JPS5953275B2 - Antibacterial agent manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION -Z-;2±''2.'.'1.'.Iτ↑Gate Z:-: relates to acid derivatives.

The novel cephalosporin derivatives of the present invention are compounds represented by the structural formula where R is C1-C4 alkyl or C1-C4 alkoxy and Het is the residue of a triazole, alkylthiadiazole or alkyloxadiazole. It becomes more.

Also included within the invention are readily cleavable esters of compounds of formula 1 and pharmaceutically acceptable salts of the compounds and esters. The above pharmaceutically acceptable salts include non-toxic carboxylic acid salts, such as sodium, potassium,
Non-toxic metal salts such as calcium and aluminum, ammonium salts and non-toxic amines such as trialkylamines, procaine, dibenzylamine, N-benzyl-beta-phenethylamine, 1-ephenamine, N
, N'-dibenzylethylenediamine, N-alkylpiperidine and other amines used to form salts of penicillin.

Non-toxic acid addition salts (salts of amines) with mineral acids such as hydrochloric, hydrobromic, hydriodic, phosphoric, sulfuric acids and maleic, acetic, citric, oxalic, succinic acids Also included within the definition of pharmaceutically usable salts are salts with organic acids such as , benzoic acid, slaked acid, fumaric acid, mandelic acid, ascorbic acid, malic acid. The term "pharmaceutically acceptable salts" is also meant to include non-toxic acid addition salts of readily cleavable esters of compounds of formula 1. The easily cleavable esters mentioned above are removed by methods such as chemical or enzymatic hydrolysis;
It includes an ester group that does not result in appreciable degradation of the remaining portion of the cephalosporin molecule.

Examples of suitable esters are U.S. Pat. Nos. 3,284,451 and 3,249,622 and British Pat.
453 and 1,073,530.

Particularly preferred esters are pivalyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl and phenacyl esters. There is extensive literature regarding cephalosporin antibiotics.

Relatively relevant prior art in this field is shown below. Various 7-[alpha-amino-arylacetamido]cephalosporanic acids and the corresponding desacetoxy compounds in which aryl is unsubstituted or substituted phenyl or 2- or 3-thienyl (1, e.g. British Patent Specification 696,0
26, U.S. Patent 3,311,621; 3,352,85
8;3,48'9,858;3,489,750;3.
489,751; 3,489,752 and 3.518
．． 260 Japanese Patent No. 16871/66, Spencer et al.
Correct. Yrdan. Chem. Gangbao, 746-750 (196
6) and Kurata et al., J. AntiblOtics (T
OkyO)(A)? , 243-249 (1966) and in U.S. Pat. No. 3,485,819.

Dutch patents 68/11676 and 68/12382
and U.S. Pat. No. 3,489,750;
51 and 3,489,752 disclose ring-substituted cephaloglycines.

In various 7-[α
-Amino-arylacetamide cephalosporin has been reported.

The earliest were cephaloglycine and cephalexin precursors, in which U.S. Patent No. 3,364,212;
Pelkey Patent 675,298, South African Patent 67/1
Common peptide protecting groups such as carbopendyloxy as exemplified by Pelkey Patent No. 260 and Pelkey Patent No. 696,026 have been used. Related compounds are U.S. Pat. Nos. 3,303,193; 3,311,621 and 3,
518.260. Compounds having the structure have been prepared by reacting various cephalosporins (sometimes including cephalosporin C) with nucleophilic, aromatic mercaptans.

In US Pat. No. 3,278,531, Ar is phenyl or certain substituted phenyls or certain aromatic heterocycles. Similar nucleophiles, such as 2-mercaptopyridines, are used in U.S. Pat. No. 3,261,832 and British Pat.
No. 01,422, US Pat. No. 3,479,350 and US Pat. No. 3,502,665. This type of nucleophile further includes compounds named cefazolin, which include Pelkey Patent 714,518, Canadian Patent 818.501, British Patent 1,187.323 and US Patent 3,516,997 - -tetrazolylacetyl side chain on the amino group and a 5-methyl-thiadiazolylthiomethyl group in the 3-position, and has a 5-methyl-thiadiazolylthiomethyl group in the scientific literature, e.g.
entsandChemOtherapy-1969,
pp. 236-243 and J. AntibiOtics (
Japan) 23(3), 131-148 (1970)
Disclosed at some length in one. Substitution of the 3-acetoxy group of cephalosporins by various heterocyclic thiols has been described in US Pat.
-α-aminophenyl acetamide, typical heterocyclic thiols are 2-methyl-1,3,4-thiadiazole-5-thiol and 1-methyl-1,2,3,4-
Tetrazole-5-thiol is disclosed herein.

The prior art documents describe phenylglycylacetamide phenyl moiety at position 7 as 3 monoheterocyclic thiomethyl having one side chain which is replaced by hydroxy at position 4 and an alkyl or alkoxy radical at position 3. Does not disclose cephalosporin.

The most preferred compounds of the invention are those in which R is methyl and R is methoxy and Het is 1,2,3-triazolyl. or 2-methyl-1,3,4-thiadiazol-5-yl. Owing to the asymmetric carbon atom of the 7-side chain of the compounds of formula 1, these compounds may exist in optically active form.

The present invention includes within its scope resolved epimeric forms and racemic mixtures thereof. Preferred and most active compounds of formula 1 are those with a D configuration at the α one carbon atom in the 7-side chain, i.e. D-←)-α-amino-m-alkyl-p-hydroxyphenylacetic acid or D-(-)-
It is made from α-amino-m-alkoxy-p-cedroxyphenylacetic acid or its functional equivalent.
Amino group is t-butoxycarbonyl, carbobenzyloxy, formyl, o-nitrophenylsulfenyl, β,
Compounds protected by substituents such as β,β-trichloroethoxycarbonyl, 4-oxo-2-pentenyl-2,1-carbomethoxy-1-propenyl, etc. (either as an intermediate or as a metabolic precursor) Uses) are also encompassed within the invention.

In particular, for example, U.S. Pat.
Ketones (especially acetone) disclosed in 47.851
and aldehydes (particularly formaldehyde and acetaldehyde) and e.g. U.S. Pat.
β-diketones disclosed in No. 79 and Japanese Patent No. 71
Included among such protecting groups are the β-ketoamides disclosed in US Pat.

The present invention also relates to formulas (wherein R village C, ~C, alkyl or C, ~C4
Al b guisi and l! No. 11 includes compounds having triazoles, alkylthiadiazole (residues of azole), as well as processes for preparing easily cleavable esters and pharmaceutically usable salts thereof. ;This manufacturing method is (A). A compound of the formula or a readily cleavable ester or salt thereof, wherein R is as defined above and B is an amino protecting group.

) to remove the amino-monoprotecting group B to produce the desired compound of formula 1 or a readily cleavable ester or pharmaceutically usable salt thereof, if desired. is before or after the removal of B (a
) converting the product in the form of the free acid or its salt into the corresponding easily cleavable ester or its pharmaceutically usable salt by methods known per se; or (b)
converting the product in the form of an ester or its salt which is easily cleavable by methods known per se into the corresponding free acid compound or its pharmaceutically usable salt; or a compound of formula (8) or its salt; A readily cleavable ester or salt thereof is reacted with formula HS-Het, where Het is as defined above, or a salt thereof to prepare a readily cleavable ester or salt of a compound of formula 1 or as a pharmaceutical preparation. the corresponding readily cleavable ester or pharmaceutically usable salt thereof to form a usable salt and, if desired, (a) the free acid or the product in its salt form by methods known per se; or (b) converting the product in the form of an ester or its salt, which is easily cleavable by methods known per se, into the corresponding free acid compound or its pharmaceutically usable salt. shall be.

In one method of making the novel cephalosporin compounds of the present invention, a 3-thiolated 1J aminocephalosporanic acid compound of the formula or a readily cleavable ester or salt of the acid or ester is combined with a suitable compound of the formula IO ) Acylation with m-alkyl-p-hydroxyphenylglycine or m-alkoxy-p-hydroxyphenylglycine acylated derivatives.

The 3-thiol-J-aminocephalosporanic acid intermediate of the formula is prepared by replacing the 3-acetoxy group of 7-aminocephalosporanic acid with a suitable heterocyclic thiol or salt thereof. be able to.

The replacement of acetoxy groups by thiol groups is a known reaction, which is preferably carried out in the form of an aqueous solution under heat. Intermediate H is then converted to 7 with an acylating agent of formula l according to known methods.
-The claimed compounds can be obtained by acylating the amino group.

If desired, the intermediate can be converted to its easily cleavable ester or acid addition salt prior to the acylation reaction.

Procedures for preparing such esters have been disclosed in the literature and are well known to those skilled in the art of penicillin and cephalosporin chemistry. One preferred method particularly useful for making the most preferred easily hydrolyzed esters, namely pivaroyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl and phenacyl esters, is described in U.S. Pat. No. 3,284. No. 451. This reference describes the esterification of cephalothin sodium with a suitable active chloro or bromo compound (e.g., phenacyl bromide, chloroacetone, chloromethynole.ether, pivaloyloxymethyl chloride, acetoxymethyl chloride) followed by thienyl acetate side chains. It describes enzymatic removal of . In another good method, the triethylamine salt of 7-aminocephalosporanic acid is
, 229, 453, directly with an active halogen compound. Literature e.g. U.S. Pat. No. 3,249,62
Compounds of formula can also be converted into silyl esters as by the methods described in 2. The silyl ester group can be removed by acylation followed by hydrolysis or hydroalcohollysis. Before the acylation reaction, the amino group of acylating agent I is protected with a conventional amino protecting group B.

This material can be easily removed at the end of the reaction. Examples of suitable amino protecting groups are t-butoxycarbonyl, carbobenzyloxy, 2-hydroxy-1-naphthocarbonyl, trichloroethoxycarbonyl, 2-ethoxycarbonyl-1-methylvinyl and 2-methoxycarbonyl-1-methylvinyl. includes. A particularly valuable protecting group is a proton, as in the formula.

Suitable amino protecting groups are t-butoxycarbonyl, proton and β-diketone or those described in British Patent No. 1,123,3
33 or U.S. Patents 3,325,479 and 3,31
6,247, such as methyl acetoacetate, or a β-keto amide as in JP 71/24714. When a t-butoxycarbon, β-ketoester, β-diketone or β-ketoamide protecting group is used, the compound or its
IV or before the reaction with the salt, for example ethyl chloroformate.
It is preferred to convert the acylating agent with a protected amino group into a mixed anhydride by -or by isobutyl. After the acylation coupling reaction, the amino protecting group B can be removed by methods known per se to form the desired product of formula 1. Thus, for example, t-butoxycarbonyl groups can be obtained by using formic acid, carbobenzyloxy groups can be obtained by catalytic hydrogenation, 2-hydroxy-1-naphthocarbonyl groups can be obtained by acid hydrolysis, and trichloroethoxycarbonyl groups can be obtained by untreated zinc in glacial vinegar. It is possible to remove protons by neutralizing 6. Obviously other functional isoprotective groups for the amino group can be used,
Such protecting groups are considered within the scope of this invention. Acylation of the 7-amino group of cephalosporin is a well-known reaction, and any of the functional equivalents of formula 1 commonly employed as acylating agents for primary amino groups can be used.

