Title of Invention

PROCESS FOR PRODUCING 1-OXACEPHALOSPORIN - 7 ALPHA METHOXY-3-CHLOROMETHYL DERIVATIVE

Abstract

[Problem to be solved] To provide a novel production method of oxacephem compound. [Solution] A method of producing Compound (IV) shown by the formula- [Chemical formula 2] (wherein R represents an acyl residue R1 represents carboxy protecting group! Me represents methyl), the method comprising the steps of-(First step) letting Compound (I) shown by Formula: [Chemical formula l] (wherein, R represents an acyl residue; R1 represents carboxy protecting group) react with a halogenating agent in the presence of a base; (Second step) adding MOMe (M represents alkaline metal; Me represents methyl) in the presence of a halogenating agent after completion of the first step; and (Third step) adding a reducing agent after completion of the second step.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See Section 10) TITLE PROCESS FOR PRODUCING l-OXACEPHALOSPORIN-7 ALPHA-METHOXY- 3-CHLOROMETHYL DERIVATIVE" APPLICANT Shionogi & Co., Ltd. 1-8, Doshomachi 3-chome Chuo-ku, Osaka-shi Osaka 541-0045 Japan Nationality: a Japanese company The following specification particularly describes the nature of this invention and the manner in which it is to be performed Specification Method of producing l-oxacephalosporin-7a-methoxy-3-chloromethyl derivative Technical field [0001] The present invention relates to a method of producing an intermediate for synthesis of I-oxacephalosporin which is useful as an antimicrobial. Background art [0002] As an important intermediate for industrially producing 1-oxacephalosporin such as latamoxef or flomoxef with high efficiency, l-oxacephalosporin-7α-methoxy-3-chloromethyl derivative (hereinafter, also referred to as a 7a-methoxy-3"chloromethyl compound) is known. As a production method thereof, there is known a method wherein a 3-exomehylene compound which is a raw material is subjected to 7a-methoxylation after addition of CI2 by light irradiation. However, light irradiation generally requires expensive optical reaction equipment, and hence is not industrially advantageous. For example, Non-patent document 1 describes the following reaction. [Chemical formula l] I Non-patent documents 2 and 3 describe the following method. [Chemical formula 2] * The above process is not an one-pot reaction because Intermediate 6 is synthesized and isolated first in order to obtain 7crmethoxy-3-chloromethyl compound 4 from 3-exomehylene compound 1. In Example 4, Intermediate 6 is synthesized by letting 3-exomehylene compound 1 react with chlorine in the presence of quinoline as a base, however, the yield is as poor as about 9.6%. In Example 5, chlorination is effected using crpicoline as a base, however, optical reaction is used as well and the yield is still undesirable. In the step from Intermediate 6 to Compound 4, NaOMe/MeOH is used as a methoxylating agent, however, column chromatography is also used for removal of byproducts, so that the method cannot be regarded as being industrially advantageous. [Patent document l] Japanese Unexamined Patent Publication JP-A 59*67289 ' [Non-patent document l] ' Tetrahedron Letters Vol. 21, pp351-354, 1980 [Non-patent document 2] Kinki Kagaku Kogyo Kai (June 1988, P10) [Non-patent document 3] Yakugaku Zasshi (lll(2), P77, 1991) Disclosure of the Invention Problems to be solved by the invention [0003] Therefore, there is need of developing a production method that is simple because of avoidance of light irradiation reaction and preferably allows production of an objective product with high yield, as an industrial production method of l-oxacephalosporin-7a-methoxy3-chloromethyl derivative. Means for solving the problem [0004] As a result of diligent effort, inventors of the present invention found that 7a-methoxy3-chloromethyl compound can be obtained with high yield without use of light irradiation reaction, by using a 3-exomehylene compound as a starting material, preferably through continuous reaction, more preferably through one-pot reaction, and accomplished the present invention, (l) A method of producing Compound (IV) shown by the formula. [Chemical formula 5] (wherein R represents an acyl residue; R1 represents carboxy protecting group; and Me represents methyl), the method comprising the steps of: (First step) letting Compound (I) shown by Formula. [Chemical formula 4] (wherein, R represents an acyl residue; R1 represents carboxy protecting group) react with a halogenating agent in the presence of a base; (Second step) adding MOMe (M represents alkaline metal; Me represents methyl) in the presence of a halogenating agent after completion of the first step; and (Third step) adding a reducing agent after completion of the second