JPS6041682A - Novel cephalosporin compound and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> and R<2> are H or lower alkyl; R<3> is lower alkanoyloxy, heterocyclic group or heterocyclic-thio; n is 0-3) and its salt. EXAMPLE:syn-7-[2-( 2-Aminothiazol-4-yl )-2-( 3D,L-3-amono-3-carboxy )-propyloxyiminoacetamido]-3-( 1-methyl-1H-tetrazol-5-y1 )thiomethyl-3-cephem-4-carboxylate. USE:An antibacterial agent effective to Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. PREPARATION:The compound of formula I can be produced e.g. by reacting the 7-aminocephalosporanic acid compound of formula II (R<4> is H or carboxyl-protecting group) or its salt with the compound of formula III (R<5> is H or amino- protecting group; R<6> is amino-protecting group; R<7> is carboxyl-protecting group; n is 0-3) or its derivative, and removing the protecting groups.

Description

[Detailed description of the invention]

The present invention relates to a novel cephalosporin compound and its structurally acceptable salt, and also to a method for producing the same. The cephalothorax of the present invention, I? IJ derivatives are new compounds that have excellent antibacterial effects and are widely used in medicine.
Cephalosporin compounds have antibacterial properties, and research on their synthesis is actively being conducted.
Many compounds have been produced so far, and some of them are currently of clinical importance as excellent broad-spectrum antibiotics. The present inventors have revealed that a compound in which the terminal end of the side chain at position 7 is a D-amino acid has excellent bactericidal activity and has a remarkable infection-preventing effect in VIVQ (Special e1)
No. 56-1.56286, No. 56-4611185
No. 1984-46884 and No. 56-12'87
Based on this knowledge, the present invention has conducted repeated research with the aim of finding even better compounds, and as a result, a new compound represented by the following general formula [■] having an amino acid in the lead has a green color. They discovered that it has excellent antibacterial activity against Durham positive and negative bacteria including Pseudomonas, and completed the present invention. In other words, the present invention (R4, the following general formula % formula %) [wherein R and R are hydrogen atoms or lower (Cq to Cb)
It represents an alkyl group, and R is a lower (C+ to C6) alkanoyloxy group, especially an acetoxy group. or represents a multicyclic cyclic group or a multicyclic thio group, and n is 0 to 3
cephalosporin compound represented by ] representing an integer of
and its 8 Salts, ammonium salts or salt-containing amino acids such as L-Ritz groups are preferred. The compound of general formula [I] is a syn isomer;
Regarding the asymmetric carbon atom in the 7-position side chain, the existence of 0-form and L-form is possible; however, in the present invention, both of them and the DL form Dl+ include 2-amino-2-calzxyethyl,
2-amino-2-carboxy-1-mer-7-ethoxy group, 3-amino-3-carbogicipropyloxytin, 2-amino-2-carboxy-1-inpropyl-
Ethoxyg, 4-amino-4-carboxy-butoyamu, etc. are used alone. Specific examples of the heterocyclic thio group (hereinafter also simply referred to as S-heterocycle) of the group R in the compound of formula (2) are (1-methyl-IH-tetrazol-5-yl). )thio group, (+-carboxymethyl-IH-tetrazole-
5-yl)thio group. (1-dimethylamineethyl-+ ti-tetrazol-5-yl)thio group, (2-methyl-1,3゜4-thiadiazol-5-yl)thio group, (2-N-methylcarbamoyl- 1,3,4-thiadiazole-5-・``
) thio group, (IH-1,2゜3-triazole-5-
yl)thio group, (N-methyl-pyridinium-2-yl)thio group. (2,5-dihydro-6-hydroxy-2-methyl-5
-oxy-1.2.4-triazon-3-yl)thio group, and specific examples of the heterocyclic group (hereinafter also simply referred to as heterocycle) of R include pyridinium group, 4-carbamoyl- Pyridinium group, 3-amino-pyridinium group, 4-methylpyrizonium group, 4
-(2-sulfoethyl)-pyridinium group, quinolinium group, inquinolinium group, pyrazinium group. Examples include: Although the substrate 91 of the compound of the present invention represented by the general formula [■] is not limited to the following, examples thereof include compounds represented by the following formula. As a method for producing the compound of general formula (I), the following (a) is used. There are three methods of the present invention: bl, (c). That is, the method (al) 7-amine represented by the following formula C, where R represents a lower alkanoyloxy group, a dicyclic group, or a heterocyclic thio group, and R represents a hydrogen atom or a protecting group for a carzaxyl group. A cephalosilyanic acid compound or a salt thereof is prepared by the following formula [wherein R and R represent a hydrogen atom or a lower alkyl group, R represents a hydrogen atom or a protecting group for an amine group, and R
represents a protecting group for an amine group, R represents a retaining group for a carboxyl group, and n represents an integer of 0 to 3] or a carboxylic acid active i1 conductor thereof is reacted to form the following A compound of the formula % formula % [) [in the formula, R, R, R, R, R, R, R and n have the above-mentioned meanings] is produced, and later from this compound an amino protecting group and a carboxyl group protecting group are formed. % [wherein R, R, R and n has the above-mentioned meaning], and Toreno Shiba Jul!
Method for producing a chemically acceptable salt (bl) The following formula [wherein R represents a lower alkanoylmexyl group, a heterocyclic group, or a heterocyclic thio group, and R4 represents a hydrogen atom or a protecting group for a carboxyl group] R5 represents a hydrogen atom or a protecting group for an amino group] to a compound represented by the following formula [wherein, R1 and R2 represent a hydrogen atom or a lower alkyl group, R represents a lip-retaining group for an amino group, and R7 represents a pupil retaining group of a cardoxyl group, and n represents an integer of O to 3] is reacted with a hydroxylamine compound represented by the following formula [where R, R, R, R, R, R, R and n are 0i2 before
], and later from this compound an amino protecting group and a calHf xyl group H! Hj 1.