Examples of suitable acylated derivatives of free acids include the corresponding acid anhydrides, mixed anhydrides such as alkoxyformic anhydrides, saponyl halides, azides, active esters and active thioesters. The free acid is first converted to N chloride,
after reaction with N5-dimethylchloroforminium, or an enzyme or N,N'-carbonyldiimidazole,
N,N'-carbonyl ditriazole, carbodiimide reagents such as N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide or N,N'-dicyclohexylcarbodiimide
-Cyclohexyl-N'-(2-morphylinoethyl)
Coupling with the compound can be achieved through the use of carbodiimide or alkylamine reagents or isoxazolium salt reagents. Azolates corresponding to other equivalents of the free acid, i.e. semi-aromatic five-membered rings in which the amide nitrogen has at least two nitrogen atoms, i.e. imidazole, pyrazole, triazoles, benzimidazole, benzotriazole and their It is a member of derivatives. Another reactive derivative of phenylglycinate of the formula is N-carboxyanhydride (anhydride). In this structure, the group activating the carbonyl group also serves to protect the amino group. A particularly suitable acylating agent is the formula Todoroki 1●Vo≦VoV
The acid chloride hydrochloride of V, which also mentioned above the use of enzymes for carboxyl activation and coupling of free acid compounds with amino groups.

Various fungal organisms, such as T. Takahashi et al., J. Amer.
Chem. SOc. , 94(11), 4035-403
7 (1972) and T. Nara et al., J. Antibull
lcs (Japan), 24(5), 321-323(
The use of esters of this free acid, such as the methyl ester, as described by German Pat.

The particular processing conditions chosen for this coupling reaction, such as temperature, solvent, reaction time, etc., will be determined by the type of acylation method used and are known to those skilled in the art. Generally, organic tertiary amines such as triethylamine, N,N'-dimethylaniline, "ethylpiperidine, 2,6-lutidine or quinone can be added to serve as proton acceptors or salt formers. Useful.
The compounds of the present invention can be isolated by any of the methods commonly used to isolate similar cephalosporins.

The product can thus be obtained as a neutral molecule (though perhaps more accurately represented as a zwitterion) or isolated as a salt. The production of the desired pharmaceutically usable carboxylic acid or acid addition salts is carried out by known methods, by reaction of the acid with a suitable base or acid. At the end of the acylation reaction, the products obtained can be converted into other desired products of formula 1 (before or after removal of the amino protecting group) by methods known per se.

Thus, a compound of formula 1 in the form of the free acid or its salt can be converted into the corresponding easily cleavable ester or its pharmaceutically usable salt by methods known per se. The product of formula 1 in the form of a similarly easily cleavable ester or salt thereof can be prepared by removal of the esterifying group, for example by aqueous or enzymatic hydrolysis (such as with human or animal serum) or acidic or alkaline hydrolysis or by 3,284,451 to the free acid product or its pharmaceutically usable salt by treatment with sodium thiophenoxide. In another method for producing the compounds of the present invention,
Acylation of 7-aminocephalosporanic acid or a salt thereof with an acid of the formula or an acylated derivative thereof to produce a 7-acylated cephalosporin compound of the formula.

The heterologous thiol of the formula or its salt, most preferably the sodium or potassium salt, is then reacted with the compound in the form of the free acid or its easily cleavable ester according to the method of the invention. This displacement reaction is preferably carried out in the form of an aqueous solution at a temperature of 50° C. or higher in an inert atmosphere, for example a stream of nitrogen. The products of the displacement reaction can, if desired, be converted into pharmaceutically usable salts by treatment with a suitable acid or base. As in the alternative process described above for the preparation of compounds of formula 1, it is possible to convert the product in the form of the free acid or its salt into the corresponding easily cleavable ester or its pharmaceutically usable salt. Alternatively, the product in the form of a readily cleavable ester or salt thereof can be converted into the free acid or its pharmaceutically usable salt. Easily cleavable esters of compounds of Formula 1 are useful as intermediates in the preparation of free acid products. Pivaloyloxymethyl, acetoxymethyl, and methoxymethyl esters are also useful as active antimicrobial agents because they are rapidly hydrolyzed to active metabolites upon oral administration. These esters are of interest because they provide different rates and amounts of absorption upon oral administration and different concentrations of active antimicrobial agent in the blood and tissues. The pharmaceutically active compounds of this invention are potent antibacterial agents useful in the treatment of infectious diseases caused by many Gram-positive and Gram-negative bacteria in homes and animals, including humans.

These active compounds are also of value as nutritional supplements in animal feed (for the treatment of mastitis in cattle).

It has surprisingly been found that suitable compounds are efficiently absorbed when administered orally. The novel medicament provided by the present invention can be formulated as a pharmaceutical composition comprising, in addition to the active ingredient, a pharmaceutically acceptable carrier or diluent. These compounds can be administered both orally and parenterally. Pharmaceutical preparations can be in solid form, such as capsules, tablets or dragees, or in liquid form, such as liquids, suspensions or emulsions. In the treatment of bacterial infections in humans, the compounds of the present invention may be used in doses of about 5 to 200 η
/Kg/day, preferably in divided doses of about 5-20η/Kg/day;
For example, it can be administered parenterally 3 to 4 times a day.
These are administered in the form of dosage units containing, for example, 125, 250 or 500 η of active ingredient, together with suitable physiologically acceptable carriers or excipients. Preparation of the starting material 1,2,3-triazole-5-thiol sodium The synthesis of thiols is described in the literature [J. Geldrel and G.
．． Gunado Chem. Ber. 99, l6l8 (1966
)] was carried out by essentially the same procedure as described.

5-Benzamide-1,2,3-thiadiazole A solution of benzoyl isothiocyanate (50.69,310 mmol) in commercially available anhydrous ether (400d) was heated at 0°C.
0.685N under stirring (vigorously) in a nitrogen stream
of ethereal diazomethane (4531f11, 310 mmol) was added dropwise.

When the addition was complete, the mixture was stirred at 0° C. for 1 hour, and the solid was collected by P filtration and dried in vacuo. The Mp of the thus obtained crude (23.3fI) was observed around the region of 232-257. Geldrell reported Mp267 detection for the pure product. A small amount of second crop was obtained by vacuum evaporation of the mother liquor. The total yield was therefore 40%. 1,2,3-triazole-5-thiol 2
N Caustic soda (80-, 160 mmol), Nakayo's benzamide compound VB (8.2f!.40 mmol) Heated ◆ 5, SFIII, ◆ Port d Todoro JC, Ari ● 1 tank L!
-Shiogi (26-) was added while passing a continuous flow of QI element.

The precipitated benzoic acid was collected by P filtration, the P solution was saturated with common salt, and the separated benzoic acid was further removed by P filtration. The ▲ solution was immediately extracted with ethyl acetate, the extract was washed with saturated brine, dried over magnesium sulfate, and then evaporated in vacuo.
Immediately distill the remaining viscous oil using an evaporation method under vacuum to obtain oil (
2.849,70%) was obtained, which solidified spontaneously (Mp52-59 obtained; gel drain width Mp6O was reported). 1,2,3-triazole-≦-thiol potassium (2.
849, 28.1 mmol) was added 1.93N alcoholic caustic potash solution (14.5 wL0).

The solution was then diluted with anhydrous ether until complete crystallization of the salt. The solid was collected by filtration with P, washed with Kotel, and dried with a net print. The salt thus obtained (3.65 g, 93%
) had Mp225 yield (degradation). Conversion of benzamidothiadiazole to triazolethiol is 5
-amino-1,2,3-thiadiazole [G. Geldren and G. Gunado, ChemBer. 99, l6l8 (1966)].

5-amino-1,2,3-thiadiazole can be produced by another route that does not contain diazomethane [D
．． L. Behn and R. Slutsk, J. Chem. S.O.
c. 5l66 (1965)].

The synthesis reaction of 7JA amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was carried out in a nitrogen atmosphere in a reaction vessel protected from light.

Water and phosphate buffer were vigorously gassed with nitrogen to replace oxygen before use. 5-amino-1,2,3-
Thiadiazole (10.39, 0.102 mol) in 1 part water
Added to a solution of 8.169 ml of caustic soda in 00d.

The mixture was heated quickly to reflux and then refluxed for 10 minutes to rearrange the 5-amino-1,2,3-thiadiazole to 5-mercapto-1,2,3-triazole. 1100 d of ice-cold 0.1 M pH 6 phosphate buffer was added to the reaction mixture containing 5-mercapto-1,2,3-triazole cooled in an ice bath. The solution is PHLO. 5, and was adjusted to 8.5 with 42% phosphoric acid. 7-Aminocephalosporanic acid (21.89, 0.08 mol) was added and the mixture was heated to 500 °C for 4 hours.

The clear solution was cooled in a cold bath and adjusted to pH 4.5 with concentrated HCI. The precipitated product was collected by P filtration, washed with water, and air-dried. 16.2f10 The crude product (15.2f1) was mixed with 600d of methanol and concentrated H
A solution was made with CZ.

After charcoal treatment, the solution was diluted with 1.5 liters in ice and extracted once with ethyl acetate. The aqueous phase was concentrated under reduced pressure to remove methanol. The cold water concentrate was diluted with 20% caustic soda to a concentration of 4.0, and the product was crystallized. The product was collected by filtration, washed with water and methanol, and dried in vacuo over phosphorus pentoxide; 11.4 fIO IR and NMR spectra were consistent with the desired product. Analysis C, OH,
Calculated value as lN, O, S: C, 38.42; H, 3
．． 55; N, 22.4O Experimental value: C, 38.27; 38
．． 26; H, 3.76; 3.40; N, 2l. O2,2
l. OO; H2O, l. Contains about 20 mol% of 7-aminocephalosporanic acid as a purified impurity of 7O 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid () Crude 7-amino-3-(1,2,3-
Triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (16.19) was mixed with 600 d of methanol and concentrated HCl4Ol! / to make a solution.

After charcoal treatment, the solution was diluted with 1.5 liters of ice water and extracted once with ethyl acetate. The aqueous phase was concentrated under reduced pressure to remove methanol. The cold water concentrate was then diluted with 20% caustic soda Pll4. The product was crystallized. P
The product was collected by filtration, washed with water and methanol, and dried in vacuo over phosphorous pentate; the 11.4f10 NMR spectrum indicated that the product contained 7 mol% of 7-aminocephalosporanic acid as an impurity. and showed. Methanol 425Wt1 concentrated HCl 28wLl and ice water 1
The above purification procedure was repeated on 11.4 fI of the product using a small volume to give 8.0 g of product. The NMR spectrum is completely consistent with the desired product, with 7 as an impurity.
- showed no trace of aminocephalosporanic acid. Analysis Calculated value as ClOlliNiOiS:'!
ぃ゛1・゛C, 38.42lH,
3.55; N, 22.4O Experimental value: C, 39. O6,3
8.53; H, 3.56, 3.5l; N, 22. O5,
2l. 6O; H2O, l. 78 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ()0
．． Purified 7-aminocephalosporanic acid 19f1 (0.07 mol) and NaCCO35 in 350 d of 1M phosphate buffer
．． To a 9 g (0.07 mol) slurry was added 10 g (0.07 mol) of 5-mercapto-1,2,3-triazole potassium salt with stirring.
3.075 mol) was added at 55° C. in a nitrogen stream.
The mixture was heated and stirred for 5 hours.

The resulting solution was cooled to 22°C and treated with 40% H, PO4...
Adjusted to 5.5. The obtained precipitate was separated by P and cold water ((5
0d) and air dried. 7-amino-3-(1,2
The yield of 3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was 8 g, and the decomposition point was 230°C.

IR analysis showed some decomposition of the β-lactam ring, but
It was used as is in the next step. Analysis C, OHllN,
Calculated value as O3: C, 38.39; H, 3.54 Experimental value: C, 38.36; H, 3.78 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3 -Cefem-4-carboxylic acid ()0
．． 7-Aminocephalosporanic acid 2729 (1.0 mol) was suspended in 1M phosphate buffer, pH 6.4, 3OOOd and methyl isobutyl ketone 150w11, and then sodium bicarbonate 849 (1.0 mol) was added ( Note: Baking soda was added in small amounts).

