Process for preparing cephalosporin compounds

Abstract: Process for preparing cephalosporin compounds represented by the following general formula (V) which have antibacterial activity and thus are useful as antibacterial agents as well as intermediates for synthesizing cephalosporin-type antiobiotics wherein R¹ represents a phenylmethyl group or a phenyl-oxymethyl group each optionally substituted with methyl, halogen, nitro or p-methoxy on the phenyl ring; R² represents a carboxyl group or a protected carboxyl group; and Y is (a) -SC(=S)OR³ wherein R³ is C₁-C₄ alkyl optionally substituted with halogen, or phenyl optionally substituted with methyl, halogen, nitro or p-methoxy; or (b) protected hydroxyl, which provides the above cephalosporin compounds with high purities in high yields by a simple procedure from inexpensive and readily available starting compounds.

Description: Technical Field and Disclosure of the Invention This application is a divisional application divided out of European patent application No. 83 902 823. This invention relates to a process for preparing cephalosporin derivatives represented by the general formula (V) wherein: R¹ represents a phenylmethyl group or a phenyloxymethyl group each optionally substituted with methyl, halogen, nitro or p-methoxy on the phenyl ring; R² represents a carboxyl group or a protected carboxyl group; Y is (a) -SC(=S)OR³ wherein R³ is C₁-C₄ alkyl optionally substituted with halogen, or phenyl optionally substituted with methyl, halogen, nitro or p-methoxy; or (b) protected hydroxyl. The cephalosporin derivatives of general formula (V) have antibacterial activity and thus are useful as antibacterial agents. The compounds can be converted into cephalosporintype antibiotics in wide use by deacylating and reacylating the amide group at the 7-position and thus are important intermediates for synthesizing such antibiotics. "Tetrahedron Letters", 23 (June 1982), pages 2495 and 2498, and US-A-4 482 491 disclose a process for the production of certain cephalosporins having the above formula (V) in which Y is SAr, starting from thiazolone-azetidinone. The earlier application FR-A-2 504 927 of the applicant disclose a process for the production of certain cephalosporins having the above formula (V) in which Y is -SR⁴, wherein R⁴ represents an aryl group or an aromatic heterocyclic group. The earlier application DE 32 13 264 A1 of the applicant discloses a process for preparing azetidinone derivatives. An object of the present invention is to provide a process for preparing the cephalosporin derivatives of general formula (V) with high purities in high yields by a simple procedure from readily available starting compounds. This object can be achieved according to the present invention by a process for preparing cephalosporin derivative of the above general formula (V) which is characterized by the following steps: the process being characterized by the steps of: (1) (A) reacting a thiazolinoazetidinone derivative represented by the general formula (I) : wherein R¹ and R² are as defined above with a nucleophilic reagent of the general formula wherein M represents an alkali metal and R³ is as defined above in an organic solvent to produce the compound of the general formula: or (B) reacting a thiazolinoazetidinone derivative represented by the general formula (I): wherein R¹ and R² are as defined above with an alkali metal iodide in an organic solvent to produce a thiazolinoazetidinone derivative represented by the general formula (VI) wherein R¹ and R² are as defined above; reacting a thiazolinoazetidinone derivative represented by the formula (VI) with NaNO₃ or KNO₃ in an organic solvent to produce the compound of the general formula (II') wherein R¹ and R² are as defined above; reacting the compound of the formula (II') with zinc in the presence of acetic acid to obtain a thiazolinoazetidinone derivative represented by the general formula (IX) wherein R¹ and R² are as defined above, and protecting the hydroxyl group of the derivative of the formula (IX) with an agent for protecting hydroxyl group of the formula ASi(R³)₃, CF₃SO₃·Si(R³)₃, wherein R³ is as defined above and A is a chlorine, bromine or iodine atom in an organic solvent in the presence of an acid-trapping agent; (2) reacting the resulting compound represented by the general formula (II) : wherein R¹, R² and Y are as defined above in a water-containing solvent with a sulfur-containing compound represented by the general formula (III): Z - S - X wherein Z represents phenyl, phenyl substituted with halogen or nitro, 2-pyridyl, 2-benzothiazolyl, 1,3,4-thiadiazol-2-yl or 