DE19626616A1 - Process for the preparation of 1,1-dioxo-cephem-4-ketones - Google Patents

Abstract

There is provided a process for preparing a compound of formula I, endowed with antielastase activity: wherein R 1 , R 2 , R 3 , R 4 and R 5 are appropriate organic residues or hydrogen or halogen atoms. The process starts from the corresponding cephem esters and comprises the steps of acylating, oxidation and carboxylate removal.

Description

This invention relates to a method for converting Cephalosporanic acid esters in 1,1-dioxo-cephem-4-ketones, which are either inhibitors of serine proteases or their Are intermediate products. According to the present Invention compounds of formula (I) can be prepared will:

wherein R¹ is an organic radical selected from C _1-12 straight or branched alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _6-14 aryl, C _3-8 cycloalkyl, C _5-8 Cycloalkenyl, C _7-22 aralkyl, C _8-14 aralkenyl, C _8-14 aralkynyl, (cycloalkyl) alkyl, (cycloalkyl) alkenyl, heterocyclyl, (heterocyclyl) alkyl and (heterocyclyl) alkenyl; R² is either hydrogen or a group selected from methoxy, protected hydroxy, acetoxy or heterocyclylthio; and
R³ and R⁴ independently of one another mean:

• (1) hydrogen, chlorine, fluorine or bromine,
• (2) C _1-4 alkyl, C _2-4 alkenyl, 1- (protected hydroxy) ethyl, phenyl or benzyl,
• (3) methoxy, ethoxy, isopropoxy, phenoxy or Benzyloxy,
• (4) methylthio, ethylthio, isopropylthio
• (5) protected hydroxy, or
• (6) protected amino.

The C _1-12 alkyl groups are straight-chain or branched alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

The C _2-12 alkynyl group is a straight chain or branched alkenyl group such as vinyl, allyl, crotyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl, butenyl, pentenyl, etc.

The C _2-12 alkenyl group is a straight chain or branched alkynyl group such as ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, etc.

The C _6-14 aryl group is a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group with 6 to 14 carbon atoms, such as phenyl, naphthyl, phenanthryl or anthryl.

The C _3-8 cycloalkyl group is a saturated carbocyclic group having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The C _5-8 cycloalkenyl group is an unsaturated carbocyclic group such as cyclopentenyl, cyclohexenyl, etc.

The C _7-22 aralkyl group is an alkyl group having 1 to 4 carbon atoms attached to one, two or three monocyclic aromatic hydrocarbon groups having 6 carbon atoms or to a bicyclic aromatic hydrocarbon group having 10 carbon atoms. Examples of aralkyl groups are benzyl, phenylethyl, naphthylmethyl, benzhydryl or trityl.

The C _8-14 aralkenyl group is an alkenyl group having 2 to 4 carbon atoms attached to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples of aralkenyl groups are styryl, 2-phenyl-1-propenyl, 3-phenyl-2-butenyl, 2-naphthylethenyl, etc.

The C _8-14 aralkynyl group is an alkynyl group having 2 to 4 carbon atoms attached to a monocyclic or bicyclic hydrocarbon group having 6 to 10 carbon atoms. Examples of aralkynyl groups are 2-phenylethynyl, 2-naphthylethynyl, etc.

The (cycloalkyl) alkyl group is an alkyl group having 1 to 4 carbon atoms attached to a cycloalkyl group, usually a C _3-8 cycloalkyl group, as described above.

The (cycloalkyl) alkenyl group is an alkenyl group having 2 to 4 carbon atoms attached to a cycloalkyl group or an aryl group, usually a C _3-8 cycloalkyl group or a C _6-14 aryl group, as described above.

The heterocyclyl group is a 3- to 6-membered, saturated or unsaturated heterocyclyl ring containing at least one heteroatom selected from Q, S and N, which is optionally attached to a second 5- or 6-membered, saturated or unsaturated heterocyclyl group or to a cycloalkyl group or is fused to an aryl group, usually a C _3-8 cycloalkyl group or a C _6-14 aryl group, as described above. Examples of heterocyclyl groups are pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, thiadiazolyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl, pyranyl, pyridazinyl, benzothienyl, benzothiazolyl and benzoxazolyl.