Next, 14.3 f1 (1.0 mol) of 5-mercapto-1(H)-1,2,3-triazole potassium salt was added, and the mixture was stirred at 55°C±1°C in a nitrogen stream for 4 hours. After 1 hour, by adding a small amount of 40% H, PO4...
was readjusted to 6.4.

At the end of the 4-hour heating time, "Darco KB" decolorizing charcoal 509
was added and after stirring at 55°C for 15 minutes, diatomaceous earth ("
The slurry was heated through a pad ("Celite").

The pad was washed three times with 100 Wt of water each time. Combine P solution 6
By gradually adding NHCI, the heating time... was reduced to 4.5
After cooling for 30 minutes at 0 DEG C., the crude product was collected by filtration, washed twice with 200 WLI of cold water, then twice with 1000 WLI of methanol, and air-dried. The crude product was suspended in 50% methanol/water and ethanol sulfonic acid 3009 (1.5 mol) was added.

The mixture was stirred for 15 minutes and then [Darco KB] 50f!
was added. After stirring for 15 minutes at 22°C, the slurry was filtered through a pad of ``Celite'' and the pad was
Washed twice with 100 ml of 0 methanol and 100 ml of water.

The P solutions were combined and the pH was adjusted to 4.0 by adding about 210 Tn1 of triethylamine. After cooling for 1 hour at 0° C., the product was collected by filtration and washed twice with 400 wL of 50010 methanol and water, then 1000 m of methanol.
Washed twice, one at a time, and air dried.

This material was suspended in 2000 ml of water, and 849 (1 mono(c)) of sodium bicarbonate was added.

After stirring for 10 minutes at 22°C, "Darco KB" charcoal 50
9 was added and after stirring for 15 minutes at 22° C., the slurry was filtered through a pad of “Celite”.

Wash the product twice with 100ml of water each time, combine the P solution,
The... was adjusted to 3.5 by slowly adding 6NHCI. After stirring for 10 min at 22°C, the mixture was
Cooled for 1 hour at <0>C.

The product was collected by P filtration and washed twice with 200 ml of cold water each time.
Washed twice with 1,000,711 tons of acetone each. After drying for 14 hours at room temperature under P2O in a vacuum desiccator, the yield was 1009 and the decomposition point was 230°C. IR and NMR
(1 was consistent with the desired structure. Analysis ClOH,,
Calculated value as N5O3S2・1/2H20: C37.5
l; H3.75; N2l. 68', H2O2.8 Experimental value: C37.78; H3.69; N2O. 42;KF(H
,O) 2.467-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cepheme-4-
In place of the 7-aminocephalosporanic acid used above, an equimolar amount of bivaloyloxymethyl 7-aminocephalosporanate hydrochloride (British Patent No. 1, 229,453 (prepared from 7-aminocephalosporanic acid according to Example 2) to prepare the title compound.

German patent 1,904,585 (FarmdOc39,
445) {1 Equivalent to British Patent No. 1,129,453. Process B - Instead of the 0.025 mol (6.89) of 7-aminocephalosporanic acid used during the procedure of Example 2 of GB 1,229,453, an equimolar amount of 7-amino-3-(
1,2,3-triazol-5-ylthiomethyl)-3
- Prepare the title compound by using Cefem-4-1 carboxylic acid.

7-Amino-3-(1,2
, 3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid acetoxy, methoxymethyl,
Acetonyl and phenacyl esters are produced respectively.

Synthesis reference of 2-mercapto-5-methyl-1,3,4-thiadiazole U.S. Pat. No. 3,516,997 (1
970); J. AntiblOtics23. l3l~
36 (1970).

11.5 g (0.1 mol) of 2-amino-5-methyl-1,3,4-thiadiazole was added to 329 (0.1 mol) of sodium nitrite.
．． Carefully mash with 45 mono(c) and heat to -10℃.
48% HBrl containing powdered copper 50~ under stirring at
It was slowly added to 60ml.

After the addition was complete, the solution was stirred for 1 hour at -5°C and then for 1.5 hours at 20°C. The pH was adjusted to 9.5 by addition of 50% KOH and the solution was heated to 60°C.

9.5 by adding 50% KOH at 60°C.
Readjusted to.

The solution was cooled and filtered. Dissolve the precipitate in ether and P
The liquid was extracted twice with 200ml portions of ether. The combined ether solutions were dried over borax and evaporated to dryness. The product was recrystallized from benzene "Skerisolve B".
29, mp105-107°C. 2-promo-5-methyl-1,3,4-thiadiazole 129 (0.07 mol)
and thiourea 59 (0.07 mol) in 100% ethanol 40Tn1. and refluxed on a steam bath for 1.5 hours.

This solution was mixed with H,O65Wllll4]KOH4.5f! (
0.08 mol) and the mixture was heated to boiling for 5 minutes. Ethanol was removed under vacuum and the state was adjusted to 3 by addition of 3N HCI. The product crystallized and was collected by filtration after cooling to 0°C for 1 hour, washed with cold water and recrystallized from 100'10 ethanol, Shodo 59, Mpl 86-18.
7℃. Analysis C, H, N, S, and t Calculated value: C27.25; H3. O5; N2l. l9;S
48.5l Experimental value: C27.2O; H3.34; N2l
．． l8;S48.487-amino-3-(5-methyl-
1,3,4-thiadiazol-2-ylthiomethyl)-
3-cephem-4-carboxylic acid 0.1M, pF16.4
7-ACA2.729 (0.0
1 mol) of NallCO, 1 mol) with stirring. 689(
0.02 mono(c), then 2-mercapto-5-methyl-1,3,4-thiadiazole 1.45f1 (0.01
1 mol) was added thereto, and the mixture was heated and stirred at 60° C. for 5 hours.

The resulting slurry was then allowed to cool to about 22° C. over 1 hour. The crystalline precipitate was collected by P filtration, washed with water, and air-dried. Yield 1.39, decomposition point 206°C. The reaction was scaled up 10 times to yield 18.0f1. Analysis CllHl
,N,O8S,Best calculation 11L5:1,C3,34th 37;H3.52;N
27.96 Actual value: c''9.06;H3.9l; N26
．． 677-Amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid bivaloyloxymethyl Method A by using instead of equimolar amounts of 7-aminosephalosporanic acid pivalyloxymethyl hydrochloride (prepared from 7-aminosephalosporanic acid according to Example 2 of British Patent 1,229,453). The title compound is prepared.

German patent 1.904,585 (FarmdOc39,
445) is equivalent to British Patent No. 1.229,453.
Process B - Instead of the 0,025 mol (6.8 f1) of 7-aminocephalosporanic acid used during the procedure of Example 2 of GB 1.229.453, an equimolar amount of 7-amino-3-(
Compound 11114 is prepared by using 2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxone.

7-Amino-131 (2-methyl-1,3, 4-
thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid acetoxymethyl, methoxymethyl,
Acetonyl and phenacyl esters are produced respectively.

Production of D-(1)-2-(y-methyl-1-hydroxyphenyl)glycyl chloride D-(-)-2-(
3'-Methyl-1-hydroxyphenyl)glycyl hydrochloride is prepared in high purity and very efficiently by the following procedure: D-(1)-2 in 100 d of dioxane.
-(35-Methyl-l-hydroxyphenyl)glycine is made into a slurry.

COCl2 (phosgene) is introduced while stirring the slurry and maintaining the temperature of the slurry at 50-58°C. 3.5 in total
Introduce COCl2 between questions. A yellow solution is obtained. Purge the solution with nitrogen to drive off excess COCI. Bubble HCI gas through the solution for 2.5 hours. Stir the solution;
A small amount is diluted with some ether to give some crystals which are added to the batch as seeds. The solution is stirred at 20-25°C for 16 hours. The obtained crystalline chloride D-(-)
-2-(35-Methyl-l-hydroxyphenyl)glycyl hydrochloride slurry is filtered through P filter to collect the product. The filter cake was washed with dioxane and methylene chloride, then dried in a vacuum dessicator over P, O, and about 79% D chloride.
-(-)-2-(3'-methyl-l-hydroxyphenyl)glycyl hydrochloride is obtained. 2-(3'-methoxy-1
-Hydroxyhuecole) Glycine production water 100-7
5% glyoxylic acid 59.2f! (0.6 mol) of 2-methoxyphenol in 400 d of water
! (0.5 mol) and 140 d of concentrated aqueous ammonia at room temperature.

The temperature of the hybrid material rose to 35°C. Mixture at room temperature 6J
It was stirred from time to time. The crystallized product was collected by phosphorus filtration, washed with water and then acetone, dried over phosphorus pentoxide for 2 hours.
-(3'-methoxy-l-hydroxypheno(ha)glycine 57.4y (58.2%); decomposition point 218-22
0g (Reference 2404) was obtained. Infrared and nuclear magnetic resonance spectra were consistent with the desired product. Analysis C,H
Calculated value as llNO4: C54.82; H5.62; N7. 1O experimental value: C53.77; H5.9l; N6.97; H2Ol.
Experimental values corrected for l3l, l3% H2O: C54,38; H5.85; N7. O5 Reference: B. Block, 1. ? K. K-ko. 9shoko. Lord, 2
26 (1917).

Resolution of 2-(3'-methoxy-4'-hydroxyphenyl)glycine A. Methyl 2-(3'-methoxy-4'-hydroxyphenyl)glycinate Anhydrous methanol 500
A cold suspension of 2-(3'-methoxy-4'-hydroxyphenyl)glycine 949 (0.476 mono(ha)) in m1 was quickly gassed with HCI for 20 minutes.

At first a clear solution was obtained, then a large amount of crystalline product separated out. After 20 hours, the methyl ester hydrochloride was filtered and washed slightly with methanol; 99.6 g after air drying.

A cold solution of this hydrochloride in 800 d of water was adjusted to pH 8 (N
aOH), a crystalline precipitate of the ester free base was obtained; 81
．． 89. IR and NMR spectra were consistent.
Analysis Calculated as ClOH, 3NO4: C56.86; H6.2O; N6.63 Experimental value: C56.46; H6.28; N6.55; H2OO.
59B. Methyl D-(-)-2-(3'-methoxy-l-hydroxyphenyl)glycine (3'-methoxy-l-hydroxyphenyl)glycinate 50g (0.237
A mixture of mono(he), acetic acid 19w11 (0.333 mol) and 1 liter of i-PrOH (isopropyl alcohol) was heated to boiling to form a partial solution.

While stirring well, add dibenzoyl-d-monotartrate monohydrate. thing(
89.29,0.237 mol) was added and the mixture was then refluxed. Salt immediately began to crystallize. Stop heating and
The flask was allowed to cool slowly to room temperature. After cooling in an ice bath, the precipitate was collected by P filtration. The P solution was concentrated to ⅓ of the original volume to obtain a second crop of small amounts of salt; total yield of both crops after air drying was 54.19 (Solid A: see below). The P solution was concentrated to remove the solvent.

Combine the viscous residue with 1N HCI and dilute the mixture with CHCl3
Extracted with 4OO7!11. CHCl3 phase to 1N HCI
Extraction was carried out twice at 100 d each. The combined HCI extracts were briefly concentrated to remove residual CHCl3 and refluxed for 1 hour. The solution was concentrated to a small volume to crystallize the amino acid HCI salt. The product was collected by filtration with 1N HCl 150
Recrystallized from T1L1. A solution of the product in 200 ml of water was adjusted to pH 4.5 (NaOH). The mixture was heated to near the boiling point and allowed to cool to precipitate D-(-)-2-(3'-methoxy-4'-hydroxyphenyl)glycine as fluffy needle-like crystals. After cooling overnight, the product was collected by P filtration, slightly washed with water, washed with methanol, and dried at 400 °C; 8.79·[α]D =
-136.5 (Cl.lNHCI). IR and NM
The R spectra were completely consistent. Analysis C, H, l
NO4・Hμ} and calculated value: C5O. 23;H6. O9
;N6.5l;H2O8.37 Experimental value: C5O. 43; H6.23; N6.5l; N8.95C. Solid A (54,19) on L-(+)-2-(3'-methoxy-l-hydroxyphenyl)glycine was mixed with 1300 ml of 1N HCl and 350 ml of CHCl while stirring well.
d.