(%) [wherein R, R, R and n has the above-mentioned meaning] and a method for producing a cephalosporin compound and a physiologically acceptable salt thereof. Method (cl The following formula % Formula % [In the formula, R and R represent a hydrogen atom or a lower alkyl group, R and R represent a hydrogen atom or a salivary group of CalHf xyl group, R is a hydrogen atom, or represents a protecting group for an amine group, R represents a protecting group for hydrogen or an amino group, R represents a substitutable group 9 such as an acetoxy group, chloro, bromo, iodo q, n represents an integer from O to 3], a heterocyclic thiol compound of the following formula % [[wherein R represents a heterocyclic group]] or a heterocyclic thiol compound of the following formula [wherein R represents a hydrogen atom, Hydroxyl group, amine group, carboxyl group, sulfonic acid group, alkyl group, )゛0 group, carboxyl group, or formula = (CTT, )□-R (However, RIO
has the same meaning as above, m represents an integer from 1 to 3)
represents a group in which RII, R12 and R13 are each a hydrogen atom, or two of RI + , R12 and R13 that are compatible with each other form an aromatic ring or a heterocycle. group and the remaining one is hydrogen], or a nitrogen-containing or sulfur-containing double purple ring compound containing two or more nitrogen atoms or containing a sulfur atom as a different atom. The following formula cn-cooR' 11°, 11. [In the formula, R'+'R21rt'l'R51rt6. u
7 and n have the same meanings as above, and are R or O or a heterocyclic group derived from the above-mentioned nitrogen-containing or sulfur-containing heterocyclic compound. The general formula % formula % (wherein R, R, rt and n have the above meanings) is formed by forming a compound and removing the protecting group.
A method for manufacturing cephalosporin compounds is shown. The protected 4 5 6 7 groups (R, wo, 1?, , R, etc.) of the amino group and carbyxyl group in the compound of the above general formula [old, [m], If), rV] or [■] are as follows: , β−
Those used for this purpose in the decomposition of lactam and -2f tide synthesis are conveniently employed. As a protecting group for an amino group, "1j is fluoroyl,
Formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methoxycarvinyl,
Ethical d? Nyl, t-butoxy7carbonyl,
Examples include trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbinyl, diphenylmethyloxycarbinyl, methoxymethyloxycarbinyl, trityl, trimethylsilyl, and the like. Cal on the other hand? Ti, f as the n group of xyl group
MLt is t-butyl, t-amyl, benzyl,
p-nitrobenzyl, I)-/') gicibenzyl, benzhydryl, phenyl, p-nitrophenyl,
Methoxymethyl, ethoxymethyl, be/zyloxymethyl, acetoxymethyl, methylthiomethyl,
trityl, trichloroethyl, trimethylsilyl,
Dimethylsilyl, diphenylmeth, cybenzenesulfonylmethyl, dimethylaminoethyl, etc. are exemplified.The acylation reaction in the above H production method (at)
This is carried out by reacting 1 to 3% of the carboxylic acid-reactive derivative of the compound [■] with 1 mole of [11]. Examples of reactive derivatives include acid halides, acid anhydrides, active amides, and active ester derivatives. Preferred examples include mixed acid anhydrides with acid chlorides, acid bromides, acetic acid, piparic acid, isovaleric acid, trichloroacetic acid, etc.
active amides of pyrazole, imidazole, dimethylpyrazole, benzotriazole, etc., p-nitrophenyl ester, 2,4-dinitrophenyl ester, )IJ
/lorophenyl ester, 1-hydroxy-1)I-2
-Pyridone, N-hydroxysuccinimide. Examples include active esters of N- and doro-shiphthalimide. In addition, in this reaction, when the compound [■] is used in the form of a free acid, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of the condensing agent include, for example, N,N-dicyclo Hexylcarbidimide. 1q-cyclohexyl-N'-morpholinoethylcarbidimide, N-cyclohexyl-N'-(4-noethylaminocycloheyacyl) car? Cal sequence such as soimide?
Neumide compound, N-methylformamide, N,N-
Amide compounds such as dimethylformamide, thionyl chloride, and phosphorus oxychloride. It can be carried out in the presence of a reagent (so-called male Lussmeyer test mulberry) produced by reaction with a monorodanide such as phosgene. Among the reactive mR conductors in this reaction, the acylation reaction with acid halides and acid anhydrides requires the presence of an acidic binder, such as triethylamine, triethylamine,
Trimethylamine, ethylnoisopropylamine, N
, N-dimethylamine, N-methylmorpholine, organic bases such as pyridine, alkali golds such as sodium, potassium or calcium hydroxides, carbonates, bicarbonate, and oxiranes such as ethylene oxide, fa-pyrene oxide, etc. Can be mentioned. This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as water or acetone. Acetonitrile, -)oxane, tetrahydrofuran, methylene chloride, chloroform, -,)chloroethane, N,N-dimethylformamide, or a mixed solvent thereof is used. The reaction temperature is not particularly limited, but is usually -30 to 40°C.
The reaction time is 30 minutes to 10 hours to complete the reaction. The acylated product (1'll'i) thus obtained usually has a protecting group and therefore requires removal of the protecting group.