The (heterocyclyl) alkyl group is an alkyl group with 1 up to 4 carbon atoms bound to one Heterocyclyl group, usually a heterocyclyl group, as described above.

The (heterocyclyl) alkenyl group is an alkenyl group with 2 to 4 carbon atoms bound to one  Heterocyclyl group, usually a heterocyclyl group, as described above.

The term halogen (or halo) preferably includes Fluorine, chlorine, bromine or iodine.

The C _1-4 alkyl group is a straight-chain or branched alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

The C _2-4 alkenyl group is a straight-chain or branched alkenyl group, such as vinyl, allyl, crotyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl or butenyl.

The above-mentioned alkyl, alkenyl, alkynyl, Cycloalkyl, cycloalkenyl, aryl, aralkyl, aralkenyl, Aralkynyl, (cycloalkyl) alkyl, (cycloalkyl) alkenyl, Heterocyclyl, (heterocyclyl) alkyl and (Heterocyclyl) alkenyl groups can either unsubstituted or with one or more, such as one or two or three substituents selected from:

• - halo (e.g. fluorine, bromine, chlorine or iodine);
• - nitro;
• - azido;
• - cyano;
• - protected mercapto;
• - protected hydroxy;
• - Protected primary or secondary amino, or a tertiary amino, the radicals of the secondary and tertiary amino are selected from C _1-12 straight-chain or branched alkyl groups or phenyl or benzyl;
• - protected carboxy or esterified carboxy -C (O) OR ', where R' is a C _1-12 straight-chain or branched alkyl group or phenyl or benzyl;
• - Sulfo (e.g. -SO₃H);
• - Acyl (e.g. -C (O) R '), where R' is as defined above or Trifluoroacetyl (e.g. -C (O) CF₃);
• - carbamoyl (e.g. -CONH₂) or (N-substituted) Carbamoyl;
• - CONHR ', where R' is as defined above;
• - carbamoyloxy (e.g. -OCONH₂);
• - Acyloxy (e.g. -OC (O) R '), where R' is as defined above or formyloxy (-OC (O) H);
• - alkoxycarbonyl or benzyloxycarbonyl (e.g. -C (O) QR ′), where R ′ is as defined above;
• - alkoxycarbonyloxy or benzyloxycarbonyloxy (e.g. -OC (O) OR '), where R' is as defined above;
• - alkoxy, phenoxy or benzyloxy (e.g. -OR ′), where R ′ is as defined above;
• - alkylthio, phenylthio or benzylthio (e.g. -SR ′), where R 'is as defined above;
• - alkylsulfonyl, phenylsulfonyl or benzylsulfonyl (e.g. -S (Q) ₂R '), where R' is as defined above;
• - acylamino (e.g. -NHC (O) R ′ or -NHC (O) QR ′, where R ′ is as defined above;
• - Sulfonamido (e.g. -NHSO₂R '), where R' as above is defined;
• - C _1-4 alkyl, C _2-4 alkenyl or alkynyl;
• - C _3-6 cycloalkyl; and
• - Substituted methyl, selected from trifluoromethyl, N, N-dimethylaminomethyl, azidomethyl, cyanomethyl, (protected carboxy) methyl, sulfomethyl, carbamoylmethyl, carbamoyloxymethyl, (protected hydroxy) methyl, C _1-4 alkoxycarbonylmethyl.

The amino, hydroxy or mercapto protecting groups that possibly present may be the ones usually in the chemistry of penicillins and Cephalosporins are used for this type of function will. You can e.g. B. optionally substituted, especially halo-substituted acyl groups, e.g. B. acetyl, Monochloroacetyl, dichloroacetyl, trifluoroacetyl, benzoyl or p-bromophenacyl; Triarylmethyl groups, e.g. B. Triphenylmethyl; Silyl groups, in particular Trimethylsilyl, dimethyl-tert-butylsilyl, diphenyl-tert butylsilyl; or groups such as tert-butoxycarbonyl, p-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, Benzyl and pyranyl.