This salt in the system does not decompose easily, so CH
Separate Cl3 and add MIBK3OOml while stirring well.
was added. Furthermore, divide it into 3 times with 1NHCI200d M
The IBK phase was extracted. The HCI extracts were combined, filtered through P, briefly concentrated to remove residual solvent, and heated to reflux for 1 hour to hydrolyze the ester. The reaction mixture was concentrated to a small volume. After cooling in an ice bath, the amino acid HCI salt was collected by P filtration. The salt was recrystallized from 175 d of 1N HCl, dissolved in 500 ml of water by heating, the solution was filtered through P.
was adjusted to 4.5 to crystallize the (NaOH) zwitterion. The mixture was heated to boiling, filtered and stored in a cold place to give a crystalline product L-(+)-1-(3'-methoxy-4'
-hydroxyphenyl)glycine was precipitated. The product was collected by p-filtration, washed slightly with water and methanol,
Dried in collection 40; 9.69. [α]240-+
727.2 Dry (Cl, lNHCI). DIR and NM
The R spectra were consistent.

Analysis C, HllNO4・H2O! ．． Calculated value: C5
O. 23; H6.99; N6.5l; H, O8.37 Experimental value: C5O. 53;H6. O6; N6.62; H2
O7.46 Chloride D-(-)-2-(3'-methoxy-
Production of 1-hydroxyphenyl)glycyl hydrochloride D-(-
)-2-(3'-methoxy-l-hydroxyphenyl)
Glycyl hydrochloride is produced: 1, dioxane 100d
0.06 mol of D-(-)-2-(3'-methoxy-l-hydroxyphenyl)glycine was made into a slurry.

COCl2 (phosgene) is introduced while stirring the slurry and maintaining the temperature of the slurry at 50-58C. 3.5 in total
Introduce COC4l for an hour. A yellow solution is obtained. Purge the solution with nitrogen to remove excess COCI. Bubble HCI gas through the solution for 2.5 hours. Stir the solution and dilute the powder with some ether to obtain some crystals, which are added to the batch as seeds. Stir the solution for 16 hours at 20-225°C.

The resulting slurry of +-11% P-(1,)-2-(3'-methoxy-1-hydroxyphenyl)glycyl hydrochloride was filtered to collect the product. The filter cake was washed with dioxane and methylene chloride, then dried over P2O in a vacuum 2-desiccator to give D-(1)-2-(3' chloride).
-Production of methoxy-1-hydroxyphemo-2-(3'-methyl-l-cedroxyphenyl)glycine
75% glyoxalic acid 59.02f in 100ml water
1 (0.6 mol) in 400 WII water at room temperature.
Medium 2-methylphenota 54.6ml (0.5ml) and concentrated ammonia water 140d (D) were added to the suspension. The temperature of the mixture rose to 1a370. The mixture was placed in a room and stirred for 65 hours! Left, ;.:!Jlf)11TllO
．． 1 solution was adjusted to pH 6.8 with 6N hydrochloric acid to crystallize the product. The product was collected by P filtration, washed with water, and dried under vacuum over phosphorus pentoxide to yield 2-(3'-methyl-4'-hydroxyphenyl)glycine 31.5f1 (34.8%); Points 196-1991. Infrared and nuclear magnetic resonance were consistent with the desired structure. References: Beach Yam
Pelkey Patent No. 774,0 belonging to Group Limited
No. 29 (1972) (FarmdOc27, l22T)
, which reports Mp2O4~207°C.

Analysis Calculated value as C, Hl, NO: C59.66; H6. l3;N7. l3 Experimental value: C57.68; H6.23; N7.47; H,
Experimental value corrected for 2.34% water: C59. O6; H6. 12; N7.67 D,L-N-chloroacetyl-2-(3'-methyl-1-hydroxyphenyl)glycine D,L-1-(ymethyl-1-hydroxyphenyl)glycine in water 1757n1 20. 29(
A suspension of 0.112 mol) was mixed with 20% caustic soda to prepare a solution.

Cool the solution in an ice bath. Chloroacetic anhydride (38.29,
0.224 mol) was added all at once, and the reaction mixture was kept at 10 with 20% caustic soda until no change was observed. The cold reaction mixture was stirred for an additional 10 minutes. The reaction mixture was then acidified to PI]2.0 with 6N hydrochloric acid to crystallize the product. The product was collected by P filtration, washed with water, and air dried. Recrystallized from 200 d of hot water to give D,L-N-chloroacetyl-2-(3'-methyl-1
-hydroxyphenyl)glycine 13.7g (47.4
9) was obtained. Infrared and nuclear magnetic resonance spectra were consistent with the desired product. Analysis CllHl2NO4Cl
Calculated value as -H2O: C47.92; H5. ll8;
N5, O8l experimental value: C48. Jl;H5. l6;N5
．． l5D-(-)-N-chloroacetyl-2-(3'-methyl-l-hydroxyphenyl)glycine D,L-N
-chloroacetyl-2-(3'-methyl-l-hydroxyphenyl)glycine (5.09, 0.0194 mol)
and L-efenamine acetate (6.19, 0.0218 mol) were dissolved in 50 d of isopropyl alcohol by heating on a steam bath.

Water (50111) was added and upon cooling, L-ephenamine salt crystallized out. Salt was collected by P filtration and air dried. Suspend the salt in 30 WLI of water and 50 d of methylene chloride, and add 20%
PFllO with caustic soda. It was adjusted to O.

The phases were separated and the aqueous phase was further extracted twice with methylene chloride.
Next, the aqueous solution was diluted with 6Δ hydrochloric acid to PFl2. The product was crystallized by adjusting to O. The product was collected by P filtration and dried in vacuo over phosphorus pentoxide to give D-(-)-N-chloroacetyl-2-(
3'-Methyl-1-hydroxyphenyl)glycine 0.
99 (36.1%); Mpl7OO-172g, [α]
249=185.9) (Cl, 95% 5DEtOH) was obtained.

Infrared and nuclear magnetic resonance spectra were consistent with the desired product.

Analysis Calculated value as Cl, Hl2NO4Cl: C5l.
27; H4.696; N5.436 Experimental value: C5l. 2
l;H4.

77; N5.29 commonly called efenamine, 1,2
-diphenyl-2-methylaminoethanol (Fede
ralRegister, June 7, 1951)
has the following structure.

This compound is N-methyl-1,2-diphenyl-2-
Hydroxy-ethylamine or alpha, beta
Hydroxy-N-methyl-ethylamine or 1,2-
Also called diphenyl-2-methylamino-1-ethanol.

The present invention utilizes only the levorotatory mono-erythro isomer.

Its manufacturing method and reaction with penicillin G are described in U.S. Pat.
645,638 (, Young) and US 2,768.08
1 (F.H. Backwalter). 11 to the latter, W. B. Wheatley et al., J. Org. Chem
．． , l8(11), 1564-11571 (1953)
We review previous literature as follows. It is Sheehan et al., J.
．． Am. Chem. SOc. ,8l,3O89~309
4 (1959) to resolve racemic phenoxymethylpenicillin; see especially page 3091.
D-(-)-2-(3'-methyl-4'-hydroxyphenyl)glycine D-(-)-N-chloroacetyl-2
-(3'-methyl-4'-hydroxyphenyl)glycine (11.1f!, 0.0431 cells) in 2N hydrochloric acid 10
0 ml and the mixture was refluxed for 1.5 hours.

The solution was cooled and the pH was adjusted to 5.0 with 20% caustic soda to crystallize the product. The product was collected by P filtration, washed with water, and dried under vacuum over phosphorus pentoxide to give D-(-)-2-
(Ryoichimethyl-1-hydroxyphenyl)glycine 7.
49 (94.7%); decomposition point 205-209: [α]2
152.6% (Cl, 1NHCI) of 4-1 was obtained. D
- Infrared and nuclear magnetic resonance spectra were consistent with the desired product.

Analysis Calculated as C, HllNH3: C59.66; H6. l3; N7.73 Experimental value: C58.62; H5.49; N7.78; H2
Ol. 46l. Experimental values corrected for 46% H2O: C59.48; H5.4l; N7.84D-(-)-
N-t-butoxycarbonyl-2-(3'-methyl-4
'-Hydroxypheno(ha)glycine D-(-)-2
t-Butoxy azide was added to a slurry of 7.29 (0.0397 mol) of -(3'-methyl-l-hydroxyphenyl)glycine and 3.2 g (0.08 mol) of powdered magnesium oxide while stirring at room temperature. Carbonyl 9.7f! (0.0
68 mol) was added dropwise.

The reaction mixture was then mixed with 42-45. 19 in a nitrogen stream at
heated for an hour. The mixture was then diluted with 100 ml of ice water. The solution was layered with ethyl acetate and filtered through P to remove the separated insoluble matter. The aqueous phase of liquid P was separated and further extracted twice with ethyl acetate. Next, add 42% phosphoric acid to the aqueous solution to pH 5. The mixture was extracted with ethyl acetate five times. The combined organic extracts were washed three times with water, dried over borax, and the solvent was removed under reduced pressure, leaving an oil. The oil was dried in vacuo over phosphorus pentoxide to give D-(1)-N.
-t-butoxycarbonyl-2-(3'-methyl-4'
-Hydroxyphenyl)glycine 10.6f! (95%
) was obtained. The infrared spectrum was consistent with the desired structure. D-(1)-N-(t-butoxycarbonyl)-2-
Production of (3'-methoxy-1-hydroxyphenyl)glycine D-(-)-2-(3'-methoxy-1-hydroxyphenyl)glycine 8.69 (0.04 mono(c)
, 3.29 (0.08 mol) of magnesium oxide, 9.79 (0.068 mol) of t-butoxycarbonyl azide, and 240 d of 1:1 dioxane-water were stirred for 20 hours at 45-50 liters in a nitrogen stream. Heated.

The cooled reaction mixture was diluted with 240 Tn1 of ice water, filtered tp, and extracted once with ethyl acetate. Acidified (PI)2
) The aqueous phase was extracted 5 times with ethyl acetate, the combined ethyl acetate extracts were dried (Na2SO4) and concentrated under reduced pressure to remove the solvent to give the product as a viscous oil; 6.3 g. D-
Preparation of sodium N-(2-methoxycarbonyl-1-methylvinyl)-α-amino-(g-methyl-1-hydroxyphenynolyacetate)NaOH in 320 ml of methanol
3. D-(
1) Add 0.08 mol of -2-(35-methyl-1-hydroxyphenynoliglycine) and heat the resulting mixture under reflux to prepare 9.67 nt (0.088 mol) of methyl acetoacetate in 80 ml of methanol. solution over 30 minutes.

After stirring for an additional 30 minutes, the methanol is distilled off, while toluene is added at the same rate to maintain approximately the same content. When the internal temperature reached 100°C, the suspension was cooled in ice water for 4 hours, filtered with P, washed thoroughly with toluene, air dried, and vacuum dried over P2O5 to a constant weight to give a solid D- N-(2
Sodium -methoxy-carbonyl-1-methylvinyl)-α-amino-α-(3'-methyl-4'-hydroxyphenyl)acetate is obtained. D-N-(2-methoxycarbonyl-1-methyA!2vinyl)-a-amino-α-(
3′-Methoxy” IP-! ←Production of Sodium Sodium Acetate NaO in 320ml of methanol
H3. D-(
-) -2-(3'-Methoxy-4'-hydroxyphenyl)glycine 0.08 mol was added and the resulting mixture was heated under reflux while 9.6 ml (0.088 ml) of methyl acetoacetate in 80 ml of methanol was added. mol) over a period of 30 minutes.