Methods for removing protecting groups include methods using acids, bases, hydrazine, etc., depending on the type of the protecting group, and these include conventional methods used in the field of β-lactam and peptide synthesis. It can be selected and carried out as appropriate. The above production method (general formula as a starting material in bl [
■] The compound of
, 5 has the meaning of the preceding RC) can be converted into 1 m 12 by subjecting it to an acylation reaction with a compound of the general formula [■] similar to the above. - A compound of the general formula CIVI and a compound of the general formula [■] The reaction of [v] with a hydroxylamine inductor is usually carried out using dimethylformamide,
Dimethylacetamide, ace)nitrile, dioxane, tetrahydrofuran. The time required for 6 anti-F5, which is carried out in a solvent such as T /1'''-1 or #1: a solvent that does not affect the reaction, VJ, or a mixture of these and water, is usually 30 minutes to The reaction temperature is not particularly limited, but is usually carried out between room temperature and 60°C. The reaction product thus obtained [■''] is subjected to the same method as described above to remove the protective group. In particular, a compound of general formula [I] can be obtained. Furthermore, the reaction of a compound in which R of the compound of the general formula [■] in cl is an acetoxy group with a compound of the general formula [11T name-heterocyclic compound or a heterocyclic compound of the formula [■]] in the above production method (cl) is usually water, phosphate buffer, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dimethylsulfoxide, methanol,
It is preferable to carry out the reaction in an aqueous solvent such as ethanol or a mixed solvent with water. The reaction is carried out at a neutral pH (it is preferable to carry out the reaction near 1).Reaction temperature (II) is not particularly limited, but is usually between room temperature and 70°C.
It is preferable to do this before and after. The time required for this reaction varies depending on the reaction condition and the desired water exchange at the 3-position, but it is usually 1 to 7 hours.
The reaction with pyridine compounds, quinoline compounds, or pyrazines is preferably carried out in the presence of an alkali metal compound such as sodium iodide or potassium iodide. On the other hand, in the case of an S-heterocyclic compound (1) with weak nucleophilicity, R8 of the general formula [VI'] can be reacted with a compound in which R8 has -logen to produce the υ target compound [1]. is preferred. - Logons include salt purple and bromine. Generally, iodine is decapitated due to its reactivity, and compounds having iodine at R8 of the general formula [~1] can be prepared by known methods (for example, JP-A-56-1315
'70), the above-mentioned Iζ8 is easily prepared from a carrier of an amino group or carboxylic group of a compound having an acetoxy group. For this reaction, usually setone and dimerin are used. Detrahydrofuran, ethyl acetate, acetonitrile,
The reaction is preferably carried out in a solvent such as dimethylformamide or dimethylacetamide. The reaction is usually carried out at 0°C to 5°C, preferably
The reaction was carried out at 10°C to 30"C and allowed to cool down in 1 to 5 hours. The reaction product thus obtained [I' was removed by a conventional method to obtain a compound of the general formula C1"') can be obtained. The compound of general formula [I] obtained by the above method is isolated from the reaction mixture by a conventional method.
, Amberlite
It can be made into a sheath by adsorbing it on adsorbent renone such as 2) and eluting it with a water-containing organic solvent. If necessary, z1 chromatography using Sephadex LT (-20, G-10 (Pharmacia Co., Ltd.) is also effective. In addition, the general formula [!I+] used in the production method fa>) The compound of formula [■] can be produced by reacting the compound of general formula [■] with the hydro=V cyamine compound of general formula [v].This reaction can be carried out with the compound of general formula IJV) mentioned above. and general formula [v]
It can be carried out in a similar manner to the reaction with This reaction generally proceeds more quickly with free caf t-bonic acid without any reaction. Compounds of the general formula [V'll can be prepared by known methods (for example, JP-A-57-131758, the same method 55-
No. 149239), i.e., Federal. ptR can be produced by hydrazine decomposition after reaction with 1-hydroxyphthalimide and the corresponding active molecule in the presence of triphenylphosphine, Azocica A11-one. It has been found that the relaxation process [V] can be reduced by using diethyl acid. That is, a compound represented by the general formula [X] 1 (in the formula, I R' l R2+ R6* R' and n have the above-mentioned meanings) in the presence of triphenylphosphine and diethyl azozocarbonate,
N-Hydokuki/phthalimide is reacted with the general formula C)2'] (wherein R, R, R, R and n have the above meanings)
A compound represented by is obtained, which is decomposed with hydrazine,
Obtainable. The reaction of the general formula Cyi], - is carried out by reacting triphenylphosphine and 1 to 2 moles of diethyl azodicarformate with 1 mole of the compound [X]. This reaction is usually carried out using dioxane, tetrahydrofuran, acetonitrile, @
The reaction is preferably carried out under non-horizontal conditions in an inert atmosphere such as ethylene chloride, benzene, ether or the like. The reaction temperature (dimensions are not particularly limited, but it is usually carried out at 0°C to 30°C, and the reaction time is 1 to 10 hours to complete the reaction. Compound 1[] thus obtained is treated with hydroxide by a conventional method. /The target compound [v] can be obtained by decomposition.In the compound of general formula [v], R and R are hydrogen, and n is 00
Compounds, i.e. compounds of formula
, Vol. C27, p. 2957, 1962), after subjecting cyclo-1non to a hydrolysis reaction, the amino group,
It can also be easily obtained by protecting the carboxyl group. The novel cephalosporin/compound of the present invention having the general formula CI) and its salts exhibit excellent antibacterial activity against a wide range of pathogenic bacteria. The concentration (MIC) is shown in the following table. The compound of the present invention can be used as a medicinal tea for treating phlegmatic diseases.
The dosage forms for this purpose are generally parenteral via intravenous injection, intramuscular injection, or lozenges, or oral via tablets, powders, capsules, syrups, etc. Application by administration is possible. The present invention will be further explained in detail in the following practical examples, but these examples are merely illustrative and do not limit the present invention, and moderate modifications may be made without departing from the scope of the present invention. Needless to say, modifications are possible. Actual relationship II 1 (alDL-homoseri y11.qr to water 200-sweat i
Head, tva2Co3109 and dioxane 150mg
Add. To this, di-t-butyl cica-i sonnet) 2
50me of geogysan solution containing 7.5r was added for 1 hour under ice cooling.