The carboxyl protecting group can e.g. Legs Lower alkyl group such as methyl, ethyl, propyl, isopropyl or tert-butyl; a halogenated lower alkyl group such as 2,2,2-trichloroethyl or 2,2,2-trifluoroethyl; a Lower alkanoyloxyalkyl group such as acetoxymethyl, Propionyloxymethyl, pivaloyloxymethyl, 1-acetoxyethyl, 1-propionyloxyethyl; a Lower alkoxycarbonyloxyalkyl group, such as 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl; a lower alkenyl group, such as 2-propenyl, 2-chloro-2-propenyl, 3-methoxycarbonyl-2- propenyl, 2-methyl-2-propenyl, 2-butenyl, cinnamyl; a Aralkyl group, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, Benzhydryl, bis (p-methoxyphenyl) methyl; a silyl group, such as trimethylsilyl, tert-butyldimethylsilyl, tert- Butyldiphenylsilyl, triphenylsilyl; or one Indanyl group, a phthalidyl group; a pyranyl group,  a methoxymethyl or methylthiomethyl group; a 2-methoxyethoxymethyl group. Particularly preferred are a p-methoxybenzyl group, a benzhydryl group, a trimethylsilyl group, tert-butyldimethylsilyl, a tert-butyldiphenylsilyl group, a propenyl group, a tert-butyl group, a p-nitrobenzyl group or one Methyl group.

The compounds of formula (I) are as follows Reaction scheme prepared, wherein R¹, R², R³ and R⁴ as are described above and R⁵ is a carboxyl protecting group, is as defined above.

The method of the present invention is characterized by the following steps:

• (i) acylating a cephemcarboxylic ester Formula (II)
• (ii) oxidizing to a sulfone and
• (iii) removing the CQOR⁵ unit from the resulting compound,
  wherein steps (ii) and (iii) can be carried out in any order.

In the acylation step mentioned under (i), a Compound of formula (II) in succession with a strong one Base and treated with an acylating agent R 1 C (O) X, where R1 is as defined above and X is a typical one leaving group is. Close suitable bases Alkali alkoxides, such as potassium tert-butoxide or Sodium methoxide, alkali metal hydrides, such as sodium or Potassium hydride, alkali amides, such as lithium or Sodium diisopropylamide, or alkali carbides, such as Butyllithium or triphenylmethyllithium. The leaving group X is a halogen atom, preferably Chlorine or bromine, an OC (O) R¹ group, wherein R¹ is as above is defined, or an alkylsulfonyloxy or Arylsulfonyloxy group. The starting material, the strong one Base and the acylation unit are caused to an inert anhydrous organic solvent that does not interfere in the reaction to react. Suitable reaction solvents are tetrahydrofuran (THF), diethyl ether, benzene, toluene,  Hexamethylphosphoramide, dimethoxyethane, dioxane, n-hexane or mixtures thereof. The reaction is usually at a temperature between -100 and + 30 ° C, preferably between -80 ° C and room temperature for a period of 1 to 20 hours.

In the oxidation stage, the compounds (III) or (V) oxidized to the corresponding sulfones. Preferred oxidizing agents are inorganic or organic peracids or their salts in an inert organic solvents or in a mixture of Water and an organic solvent. Suitable Peracids are e.g. B. peracetic acid, m-chloroperoxybenzoic acid (MCPBA), monoperphthalic acid, alkaline monoperoxysulfates and Tetrabutylammonium peroxydisulfate; suitable solvents are chloroform, dichloromethane, acetonitrile, ethanol, Acetic acid, ethyl acetate or mixtures thereof. The Oxidation is usually at a temperature of -20 up to + 80 ° C.

The split off of the COOR⁵ unit is with the split off the R⁵ group (i.e., exemption from the carboxy function) of Compounds of the formulas (III) or (IV) and subsequent decarboxylation. The secession the R⁵ group is carried out under conditions determined by depends on the nature of the carboxy protecting group R⁵.