After refluxing for an additional 30 minutes, methanol is distilled off, while toluene is added at the same rate to maintain approximately the same content. When the internal temperature reached 100°C, the suspension was cooled in ice water for 4 hours,
Filter, wash thoroughly with toluene, air dry, and vacuum dry over P2O5 until constant weight to give a solid D-N-(2-methoxy-carbonyl-1-methylvinyl)-α-amino-
α-(3'-methoxy-1-hydroxyfenino(c)
Obtain sodium acetate. Preparation of various thiolated 7-aminocephalosporan derivatives The above 7-amino-3-(5-methyl The same experimental procedure used in the preparation of -1,3-4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid was repeated.

The thiols used are as follows. That is, 5-
Mercapto-2-methyl-1,3,4-oxadiazole 5-mercapto-1-methyl-1,2,3,4-tetrazole 5-mercapto-1,2,3,4-tetrazonole 4-mercaptopyrimidine 2 -Mercaptopyramidine 5-mercapto-3-methylisothiazole 2-mercaptoimidazole The following compounds were synthesized.

That is, 7-amino-3-(2-methyl-1,3,4-
Oxadiazol-5-ylthiomethyl)-3-cepheme-4-carboxylic acid 7-amino-3-(1-1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl)-3-cepheme-4- Carboxylic acid 7-amino-3-(
1,2,3,4-tetrazol-5-ylthiomethyl)
-3-cephem-4-carboxylic acid 7-amino-3-(pyrimid-4-ylthiomethyl)-3-cepheme-4-carboxylic acid 7-amino-3-(pyrazin-2-ylthiomethyl)-3-cepheme-4-carvone acid 7-amino-3
-(pyrazin-2-ylthiomethinol-3-cepheme-4-carboxylic acid)7-amino-3-(3-methylisothiazol-5-ylthiomethyl)-3-cepheme-4-
carboxylic acid and 7-amino-3-(imidazole-2
-ylthiomethyl)-3-cephem-4-carboxylic acid 2
- Preparation of (3'-1-ethoxy-4'-hydroxyphenyl)glycine 2-(3'-methoxy-4) except that 2-ethoxyphenol was used instead of 2-methoxyphenol.
2-(3'-ethoxy-1-hydroxyphenyl)glycine was synthesized using the same synthetic method used to synthesize '-hydroxyphenyl)glycine.

Elemental analysis: Calculated value of C, OHl3NO4: C56.86; I{6.202; N6.632 actual value:
C56.4l; H6.44; N6.63DL-N-(t
-Production of butoxycarbonino(c)-2-(3'-1ethoxy-4'-hydroxyphenyl)glycine D-(-)
The above D-(-
)-N-(t-Butoxycarbonyl)-2-(3'-methoxy-l-hydroxyphenyl)glycine was synthesized using the same method.

The title compound was confirmed by IR and NMR analysis. Elemental analysis: Calculated value (Cl5H21NO,): C57.86; H6.8OO; N4.499 Actual value: C
58.43; H7.22; N4.223-Hydroxy-
Preparation of 6-mercaptopyridazine A. 3-chloro-6-
A mixture of 22.479 (0.15 mol) of hydroxypyridazine in 3,6-dichloropyridazine and 50 ml of acetic acid was refluxed for 2 hours.

The reaction mixture was cooled, diluted with 50 ml of water and then concentrated to dryness under reduced pressure. The residue was recrystallized from water for 15
．． 89 (80C10) of 3-chloro-6-hydroxypyridazine was obtained. Colorless prismatic crystals, melting point 133-
7°C (literature value 138-140°C) Reference Takebayashi, Pharmaceutical Journal, 75,778 (1955) B. 3-hydroxy-
2.69 (0.02 mol) of 6-mercaptopyridazine, 5.09 (0.02 mol) of 3-chloro-6-hydroxy-pyridazine,
0.07 mol) of freshly prepared potassium hydrogen sulfide and 30 ml of ethanol in a sealed tube for 6 hours at 130-14
Heated to 0°C. The reaction mixture was cooled and diluted with 200ml of water. All organic solvents were distilled off under reduced pressure.
The remaining aqueous solution was acidified to PF13 with dilute hydrochloric acid and extracted with ethyl acetate (6X50d). The extracts were combined and evaporated to dryness, and the residue was recrystallized from 30 Tn1 of ethanol-ligroin (1:) to yield 2.29 (87%) of amorphous 3-hydroxy-6-mercaptopyridazine. Melting point 158-159℃ (literature value 157-1580J.Dr.
uey et al., HelvChemActa. 3l 121 (
(1954). C. 3-Hydroxy-6-mercaptopyridazine 5.69 (0.05 mol) of 3,6-dihydroxypyridazine and 150 TILI! 2.7 g of phosphorus pentasulfide was added little by little to a solution consisting of pyridine of , while stirring vigorously while maintaining the solution under reflux.

Refluxing was continued for 1 hour, then diluted with 200 d of water and further concentrated to remove the pyridine. The resulting oily residue was dispersed in water and extracted with ethyl acetate. The organic phases were combined and concentrated again to give an oil. This was decomposed and purified with a small amount of water to obtain 3-hydroxy-6-mercaptopyridazine as a yellow solid. Recrystallized from water to 0.629 (
12%) of the title compound was obtained. D. To a boiling solution of hydrazine dihydrochloride of 3,6-dihydroxypyridazine 3159 (3 mol) and water of 21, 295 g (3 mol) of maleic anhydride fine powder was added dropwise while stirring the liquid.

Heating was continued for 4 hours after the addition was complete and then left in the freezer overnight to yield 2859 (85%) of 3,6-dihydroxypyridazine as bulky pillars. Melting point 7290
℃ E. 3,6-dichloropyridazine A mixture of 150f1 (1.33 moles) of 3,6-dihydroxypyridazine and 2509 phosphorus oxychloride was refluxed for 3 hours without moisture.

Excess phosphorous oxychloride was removed under reduced pressure and the dark residue was poured onto 1 kg crushed ice. The resulting precipitate was collected using P filter. The product was further collected by extracting the mother liquor 5 times with 300 ml of chloroform, then treating it with 19 ml of activated carbon and evaporating the solvent. The primary and secondary products were combined, dissolved in 500 ml of chloroform, treated again with 19 activated carbon and further concentrated to yield 1659 (83%) of 3,6-dichloropyridazine, mp 60-61 °C. It was obtained as a thin needle-like body. ? A suspension of 6-chloro-3-hydroxypyridazine 609 (0.4 mol) in 20 ml of 10% hydrochloric acid was refluxed for 2 hours until a clear solution was obtained.

The clear solution was treated with 1.59 activated carbon and filtered through P. P
The liquid was concentrated under reduced pressure to obtain 6-chloro-3-hydroxypyridazine as colorless needles. Yield 49.5f1 (
98%) Melting point 137-139°C. G. 3-hydroxy-6-mercaptopyridazine 50fI (0.38 mol)
6-chloro-3-hydroxypyridazine, 609(0
．． A mixture of 83 mol) of potassium hydrogen sulfide and 250 d of ethanol was heated to 140° C. with magnetic stirring for 14 hours in a 5007R1 autoclave.

A pressure of 15-20K9/Cd was reached. The mixture was evaporated to dryness and the residue was dissolved in 300 d of water. The aqueous solution was acidified to PH3 with dilute hydrochloric acid and extracted 10 times with 200 WLI of ethyl acetate. The extract was concentrated to 34.39 (7
0%) of amorphous 3-hydroxy-6-mercaptopyridazine was obtained. Melting point 151-152℃ 7-amino-3-(
6-hydroxypyridazine; ylthiomethyl)-
3-Cefm-4-carvone 0.609 (0.004
mol) of 3-hydroxy-6-mercaptopyridazine,
1.27f1 (0.0047 mol) of 7-aminocephalosporanic acid, 0.789 (0.0094 mol) of sodium bicarbonate and 0.1 M phosphate buffer (pH 6.
4) A mixture consisting of 257111 was heated at 60°C for 5 hours.

The reaction mixture was filtered through phosphorus to remove traces of insoluble material, adjusted to a pH of 5 with acetic acid, and a color precipitated. P this
Collected by filtration, washed successively with water and acetone, and dried in vacuo to yield 7-amino-3-(6-hydroxypyridazin=3-ylthiomethyl)-3-cephem-4-carboxylic acid, 1. 039 (71%). Melting point 290-300
°C (decomposition). KBr IRν 1805, 1680, 1650Maxν
Storehouse 91580, 1415c! n
−1 U:λ? AOH249nm (ε19400) NMR: δ
? 0? K2nO33.22 (1H, d, 19Hz), 3
．． 37 (1H, d, 14Hz), 3.65 (1H, d,
14Hz), 3.72 (1H, d, 19Hz), 4.9
0 (1H, d, 4Bz), 5.30 (1H, d, 4Hz
), 6.75 (1H, d, 10Hz), 7.30 (1H
, d, 10Hz) Elemental analysis calculation value (Cl2H, 2N4O4S2・!/(2H, 0)
:C4l. 25; H3.75; Nl6. O4; Sl8.
36 Actual value: C4l. 45; H3.7O; Nl5.83
;Sl8. O3 The present invention will be explained by the following Examples, but the present invention is not limited thereto.

All temperatures are in °C. 7-Aminocephalosporanic acid is 7-ACAl methyl isobutyl ketone {1MI
BK, tetrahydrofuran is abbreviated as THF.

6SKe11ys01veB'' is a petroleum ether consisting primarily of n-hexane with a boiling point of 60-68°C.

LA-1 resin {1 below formula It is a mixture of various secondary amines shown in

Note that each of R1, R2 and R3 (G) is a monovalent aliphatic hydrocarbon group, each having 11 to 14 carbon atoms. It is called a one-liquid amine mixture.461!, and is a transparent amber-colored liquid with the following physical properties: Physical properties: 1. Viscosity at 25°C: 70 cpd.. ~ Specific gravity at 0°C: 0.826; Refractive index at 25℃ 1.46 Boiling point range (101!L) below 170℃ - 0J1% 7170-22
0℃-3%, 220-230℃-I-●5δS, 23O
℃ or more -6.5%. Example 1゛1-=[D-2
-amino-2-(3'-methyl-4'-monohydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)=3-cephem-4-carboxylic acid A. Mixed anhydride2. A bath solution consisting of D-(1)-N-t=wothoxycarbonyl-2-(y-methyl-l-hydroxyphenyl)-glycine and 100i of tetrahydrofuran was prepared. Cooled to −15° C. in an ice-salt-acetone bath.

N-methylmorpholine (1.019, 0.01 mol) was added followed by 1.379 (0.01 mol) isobutyl chloroformate and the reaction mixture was reduced to -15--20
The mixture was stirred at ℃ for 8 minutes. A precipitate of N-methylmorpholine hydrochloride separated immediately. B. Coupling J Me[amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.
1 g, 0.01 mol) was dispersed in 100 d of water, and then 1.01 f1 (0.01 mono(c)) of N-methylmorpholine was added.