Add dropwise over time. Furthermore, the reaction is carried out for two times at room temperature. After the reaction, dioxane is removed under reduced pressure and H'
+; After washing with Fy ethyl, 5Na under cooling, t m -c
p+] 2 K l'f! and extract twice with 400 rrtl of acetic acid. Wash the vinegar 62 ethyl scraps with saturated saline, dry with MrL2 magnesium basket,
Nodal drying was performed to obtain N-t-butoxycarbonyl-DL-homoserine 1B, 5. The obtained N-t-butoxycarbonyl-D L -homoserine 62 was dissolved in 100 methylene chloride, and in this,
A solution of IIJU-modified methylene ethylene containing 6v of nophenyldiazomethane is added dropwise over 50 hours.b After the reaction is complete, the reaction solution is concentrated to a small volume and petroleum ether is added. The resulting crystals were collected to obtain N-t-butoxycarbonyl-DL-homoserine penthydryl ester s,by. (blN-t~butoxycarvinyl-〇L-homoserine benzhydryl ester 6.75t was dissolved in dry tatrahydrofuran+50-, N-/% idroxyphthalimide 2.85f and hydrophenyl 7F, 6 f was added thereto, and 2.75 m of diethyl azodicarboxylate was added thereto and reacted for 3 hours at a constant temperature under an argon atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure and dissolved in ether 30-. The precipitated crystals The number of households is N-t-
Butoxycarvinyl -〇-7 talimide DL-homosely/penthydryl ester 7? get. NMR (δf+# from TMs in CDC/3) 1.4
4 (a, 9T(), 2.33 (m, 214), 4
．． 27 (t, 2Tl), 4.68 (mII T(
), 5.79 (d. I Tl), 6.93 (s, I H), 7.34
(m, l0II). ? . 81 (+n, 4 T(). rclN-troxycargenyl-〇-phthalimide-DL-homoserine-benzhydryl ester 5.52
Dry cyclized methylene F loOwl! 0.51 fnl'e of hydrazine hydrate was added thereto, and the mixture was allowed to react for 1 hour under ice-cooling. Furthermore, Hi1° Radin O, 12*+1! was added and allowed to react for 1 hour. After the completion of the reaction, remove the insoluble part and drain the RP solution with water, diluted ammonia solution [after 14th washing,
Dry with magnesium sulfate and concentrate to dryness under a wave pressure T. Dissolve the residue in 100 ml of ether, remove the precipitated crystals,
Concentrate the furnace solution, remove the precipitated crystals, and dry the P solution on both lines to obtain the target product N-t-butoxycarbyl-〇-
Amino D. L-Homo Shichisumbe/Tsuhydryl Ester 3.8 g f
get. NMR (in CDCl2, δ straight from 1” MS) 1.
43 (a, 9B), 2-08 (m, 2H), 3.
68 (t, 2H), 4.53 (m, IT (), 5.
27 (m. 2H), 6.93 (s, l H), 7.35 (m.
, 10H). (d) (2-chloroacetylaminoruthiazole-4-
B) Dissolve 1.71 P of glyoxylic acid in a 1:2 mixture of detrahydrofuran water and Nt-
Butoxycarbonyl-〇-a-di-DL-homoserine benzhydryl ester 2.88tf: Contains

[Add 30 g of a hydrofuran solution, adjust to -5.1 with I N -Na0I, and react at room temperature for 6 hours. After the reaction, -1 of the reaction solution was adjusted to 6.5, concentrated under reduced pressure, tetrahydrofurano was removed, water 100F76 was added, the pIi of the solution was adjusted to 8, washed with 1 ootJ of ether, and then cooled with water. Then, the pH was adjusted to 2 with 2N 11Cl and extracted with ethyl acetate. After washing the ethyl acetate layer with water,
Dry over magnesium sulfate and concentrate under reduced pressure. The residue was soaked in ether (10m/l), the incurable areas were removed, and
-(2-chloroacetylaminothiazol-4-iA
315 g of )-2-(3DL-3-t-butoxycarbinylamino-3-diphenylmethoxycarbonyl)f-ropyloxyiminoacetic acid are obtained. NMR (δ value from acetone-d6TMS) 1.48
(8,97(), 2.28 (m, 2H), 4.3
0 (L 2H), 4.51 (m, l H), 4.5Q
(s. 2H), 6.88 (B-l'H), 7-36
(m, l0T(). 7.56 (s, I H). -3-diphenylmethoxycarbonyl)propyloxyiminoacetic acid n475myfN,N
-Dissolved in dimethylformamide 5-, N-hydroxy-benztriazole 100 ~ and H, N, br'
- Add 160~ of dicyclohexyl cardacidamide and allow to react at room temperature for 1 hour. To this, 7-amino-
3-(1-methyl-IH-tetrazol-5-yl)-
370 μm of thiomethyl-3-cephemu-4-carboxylic acid benzhydryl ester was added and reacted at the same temperature for 6 hours. After the reaction is complete, the insoluble portion is removed, 70 ml of methylene chloride is added, and the mixture is washed successively with diluted hydrochloric acid and water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. This was subjected to silica gel column chromatography (developing solvent benzene-ethyl acetate 5
:2) to purify syn-7-(2-(2-chloroacetylaminothiazol-4-yl>-2-(3DL
-3-L-butoxycarbonyl-3-diphenylmethoxycarbonyl)-7J lobilmexiimileaacetamide-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-caldenic acid benzhydrin Le Esther 430#vtllru. (f) Dissolve this in anisole 3.5-, add trifluoroacetic acid 3.5- while cooling with water, and add at the same temperature ``1:''1.5''.