step. (2) The method of producing Compound (IV) according to the above (l), the method comprising the steps of-' (First step) letting Compound (I) shown by the formula-[Chemical formula 6] (wherein R represents an acyl residue; R1 represents a carboxy protecting group) react with a halogenating agent in the presence of a base, to synthesize Compound (II) shown by the formula-' [Chemical formula 7] (wherein R and R1 are as defined above; X represents halogen); (Second step) adding MOMe (M represents alkaline metal; Me represents methyl) in the presence of a halogenating agent after completion of the first step, to synthesize Compound (III) shown by the formula: [Chemical formula 8] (wherein R, R1, Me and X are as defined above); and (Third step) letting Compound (III) react with a reducing agent to synthesize Compound (IV) shown by the formula; [Chemical formula 9] (wherein R, R1, Me and X are as defined above). (3) The production method according to the above (l) or (2), wherein the first to the third steps are conducted in a one-pot manner. (4) The production method according to any one of the above (l) to (3), wherein the base is an aromatic amine, and/or the halogenating agent is chlorine. (5) The production method according to any one of the above (l) to (4), wherein the MOMe is LiOMe. (6) The production method according to any one of the above (l) to (5), wherein the reducing agent is sodium thiosulfate or sodium sulfite. (7) The production method according to any one of the above (l) to (6), wherein R is optionally substituted phenyl, and R1 is benzhydryl. (8) The production method according to any one of the above (l) to (7), wherein 3 mol equivalent or more of chlorine is used as the halogenating agent, and 4 mol equivalent or more of LiOMe is used as the MOMe, with respect to Compound (I). (9) The production method according to the above (8), wherein 3 to 4 mol equivalent of chlorine is used as the halogenating agent and 4 to 6 mol equivalent of LiOMe is used as the MOMe, with respect to Compound (I). (10) The production method according to any one of the above (l) to (9), wherein reaction temperature of the first step is 0°C to 5°C, and reaction temperature of the second step is -40 to -60°C. (11) A method of producing Compound (IV) shown by the formula; [Chemical formula 12] (wherein R represents an.acyl residue, R1 represents carboxy protecting group; Me represents methyl and X represents halogen), comprising the steps of- letting Compound (II) shown by the formula-[Chemical formula 10] (wherein R and R1 are as defined above; X represents halogen) react with MOMe (M represents alkaline metal; Me represents methyl) in the presence of halogenating agent, to synthesize Compound (III) shown by the formula; [Chemical formula 11] (wherein R, R1, Me and X are as defined above), and letting Compound (III) react with a reducing agent. (12) A method of producing Compound (IV) shown by the formula; [Chemical formula 14] (wherein R represents an acyl residue R1 represents carboxy protecting group; Me represents methyl and X represents halogen), comprising the step of: letting Compound (III) shown by the formula-[Chemical formula 13] (wherein R, R1, Me and X are as defined above), react with a reducing agent. (13) Compound (III) shown by the formula- [Chemical formula 15] (wherein R, R1, Me and X are as defined above). (14) A method of producing a 7a-methoxy-oxacephem compound wherein production of Compound (IV) by the method according to any one of the above (l) to (12) is followed by at least one reaction selected from: l) side chain forming reaction at 3-position, 2) deacylation reaction at 7-position, 3) side chain forming reaction at 7-position, 4) deprotecting reaction at 4-position carboxy, 5) esterification reaction at 4-position carboxy, and 6) salt forming reaction. Effect of the invention [0005] According to the present invention, it is possible to readily produce Compound (IV) which is 7crmethoxy-3-halogenomethyl compound with high yield from Compound (I) which is 3-exomehylene compound. The reaction is preferably conducted by continuous reaction, more preferably by one-pot reaction. Advantageously, the one-pot reaction of the present invention requires no reaction stopping agent, and dispenses with operations such as concentration of reaction solution, extraction during the process, and solvent substitution, and hence is very advantageous as an industrial production method. Also, the present invention provides Compound (III) which is a novel intermediate in such a production method. The present production method is applicable to industrial production of a variety of 7α methoxy-oxacephem compounds. Best mode for carrying out the invention [0006] Now, production methods of Compound (IV) from (I) will be explained. (First step) By letting Compound (I) shown by the formula; [Chemical formula 16] (wherein K represents an acyl residue; R1 represents a carboxy protecting group) react with a halogenating agent in the presence of a base, in a solvent as desired, Compound (II) shown by the formula- [Chemical formula 17] (wherein R and R1 are as defined above X represents halogen) is synthesized. The base may be either an organic base or an inorganic base. As an organic base, aromatic amines, preferably pyridine derivatives (e.g., pyridine, 4-dimethylaminopyridine, picoline (e.g., 2-picoline), lutidine (e.g., 2,6-lutidine), collidine (e.g., 2,4,6-collidine)) or aliphatic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo [5.4.0]undeca-7-ene (DBU), 1,5-diazabicyclo [4.3.0]nona-5-ene (DBN)) are used. Preferably, aromatic amines, especially, pyridine derivatives, in particular, pyridine, 2-picoline, 2,6-lutidine, 2,4,6-collidine are exemplified. A use amount of the base is about 1 to 5 mol equivalent, preferably about 1 to 1.5 mol equivalent, with respect to Compound (I). Addition of the base promotes the reaction, and has effects of keeping the reaction solution neutral by capturing hydrogen chloride generating as a byproduct, and preventing a starting material or a product from decomposing. As the halogenating agent, chlorine, bromine and the like are exemplified, with chlorine being preferred. A use amount of the halogenating agent is 3 mol equivalent or more, preferably 3 to 5 mol equivalent, more preferably 3 to 4 mol equivalent, and particularly preferably 3.1 to 3.5 mol equivalent, with respect to Compound (I). For the exclusive purpose of conversion from Compound (I) to Compound (II), 2 mol equivalent theoretically suffices as the use amount of the halogenating agent. In the present invention, however, it was also found that when the base is used in an amount exceeding the above range, remaining base efficiently allowed proceeding of the reaction of the second step. Therefore, when continuous reaction is executed in one pot system, for example, it is preferred to use the base in an amount exceeding the theoretical value. This is one feature of the present invention. As the reaction solvent, various kinds of solvents can be used as far as they do not adversely influence on the reaction, and it is, for example, selected from methylene chloride, acetonitrile, ethyl acetate, toluene, chloroform, tetrahydrofuran, dimethyl formamide, dimethyl acetamide or mixed solvents thereof, but it is preferably methylene chloride. Reaction temperature is usually "20°C to 50°C, preferably -10°C to room temperature, and more preferably from 0°C to around room temperature. Reaction time is several hours to several tens hours, and preferably 2 to 3 hours. Compound (II) produced at the first step may be isolated first, however, the next step may be started in the form of its reaction solution without isolation process. [0007] (Second step) After completion of the first step, the isolated Compound (II) or the reaction solution of the first step is added with MOMe (M represents alkaline metal; Me represents methyl) in the presence of a halogenating agent, to synthesize Compound (III) shown by the formula-[Chemical formula 18] (wherein R, R1, Me and X are as defined above). As the halogenating agent, those recited above are exemplified. When the reaction continues from the first step, as is previously described, the halogenating agent remaining after completion of the first step can desirably be diverted. A use amount of the halogenating agent is 1 mol equivalent or more, preferably about 1 to 2 mol equivalent, with respect to Compound (II). After reaction, a part of halogen forms a salt (MX, (X is halogen atom)) with alkaline metal derived from MOMe. As M(alkaline metal) in the MOMe(Me is methyl), Li and Na are exemplified, however it is preferably Li. As a methoxylating agent, Mg(OMe)2 or the like may be used. A use amount of the MOMe is 4 mol equivalent or more, preferably about 4 to 6 mol equivalent, more preferably about 4.5 to 5.2 mol equivalent, with respect to Compound (II). In order to improve the yield of the second step, selection of a use ratio of the halogenating agent and the MOMe is important. Especially when the second step continues from the first step, the halogenating agent is used in an amount of preferably 3 to 4 mol equivalent, more preferably of 3.1 to 3.5 mol equivalent, with respect to Compound (I), and the MOMe is used in an amount of preferably about 4 to 6 mol equivalent, more preferably about 4.5 to 5.2 mol equivalent, with respect to Compound (II). MOMe is preferably added in the form of a methanol solution. As the reaction solvent, those recited above may be used