -phenyloxazolidin-2]. on-3-yl] -4-hydroxymethyl azetidin-2-one is obtained in the form of white needle crystals.

M.p. 159.5-160.0 'C.

[α] D = + 109.1 '(c = 2.2, CHCl ₃ ).

IR (CHC1 _3): 3450 (br), 3010, 1760, 1500, 1480, 1460, 1410 ^cm-1 'H-NMR, δ: 7.50-7.00 (m, 10H, Ar-H), 5.09 (dd, 1H, J = 6.5 and 9.1 Hz, ArCHCH _2), 4.74 (t, 1H, J = 9.0 Hz, one of the _two ArCHCH). 4.49 (d, 1H, J = 4.7 Hz, C-3 H), 4.32-4.26 (m, 3H, AB, _ArCH2 N and one of ArCHCH _2), 3.71 (dt , 1H, J = 5.0 and 7.2 Hz, C-4 H), 3.56 to 3.34 (m, 2H, _CH2 CO), 2.32 (dd, 1H, J = 5.1 and

6.5 Hz, OH).

Example 12

To prepare 3β-0εηζί1-οχί ^ 3Η> οηί1-3πΰηο-4β-1ιί0Γθχί-ΐϊΐεύ1-azetidin-2-one, 849 tetrahydrofuran / butanol (7: 1) was dissolved in 0.497 g (1.41 mmol) of 4β-ΗΗΓ with heating. And a solution of 0.087 g (12.6 mmol) of lithium in 23 ml of anhydrous ammonia at -78 ° C is added over 2 minutes. After stirring for a further 2 minutes, the excess lithium was removed by addition of 2 ml of benzene containing 50% tert-butanol. Powdered ammonium chloride (0.68 g, 12.7 mmol) was added to the reaction mixture and the ammonia was distilled off. The solvent and residual ammonia were removed under reduced pressure. The residue was dissolved in 15 ml of water, briefly acidified to pH = 3 with 1N aqueous sodium hydrogen sulfate, and then adjusted to pH = 8 with aqueous sodium hydroxide. Benzyl chloroformate (0.42 mL, 3.0 mmol) was added to the reaction mixture, stirred at room temperature with the addition of aqueous sodium hydroxide solution maintaining the pH at 8. After 3 hours, the excess benzene chloroformate was quenched by the addition of aqueous ammonia and extracted with dichloromethane (150 mL, 50 mL). The organic layer was dried over sodium sulfate and evaporated. Chromatography on silica gel (35 g) with dichloromethane (12%) gave the residue as a solid (0.219 g, 62%). Recrystallization from hexane / ethyl acetate gave an analytical sample.

Mp 128.5-129.5 'C.

[a] D = + 7, l '(c = 0, _CHCl3).

IR (CHCl ₃ ): 3400 (very broad), 3010, 2950, 1765,

1720, 1520, 1320, 1230, 1050 cm -1.

1 H-NMR, δ: 7.33 (s, 5H, ArH), 6.94 (s, 1H,?

NH), 6.32 (d, 1H, J = 10 Hz, NH at C-3), 5.14 (dd, 1H, J = 4.9 and 10.0 Hz, C-3 H). ), 5.07 (s, 2H,

ArCH ₂ ), 3.85-3.55 (m, 4H, C-4H, CH ₂ OH).

Example 13

To obtain 1-benzyl-4- [4 (S) -phenyloxazolidin-2-one-3-yl] 4β- [2- (2-Πιπ1) -εΐί1] -3ζεύ0ίη-2-οη (5 g) was dissolved in methylene chloride (10 ml) and hydrogenated for one hour at room temperature and pressure (3.5 psi) in the presence of 0.05 g of 5% palladium on carbon catalyst. The reduction mixtures were filtered off and the clear filtrate was evaporated to give the desired compound as a white solid.

Example 14

To make 3β-ΐεΓο-0υύΙ-οχί ^ 3τόοηϊ1 ^ πιίηο-4β- [2- (2-Οτπ1) ethyl] azetidin-2-one, a 500 mL 5-neck round bottom flask with nitrogen inlet, stirrer, thermometer and dryer was used. The apparatus was cooled to -70 ° C with nitrogen gas in an acetone / dry ice cooling bath. The ammonia injection is started, the nitrogen flow is interrupted, and ca. Collect 200 ml of ammonia in the vessel. The crushed lithium wire (1.66 g, 240 mmol) was washed with benzene and diethyl ether under argon and then added to the ammonia.

HU 212 104 Β

A solution of 10 g (24 mmol) of 1-benzyl-3β- [4 (S) -phenyloxazolidin-2-one-3-yl] -4β- [2- (2-furyl) dropwise is added dropwise to a blue ammonia solution of lithium over 4.5 minutes. ) -ethyl] azetidin-2-one in 80 ml of tetrahydrofuran containing 3.85 ml (72 mmol) of tert-butyl alcohol. The temperature of the reaction mixture was allowed to rise to -46 ° C and stirred for 3 minutes. The reaction was quenched by addition of 18.9 mL of 1,2-dichloroethane and 3.14 mL of acetic acid. After raising the temperature of the reaction mixture to room temperature, the ammonia was evaporated and the tetrahydrofuran was distilled off. By adding another tetrahydrofuran, any residual ammonia was distilled off. To the residue was added aqueous tetrahydrofuran followed by di-tert-butyl dicarbonate (11.58 mL, 4.8 mmol) and the reaction mixture was stirred overnight at room temperature.