Allow time to react. After completion of the reaction, trifluoroacetic acid is removed under reduced pressure, and the residue is poured into 50 liters of Hemusan cooled to -20°C to -30°C, Needel 20v4 is added thereto, and the supernatant is removed. The residue was washed with ether, the precipitate was collected, and the residue was washed with ether.
3DL -3-amino-3-carboxy)probyloxyiminoacetamide 3-(1-methyl-1-tetrazol-5-yl)thionozuru 3-cephem-4-
Caldoxi 1. '-Totrifuro [1 acetate] 235° was obtained. This was suspended in water, adjusted to pH 6.5 with saturated sodium carbonate solution, and then added with 50 portions of sodium N-methyl-dithiocarbamate to a pH of 1.5 at room temperature.
Allow time to react. After the reaction, after washing with ethyl acetate,
(P-20 Column "Purify by gelatinization, concentrate the fraction containing the target substance, freeze-dry it and make the standard.
Obtain 150 my of A2 compound ONMn (during D20,
External [lv, δ value from TMS) 2.11 (m, 2
H), 3.64 (AB(1,2H), 4.12(AB
q, 2)T), 4.14 (m, I H), 4.4
0 (m. 2H), 5.16 (d, IT (), 5.75 (d,
IH) 7.02 (s, IH). Example 2 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(3DL-3-amino-3-carboxy)propyloxyiminoacetamide]-3-pyridiniummethyl-3-cephem-4-carboxylate (a) Example 1-(Syn-2 obtained by di −(
2-chloroacetylaminothiazol-4-yl)-2
-(3DL-3-t-butoxycarbonyl-3-diphenylmethodicarbonyl)propyloxyiminoacetic acid 640q, N-dimethylformamide 6ml
Noztriazole 14 is dissolved in N-hydroxy.
0■,N,N'-dicyclohexylcarbidimide 21
Add 0.0ml and allow to react at room temperature for 1 hour. 7-amino-3-pyridiniummethyl-3-cephem-
Dissolve 400 μl of 4-carboxylic acid dihydrochloride in 6 ml of N,N-dimethylformamide, add 0.56 m6 of triethylamine under water cooling, add the above reaction solution after 15 minutes, and react overnight at 5°C. let After the reaction is completed, the insoluble part is removed from the furnace, and twice the amount of ether is added to the p solution by pressing down on the p liquid. The resulting precipitate was collected, washed with ether and then with water, and then dried with Makabe in the presence of P2O5 to give syn-7-[2-(2-chloroacetylaminothiazole-
4-yl)-2-(3DL-3-t-7"toxycarvinyl-3-diphenylmeth=Vcical?nyl)propyloxyiminoacetamide]-3-pyridiniummethyl-3-cephem-4-carboxylate Obtained 540η.
- Butogishiruru d? Niru-3-sophenylmeth=? (Cicalhinyl) propyloxyiminoacetamide] 440 Wv of 3-pyridinium methyl-3-cephem-4-carboxylate was added to anisole 3 art K ke/v. Under ice-cooling, trifluoroacetic acid 4- was added and reacted at the same temperature for 2 hours. The reaction solution was cooled to -30°C with 50ml of hexane.
1, and add 25ml of ether to it. The formed precipitate was collected, washed with ether and methylene chloride, and dried in vacuum to give syn-7-[2-(2-chloroacetylaminothiazol-4-yl)-2-(3DL-3-).
Amino-3-carboxy)propyloxyiminoacetamide]3-pyridiniummethyl-3-cephem-4-
350 Tng of carbo/acid citrifluoroacetate are obtained. Add this to 0.7% sodium hydrogen carbonate water 7-? 140 q of sodium N-methyldithiocarbamate is added to solution a (approximately 6.8 L) and reacted at room temperature for 8 hours. After the reaction was completed, the insoluble portion was removed, washed with ethyl acetate, and the aqueous layer was concentrated to the left under reduced pressure and purified using a T (P-20 column chromatograph) (lo 5g of water was extracted) to obtain the title. Obtain 80% of the target product. (I) δ value from external standard TMS of 20) 2.34
(m, 2(I), 3.42 (AB(1,2T(),
3.86 (q, ITI), 4.41 (m, 2H),
5.26 (d. IH), 5.44 (ABq, 2 H), 5.85
(d, ■). 6.98 (8, l H), 8.06 (t, 2H)
, 8.53 (t, 1II), 8.92 (d, 2H)
. Example 3 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(3DL-3-amino-3-carboxy)propyloxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylate 7-amino-3-acetoxymethyl-3-cephem-4
-Carboxylic acid Bench 1° Lyle ester 2.22 and Nnow 2-(2-chlora ± thylaminotizol-4-
) -2-(3DL -3-t-Butona Shikaroo(
By treating nylamino-3-diphenylmethoxycarbonyl)propylmethane with 3.15r of diiminoacetic acid in the same manner as in Practical Example 1, 1.23r of the Oh8G compound was obtained.
Get it. (1) 20 medium, δ itri from external standard TMS)
2-06 (n, 3H), 2.09 (m, 2TI)
, 3.51 (ABq, 2T(), 4.09 (m,
l IT), 4.5S Cm. 2H), 4-77 (ABq, 2Tl), 5.2
0 (d, IT+). 5.79(a, In), 7. Cl6(s, tri)
. Example 4 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-(l-methyl-lH-tetrazol-5-yl)theomethyl-3-cephem-4-
Carboxylate (a) D-Zaic Cff Serine 29-f 50% concentrated) IC/11fnf! and acid hydrolyze for 3 hours at 6o0c. After the reaction was completed, it was concentrated under reduced pressure, azeotropically distilled with ethanol several times, and then dried under reduced pressure overnight to obtain β-ruaminoxy-D-
Arani y2 salt flJt2m'cr is obtained. This was dissolved in 1 oorye of ethanol and heated at 5 to 10°C.