as necessary. Reaction temperature is usually "70°C to "20°C, preferably -60°C to -30°C, more preferably -50°C to -40°C. Reaction time is several hours to several tens hours, preferably 2 to 3 hours. Compound (III) produced at the second step may be isolated first, however, the next step may be started in the form of its reaction solution without isolation process. Compound (III) is a novel compound and is an intermediate which is suited for the present production method. [0008] (Third step) After completion of the second step, the isolated Compound (III) or the reaction solution from the second step is added with a reducing agent, to synthesize Compound (IV) shown by the formula; [Chemical formula 19] (wherein R, R1, Me and X are as defined above). As the reducing agent, various kinds of agents may be used insofar as they are capable of reducing N-Cl at 7-position of Compound (III) to NH, and examples include sodium sulfite, sodium thiosulfate, acidic sodium sulfite, dialkylsulfide (e.g., dimethylsulfide), and phosphines (e.g., tripmehylphosphine), with sodium sulfite or sodium thiosulfate being preferred. In the case of sodium sulfite, it is added in the form of an aqueous solution of preferably about 1 to 10%, more preferably about 5 to 10%. A use amount of the reducing agent is about 1 to 10 mol equivalent, preferably about 1 to 6 mol equivalent, with respect to Compound (III). Reaction temperature is usually 0°C to 50°C, preferably 5°C to room temperature. Reaction time is several minutes to several hours, preferably 10 minutes to 1 hour. Since Compound (III) which is an intermediate synthesized in the second step is not deprotonated even in the presence of MOMe, it is stable because intramolecular cleavage in the B-lactam ring will not proceed. Further, since Compound (IV) which is the final product is isolated without exposure to a basic condition, such cleavage can be avoided. As described above, one feature of the present production method lies in generating first Compound (III) from Compound (II) by controlling the reaction condition, and as a result, generation of a byproduct is prevented, and the objective Compound (IV) is unexpectedly obtained with high yield (e.g., 75% or more, preferably 80% or more, more preferably 90% or more) even with the triple steps. [0009] (Definition of substituents) The acyl residue represented by R is commonly available in the field of cephalosporin chemistry, and various acyl residues can be used insofar as they are derived from acyl groups capable of bonding with 7-position amino group in an oxacephem backbone. Such acyl may be an acyl that forms 7-position side chain of an objective antibiotic compound, or may be an acyl serving as an amino protecting group in the course of synthesizing the same. As the R, an acyl residue derived from an amino protecting group is preferred, and examples of such acyl residue include optionally substituted phenyl or benzyl (substituents lower alkyl (e.g., methyl, ethyl), halogen, nitro, lower alkoxy (e.g., methoxy)) or phenoxymethyl. Preferably, it is optionally substituted phenyl. The carboxy protecting group represented by R1 includes carboxy protecting groups that are well-known in the art of cephalosporin chemistry as being attachable/detachable without causing any undesired change on other parts in the molecule. Typical examples include ester-forming alkyls having 1 to 8 carbons (methyl, methoxymethyl, ethyl, ethoxyethyl, iodoethyl, propyl, isopropyl, butyl, isobutyl, ethoxyethyl, methylthioethyl, methane sulfonylethyl, trichloroethyl, t-butyl and the like), alkenyls having 3 to 8 carbons (propenyl, allyl, isopropenyl, hexenyl, phenylpropenyl, dimethylhexenyl and the like), aralkyls having 7 to 19 carbons (benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, benzhydryl, phenylethyl, trityl, di-t-butyl hydroxybenzyl, phthalidyl, phenacyl and the like), aryls having 6 to 12 carbons (phenyl, toluyl, diisopropylphenyl, xylyl, trichlorophenyl, pentachlorophenyl, indanyl and the like), amino groups having 1 to 12 carbons (acetone oxime, acetophenone oxime, acetoaldoxime, groups that form an ester such as N-hydroxy succinic imide or N-hydroxy phthalimide), hydrocarbonated silyls having 3 to 12 carbons (trimethyl silyl, dimethylmethoxy silyl, t-butyldimethyl silyl and the like), and hydrocarbonated stannyl having 3 to 12 carbons (trimethyl stannyl and the like). Aralkyls are preferred, and benzhydryl is more preferred. Compound (IV) that is obtainable in the present production method is useful as an intermediate for synthesis of oxacephem antibiotics. For example, according to procedures well known in the art, an objective 7crmethoxy-oxacephem compound can be obtained by conducting on Compound (IV) appropriate