5-methyl-1,3,4-thiadiazol-2-yl and X represents a halogen atom to obtain an azetidinone derivative of the general formula (IV) wherein R¹, R², Y and Z are as defined above; and (3) reacting the compound of the formula (IV) with ammonia in an organic solvent to effect the ring closure. The claimed process provides the desired compounds of formula (V) in high yield and purity and can be carried out easily in a technical manner. The present invention is further illustrated below. Examples for R¹ representing optionally substituted phenylmethyl or pheyloxymethyl groups are tolymethyl, p-chlorophenylmethyl, p-nitrophenylmethyl, p-methoxyphenylmethyl, tolyloxymethyl, p-chlorophenoxymethyl, p-nitrophenoxymethyl and p-methoxyphenylmethyl. Examples of the protected carboxyl groups represented by R² are esters of the formula COOR' and acid amides of the formula CONHR'. Examples of the groups represented by R' in the foregoing formula are methyl, 2,2,2-trichloroethyl, diphenylmethyl, benzyl, p-nitrobenzyl, isobutyl, tert-butyl or like carboxylic acid protecting groups commonly used. Examples of the groups represented by R³ are C₁-C₄ alkyl groups having 1 to 4 carbon atoms (optionally substituted with halogen), such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl; phenyl group; phenyl groups substituted with methyl, halogen, nitro, or p-methoxy, such as tolyl, p-chlorphenyl, p-nitrophenyl, p-methoxyphenyl. Examples of the protected hydroxyl groups are groups -OSi(R³)₃, wherein R³ is as defined above. The compound of the formula (I) to be used as the starting material in the present invention can be easily synthesized for example from a known thiazolinoazetidinone derivative of the formula (VII): wherein R¹ and R² are as defined above by a conventional method, for instance, as disclosed in Tetrahedron Letters, 22 , 3193 (1981). The compound of the formula (II) serving as the intermediate in the present invention is prepared by reacting the starting compound of the formula (I) with a nucleophilic reagent. Essentially this reaction is conducted to replace the chlorine atom at the allyl position by the nucleophilic reagent without changing the position of the C=C double bond of the compound having the formula (I), thereby giving the compound of the formula (II). There has been reported a process for synthesizing the compound of the formula (II) (wherein R¹ is methyl or tert-butyl, R² is a group COOCH, and Y is a group which process involves a number of procedures (J. Am. Chem. Soc., 99 , 248 (1977)), as shown in the following reaction equation. However, this process is far from practical because it has the drawbacks of using e.g. N-bromosuccinimide (NBS) , requiring a number of procedures due to change in the position of the double bond and giving an end product in low yields. On the other hand, the process of the present invention can provide the compound of the formula (II) in high yields by a simple procedure (or procedures) without involving the movement of the double bond. According to the present invention, the compound of the formula (I) can be transformed into the compound of the formula (II) by the processes as illustrated hereinafter by reaction equations (A) and (B). Reaction Equation (A) Reaction Equation (B) (1) The process as shown by the reaction equation (A) is especially advantageous in preparing the compound of the formula (II) wherein Y is a group (in which R³ is as defined above). More specifically, the compound of the formula (II) wherein Y is the group can be prepared in a high yield without varying the position of the double bond by reacting the compound of the formula (I) in an organic solvent with a nucleophilic reagent represented by the formula wherein M is an alkali metal and R³ is as defined above. The nucleophilic reagent of the formula (1) is a known compound which is preferably used in the form of its sodium or potassium salt. The kind of the organic solvent to be used in this reaction is not particularly limited so far as the solvent is capable of dissolving the compound of the formula (I) and the nucleophilic reagent. Preferred examples of useful organic solvents are acetone, ethyl acetate, dimethyl sulfoxide, dimethylformamide and like aprotic polar solvents. The amount of the organic solvent to be used is not particularly limited insofar as the amount is sufficient to dissolve the reactants. The solvent is used in an amount of usually 5 to 100 times, preferably 5 to 50 times, the weight of the compound of the formula (I). The amounts of the starting compound of the formula (I) and the nucleophilic reagent of the formula (I) to be used can be also adequately determined