A complete solution 11 was not obtained. Then 1, 1, 3, 3
-Tetramethylguanidine was added to the suspension until the liquid became clear. The solution was then cooled to 4°C in an ice bath and it was added to the -15°C mixed anhydride solution. The cooling bath was removed and the mixture was stirred for 1.5 hours. Tetrahydrofuran was then removed under reduced pressure and the concentrated aqueous solution was phase separated with ethyl acetate. The aqueous phase was diluted with 42% phosphoric acid to pH 2. O and insoluble matter was separated. The solid was separated from P. The aqueous phase of liquid P was separated and extracted twice with ethyl acetate. The organic extracts were combined, washed twice with water, and dried over sodium sulfate. The solvent was then removed under reduced pressure to obtain a viscous oil.
6SKe oil containing a small amount of diethyl ether
A solid was obtained by dispersion purification on 11ys01veB1.
The obtained solid was collected by P filtration and 6Ske11ys01v
Washed with eB8 and air dried. TLC (silica gel; solvent 97:3 acetone monoacetic acid) of the product showed the material to be a mixture of desired product and side chain acid. This material was mixed with 100ml of anhydrous diethyl ether and stirred for 1 hour. The insoluble solids were collected and air dried to yield 0.959 (16.4%) 7-[D-2-t-
butoxycarbonylamino-(3'-methyl-l-hydroxyphenyl)acetamide]-3-(1,2,3-
Triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was obtained. TIC (silica gel; solvent 97
:3 acetone monoacetic acid), this sample was found to contain only trace amounts of side chain acids. The IR spectrum matched that of the target product. C. Removal of protecting group 7-[D-2-t-butoxycarbonylamino-(3'
-Methyl-l-hydroxyphenyl)acetamide]-
3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (0.959,0.
002 mol) to 15 ml of cold trifluoroacetic acid,
The solution was stirred for 15 minutes.

The trifluoroacetic acid solution was then added to 200 wL of 6Ske
11ys01veB'' monoanhydride diethyl ether (2:1
) and the mixture was cooled. Product 71 [D-2-
Amino-(3'-methyl-l-hydroxyphenyl)acetamide]-3-(1,2,3-triazole-5-
The precipitate of trifluoroacetate of (ylthiomethyl)-3-cephem-4-carboxylic acid was collected by P filtering and 2:16Sk
e11ys01veB'' was washed with monoanhydrous diethyl ether and dried under vacuum over phosphorus pentoxide to obtain the desired product of 0.759. The above salt (0.759) was mixed with 50 ml of water and 25 ml of water.
of Amberlite LA-1 resin (25% methyl isobutyl ketone solution) and 25 ml of methyl isobutyl ketone and stirred at room temperature for 2 hours.

The phases were separated and the methyl isobutyl ketone phase was extracted once with water. The aqueous phases were combined and then extracted eight times with diethyl ether. The aqueous phase was filtered and the solvent was removed under reduced pressure. The residue was purified by dispersion in methyl isobutyl ketone to obtain a solid. The product was filtered, washed with methyl isobutyl ketone and acetone, and dried over phosphorus pentoxide in vacuo at 65°C to give 0.369 (59.0%) 7-[D-2-amino- (3'-Methyl-4'-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl-3-cephem-4-carboxylic acid was obtained.Decomposition temperature>150℃ infrared and The target product was confirmed by NMR spectrum.The thus obtained 71[D
-α-Amino-α-(3'-methyl-l-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (BL-S638 ) is made into an aqueous solution, Nu
Minimum inhibited concentration (M.I.C., mcg/ml) for a given bacterial body determined by in vitro dilution of a sample diluted with lrientBrOth and aged overnight at 37°C.
is as shown below.

Shown with other traditional cephalosporins. *i1 animals were treated twice for the above diseases; 1 after challenge
and 3 hours** Sodium citrate, Tween4O
and administered as an aqueous zwitterionic solution (10-20 ηm/ml) containing CMC (carbomethoxycellulose).

This diluent has the following composition:
Triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid A. 14.06 g (0.05 mol) of mixed anhydride D-(-)-Nt-
A solution consisting of butoxycarbonyl-2-(3'-methyl-4'-hydroxyphenyl)glycine and 500 ml of tetrahydrofuran was prepared in an ice-mono-acetone bath at -1
Cooled to 5°C.

To it was added N-methylmorpholine (5.06 g, 0.05 mol), followed by 6.839 (0.059) of isobutyl chloroformate and 10
Stir for 1 minute. N-methylmorpholine hydrochloride was immediately separated. B. Silyl ester
r) 8.09 (0.025 mol) of 7-amino-31 (
1,2,3-triazol-5-ylmethino-0-3-cephem-4-carboxylic acid, 7.0 ml (0.05 mol)
of triethylamine 6.9 ml (0.0545 mol) of N,N-dimethylaniline, 9.5Tf1I! (0.0
75 mol) of chlorotrimethylsilane and 650 ml
of methylene chloride was heated at reflux temperature for 3 hours. After refluxing for 1 hour, an additional 1.6 ml of chlorotrimethylsilane was added, the cloudy solution was cooled and the methylene chloride was removed under reduced pressure.

The residue was poured into 500 d of tetrahydrofuran. C
．． Cool the coupling silyl ester solution to 10-15°C in an ice bath,
Pour all at once into the mixed anhydride solution cooled to -15°C.

The cooling bath was removed and the reaction mixture was stirred for 2 hours. Then 500 d of water was added and the tetrahydrofuran was removed under reduced pressure. A rubbery oil was then separated. The oil was extracted into ethyl acetate and the phases were separated. Aqueous phase (PH3.
8) was separated into layers, during which a small amount of solid material was separated. The aqueous solution was adjusted to Pl]2,3 with phosphoric acid and extracted again with ethyl acetate. The ethyl acetate extracts were combined, washed three times with water, dried over sodium sulfate, and the solvent removed under reduced pressure to give a viscous oil. The product was stirred with 100 ml of anhydrous diethyl ether for 1.5 hours to obtain a solid.
The solid was filtered, washed with a small amount of anhydrous diethyl ether, and air dried. Analysis of the product by TLC (silica gel: solvent 99:1 acetone monoacetic acid) resulted in the desired product,
It was found to contain a side chain product and a third unidentified substance. The product was again stirred with 100 ml of anhydrous diethyl ether for 1.5 hours to remove the insoluble solids.
7 of 10.79 (74.4%) was overcollected and air dried.
-[D-2-t-butoxycarbonylamino-(3'-
Methyl-l-hydroxyphenyl)acetamide]-3
-(1,2,3-triazol-5-ylthiomethyl)
-3-Cefem-4-carboxylic acid was obtained. Analysis by TLC (silica gel; solvent 99:1 acetone monoacetic acid) revealed that the present sample contained traces of side chain acids and unidentified third acids.
It has become clear that it contains a substance. IR spectrum {1 revealed that it was identical to the desired product. D.
Removal of protecting group 7-[D-2-t-butoxycarbonylamino (y-
Methyl-4'-hydroxyphenyl)acetamide]-
3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (10.79,0.
0186 mol) was added to 150 ml of cold trifluoroacetic acid and stirred in an ice bath for 15 minutes.

Trifluoroacetic acid solution was then added to 2100 ml (7) 6S
ke11ys01veB'' monoanhydride diethyl ether (2
:1) and cooled the mixture. The trifluoroacetate of the precipitated product was collected by filtration and 2:1″SkeI
lysOlveB'' washed with anhydrous diethyl ether;
Dry over phosphorus pentoxide under reduced pressure to 10.6f! of product was obtained.

The salt (10.69) was mixed with 500i of water, 115- of Amberlite LA-1 resin acetate type (25% methyl isobutyl ketone liquid) and 1157! It was dispersed in a liquid mixture consisting of methyl isobutyl ketone and stirred at room temperature for 2 hours.

The phases separated and a small amount of insoluble solid was removed by filtration. The aqueous solution was extracted twice with methyl isobutyl ketone and eight times with diethyl ether. The aqueous solution was filtered through P filter and then concentrated slightly to separate the solids. The solid content was removed by P filtration, and the aqueous P solution was treated with activated carbon and further treated under reduced pressure to obtain a solid. The product was collected by P filter, washed with a small amount of water, and dried under vacuum over phosphorus pentoxide to yield 2.99 (33.3%) of 7-[D-2-amino-(3'-methyl-4 '-Hydroxyphenyl)acetamide]-3-(1,2,3-triazole-5-
ylthiomethyl)-3-cephem-4-carboxylic acid was obtained. Concentration of the mother liquor gave more product (0.759).
The product was confirmed to be the desired product by IR and NMR spectra. Example 3 7-[D-2-amino-2-(3'-methyl-1-hydroxyphenyl)acetamide]-3-(1,2,3-
Triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid A. 12.2 g (0.0434 mol) of mixed anhydride D-(-)-N-t
-Butoxycarbonyl-2-(3'-methyl-4'-hydroxyphenyl)-glycine and a solution of 4259 in tetrahydrofuran in an ice-mono-acetone bath-
Cooled to 15°C.

and N-methylmorpholine (4.359, 0.043
4 mol) was added followed by 5.879 (0.0434 mol) of isobutyl chloroformate and the reaction mixture was stirred at -15°C for 10 minutes. A precipitate of N-methylmorpholine hydrochloride formed immediately. B. 6.89 (0.0217 mol) of silyl ester 7-amino-3-(1
,2,3-triazol-5-ylthiomethyl)-3-
Cefem-4-carboxylic acid, 6.02 ml (0.043
mol) of triethylamine, 6.0 ml 10) N,N-dimethylaniline (0.047 mol), 8.26 d (0.
0651 mol) of chlorotrimethylsilane and 550
wL1 of methylene chloride was heated to reflux for 2 hours.

The cloudy solution was cooled and the methylene chloride was removed under reduced pressure.
The residue was poured into 425 ml of tetrahydrofuran. C. Coupling silyl ester solution in an ice bath for 10
It was cooled to -15°C and added in one portion to the mixed anhydride solution cooled to -15°C.

The cooling bath was removed and the reaction mixture was stirred for 2 hours. 42
57n1 of water was added and the mixture was stirred for 5 minutes.

Tetrahydrofuran was removed under reduced pressure and a gummy oil separated. The oil was extracted into ethyl acetate and the insoluble solids were separated. The aqueous phase of P solution was separated, adjusted to 2.0 with 42% phosphoric acid, and extracted twice or more with ethyl acetate. The ethyl acetate extracts were combined, washed three times with water, dried over sodium sulfate, and the solvent removed under reduced pressure to give a viscous oil. The oil was dissolved in 30d of acetone and added dropwise into 300d of well-stirred diethyl ether. The mixture was stirred at room temperature for 2.5 hours. The separated insoluble solid was collected by filtration and air dried. Analysis of the product by TLC (silica gel; solvent, 99:1 acetone monoacetic acid) revealed it to be a mixture of the desired product side chain acid and a third unidentified substance. The solid was again stirred in 80 d of anhydrous diethyl ether for 1 hour.
The insoluble solids were collected by filtration, washed with a small amount of anhydrous diethyl ether, and air dried to give a solution of 5.89 (46.5%).
-[D-2-t-butoxycarbonylamino-(3'-
Methyl-1-hydroxyphenyl)acetamide]-3
-(1,2,3-triazol-5-ylthiomethyl)
13-cephem 14-carboxylic acid was obtained. TLC (silica gel; solution, 99:1 acetone-acetic acid) analysis revealed that the sample contained only trace amounts of side chain acids and a third, unidentified substance.

It was confirmed by IR spectrum that it was the desired product. )
．． Removal of protecting group 7-[D-2-t-butoxycarbonylamino (y-
Methyl-4-hydroxyphenyl)acetamide]-3
-(1,2,3-triazol-5-ylthiomethyl)
-3-Cefem-4-carboxylic acid (5.89, 0.01
82 DO) was added to cold trifluoroacetic acid and stirred in an ice bath for 15 minutes.