Typical R⁵ groups are groups that the under (i) and (ii) withstand the described transformation and still be removed under selective and mild conditions can. Typical R⁵ groups are sensitive to acids Groups such as tert-butyl, p-methoxybenzyl,  Tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, Methoxyethoxymethyl, etc. (which in mild conditions in Presence of organic or inorganic acids, e.g. B. Formic acid, trifluoroacetic acid, p-toluenesulfonic acid, Methanesulfonic acid, aluminum trichloride and boron trifluoride can be removed) or groups under neutral Conditions such as p-nitrobenzyl, Benzyl (removable by hydrogenolysis), allyl (removable in the presence of palladium catalysts or equivalents Catalysts) or groups by variation of Conditions can be removed, such as methyl, Benzyloxymethyl, trialkylsilyl, etc.

Loss of carbon dioxide can occur spontaneously after Removal of the carboxy protecting group R⁵, through which Reaction conditions or during workup or Purification (e.g. silica gel chromatography or treatment with aqueous sodium bicarbonate solution) or finds easily in the presence of tertiary or aromatic amines in either polar or apolar aprotic solvents instead of.

It can be seen that in each of steps (i) to (iii) the groups R¹, R², R³, R⁴ and R⁵ of the compounds of the formulas (I), (II), (III), (IV), (V) with conventional methods in other R¹-, R²-, R³-, R⁴- and R⁵ groups, especially those previously defined have been converted. These conversions are on cephemes of the formulas (I) to (V) or their Analogs well known. Are compounds of formula (II) known compounds or can from known Connections are made by known methods.  

The compounds of formula (I) are useful Connections z. B. are described in US-A-5 077 286.

The following examples illustrate the invention.

EXAMPLE 1 p-methoxybenzyl-7α-methoxy-3-methyl-3-cephem-4-carboxylate

To a suspension of 7β-amino-3-deacetoxycephalosporanoic acid (20 g) in methyl alcohol (1200 ml), cooled at -5 ° C., methanesulfonic acid (38.8 ml) was added dropwise over 10 minutes. Then sodium nitrite (38.6 g) was added and the resulting mixture was stirred for 21 hours at room temperature. After adding sodium bicarbonate (3.14 g) and stirring for 15 minutes, the mixture was filtered through Celite. The filtrate was concentrated in vacuo to half of its initial volume, diluted with dichloromethane (400 ml) and washed with an acidic (pH 1) aqueous solution containing 20% NaCl. The aqueous phase was extracted three times with dichloromethane. The organic phase was dried (Na₂SO₄) and concentrated under reduced pressure to obtain crude 7α-methoxy-3-methyl-3-cephem-4-carboxylic acid (21.5 g). A solution of this product (21.4 g) in N, N-dimethylformamide (320 ml) was treated with sodium bicarbonate (8.6 g) and stirred for 15 minutes at room temperature. Sodium bromide (19.2 g) was added, followed by p-methoxybenzyl chloride (21.25 g). The resulting mixture was stirred at room temperature for 18 hours, then poured into 20% aqueous NaCl (500 ml) and extracted with EtOAc (3 x 300 ml). The organic phase was dried (Na₂SO₄) and rotary evaporated. The oily residue was chromatographed on silica gel and eluted with hexane / EtOAc (4: 1) to isolate the title product as a white solid (13.5 g).
IR (KBr) ν _max : 1770, 1720 cm ^-1
NMR (200 MHz, CDCl₃) δ: 2.04 (3H, s), 3.14 (1H, d, J = 17.8 Hz), 3.46 (2H, m), 3.52 (3H, s ), 3.80 (3H, s), 4.48 (1H, d, J = 1.6Hz), 4.65 (1H, d, J = 1.6Hz), 5.18 and 5.26 (2H , each d, J = 11.9 Hz), 6.88 (1H, d, J = 8.6 Hz), 7.26 (1H, d, J = 8.6 Hz).