combination of the reactions selected from- 1) side chain forming reaction at 3-position (e.g., nucleophilic reaction on 3-position methylene), 2) deacylation reaction at 7-position (e.g., deprotecting reaction at amino group), 3) side chain forming reaction at 7-position (e.g., acylation reaction on amino group), 4) deprotecting reaction at 4-position carboxy, 5) esterification reaction at 4-position carboxy, and 6) salt forming reaction. [0010] 35.2 g (75.1 mmol) of 7-benzoyl-exomethylene (Compound l) was dissolved in 260 mL of methylene chloride, and added with 6.5 g (1.1 eq) of pyridine over 5 minutes at 0°C. After stirring for 5 minutes at the same temperature, 18.5 g (3.29 eq) of chlorine was introduced over 150 minutes at 0°C. Then generation of Compound 2 (mixture of 3-position isomers) in the reaction solution was confirmed by HPLC (high performance liquid chromatography). Further, a part of reaction solution was taken out and extracted with methylene chloride, and treated with aqueous hydrochloric acid, and aqueous sodium hydrogen carbonate, to isolate Compound 2. Then, after stirring for 20 minutes at the same temperature, 157 mL (4.75 eq) of 10% LiOMe (lithium methoxide) solution in ethanol was added dropwise over 140 minutes at -40 to -50°C. Then a part of the reaction solution was take out, extracted with methylene chloride, and treated with aqueous hydrochloric acid, and aqueous sodium hydrogen carbonate, to isolate Compound 3. Then after stirring for 5 minutes at the same temperature, 4.4 mL (1.02 eq) of acetic acid was added. The above reaction solution was added to 5.5% sodium sulfite solution in water (351 mL, 2.2 eq) over 20 minutes at 10°C, and then added with 13.4 mL (2.0 eq) of 35% hydrochloric acid. The methylene chloride layer was separated, washed with a diluted sodium bicarbonate aqueous solution, and dried over sodium sulfate, and then solvent was concentrated. Then methanol was added to allow precipitation of 76-benzoyl-7crmethoxy-3-chloromethyl compound (Compound 4). After cooling on ice, Compound 4 was obtained through filtration. (Compound 4) 1 NMR (CDCla) 8: 3.63 (3H, s, C7-OCH3), 4.50 (2H, s, C3H or C2-H), 4.55 (2H, s, C2-H or Cs-H), 5.25 (1H, s, Ce-H), 7.00 (1H, s, CHPh2), 7.10-7.95 (16H, m, C6H5) NH) [0011] Example 2 [Chemical formula 21] To a solution of Compound 4 (16 g) obtained in Example 1 in methylene chloride (850 mL), an aqueous solution (120 mL) of sodium-l-methyl-lH-tetrazole-5-thiolate dihydrate (5.43 g) and tetra-n-butylammonium bromide (300 mg) was added. The mixture was vigorously stirred at room temperature, and after an hour, added with sodium-l-methyl-lH-tetrazole-5-thiolate dihydrate (2.8 g) and quaternary ammonium salt (300 mg), and stirred for another hour. The reaction solution was separated, and the aqueous phase was extracted with methylene chloride, to give tetrazolyl thiomethyl compound (Compound 5)(l8.1 g). This was then crystallized from benzene-ether (1-2), to give crystalline Compound 5 containing benzene as crystalline solvent. Compound 5 is useful, for example, as an intermediate for synthesis of latamoxef described in JP-A 52-133997. mp 88 to 89°C 1H NMR (CDCb) 8: 3.63 (3H, s, C7-OCH3), 3.82 (3H, s, N-CH3), 4.28 (2H, s, C2-H), 4.65 (2H, s, C3-H ), 5.17 (IH, s, C6-H), 6.95 (1H, s, CHPh2), 7.20-8.00 (15H, aromatic-H) According to the above method, the following Compound 6 is synthesized. [Chemical formula 22] K = rn vpnenyi; R, = BH(benzhydryl) Compound 6 is useful, for example, as an intermediate for synthesis of flomoxef described in JP-A 59-139385. [0012] Example 3 According to the method of Example 1, for the case of R=tolyl, Compound (IV) is obtained from Compound (I) in high yield (R1=BH, X=C1) by conducting reaction in similar manner, with the use of pyridine, 4-dimethylaminopyridine, picoline, lutidine, or collidine as a base. Example 4 According to the method of Example 1, for the case of R=4-chlorophenyl, Compound (IV) is obtained from Compound (I) in high yield (R1=BH, X=C1) by conducting reaction in similar manner with the use of pyridine, 4-dimethylaminopyridine, picoline, lutidine, or collidine as a base. Example 5 According to the method of Example 1, for the case of R=phenoxymethyl, Compound (IV) is obtained from Compound (I) in high yield (R1==BH, X=C1) by conducting reaction in similar manner with the use of pyridine, 4-dimethylaminopyridine, picoline, lutidine, or collidine as a base. Example 6 Through deacylation of a 7-position amino side chain moiety in Compound (IV) obtained by the method described in any one of - Example 1 or Examples 3 to 5, 76-amino"7-a-methoxy3-chloromethyl"l-dethia-l-oxa-3-cephem-4-boxylic acid diphenyl methyl ester can be obtained.

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