The trifluoroacetic acid solution was then added to 1140d of 6Ske1
1ys01veB'' monoanhydride diethyl ether (2:1)
and the mixture was cooled. The trifluoroacetate precipitate of the product was collected by filtration and 2:1″ Skellysnl
veB'' was washed with anhydrous diethyl ether and air dried to give 5.9 fI of trifluoroacetic acid of 7-[D-2-amino-(3'-methyl-l-hydroxyphenyl)-3-cepheme-4-carboxylic acid]. I got salt. 1 The salt (5.9
9) 280i water, 65d 6 amber light LA-
17 resin acetate type (25 in methyl isobutyl ketone)
%) and 65d of methyl isobutyl ketone at room temperature for 2 hours. The phases were separated and the aqueous phase was extracted twice with methyl isobutyl ketone. A small amount of insoluble solid separated into the aqueous phase and was separated from P. The aqueous phase of the P liquid was extracted three times with methyl isobutyl ketone and then eight times with diethyl ether. The aqueous solution was filtered through P and concentrated slightly to separate two solids. The solid content was separated from P, and the aqueous P solution was treated with activated carbon and further concentrated under reduced pressure to obtain a solid. The product was collected by P filter, washed with a small amount of water, and air dried to 1.89
solid 71 [D-2-amino-(3'-methyl-4'-
hydroxyphenyl)acenitamide]-3-(1,2
, 3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was obtained. The solid (1.8fI)
was dispersed in 10 i of water, 10 d of tetrahydrofuran was added, and the mixture was heated slightly on a steam 5 bath to dissolve.

Then 70 TILI of tetrahydrofuran were added and the product crystallized. The product was collected by filtration, washed with a small amount of tetrahydrofuran, and dried under vacuum at 65°C over phosphorus pentasaponide to yield 1.349 (28.1%) of 7-[D-2-amino-(3'-methyl -l-hydroxyphenyl)-acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was obtained.
Decomposition temperature 199-202°C. The IR spectrum matched that of the target product. The NMR spectrum revealed that the product was the same substance as the target product and further contained 0.6 mol % of tetrahydrofuran. Elemental analysis calculation value (ClOH2ON6O, S2・0.6C4H80
・0.5H20): C48.83; H4.96; Nl5
．． 89; H2Ol. 7 Actual measurement value: C49. O4; H4.7
4; Nl6.37; H2Ol. 7l Example 4 7-[D-α-amino-α-(3'-methyl-l-hydroxyphenyl)acetamide]-[S-(1,2,3
-triazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid 93.9 g (0.3 mol) of 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem -4-carboxylic acid and 140
0T! 11 dried CH2CZ, 81 to a suspension consisting of
m1 (0.58 mol) of triethylamine, then 50
d (0.39 mol) of N,N-dimethylaniline was added with stirring.

After cooling to 12° C., 76.2 d (0.6 mol) of trimethylchlorosilane was added over 15 minutes.

After a further 15 minutes the mixture began to slowly reflux. After refluxing for 45 minutes, the almost clear solution was cooled to 5°C and 0.354
Mol of D-(-)-α-amino-α-(3′-methyl-
l-Hydroxyphenyl)-acetyl chloride hydrochloride was added portionwise over 30 minutes.

The mixture was stirred at 5°C for 1 hour and the ice bath removed for an additional hour (maximum temperature 18°C). 12 of water was added, and while stirring vigorously... was gradually adjusted to 2.2 with 20% NaOH.

The aqueous and CH,Cl2 phases were separated and the gummy precipitate was removed. Ether (11) was added and the solution was adjusted to 2 while stirring vigorously. Water phase at 209″Da
treated with rcOKB'' (activated carbon), filtered with P, and newly
1 of ether was added and... was adjusted to 4. After adding seed crystals and stirring at 20° C. for 1 hour, the crystals were separated from P, thoroughly washed with water and acetone, and air-dried. Vacuum drying over P2O gives a solid 7-[D-α-amino-α-
Methyl-l-hydroxyphenyl)acetamide]-3
-(S-(1,2,3-triazol-5-yl)-thiomethyl]-3-cephem-14-carboxylic acid was obtained. Example 5 7-[D-α-amino-α-y-methyl -l-hydroxyphenylacetamide]-3-[S-(1,2,3-
0.02 mol of sodium D-α-[triazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid
1-carbomethoxypropen-2-yl)-amino-y
-To a suspension consisting of methyl-4'-hydroxyphenylacetate and 50 ml of acetonitrile were added 2 drops of N,N-dimethylbenzylamine, the slurry was cooled to -10°C, stirred, and .14g (0
．． 02 mol) of ethyl chloroformate were added.

After 20 minutes at -10°C, 6.269 (0.02 mono(c) of 7-amino-3-[S-(1,2,3-triazole-
5-yl)thiomethyl)-3-cephem-4-carboxylic acid, 2.8 ml (0.02 mol) of triethylamine,
A solution of 40 Tn1 of acetonitrile and 40 ml of water, precooled to 0° C., was added at once with vigorous stirring.

After 45 minutes the solution was saturated with common salt (excess NaCl) at 0°C.

The organic phase (upper layer) was separated, 40 ml of water was added to it, and it was concentrated to 50 wL1 under reduced pressure at 20°C. This solution 1ζ70d of methyl isobutyl ketone (MIBK)
and 8d of 90% formic acid were added. The mixture was first shaken and then stirred for 3 hours at 0°C. Separate the aqueous phase and then add another 70 ml (7) of MIBK and O
The mixture was stirred at ℃ for 30 minutes and separated again. The aqueous phase was concentrated to dryness at 20° C. under reduced pressure. The residual oil was purified by dispersion in acetonitrile to obtain a solid. The solid was collected by filtration and then vacuum dried over P2O5 for 14 hours to yield the solid 7-[D-α-amino-α-3'-methyl-l-hydroxyphenylacetamide]-3-[S-(1 ,2,3
-triazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid was obtained. It was clear that this substance contained impurities. These impurities were removed by the following method. That is, the product is dissolved in 25 ml of water,
P filtered,...adjusted to 1.5 with 40% phosphoric acid, added 19"1Darc0KB" decolorizing carbon, stirred for 10 minutes, P filtered on diatomaceous solution,... was adjusted to 1.5 with solid NaHCO3.
Adjust to 5. The clear white solution was then concentrated to about 15 d and the white precipitate was collected by filtration. It was then air dried and vacuum dried over P2O5. Amorphous, water-soluble product, 7-[D-α-amino-α-3′-methyl-4
'-Hydroxyphenylacetamide]-3-[S-(
1,2,3-triazol-5-yl)-thiomethyl]
-3-cephem-4-calS)4phonic acid was obtained.

No significant amounts of contaminants were observed in the product. Example 6 Sodium JYokD-(α-amino-α-1-methyl-
1-Hydroxyphenylacetamide 3-[S-(
1,2,3-triazol-5-yl)-thiomethyl]
-3-Cefem-4-carboxylic acid 7-[D-(α-amino-α-3'-methyl-l-hydroxyphenylacetamide)]-3-[S-(1,2,3-triazole-
5-yl)methyl]-3-cephem-4-carboxylic acid (
Stir a zwitterionic water suspension of 0.8 mm01e).
1N aqueous sodium hydroxide solution was added in portions at room temperature until a clear solution was obtained (PHlO.8).

This solution was immediately frozen and lyophilized to form a solid sodium chloride containing impurities.
Methyl-l-hydroxyphenylacetamide)]-3
-[S-(1,2,3-triazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid was obtained. Example 7 J-(-)-α-amino-α-(3'-methyl-
l-hydroxyphenyl)-acetamide]-3-[S
-(1,2,3-triazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid 16f! (0.0
5 mono(c) 7-amino-3-[S-(1,2,3-
13.5d (0.092 mol) of triethylamine, 15d (0.118 mol) in a suspension of triazole-5-ino(ha)-thiomethyl]-3-cephem-4-carboxylic acid and 1507f11 of methylene chloride. N of
, N-dimethylaniline and 1 at low temperature (7-15°C)
9.1 d (0.15 mol) of trimethylchlorosilane were each added with stirring.

After cooling for 15 minutes, the mixture was refluxed for 25 minutes, cooled again to 5°C, and 0.061 mol of D-(-)-α-amino-α-
(3'-Methyl-4-hydroxyphenyl)acetyl chloride hydrochloride was added.

The mixture was stirred at 10-12°C for 1 hour and then heated to 150°C.
w11 of water was added and after stirring for 15 minutes the mixture was filtered. Separate the aqueous phase and adjust to 2 with 20% NaOH,
Activated carbon (109, "DarcOKB") was added and the mixture was filtered after stirring for 15 minutes. The pale yellow solution was phase separated with ether (150d) and adjusted to 4 with 20% NaOH. The aqueous phase was separated, filtered and 50 d of acetonitrile was added to it. It is crystallized by adding Masatsu or seed crystals to form a solid 7-[D-(1)-α-amino-α-(3′-1methyl-4-hydroxyphenyl)acetamide]-3-[S-( 1,2,3-triazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid was obtained. Example 8 7-[D-α-amino-α-(3'-methyl-1-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4
-Sodium carboxylate mono[α-(3'-methyl-l-
By thiolation of hydroxyphenyl)-α-D-(-)-(t-butoxycarbonylamino)acetamide]cephalosporanate and its deprotection.

A. 7-[α-(3'-methyl-4-hydroxyphenyl)-α-D-(t-butoxycarbonylamine)acetamide]-3-(1,2,3triazol-5-ylthiomethyl)-3-cephem -4-Carboxylic acid 6 Acylated 7-amino-3-[S-(1
, 2,3-triazol-5-ylthiomethyl]-3cephalosporanic acid by replacing equimolar amount of 7-aminocephalosporanic acid. )-(t-butoxycarbonylamino)
- 0.27 mol of acetamidocephalosporanate is dispersed in 1000 ml (7) pl]6 phosphate buffer and then 4,3 f! (0.31 mol) of 5-mercapto-1,2,3-triazole potassium salt was added.

The solution was heated to 55° C. for 5 hours under nitrogen atmosphere. After 1 hour, a small amount of H3PO4 was added to adjust the resistance to 6.4.

After heating for 5 hours the solution was cooled to 23° C. and adjusted to 2 with 3N0) HCZ under a layer of ethyl acetate.

The product was extracted into ethyl acetate and 29 CDarcOKB
'') Stirred with decolorizing activated carbon for 15 minutes at 23°C.
The mixture was then filtered through 1 pad of 6-celite and ethyl acetate was removed under reduced pressure. The solid was purified by dispersion in ethyl ether,
P was collected and dried under vacuum over P2O5. B. 7-
[α-D-(3'-methyl-1-hydroxyphenyl)
Acetamide]-3-(1,2,3-triazole-5
-ylthiomethyl)-3-cephem-4-carboxylic acid 0
．． 105 moles of 7-[α-(J-methyl-l-hydroxyphenyl)-α-D-(t-butoxycarbonylamino)-acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)- 3-Cefem-4-carboxylic acid was dissolved in 30d trifluoroacetic acid at 5°C.

It was brought to 23° C. and stirred for 30 minutes. This solution was gradually poured into 1000 d of anhydrous ethyl ether and stirred vigorously. The precipitate was collected by filtration, washed with 100 d of ethyl ether, and dried under P,O, upper vacuum for 1 hour.

It was dissolved in 75 d of water, stirred at 23°C for 30 minutes, and the solid was separated from P. 29 6 Darc0KB in P liquid
After adding decolorizing activated carbon and stirring at 23°C for 1 minute, the slurry was filtered through 1 pad of 6 ceride. was evaporated under high vacuum to give an oil, which was dispersed and purified with acetonitrile.Product 71 [D-α-
Amino-α-(V=methyl-1-hydroxyfenino(
c) Acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was filtered with P, collected, and air-dried. Example 9 Enamin 71 [D-α-amino-α-] by mixed anhydride method
Preparation of (3'-methyl-l-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cepheme-4-carboxylic acid 150
Stir W1t of dry acetonitrile at -19°C for 11 hours,
゛And 5 ml (0.05 mol) of ethyl chloroform, 7.5 Tf12 of 1% N-methylmorpholine.
Acetonitrile solution and 0.05 mol sodium D
-(-)-N-(2-methoxycarbonyl-1-methylvinyl)-α-amino-α-(3'-methyl-4-hydroxyphenyl)acetate was added one after another.