- 80m1 of ethanol swamp containing 9.52% of soazomethane
! f Feed in 25 hours. After the reaction is completed, the reaction solution is concentrated in a stone, and 60 ml of ether and 8 ml of hexane are added thereto.
Add 0 me. and remove clear. The residue was crystallized from ethanol-ether and β-aminoxy-D-7 ranine penthydryl ester (2f, %) > salt 5
．． Get 5f. fl]+(2-chloroacetylaminothiazole-4-
a) 1.86 F of glyoxylic acid was dissolved in 15 ml of a 2:1 mixture of 190 furan water on tetrahydrofuran and cooled with water.
β-aminoxy 1)-chlorinobenohydryl ester 2 salt + 1'21Ai 2-96 t 7JII D. The pTI of the reaction solution was dissolved in saturated hydrogen carbonate) I
Jum water tears? ) Adjust to 5 with N and react at room temperature for 3 hours. Next, the pH of the reaction solution was adjusted to 8.5 to dissolve the formed crystals, and 20% of a tetrahydrofuran solution containing 2.152% of di-t-dityl dicarbonate was added thereto.
Mef 7JII and react at room temperature for 4.5 hours. After the reaction is completed, the tetrahydrofurano is removed under reduced pressure, and 5N is removed under cooling. The a1 dispersed ethyl layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure T-concentration 1. This was crystallized from ethyl acetate-petroleum ether,
Syn-2-(2-chloroacetylaminothiazole-4
-yl)2-(2p-z-t-butoxycarbonylamino-2-diphenylmethoxycarbonyl)ethoxyiminoic acid e 3.6 f t Kn ru. (c) Cy-2-(2-chloroacewal-1"minothiazol-4-yl)-2-(2D-z-t-butoxycarbinylamino-2-diphenylmethoxycarbonyl)ethoxyiminoacetic acid 617■ and 7-amino-3-
(1-Methyl-I-tetrazol-5-yl)thiomethyl-3-7-phemo-4-carbic acid henzhydryl ester 495 was treated in the same manner as in Inner Decoration Example-1 to obtain the title target compound 250. 〇 (during D20, δ value from external standard TMS) 3・60 (
ABq, 2H), 4.00 (8,3H), 4.1
2(ad, lH), 4.14(A[1q, 2H
), 4. ．． 60 (m, 2H), 5.14 (d, I
H), 5.74 (d, IT(). 7.03 (8,l H). Example 5 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylate syn-2-C2-chloroacetylaminothiazole-4
-yl)-2-(2D-2-t-butoxycarbinylamino-2-diphenylmethoxycarbonyl)ethoxyimino acid: n'12.458 and 7-amino-3-acetoxymethyl-3-cephem-4- carbon 1j2t
-Gutyl ester 1.238fX was treated in the same manner as in Example 1 to obtain the title target product 1.051. (during D20, δ value from external standard TMS) 2.06 (s
, 3H), 3.51 (ABq, 2H), 4.12
(dd, l H), 4.60 (m, 2H), 4.
77 (ABq. 2H), 5.19 (d, IT (), 5.79 (d,
l7(). 7.05 (8,1H). Example 6 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-pyridiniummethyl-3-
Cefem-4-carboxylatesin-2-(2-chloroacetylaminothiazole-4
-yl)-2-(2D-2-tbutquincarbinylamino-2-diphenylmethoxycarbinyl)ethoxyiminoacetic acid 1.02 -7 minnow 3-viridinium methyl-3-cephem-4 -Carpic dihydrochloric acid 700
t'N
ajl: Target compound 250r? get. (+) 2',) Medium, δ value of externally marked parrot TMSka4 et al.) 3.40 (ABq, 2H), 4.09 (m,
l H), 4.58(m, 2T(), 5,23(d
, IH), 5,42 (ABq. 2B), 5.82 (d, IH), 6.98 (s, ITJ
). 8, C14 (t, 2Tl), 8.52 (t, l
u), g, q. (d, 2H). Example 7 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-(4-carpamoylpyridinium)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole) -4-yl)
-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-cal? xylate 07F water 20ml1K
Dissolve and add potassium iodide 3.32 and O isoni J
Add 615 grams of tinic acid amide, adjust the - of the reaction solution to 6.5, and react at 65"C for 6 hours. After the reaction is complete, the reaction solution is coated with TIP-20 column chromatography. , obtain the title object 320η. (During D20, δ value from external standard TI + I S) 3.41
(m, 2T(), 4-10('dd, l'H)
, 4.60 (rn, 2TI), 5. z2(d, N(
), 5.46 (AHq. 2T(), 5.30 (a, I)n, 6.94 (
s, IH). 8.29 (a, 2T(), 9.06 (a, 2T
(). Example 8 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(3DL-3-amino-3-carboxy)propyloxyiminoacetamide]-3-(N-methylpyridinium-4-yl)thiomethyl-3-cephem-4-
Carboxylate syn-7-[2-(2-aminothiazol-4-yl)
-2-(3\DL-3-amino-3-calexy)propyloxyiminoacetamide]'''3-acetoxymethyl-3-cephem-4-cal d?key/late 550 g dissolved in 5 g water and to this, tV-nonalviride-4-
Add thioyl q O+, v, l''-1+'l; pH of the solution to 4-6, 8 and 11, and react at 608C for 3 hours. After reaction route f, carry out reaction 'N1. It was purified by chromatography using a Diamond LIP-20 column to obtain smoke GC target compound 330q. (δ value from standard TMS during D20) 2-10
(m, 2.H), 3-62 (ABq, 2H), 4
．． 09(m, Ill 4.14 C813T()1
4.21 (AB(IT2H)1 4.58 (m,
21(), 5.11 (a, l H). 5.71 (d, I H), 'b, qsc s, I
n), 7.71 (d, 211), 8.30 (d, :
2)(). Example 9 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-(4-sulfoethylpyridinium)methyl-3-cephem-4-carboxylic acid sodium salt Substituted for isonicotinamide in Example 7 Te, 4-