over a wide range. The latter is employed in an amount of usually 1 to 10 moles, preferably 1 to 5 moles, per mole of the former. The reaction is conducted at a temperature in the range of usually -10 to 40°C, preferably at room temperature and is completed usually in 0.5 to 2 hours. More specifically stated, first the compound of the formula (I) serving as the starting material is reacted in an organic solvent with an alkali iodide, preferably sodium iodide or potassium iodide, whereby a compound of the formula (VI) : wherein R¹ and R² are as defined above is obtained without involving the change in the position of the double bond. Subsequently the compound of the formula (VI) is reacted in an organic solvent with a nucleophilic reagent of the formula wherein M represents an alkalimetal and R³ is as defined above whereby the compound of the formula (II) is obtained in a high yield without changing the position of the double bond. The organic solvents useful in the reaction between the starting compound of the formula (I) and the alkali iodide include a wide variety of those which are capable of dissolving the two materials. Preferred solvents are aprotic polar ones, such as acetone, dimethyl sulfoxide, dimethylformamide, among which acetone is particularly preferable to use. The amount of the organic solvent to be used is 5 to 100 times, preferably 5 to 50 times, the weight of the starting compound of the formula (I). The amounts of the starting compound of the formula (I) and the alkali iodide to be employed can be appropriately determined over a wide range. The latter is used in an amount of usually 1 to 10 moles, preferably 1 to 2 moles, per mole of the former. The reaction is performed at a temperature of usually 0 to 60°C, preferably 40 to 55°C and is completed usually in 0.5 to 4 hours. Examples of the organic solvent which can be used in the reaction between the compound of the formula (VI) and the nucleophilic reagent of the formula (2) include a wide variety of organic solvents capable of dissolving the two compounds among which it is preferred to use aprotic polar solvents, such as acetone, dimethyl sulfoxide, dimethylformamide, and acetone is especially preferable. The organic solvent is employed in an amount of usually 5 to 100 times, preferably 5 to 50 times, the weight of the compound of the formula (VI). The amounts of the compounds of the formula (VI) and the nucleophilic reagent to be used can be suitably determined over a wide range. The latter is used in amount of usually 1 to 3, preferably 1 to 1.5 moles, per mole of the former. The reaction is effected at a temperature of usually -10 to about 40°C, preferably at room temperature and is completed usually in 0.5 to 4 hours. (2) The compound of the formula (II) wherein Y is -ONO₂ can be prepared also by the process of the reaction equation (B). More specifically stated, the iodine compound of the formula (VI) which can be produced for example by the process described above in (2) is reacted in an organic solvent with NaNO₃ or KNO₃, whereby the compound of the formula (II) wherein Y is a nitroxy group is given in a high yield without change in the position of the double bond. Useful organic solvents include aprotic polar solvents among which dimethyl sulfoxide is particularly preferred. The organic solvent is used in an amount of 0.5 to 10 times, preferably 0.5 to 5 times, the weight of the compound of the formula (VI). The amounts of the compound of the formula (XI) and the nitrate of alkali metal to be used can be appropriately determined over a wide range. The latter is used in a amount of usually 1 to 10 moles, preferably 1 to 5 moles, per mole of the former. The reaction is carried out at a temperature of usually about 0 to 100°C, preferably 40 to 60°C. In order to remove the alkali iodide produced as a by-product from the reaction system, the reaction can be conducted in the presence of methyl methanesulfonate or methyl toluene sulfonate with the reaction system maintained at reduced pressure of 30 to 80 mmHg. Although depending on the reaction conditions, the reaction is completed usually in 0.5 to 6 hours. (3) The compound of the formula (II) wherein Y is a hydroxyl group or a protected hydroxyl group can be produced particularly with advantage according to the reaction equation (B). More specifically, the compound of the formula (II) wherein Y is -ONO₂ and which can be prepared by the process described above in (2) is reacted in the presence of acetic acid with zinc to provide a compound of the formula wherein R¹ and R² are as defined above. In this reaction, the acetic acid may be used itself as a solvent