The biphasic reaction mixture was extracted with methylene chloride, and the extract was dried and evaporated to dryness. The residue was stirred with diethyl ether and the white solid was filtered off to give 1.7 g of 3β-tert-butyloxycarbonylamino-4β- [2- (2-furyl) ethyl] azetidin-2-one. The mother liquor is mixed with ether to give an additional 900 mg of the desired product.

Example 75

4; Preparation of 1-tert-butyloxycarbonylmethyl-3-tert-butyloxycarbonylamino-4 - [2- (2-furyl) ethyl] azetidin-2-one:

3P-tert-Butyloxycarbonylamino-4P- [2- (2-furyl) ethyl] azetidin-2-one (1.2 g, 4.3 mmol) was dissolved in dimethylformamide (15 mL) and stirred for 1 hour. , 94 ml of Triton B are added dropwise. The reaction mixture was stirred for 15 minutes at -30 ° C, warmed to 0 ° C for 15 minutes and then cooled to -30 ° C. Dissolved in 3 ml of dimethylformamide, t-butyl bromoacetate was added dropwise to the reaction mixture and stirred at -30 ° C for 15 minutes, 0 ° C for 1 hour and then at room temperature for 2 hours. Cold water was added to the mixture and the precipitate was filtered off. The precipitate was washed with water and dried under reduced pressure to give 1.2 g (71%) of the title compound as a white solid, m.p.

Example 16

Preparation of 1-tert-butyloxycarbonylmethyl-3-tert-butyloxycarbonylamino-4 H- (2-carboxyethyl) azetidin-2-one:

A 100 ml round bottom flask is equipped with a magnetic stirrer, nitrogen and ozone inlet, a sodium hydrogen sulfite scrubber and a thermometer. Dissolve 1.0 g of 1-tert-butyloxycarbonylmethyl-3β-:: υΐί1-οχί ^ 3Λ> οηί1-3Πΐϊηο-4β in 30 ml of methylene chloride / methyl alcohol 1: 1 (v / v). - [2- (2-Πιπ1) -εΐί1] azetidin-2-one and the solution was cooled to -78 ° C by filling in the flask. A few crystals of Sudan ΠΙ red are added and ozone mixed with air is bubbled through the solution until the red color disappears (about 40 minutes). The cooling bath was removed and 1.56 mL of dimethyl sulfide was added to the reaction mixture. After warming to room temperature, it was stirred for five hours. The mixture was poured into aqueous sodium bicarbonate and the mixture was washed with methylene chloride. The aqueous phase is acidified with hydrochloric acid and extracted with methylene chloride. The extract was washed with brine, dried over sodium sulfate and evaporated to give 400 mg of the title compound as a foam.

Example 17

Preparation of 1-tert-butyloxycarbonylmethyl-3β-tert-butyloxycarbonylamino-4- (2-phenylthiocarbonylethyl) azetidin-2-one:

350 mg of 1-tert-butyloxycarbonylmethyl-tert-butyloxycarbonylamino-4- (2-carboxyethyl) azetidin-2-one are dissolved in 6 ml of methylene chloride, which is 1 ml of dimethylformamide. contain. To the solution at 0 'C was added 26 mg dimethylaminopyridine, 0.308 ml thiophenol and 212 mg dicyclohexylcarbodiimide (DCC) under nitrogen. The mixture was stirred cold for 10 minutes and then at room temperature for 1 hour. An additional 45 mg of dicyclohexylcarbodiimide was added and stirring was continued for 2 hours. After standing overnight, the reaction mixture was poured into 40 mL of dimethyl chloride, and the mixture was quenched with aqueous sodium bicarbonate solution (half concentration saturated), 0.1 N hydrochloric acid, and saturated sodium bicarbonate solution. washed. The solution was dried over sodium sulfate and evaporated to dryness to give the desired compound as a partially crystalline oil.

Example 18

Preparation of 1-butyl-7-tert-butyloxycarbonylamino-3-hydroxy-1-carba (1-dethia) -3-cephem-4-carboxylate:

4.4 g (9.47 mmol) of the azetidinone phenylthioester of Example 18 are dissolved in 100 mL of dry tetrahydrofuran and 29.5 mL (3.12 mmol) of lithium are added under argon at -78 ° C. -hexametildiszilazánt. After 15 minutes, the reaction mixture was added to 750 ml of aqueous ammonium chloride solution (half the concentration of the solution) and the pH was adjusted to 3 with 1N hydrochloric acid. The acidified solution was extracted with methylene chloride (3 x 50 mL), the extracts were combined, washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with hexane / ethyl acetate 3: 1 then 1: 1. The eluate was evaporated to give the desired compound.

Claims (1)

Patent Claim Point A process for preparing a compound of formula (I) wherein Ar is phenyl, phenyl substituted with C 1-4 alkyl, halo or C 1-4 alkoxy, or naphthyl, R is phenyl, phenyl substituted with C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy. , or halogen HU 212 104 B is a substituted phenyl group; Y is -CH = CH or -CH ₂ -CH ₂ -; and R 'is phenyl, phenyl substituted with C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy, phenyl substituted with halo, furyl or naphthyl, wherein Y is -CH = CH. a group of a compound of formula 5a wherein X 'is chlorine, bromine, trifluoroacetoxy or -OP (= O) X ₂ , wherein X is halogen, with a compound of formula 6a - wherein R and R 'are as stated - and thereafter, if desired, for preparing compounds (1) wherein Y is -CH-CH ₂ - group of formula is hydrogenated, the resulting compound.