EXAMPLE 2 p-methoxybenzyl-4-benzoyl-7α-methoxy-3-methyl-2-cephem-4- carboxylate

A solution of p-methoxybenzyl-7α-methoxy-3-methyl-3-cephem-4-carboxylate (12.9 g) in dry tetrahydrofuran (130 ml) was cooled at -70 ° C. Under a nitrogen cloth, 2 M lithium N, N-diisopropylamide in THF (21.25 ml) was added dropwise in 20 minutes while the temperature was kept at -70 ° C. Benzoyl chloride (6.43 ml) was then added dropwise and stirred continuously at -70 ° C for 90 minutes. The reaction mixture was poured into water (500 ml) and extracted twice with EtOAc (2 x 250 ml). The organic layer was washed in sequence with 2% aqueous NaHCO and 20% aqueous NaCl, then dried (Na₂SO₄) and rotary evaporated. After purification of the residue by flash chromatography (SiO₂ eluted with hexane / EtOAc mixtures), the title product was obtained as a light yellow solid.
IR (KBr) ν _max : 1770, 1740, 1680 cm ^-1
NMR (200 MHz, CDCl₃) δ: 1.91 (3H, d, J = 1.3 Hz), 3.37 (3H, s), 3.80 (3H, s), 4.70 (2H, s ), 5.17 and 5.34 (2H, each d, J = 11.9 Hz), 6.15 (1H, q, J = 1.3 Hz), 6.8-8.1 (9H, m ).

EXAMPLE 3 p-methoxybenzyl-4-benzoyl-1,1-dioxo-7α-methoxy-3-methyl-2- cephem-4-carboxylate

A solution of p-methoxybenzyl-4-benzoyl-7α-methoxy-3-methyl-2-cephem-4-carboxylate (13.8 g) in ethyl acetate (275 ml) was cooled to 0 ° C and with 55% m- Chloroperbenzoic acid (23.8 g) treated. The reaction mixture was stirred at room temperature for 2 hours, then washed successively with 1% aqueous sodium sulfite and three times with saturated aqueous sodium bicarbonate and brine. After drying (Na₂SO₄), the EtOAc solution was concentrated under reduced pressure and the crude title product was obtained as a light yellow oil.
IR (KBr) ν _max : 1800, 1745, 1685 cm ^-1
NMR (200 MHz, CDCl₃) δ: 2.01 (3H, d, J = 1.3 Hz), 3.40 (3H, s), 3.81 (3H, s), 4.55 (1H, d , J = 1.6 Hz), 5.20 (1H, d, J = 11.8 Hz), 5.27 (1H, d, J = 1.6 Hz), 5.39 (1H, d, J = 11.8 Hz), 6.36 (1H, q, J = 1.3 Hz), 6.8-8.1 (9H, m).

EXAMPLE 4 4-benzoyl-1,1-dioxo-7α-methoxy-3-methyl-3-cephem

A suspension of aluminum trichloride (10.1 g) in dichloromethane (130 ml) was cooled to -50 ° C. A solution of p-methoxybenzyl-4-benzoyl-1,1-dioxo-7α-methoxy-3-methyl-2-cephem-4-carboxylate (19.3 g) in anisole (75 ml) and dichloromethane (75 ml) was added under nitrogen keeping the temperature at -50 ° C. The resulting mixture was stirred at -50 ° C for 20 minutes, then warmed to -20 ° C and poured into 1% hydrochloric acid saturated with NaCl. The organic layer was washed with brine, then dried (Na₂SO₄) and rotary evaporated. The addition of n-hexane (150 ml) to the oily residue with stirring caused the formation of a white precipitate. The mixture was left to stand overnight at 0 ° C before filtration. The solid was washed with n-hexane and dried under vacuum at 40 ° C to give the title product as a white powder (8.2 g).
IR (KBr) ν _max : 1770, 1690 cm ^-1
NMR (200 MHz, CDCl₃) δ: 1.67 (3H, s), 3.52 (3H, s), 3.62 (1H, d, J = 18.0 Hz), 4.00 (1H, m ), 4.82 (1H, m), 5.19 (1H, d, J = 1.7 Hz), 7.4-7.8 (5H, m).