or in mixture with another organic solvent. Useful organic solvents include a broad range of those inert to acetic acid, zinc and the compound of the formula (II) wherein Y is -ONO₂, such as ethyl acetate, methyl acetate, methyl propionate or like lower alkyl esters of lower carboxylic acid; diethyl ether, tetrahydrofuran, dioxane or like ethers; methylene chloride, dichloroethane, chloroform or like halogenated hydrocarbons; benzene, toluene, xylene and like aromatic hydrocarbons. These inert organic solvents are used in an amount of up to 90%, preferably 20 to 70%, based on the volume of the mixture with acetic acid. When singly used or mixed with another organic solvent, the acetic acid is employed in an amount of usually 10 to 200 moles, preferably 10 to 150 moles, per mole of the compound of the formula (II) wherein Y is -ONO₂. The amounts of the compound of the formula (II) wherein Y is -ONO₂ and zinc to be used can be suitably selected over wide range. Usually 3 to 10 moles, preferably 3 to 5 moles of the latter is used per mole of the former. The reaction is carried out at a temperature of usually -30 to a 50°C, preferably -10 to 30°C and is completed usually in a 0.5 to 3 hours. The procedure for protecting the hydroxyl group of the compound of the formula (IX) thus prepared is subsequently conducted, whereby the compound of the formula (II) wherein Y is a protected hydroxyl group can be produced in a high yield. The protection of hydroxyl group is performed by reacting the compound of the formula (IX) with an agent for introducing the corresponding protecting group, such as ASi(R³)₃, CF₃SO₃·Si(R³)₃, (in the formulae, R³ is as defined above and A is chlorine, bromine or iodine atom). The reaction is conducted usually in an organic solvent in the presence of an acid-trapping agent. Useful acid-trapping agents include pyridine, polymer-supported pyridine, molecular sieve, imidazole. The reaction is effected preferably at a relatively low temperature usually ranging from -50 to 10°C. The amounts of the compound of the formula (IX) and acid-trapping agent to be used can be appropriately determined over a wide range. The latter is used in an amount of usually 1 to 30 moles, preferably 1 to 10 moles, per mole of the former. While the amounts of the compound of the formula (IX) and the agent for introducing a protecting group to be used are variable depending on the kind of the agent, the other reaction conditions, the latter is used in an amount of usually 1 to 30 moles, preferably 1 to 10 moles, per mole of the former. Useful organic solvents include a wide variety of solvents inert under the foregoing reaction conditions, such as diethyl ether, tetrahydrofuran, dioxane and like ethers; methylene chloride, dichloroethane, chloroform and like haloganated hydrocarbons; benzene, toluene, xylene and like aromatic hydrocarbons. The amount of these organic solvents to be used is 1 to 20 times, preferably 1 to a 15 times, the weight of the compound of the formula (IX). The reaction takes usually 0.5 to 12 hours. The compound of the formula (II) prepared by any of the processes described above in (1) to (3) is reacted with a sulphur-containing compound represented by the formula (III) Z - S - X to obtain the compound of the formula (IV). Examples for phenyl substituted with halogen or nitro are p-nitrophenyl, pentachlorophenyl, trichlorophenyl, etc. Examples of the halogen atoms represented by X are chlorine, bromine, iodine among which chlorine is particularly preferred. The reaction between the compound of the formula (II) and the sulphur-containing compound of the formula (III) is conducted in a water-containing organic solvent. Usable as the organic solvent are dimethyl sulfoxide, dioxane, tetrahydrofuran. These solvents are used in an amount of usually 5 to 50 times, preferably 5 to 30 times, the weight of the compound of the formula (II). Although suitably selectable over a wide range, the usual water content in the organic solvent is 1 to a 500 moles, preferably 10 to 100 moles, per mole of the compound of the formula (II). While the amounts of the compounds of the formulae (II) and (III) to be used can be adequately determined over a wide range, the latter is used in an amount of usually 1 to 10 moles, preferably 1 to 4 moles, per mole of the former. The reaction is conducted at a temperature of usually -10 to 60°C, preferably at room temperature and is completed usually in 0.1 to 2 hours. In this reaction, the presence of an inorganic acid or organic acid may increase the yield. Preferred inorganic acids are sulfuric acid, hydrochloric acid or perchloric acid. and preferred