The title compound is obtained by the same treatment using 12-lysine ethanesulfonic acid. (during D20, δ value from external standard TMS) 3.42
(ABq, 2H), 3.57 (fi, 4H),
4.1゜(m, I H), 4.55(m, 2T(), 5
．． 20 (d, lH), 5.45 (ABq, 2H),
5.82 (d, I H). 6.97 (s, IH), 8.52 (d, 2H), 9-
10 (d, 2H). Example 10 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-(2-methylcarpamoyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate Syn-2-(2-chloroacetylaminothiazole-4
-yl)-2-(2D-z-t-butoxycarbonyl-
Dissolve 620 μl of 2-Schiff-based methoxycarbonyl)ethoxyiminoacetic acid in N,N-dimethylformamide, and add to this 135* of NJ~idroxibe/ztriazole* and N,N-dicyclohexyl. Power A cod? Add 206 g of diimide and allow to react at room temperature for 1 hour. This was cooled with water, and
,3゜4-thiadiazol-4-yl)thiomethyl-3
-Cephem-4-Cal? 390 mg of xylate and 0.28 ml of triethylamine are added and reacted at the same temperature for 5 hours. Dispose of the completed reaction product and insoluble part, and add methylene chloride/
100- was added thereto, washed successively with diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was thoroughly washed with ether and dried to give -r, syn-7-(2-
(2-chloroacetylaminothiazol-4-yl)-
2-C2D-2-t-butoxycarbonylamino)-2
-S, 'phenylmethoxycarboxy)ethoxyiminoacetamide')-3-(2-methylcarbamoyl-1
゜3.4-Thiadiazol-4-yl)thiomethyl-3
880 rny of -cephem-4-caldefic acid are obtained. This is treated in the same manner as x19ul to obtain the title compound 240F4. ((1) a value from external standard 9 TMS in D20)
2-95 (s, 3)1), 3.48 (ABq
, 2)■), 4.15(rn, I T(), 4
．． 28 (ABq, 2)1), 4-61 (m. 2T(), 5.16 (d, I H), 5.75 (
d, IH). 7, Of (a, I u). Example 11 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-isoquinolinium-3-cephem-4-carboxylate syn-7-(2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxy)etho to diimino-acetamidodi-3-acetoxymethyl-3-
617η of heptafemu 4-carboxylate was dissolved in methine chloride/methine chloride, and N-methyl-N-trimethylsilyltrifluoro heptamide 2- was added thereto, followed by stirring for 2 hours under an argon atmosphere. To the mixture, add 0.21 m/m of trimethylsilyl iodide and allow to react for 20 minutes. The residue was concentrated under reduced pressure, the residue was dissolved in acetonitrile, 0.1 ml of tetrahydrofuran was added thereto, and after 5 minutes, inquinoline+60η was added and the mixture was reacted at room temperature for 3 hours. to this,
A small amount of water is added and the resulting precipitate is collected, and this is purified using a Diaio7) IP-20 column chromatography to obtain 280η of the title target compound. (during D20, δ value from external standard TMEI) l II)
, 7.00 (a, l H), 8.31 (m, 5
1゜9.38 (d, l H), 9.62 (8, IH)
. Example 12 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(3DL-3-amino-3-carboxy)propyloxyiminoacetamide]-3-(l-methyl-l
H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (a) (2-chloroacetylaminothiazol-^-yl)glyoxylic acid 375η to tetrahydrofuran 9
7-7mi/-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carmenic acid benzhydryl ester 750
η, N-Nohedrogysibenztriazole 21011
+! 7 and N, N-dicyclohexylcal? Diimide 3
Add 15 ~ and react at the same temperature for 2 hours. After the reaction is complete, the insoluble portion is poured out, 100% of ethyl acetate is added to the filtrate, which is washed successively with diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. This was purified by silica gel column chromatography and 7-C(2-chloroacetylaminothiazol-4-yl)glyoxylamide)-3-(1-meg-114-tetrazol-5-
yl)thiomethyl-3-cephem-4-carbic acid benzhydryl ester 570119 is obtained. (b) 7-[(2-chloroacetylaminothiazole-
4-yl)-glyoxylamido)-3-(1-methyl-IH-tetrazo-□ru-5-yl)thiomethyl-3-
Cephem-4-carboxylic acid penthydryl ester 27
0 to f: Dissolve in 7.5 liters of N,N-methylacetamide, and add N-t-methylacetamide to this. Processing of Niru-〇-amino-DL-homoheptiline benzhydryl ester from 160°C to 450°C overnight. After the reaction is completed, 100 ml of ethyl acetate is added, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. This was purified by silica gel column chromatography. carbonyl)propyloxyiminoacetamide)-3,(1-methyl-IH-tetrazole)~3-cephemu-4-cal? 265 kg of benzhydryl ester were obtained. The n group is removed from this in the same manner as in Actual Strain Example 1 to obtain the title compound. This compound was obtained by the method of Example 1. Example 13 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamido-3-(N-methylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate Syn-7 obtained in Example 5 -[diiminoacetamide in 2-(2-aminothiazol-4-yl)-2-(2D-2-amino-2-carzoxy)eth]-3
-acetoxymethyl-3-cephem-4-carboxylate 208ray and N-methylpyrido-4-thione 1
00q, please process it in the same way as MflI8.