EXAMPLE 5

Using the in Examples 1 to 4 described methods and using the appropriate Acyl chloride instead of benzoyl chloride were the ones below Cephem-4-ketones listed:

4- (tert-butyl) benzoyl-1,1-dioxo-7α-methoxy-3-methyl-3- cephem

IR (KBr) ν _max : 1780, 1675 cm ^-1
NMR (200 MHz, CDCl₃) δ: 1.33 (9H, s), 1.66 (3H, s), 3.53 (3H, s), 3.58 (1H, d, J = 18.1 Hz ), 4.01 (1H, d, J = 18.1 Hz), 4.81 (1H, m), 5.19 (1H, d, J = 1.6 Hz), 7.51 (2H, d , J = 8.6 Hz), 7.87 (2H, d, J = 8.6 Hz).

4- (phenyl) benzoyl-1,1-dioxo-7α-methoxy-3-methyl-3-cephem

IR (KBr) ν _max : 1765, 1675 cm ^-1
NMR (200 MHz, CDCl₃) δ: 1.70 (3H, s), 3.54 (3H, s), 3.62 (1H, d, J = 18.0 Hz), 4.04 (1H, m ), 4.84 (1H, m), 5.21 (1H, d, J = 1.6 Hz), 7.4-7.7 (5H, m), 7.72 (2H, d, J = 8.5 Hz), 8.00 (2H, d, J = 8.5 Hz).

4- (α-naphthoyl) -1,1-dioxo-7α-methoxy-3-methyl-3-cephem

IR (KBr) ν _max : 1765, 1660 cm ^-1
NMR (200 MHz, CDCl₃) δ: 1.69 (3H, s), 3.45 (3H, s), 3.64 (1H, d, J = 18.2 Hz), 4.00 (1H, m ), 4.79 (1H, m), 5.20 (1H, d, J = 1.6 Hz), 7.4-8.8 (7H, m).

4- (β-naphthoyl) -1,1-dioxo-7α-methoxy-3-methyl-3-cephem

IR (KBr) ν _max : 1760, 1670 cm ^-1
NMR (200 MHz, CDCl₃) δ: 1.69 (3H, m), 3.52 (3H, s), 3.64 (1H, d, J = 18.0 Hz), 4.05 (1H, m ), 4.87 (1H, m), 5.23 (1H, d, J = 1.6 Hz), 7.5-8.1 (6H, m), 8.42 (1H, s).

4- (4-benzoyl) benzoyl-1,1-dioxo-7α-methoxy-3-methyl-3- cephem

IR (KBr) ν _max : 1760, 1670, 1650 cm ^-1
NMR (200 MHz, CDCl₃) δ: 1.72 (3H, s), 3.54 (3H, s), 3.63 (1H, d, J = 18.1 Hz), 4.03 (1H, m ), 4.83 (1H, m), 5.22 (1H, d, J = 1.6 Hz), 7.4-8.0 (9H, m).

4-valeryl-1,1-dioxo-7α-methoxy-3-methyl-3-cephem

IR (KBr) ν _max : 1790, 1705 cm ^-1
NMR (200 MHz, CDCl₃) δ: 0.93 (3H, t, J = 7.0 Hz), 1.2-1.4 (2H, m), 1.5-1.7 (2H, m) , 1.95 (3H, s), 2.5-3.0 (2H, m), 3.59 (3H, s), 3.60 (1H, d, J = 17.7 Hz), 3, 85 (1H, d, J = 17.7 Hz), 4.66 (1H, m), 5.14 (1H, d, J = 1.4 Hz).