organic acids are trifluoroacetic acid or p-toluenesulfonic acid. The amount of these acids to be used is 1 to 10 moles per mole of the compound of the formula (II). The sulphur-containing compound of the formula (III) can be prepared by dissolving the corresponding disulfide or thiol in an inert solvent such as carbon tetrachloride, chloroform, methylene chloride, dioxane, or tetrahydrofuran and reacting the solution with molecular halogen. In this reaction the inert solvent is used usually in an amount of 5 to 50 times the weight of t:he disulfide or thiol. The molecular halogen is employed usually in an amount of 1 to 1.5 moles per mole of the disulfide or thiol. The reaction favorably proceeds at a temperature of 0 to 100°C and is completed usually in 0.5 to 5 hours. The compound of the formula (III) thus prepared may be subjected to the subsequent reaction as mixed with or as isolated from the reaction mixture. The compound of the formula (IV) prepared by the reaction between the compounds of the formulae (II) and (III) is converted to the end product of the formula (V) by reacting with ammonia in an organic solvent. Preferred organic solvents are inert aprotic polar solvents such as dimethylformamide or dimethylacetamide. among which dimethylformamide is more preferable. The amount of these organic solvents to be used is a 1 to a 100 times, preferably a 1 to 50 times, the weight of the compound of the formula (IV). The amounts of the compound of the formula (IV) and the ammonia to be used can be suitably determined over a wide range. The latter is used in an amount of usually 1 to 10 moles, preferably 1 to 3 moles, per mole of the former. The reaction is conducted at a temperature of usually about -78 to 20°C, preferably -40 to 5°C and is completed usually in 0.1 to 2 hours. The foregoing process gives the compound of the formula wherein R¹, R² and Y are as defined above. The compound of the formula (V) wherein Y is -ONO₂ [hereinafter referred to as compound (X)] can be made into a compound of the following formula (XI) by reacting with zinc in the presence of acetic acid wherein R¹ and R² are as defined above. The cephalosporin compound of the formula (XI) has an antibacterial activity and is useful as an antibacterial agent. The cephalosporin compound of the formula (XI) is an important intermediate for synthesizing a cephalosporin-type antibiotic into which the compound of the formula (XI) can be converted by introducing a protective group in a conventional manner to change the hydroxyl group into one of various ether groups or ester groups such as esters of carboxylic acid and inorganic acid or by deacylation or reacylation of the amide group at the 7-position. The amount of the acetic acid which is used in the reaction for preparing the compound of the formula (XI) by subjecting the compound of the formula (X) to the action of zinc in the presence of acetic acid is not particularly limited and can be suitably selected over a wide range. The acetic acid is used usually as a solvent or preferably in mixture with another organic solvent. The organic solvent is employed in an amount of up to 90%, preferably 20 to 70%, based on the volume of the mixture. When singly used or mixed with an organic solvent, the acetic acid is employed in an amount of usually 10 to 200 moles, preferably 10 to 150 moles, per mole of the compound of the formula (X). The amounts of the compound of the formula (X) and zinc to be used are not particularly limited and can be selected over a wide range. The zinc is used in an amount of usually 3 to 10 moles, preferably 3 to 5 moles, per mole of the compound of the formula (X). The reaction is carried out at a temperature of usually -30 to 50°C, preferably -10 to 30°C. Examples of the organic solvent to be used as mixed with acetic acid include a wide variety of those inert to acetic acid and zinc under the above conditions, such as ethyl acetate, methyl acetate, methyl propionate and like esters: diethyl ether, tetrahydrofuran, dioxane and like ethers; methylene chloride, dichloroethane, chloroform and like halogenated hydrocarbons; benzene, toluene, xylene and like aromatic hydrocarbons. The reaction is completed usually in 0.2 to 3 hours. The compounds of the formulae (VI), (II) and (IV) prepared by the above reactions may be subjected to the subsequent reaction in situ or as isolated from the reaction mixture. The compound of the formula (V) eventually obtained can be purified by solvent extraction, column chromatography, recrystallization or like conventional method. Examples are given below to describe in more detail the processes of the present