The a compound +00my is obtained. NMR (during D20, δ value from external standard TMS) 3.5
6 (ABq, 2 H)= ,4.10 (dd,
IH), 4.14 (s, 3H), 4-21 (AB
q, 2H), 4.60 (m. 2■1), 5.12 (a, IH), 5.72 (d,
Iu). 6.97 (8, +u), 7.71 (d, 2H), g
, 31 (a, 2U). Example 14 Syn-7-[2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-(N-methylpyridinium-2-yl)thiomethyl-3-cephem-4-carboxylate N-methylpyrido-4 in Example 13 The title compound is obtained by the same treatment except that N-methylpyrido-2-thione is used instead of -thione. δ value from external mark TM8 in NMR (I) 2o)3.
57 (ABq, 2H), 4,10 (m, IH)
, 4.20 (s, 3H), 4.2.1 (ABq,
2H), 4.60 (m. 2H), 5.13 (a, l T(), 5.70 (a
, + u). 6.98 (s, l T()1.7.82 (m+ l
H), 8. IQ (d, l H), 8.33 (m,
l T(), 9.02 (m, IT(). Procedural amendment (spontaneous) November 21, 1980 Mr. Commissioner of the Patent Office■, Small case indication Showa 5δ Patent Application No. 148800 2, Invention Name 3, Relationship with the case of the person making the amendment Special 8″1 Applicant address: 2-4-16 Kyobashi, Chuo-ku, Tokyo (609) Name: Meiji Seika Co., Ltd. 4, Agent 5, Subject of the amendment: Akira @ Detailed Description of the Invention Column & Contents of Amendment (1) Specification Layer - Delete "Formula" on page 14, line 5. Correct as H5J CN5 J. (31 "Dimethyl" on page 35, lines 14-15) (4) “S-heterocyclic compound [■]” on page 38, line 17 of the same page.
” and insert “heterocyclic compound” fc. (5) r31 on page 50, line 7! MJ 11.1! M
Correct it with J. (6) Correct “25” in line 60, row 3, to r2.5J. (7) On page 60, line 6, insert ``ka'' next to ``crystal''. (Delete “carboxy” on page 72, line 18 of 81, and read “
Insert "carbonyl". (9) On page 22, line 9, [cephalosporanic acid j was deleted and "cephem" was inserted].

Claims (2)

[Claims] 1. It is represented by the general formula [wherein R1 and R2 represent a hydrogen atom or a lower alkyl group, R3 represents a lower alkanoyloxy group, a heterocyclic group, or a heterocyclic thio group, and n represents an integer from O to 3]. cephalosporin compounds, and chemically acceptable salts thereof. 2. The following formula [wherein R is a lower alkanoyloxy group, a polycyclic group, or a heterocyclic thio group, R is a hydrogen atom, or a carbon atom]
A 7-aminocephalosporanic acid compound or a salt thereof represented by the following formula [wherein R and R represent a hydrogen atom or a lower alkyl group, R is a hydrogen atom, or Represents a preserving group of an amino group, R
represents a protective group for an amine group, represents a protective group for a xyl group, and n represents an integer of 0 to 3] or a carboxylic acid active derivative thereof. to form a compound of the following formula [wherein R, R, R, R, R, [t, R and n have the meanings given above], from which the amine protecting group and the carboxyl protecting group were later removed. of the general formula % [wherein R, R, R and n are as defined above] A method for producing a cephalosderino compound represented by [having a meaning] and a physiologically acceptable salt thereof. 8. The following formula [In the formula, Fl represents a lower alkanoyloxy group, a heterocyclic group, or a heterocyclic thio group, R4 represents a hydrogen atom or a protecting group for a carboxyl group, and R6 represents a hydrogen atom or a protecting group for an amino group. A compound represented by the following formula [where R and R represent a hydrogen atom or a lower alkyl group, R represents an amino group-protecting group, and R represents a carxyl group-protecting group] and n represents an integer of 0 to 3] to form the following formula [wherein R, R, R, R, R, R, R and n have the above-mentioned meanings] ], and later remove the amine and xyl protecting groups from this compound and, if desired, convert the deprotected form into a physiologically acceptable salt in a conventional manner. A cephalic f-rin compound of the general formula %, characterized by Manufacturing method. 4. The following formula [wherein R and R represent a hydrogen atom or a lower alkyl group, and R and R are a hydrogen atom or a carbon d? It represents a simplified group of xyl group, and R is a hydrogen atom. or represents an amino group, R represents hydrogen or an amino group, R represents a substitutable group, and n is an integer from 0 to 3. The compound is a heterocyclic thiol compound of the following formula (% formula %) [wherein R represents a heterofip group], or a heterocyclic thiol compound of the following formula (wherein R is a hydrogen atom, a hydroxyl group, an amino group, a syl group in carddf, Sulfonic acid group, fulgyl g, /% l'ff group,
It represents a carbamoyl group or a group of the formula -(ctr East.-R (however, 0 R has the same meaning as above, and m represents an integer of 1 to 3), and RIl, R12 and R13 are each a hydrogen atom or, two adjacent ones of RIl, R12 and R13 are groups that appear together to form one aromatic ring or a heterocycle, and one of the residues υ is hydrogen.] A double-bedded cyclic compound, or a nitrogen-containing or sulfur-containing heterocyclic compound containing two or more nitrogen atoms or containing a sulfur atom as a material atom is reacted to form the following formula [(, T, R, R, R
, R and n have the same meanings as above, and R is a group -8-R, or a double hydrocyclic group formed by R8 from the nitrogen-containing or a-containing double ring compound of Fte above. A method for producing a cephalosporin compound represented by the general formula [wherein +, R1, R2, R14 and n have the above-mentioned meanings], which is characterized by producing a compound of .