4- (2-ethyl-1-oxo-propyl-1,1-dioxo-7α-methoxy-3-methyl-3- cephem

IR (KBr) ν _max : 1780, 1695 cm ^-1
NMR (200 MHz, CDCl₃) δ: 1.88 (3H, t, J = 7.0 Hz), 1.92 (3H, t, J = 7.0 Hz), 1.4-1.9 (4H , m), 1.95 (3H, m), 2.8-2.9 (1H, m), 3.60 (3H, s), 3.60 (1H, d, J = 17.6 Hz) , 3.85 (1H, m), 4.62 (1H, m), 5.14 (1H, d, J = 1.5 Hz).

4-acetyl-1,1-dioxo-7α-methoxy-3-methyl-3-cephem

IR (KBr) ν _max : 1775, 1695 cm ^-1
NMR (200 MHz, CDCl₃) δ: 2.00 (3H, m), 2.46 (3H, s), 3.60 (3H, s), 3.62 (1H, d, J = 17.8 Hz ), 3.87 (1H, m), 4.67 (1H, m), 5.16 (1H, d, J = 1.5 Hz).

4- (cyclohexyl) carbonyl-1,1-dioxo-7α-methoxy-3-methyl-3- cephem

IR (KBr) ν _max : 1780, 1695 cm ^-1
NMR (200 MHz, CDCl₃) δ: 1.0-2.0 (10H, m), 1.86 (3H, m), 2.78 (1H, m), 3.58 (1H, d, J = 18Hz), 3.59 (3H, s), 3.89 (1H, m), 4.68 (1H, m), 5.16 (1H, d, J = 1.5 Hz).

Claims (7)

1. Process for the preparation of a compound of formula (I) wherein R¹ is an organic radical selected from C _1-12 straight or branched alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _6-14 aryl, C _3-8 cycloalkyl, C _5-8 -Cycloalkenyl, C _7-22 aralkyl, C _8-14 aralkenyl, C _8-14 aralkynyl, (cycloalkyl) alkyl, (cycloalkyl) alkenyl, heterocyclyl, (heterocyclyl) alkyl and (heterocyclyl) alkenyl; R² is either hydrogen or a group selected from methoxy, protected hydroxy, acetoxy or heterocyclylthio; and
R³ and R⁴ independently of one another mean:

• (1) hydrogen, chlorine, fluorine or bromine,
• (2) C _1-4 alkyl, C _2-4 alkenyl, 1- (protected hydroxy) ethyl, phenyl or benzyl,
• (3) methoxy, ethoxy, isopropoxy, phenoxy or benzyloxy,
• (4) methylthio, ethylthio, isopropylthio
• (5) protected hydroxy, or
• (6) protected amino;

full:

• (i) acylating a cephemcarboxylic acid ester of the formula (II) wherein R², R³, R⁴ are as defined above and R⁵ represents a carboxy group;
• (ii) oxidizing the resulting compound of formula (III) to a sulfone, wherein R¹, R², R³, R⁴ and R⁵ are as defined above; and
• (iii) removing the COOR⁵ unit from the resulting compound; wherein steps (ii) and (iii) can be carried out in any order.

2. The method according to claim 1, wherein in the Acylation step (i) the compound of formula (II) in succession with a strong base and a Acylating agent R¹C (O) X, wherein R¹ is as in claim 1 is defined and X is a leaving group, is treated. 3. The method of claim 1 or 2, comprising:

• (a) oxidizing compound (III) to a sulfone; and
• (b) removing the COOR⁵ unit of the resulting compound of formula (IV) wherein R¹, R², R³, R⁴ and R⁵ are as defined in claim 1.

4. The method of claim 1 or 2, comprising:

• (a) removing the COOR⁵ unit of the compound of formula (III); and
• (b) oxidizing the compound (V) obtained wherein R¹, R², R³, R⁴ and R⁵ are as defined in claim 1.

5. The method according to any one of the preceding claims, the removal of the COOR⁵ unit by Removal of the R⁵ group is carried out and, if required using the resulting carboxy derivative a tertiary or aromatic amine in one polar or an apolar aprotic solvent is treated. 6. The method according to any one of the preceding claims, wherein the oxidation by means of an inorganic or organic peracid or its salts in one inert organic solvents or in a Mixture of water and an organic Solvent is carried out.