invention. In the examples, Ph is used to mean a phenyl group. Example 1 A 1 ml quantity of acetone was added to 37.2 mg of benzyl 2-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-chloromethyl-3-butenate to obtain a uniform solution. (35.2 mg) was added to the solution. The mixture was stirred at room temperature for 70 minutes and diluted with 5 ml of ethyl acetate and the dilute solution was washed with a saturated aqueous solution of sodium chloride, dried over Na₂SO₄ and concentrated. The colorless oily residue thus obtained was subjected to silica gel column chromatography by using benzene and then benzene/ethyl acetate (30:1), giving 34.7 mg of benzyl 2-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo-[3,2,0]hepto-2-ene-6-yl)-ethoxythiocarbonylthiomethyl-3-butenate in 79% yield. NMR (δ, CDCl₃) 1.35 (t, 3H, 7Hz), 3.80 (s, 2H), 4.60 (q, 2H, 7Hz), 4.90 (s, 2H), 5.06 (s, 2H), 5.16 (s, 1H), 5.37 (s, 1H), 5.86 and 6.00 (ABq, 2H, 4Hz), 6.7-7.4 (m, 5H), 7.32 (s, 5H) Example 2 A 1 ml quantity of acetone was added to 21.4 mg of methyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-chloromethyl-3-butenate to obtain a uniform solution. To the mixture were added 25.4 mg of and the resulting admixture was stirred at room temperature for 60 minutes. The reaction mixture was diluted with 5 ml of dimethyl ether and the dilute solution was washed with a saturated aqueous solution of sodium chloride, dried over Na₂SO₄ and concentrated. The pale yellow oily residue thus obtained was subjected to silica gel column chromatography by using benzene/ethyl acetate (10:1), giving 22.8 mg of methyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hepto-2-ene-6-yl)-3-ethoxythiocarbonylthiomethyl-3-butenate in 86% yield. NMR (δ, CDCl₃) 1.39 (t, 3H, 7Hz), 3.70 (s, 5H), 3.87 (s, 2H), 4.63 (q, 2H, 7Hz), 5.00 (s, 1H), 5.07 (s, 1H), 5.34 (s, 1H), 5.87 (bs, 2H), 7.25 (s, 5H) Example 3 A 1.2 ml quantity of acetone was added to 94.6 mg of benzyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-chloromethyl-3-butenate to obtain a uniform solution. To the solution were added 64.3 mg of NaI and the mixture was heated to 55°C while being stirred for 1.5 hours. The reaction mixture was cooled to room temperature and diluted with 5 ml of ethyl acetate. The dilute solution was washed with an aqueous solution of Na₂S₂O₃ and then a saturated aqueous solution of sodium chloride, dried over Na₂SO₄ and concentrated, affording 113.0 mg of benzyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-iodomethyl-3-butenate as a colorless oil in 99% yield. NMR (δ, CDCl₃) 3.63 (s, 2H), 3.83 (s, 2H), 4.95 (s, 1H), 5.17 (s, 2H), 5.23 (s, 2H), 5.38 (s, 1H), 5.87 (bs, 2H), 7.26 (s, 5H), 7.33 (s, 5H) Example 4 A 10 ml quantity of acetone was added to 376 mg of methyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo-[3,2,0]hepto-2-ene-6-yl)-3-chloromethyl-3-butenate to obtain a uniform solution. To the solution were added 230 mg of NaI and the resulting mixture was heated to 55°C while being stirred for 3 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The dilute solution was washed with an aqueous solution of Na₂S₂O₃ and then a saturated aqueous solution of sodium chloride, dried over Na₂SO₄ and concentrated. The pale yellow oily residue thus obtained was subjected to silica gel column chromatography, using hexane/ethyl acetate (4:1), giving 425 mg of methyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo-[3,2,0]hepto-2-ene-6-yl)-3-iodomethyl-3-butenate in 90% yield. NMR (δ, CDCl₃) 3.62 (bs, 2H), 3.74 (s, 3H), 3.87 (bs, 2H), 5.04 (s, 1H), 5.21 (s, 1H), 5.91 (bs, 2H), 7.27 (s, 5H) Example 5 A 10 ml quantity of acetone was added to 374 mg of benzyl 2-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo-[3,2,0]hepto-2-ene-6-yl)-3-chloromethyl-3-butenate to obtain a uniform solution. To the solution were added 154 mg of NaI and the mixture was heated to 55°C while being stirred for 3 hours. The reaction mixture was cooled to room temperature and the mixture was diluted with ethyl acetate. The dilute solution was washed with an aqueous solution of Na₂S₂O₃ and then a saturated aqueous solution of sodium chloride, dried over Na₂SO₄ and concentrated. The pale yellow oily residue thus prepared was subjected to silica gel column chromatography by using benzene/ethyl acetate (30:1), giving 359 mg of benzyl 2-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-iodomethyl-3 -butenate in 80% yield. IR (neat) 1796, 1736 cm⁻¹ NMR (δ, CDCl₃) 3.73 (bs, 2H), 4.90 (bs, 2H), 5.00 (s, 1H), 5.20 (s, 3H), 5.45 (s, 1H), 5.85 and 6.01 (ABq, 2H, 4Hz), 6.7-7.4 (m, 5H), 7.34 (s, 5H) Example 6 A 0.9 ml quantity of dimethyl sulfoxide was added to 103.5 mg of benzyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-iodomethyl-3-butenate to obtain a uniform solution. Thereto were added 80 mg of NaNO₃ and 40 mg of methyl methanesulfonate and they were dissolved in the solution. The reaction system was heated to 48°C and reacted for 4 hours while being maintained at reduced pressure of 45 to 50 mmHg by a water-jet pump. The resulting reaction mixture was left to stand until it was cooled to room temperature. To the mixture was added an aqueous solution of Na₂S₂O₃ and the resultant mixture was vigorously agitated and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over Na₂SO₄ and concentrated. The yellow oily residue thus obtained was subjected to silica gel column chromatography by using benzene/ethyl acetate (15:1), giving 68.5 mg of benzyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-nitroxymethyl-3-butenate in 76% yield. IR (neat) 1780, 1740, 1640, 1275 cm ⁻¹ NMR (δ, CDCl₃) 3.85 (s, 2H), 4.74 (s, 2H), 5.01 (s, 1H), 5.18 (s, 2H), 5.22 (s, 1H), 5.43 (s, 1H), 5.89 and 5.93 (ABq, 2H, 4Hz), 7.28 (s, 5H), 7.34 (s, 5H) Example 7 A 0.25 ml quantity of methylene chloride was added to 31.2 mg of benzyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-nitroxymethyl-3-butenate to obtain a uniform solution. To the solution were added 15 mg of zinc powder and the mixture was cooled to 0 to 5°C. Thereto were added 0.25 ml of acetic acid and the mixture was reacted while being stirred for 130 minutes. The reaction mixture was diluted with 3 ml of ethyl acetate. The dilute solution was washed with a saturated aqueous solution of NaHCO₃ and then a saturated aqueous solution of sodium chloride, dried over Na₂SO₄ and concentrated at reduced pressure. The pale yellow oily residue thus obtained was subjected to silica gel column chromatography by using benzene/ethyl acetate (3:1), giving 22.6 mg of benzyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-hydroxymethyl-3-butenate in 80% yield. IR (neat) 3380, 1770, 1740, 1150 cm⁻¹ NMR (δ, CDCl₃) 2.12 (bs, 1H), 3.85 (s, 2H), 3.97 (s, 2H), 5.00 (s, 1H), 5.08 (s, 1H), 5.20 (s, 2H), 5.29 (s, 1H), 5.91 (s, 2H), 7.32 (s, 5H), 7.37 (s, 5H) Example 8 A 0.5 ml quantity of dioxane was added to 32.0 mg of benzyl 2-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3hoxythiocarbonylthiomethyl-3-butenate to obtain a uniform solution. To the solution was added 0.09 ml of a 10% hydrochloric acid solution and the resulting mixture was reacted at room temperature for 15 minutes. Aside from the above procedure, 1.9 ml of dioxane was added to 66.6 mg of pentachlorobenzene thiol and the mixture was heated in a hot-water bath to obtain a uniform solution. Thereto was added 0.24 ml of a 1 M carbon tetrachloride of hydrochloric acid and the mixture was reacted for 15 minutes. The reaction mixture was added to the foregoing dioxane solution and the resulting mixture was reacted with stirring at room temperature for 30 minutes. The reaction mixture was passed through a short silica gel column using ethyl acetate and the eluate was concentrated at reduced pressure. The residue thus obtained was dissolved in benzene and the benzene was distilled off at reduced pressure. The residual mixture of colorless solids and pale yellow oily product thus obtained was subjected to silica gel column chromatography, using benzene and then benzene/ethyl acetate (40:1), giving 17.1 mg of benzyl 2-(3-phenoxyacetamide-4-pentachlorophenyldithio-2-azetidinone-1-yl)-3-ethoxycarbonylthiomethyl-3-butenate in 34% yield. Example 9 A 0.25 ml quantity of dioxane was added to 25.1 mg of methyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-ethoxycarbonylthiomethyl-3-butenate to obtain a uniform solution. To the solution was added 50 µl of water. Aside from the above procedure, 9.4 ml of 2-mercaptobenzothiazole and 14.2 mg of iodine were dissolved in 1 ml of dioxane. The solution thus obtained was added to the foregoing dioxane solution. The mixture was reacted at room temperature for 90 minutes. The reaction mixture was diluted with 5 ml of diethyl ether and the dilute solution was washed with an aqueous solution of Na₂S₂O₃ and a saturated aqueous solution of sodium chloride, dried over Na₂SO₄ and concentrated at reduced pressure. The yellow oily residue thus obtained was subjected to silica gel column chromatography, using benzene/ethyl acetate (8:1), giving 18.2 mg of methyl 2-(3-phenylacetamido-4-(2-benzothiazolydithio)-2-azetidinone-1-yl)-3-ethoxythiocarbonylthiomethyl-3-butenate in 52% yield. Example 10 A 0.15 ml quantity of methylene chloride was added to 12.9 mg of benzyl 7-phenylacetamide-3-nitroxymethyl-3-cephem-4-carboxylate to obtain a uniform solution. Thereto were added 5.2 mg of zinc powder and the mixture was cooled to 0 to 5°C. To the mixture were added 0.15 ml of acetic acid and the resulting mixture was agitated for 135 minutes. The reaction mixture was diluted with 3 ml of ethyl acetate and the dilute solution was washed with a saturated aqueous solution of NaHCO₃ and with a saturated aqueous solution of sodium chloride and dried over Na₂SO₄. The concentration at reduced pressure of the dried product gave 10.0 mg of benzyl 7-phenylacetamide-3-hydroxymethyl-3-cephem-4-carboxylate in 85% yield. NMR (δ, CDCl₃) 2.60 (bs, 1H), 3.52 (s, 2H), 3.61 (s, 2H), 4.02 and 4.48 (ABq, 2H, 13.5Hz), 4.90 (d, 1H, 4Hz), 5.25 (s, 2H), 5.81 (dd, 1H, 4Hz, 9Hz), 6.51 (d. 1H, 9Hz), 7.28 (s, 5H), 7.37 (s, 5H)

Claims: A process for preparing a cephalosporin derivative represented by the general formula (V): wherein: R¹ represents a phenylmethyl or phenoxymethyl group each optionally substituted with methyl, halogen, nitro or p-methoxy on the phenyl ring; R² represents a carboxyl group or protected carboxyl group; Y is (a) -SC(=S)OR³ wherein R³ is C₁-C₄ alkyl optionally substituted with halogen or phenyl optionally substituted with methyl, halogen, nitro or p-methoxy; or (b) protected hydroxyl, the process being characterized by the steps of: (1) (A) reacting a thiazolinoazetidinone derivative represented by the general formulator (I) : wherein R¹ and R² are as defined above with a nucleophilic reagent of the general formula wherein M represents an alkali metal and R³ is as defined above in an organic solvent to produce the compound of the general formula: or (B) reacting a thiazolinoazetidinone derivative represented by the general formula (I): wherein R¹ and R² are as defined above with an alkali metal iodide in an organic solvent to produce a thiazolinoazetidinone derivative represented by the general formula (VI) wherein R¹ and R² are as defined above; reacting a thiazolinoazetidinone derivative represented by the formula (VI) with NaNO₃ or KNO₃ in an organic solvent to produce the compound of the general formula (II') wherein R¹ and R² are as defined above; reacting the compound of the formula (II') with zinc in the presence of acetic acid to obtain a thiazolinoazetidinone derivative represented by the general formula (IX) wherein R¹ and R² are as defined above, and protecting the hydroxyl group of the derivative of the formula (IX) with an agent for protecting hydroxyl group of the formula ASi(R³)₃, CF₃SO₃·Si(R³)₃, wherein R³ is as defined above and A is a chlorine, bromine or iodine atom in an organic solvent in the presence of an acid-trapping agent; (2) reacting the resulting compound represented by the general formula (II): wherein R¹, R² and Y are as defined above in a water-containing solvent with a sulfur-containing compound represented by the general formula (III): Z - S - X wherein Z represents phenyl, phenyl substituted with halogen or nitro, 2-pyridyl, 2-benzothiazolyl, 1,3,4-thiadiazol-2-yl or 5-methyl-1,3,4-thiadiazol-2-yl and X represents a halogen atom to obtain an azetidinone derivative of the general formula (IV) wherein R¹, R², Y and Z are as defined above; and (3) reacting the compound of the formula (IV) with ammonia in an organic solvent to effect the ring closure. The process as defined in claim 1 wherein: R¹ is a phenylmethyl or phenoxymethyl group, R² is a carboxyl group or a protected carboxyl group, Y is (a) -SC(=S)OR³ wherein R³ is C₁-C₄ alkyl optionally substituted with halogen; or (b) protected hydroxyl, and Z is a phenyl group substituted with halogen or 2-benzothiazolyl, and the agent for protecting hydroxyl group in the step (1) (B) is a compound of the general formula wherein R³ is C₁-C₄ alkyl optionally substituted with halogen and A is chlorine, bromine or iodine. A process for preparing a caphalosporin compound represented by the formula (XI): wherein R¹ is phenylmethyl optionally substituted with methyl, halogen, nitro or p-methoxy on the phenyl ring and R² is a carboxyl group or a protected carboxyl group, by reacting a cephalosporin compound represented by the general formula (X) wherein R¹ and R² are as defined in claim 1 with zinc in the presence of acetic acid. The process as defined in claim 3 wherein R¹ is phenylmethyl.

Inventors: NOGAMI JUNZO, SAITO NORIO, SASAOKA MICHIO, SHIROI TAKASHI, TANAKA HIDEO, TORII SHIGERU, NOGAMI, JUNZO, SAITO, NORIO, SASAOKA, MICHIO, SHIROI, TAKASHI, TANAKA, HIDEO, TORII, SHIGERU
Applicants: OTSUKA KAGAKU YAKUHIN, OTSUKA KAGAKU YAKUHIN KABUSHIKI KAISHA
Application year: 1983
Main classification: C07D501
IPC codes: C07D501