The mixture was stirred for 1 hour at -18° C. and 20° C. While this operation was being carried out, 6.269 (0.02 mol) of 7-amino-3-(1,2,3-triazole-5- )
150m of thiomethyl-3-cephem-4-carboxylic acid
1 of dry CH2Cl2 and 5.67
! 1I1 triethylamine (0.04 mol) and 2
．． 5 (>0.02 mol) of N,N-dimethylaniline were added. 7.62d (0.06 mol) after stirring for 10 minutes
of trimethylchlorosilane was added dropwise over 20 minutes.

The mixture was then refluxed for 35 minutes, cooled and evaporated under reduced pressure to give an oil. This was again slurried in 80ml of dry acetonitrile, cooled to -20°C and poured all at once into the vigorously stirred mixed anhydride. Temperature: -200--15℃ for 30 minutes, -15℃-0℃ for 30 minutes
The mixture was held for 1 minute, then raised to room temperature (22°C) over 1 hour, and further stirred at room temperature for 1 hour. Separate the salt, 2
It was washed twice with 5 ml of acetonitrile, and the P solution was combined and stirred with 20 ml of methanol for 30 minutes. Finally, add 20ml of water and stir at 22℃ for 3 hours, approx.
It was left at 0°C overnight (15 hours). Crystallization started after 10-15 minutes.

The initial pH was 2.8 and the final pH was about 4.5.
The product was filtered, collected and thoroughly washed with acetonitrile,
Air dried and vacuum dried over P2O5. It was then ground with a motor, stirred for dispersion in 200 ml of methylene chloride for 30 minutes, collected by P, and air-dried to give 7-[D-α-amino-α-(3'-methyl-1-hydroxyphenyl)]. )
Acetamide]-3-(1,2,3-triazole-5
-ylthiomethyl-3-cephem-4-carboxylic acid was obtained. Example 10 Acetoxymethyl J-Yo-kD-α-amino-y-methyl-
l-Hydroxyphenylacetamide 0-3-(1,2,
3-triazol-5-ylthiomethyl)-3-cepheme-4-carboxylateacetoxymethyl J me[amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cepheme-4-carboxylate .00
0.020 mole of pyridine was added to a solution consisting of 9 moles of its hydrochloride salt) and 30d of ethyl acetate.

The mixture was cooled on ice, and while stirring, 0.010 mol of D-(
-)-2-3'-Methyl-l hydroxyphenylglycine chloride hydrochloride 30a solution in ethyl acetate was added over 10 minutes. After continuing cooling for an additional 20 minutes, stirring was continued for 20 minutes at room temperature. The mixture was then washed successively with aqueous sodium bicarbonate, 0.1N hydrochloric acid and water, dried and evaporated in vacuo to obtain the desired acetoxymethyl
J YorokD-α-amino-y-methyl-l-hydroxyphenylacetamide]-3-(1,2,3 triazol-5-ylthiomethyl)-3-cepheme-4-carboxylate was obtained as an oil; This was dispersed and purified in cyclohexane and crystallized. Bivaloyloxymethyl, methoxymethyl, acetonyl and phenacyl esters corresponding to the above acetoxymethyl esters were used in the above method.
, 3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylate hydrochloride to 0.009 mol of 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cepheme-4 - Synthesized by replacing the hydrochloride of pivaloyloxymethyl ester, methoxymethyl ester and phenacyl ester of carboxylic acid.

Example 117-[D-α-amino-α-(3′-methyl-1-hydroxy-phenyl)acetamide]-3-
(1,2,3-triazol-5-ylthiomethyl)-
Conversion of 3-cefemucarboxylic acid to its hydrochloride salt 71 [
D-α-amino-α-(3'-methyl-l hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (200 mg) Dispersed in 10 d of distilled water,
Then stir it up.

When concentrated hydrochloric acid was added dropwise, a clear solution was obtained at the 6th to 7th drop. At that time... was about 0.8. The solution was then freeze-dried to give a solid 7-[D-α-amino-α-(
3'-Methyl-l-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-14-carboxylic hydrochloride was obtained.
Example 127-[D-α-amino-(3!-methoxy-1-hydroxyphenyl)acetamide]-31(2
-Methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid -6.39 (0.0212 mol) of D-(-)-N cooled to 15°C
-(t-butoxycarbonyl)-2-(J-methoxy-
l-Hydroxyfenino-glycine, 2.4d (0.
2.7 d (0.02 mol) of N-methylmorpholine, 200 d of tetrahydrofuran
12 mol) of isobutyl chloroformate were added.

The mixture was stirred at -15° C. for 6 minutes to form a mixed anhydride. 7.3fI (0.0212 mol) of 7-amino-3-(2-methyl-1,3,4-thiadiazole-5)
-ylthiomethyl)-3-cephem-4-carboxylic acid,
An ice-cooled P solution prepared from 200 d of water and an amount of tetramethylguanidine sufficient to make .

The cooling bath was removed and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran. The aqueous concentrate was diluted with 200 d of water, acidified with 42% phosphoric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts were treated with activated charcoal, filtered with P, and concentrated to dryness. The residue was purified by dispersion using anhydrous ether to obtain a solid. The solid was collected by filtration, dissolved in approximately 20w11 of ethyl acetate, and the solution poured slowly into 300d0) cold ether. The solid was filtered and collected to give 3.39% of product. A mixture of the product (3.3f1) and 18d trifluoroacetic acid was held for 15 minutes with frequent shaking.

Cool the solution in 225ml of ice: 10Ske11ys01v
eB'' was poured into ether.

Cephalosporin acetate was collected by filtration and stirred with a mixture consisting of 200 d water, 50 d Amberlite LA-1 resin (acetate form) in 25% MIBK solution and 50 W 1 t MIBK for 1 hour at 40°C and 1 hour at room temperature. I hung out. The aqueous phase was washed six times with ether, treated with activated charcoal and concentrated to a small volume. The aqueous solution was decanted from the oil, further concentrated, and finally with MIBK to remove water. The solid was collected by filtration, washed with MIBK and dried under reduced pressure at 65°C. 1.2 g of product was obtained. The product is 7
-[D-α-amino-(J-methoxy-l-hydroxyphenyl)acetamide]-3-(2-methyl-1,3
,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, and its IR and NMR spectra were consistent with the target product. 7-[D-α-amino-(3'-methoxy-1-hydroxyphenyl)-acetamide]-3 prepared in Viability Data Example 12
A sample of -(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (referred to as BL-S639-rod 02) was made into an aqueous solution,
Minimum Inhibit Concentration for a given microorganism
tratiOn) was determined.

The method involved aging overnight at 37°C using the tube dilution method. Cephalexin was also tested. * 100 Immediately/K
g Single oral administration (8 mice). This administration is carried out by dilution to 10-20 mgrrv/g with a zwitterionic aqueous solution containing sodium citrate, Tvveen4O and CMC (carboxymethoxycellulose). The composition of the diluent is as follows: Tvveen4OO. OO939 Sodium citrate anhydrous 0.0057f1CMC0.
0049 Water 1 ml Table 3A Protective activity of oral administration of BL-S639 (Rod 02) (product of Example 12) and Cephalexin** in experimental diseases* of mice caused by various Gram-positive bacteria Treatment Schedule S. Pyogenes and D. 1 and 3.5 hours S. after challenge with Niumonia. 0 and 2 hours after challenge with M. aureus Table 3B Oral administration BL-S6 against experimental disease in mice caused by various Gram-negative bacteria*
Example 137-[D-α-amino-(3'-methoxy-4'-hydroxyphenyl)acetamide]-31(2) -Methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid mixed anhydride is 12.5 g (0.0422 mol)
D-(-)-N-(t-butoxycarbonyl)-2-
(3'-methoxy-4'-hydroxyphenyl)monoglycine, 5.4 ml (0.0422 mol) of isobutyl chloroformate and 4.6 ml (0.0422 mol) of N-methylmorpholine to 400 ml of Prepared in tetrahydrofuran for 6 minutes.

14.49 (0.0422 mol) of 7-amino-31 (
2-Methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, 400m
An ice-cold P-filtered solution prepared from 1 of water and enough tetramethylguanidine to give a pH of 7.5 was added to the anhydrous mixture at a rate such that the temperature did not rise above 0 ice.

The cooling bath was removed and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran. The concentrated aqueous solution was diluted with 400 ml of water, cooled in an ice bath and extracted three times with ethyl acetate acidified with 42% phosphoric acid. The mixture is P-filtered during the first extraction to remove small amounts of solids. The combined extracts are treated with carbon to remove the solvent. The residue is triturated several times with anhydrous ether to give a solid of 8.59. The solid was stirred with 160 d of 98-100% formic acid for 2 hours at room temperature. Formic acid {1 was distilled off under reduced pressure. The residue was concentrated with toluene to completely remove formic acid. The resulting solid foam was triturated with aqueous ethyl acetate and dried under vacuum over phosphorous pentoxide to give 7.19 [D-α-amino-(3'-methoxy-1-hydroxy-phenyl)acetamide]. -3-(2-methyl-
1,3,4-thiadiazol-5-ylthiomethyl)-
3-cephem-4-carboxylic acid was obtained. IR<15-
NMR spectra were consistent. Example 147-[D-
α-Amino-α-(3'-methoxy-l-hydroxyphenyl)acetamide]-3-(2-methyl-1,3,
0.3 mol of 7-amino-3-(2-methyl-1,3
, 81d (0
．． 58 mol) of triethylamine, followed by 50 d(0
．． 39 mol) of N,N-dimethylaniline was added.

After cooling to 12° C., 76.211 t (0.6 mol) of trimethylchlorosilane were added over 15 minutes.

Allow the mixture to gently reflux for an additional 15 minutes.
After refluxing for 5 minutes, the almost clear solution was cooled to 5°C and 0.354 mol of D-(-)-α-amino-α-(3
'-Methoxy-l-hydroxyphenyl)-acetyl chloride hydrochloride is added in portions over 30 minutes. The mixture was stirred at 5° C. for 1 hour, and the ice bath was removed for 1 hour (maximum temperature 18° C.). Add water 11, stir thoroughly,...
was slowly adjusted to 2.2 with 20% NaOH. The aqueous phase was separated and the CH2Cl layer and gummy precipitate were discarded.
Under the ether layer (1 liter) the solution was adjusted to 2 with stirring. The aqueous phase was stirred for 15 minutes with 20 fI of 6 Dacro KB'' (carbon) and the P filter was adjusted to 4 under a fresh ether layer (1 liter).
After stirring at °C for 1 hour, the crystals were separated from P, washed well with water, then washed with acetone and dried with air. P, O, and dried under vacuum to form a solid 7-[D-α-amino-α-(3'-methoxy-1-hydroxyphenyl)acetamide]-3-
(2-Methyl-1,3,4-thiadiazol-5-ylthiomethyl)-thiomethyl]-3-cephem-4-carboxylic acid is obtained. Example 15 7-[D-α-amino-α-y-methoxy-1-hydroxyphenylacetamide]-3-(2-methyl-1,
3,4-Thiadiazol-5-ylthiomethyl)-3-
50 d of cefem-4-carboxylic acid in 0.02 mol of sodium D-α-[1-carbomethoxypropen-2-yl)-amino-3'-methoxy-l in acetonitrile
- Add 2 drops of N,N-dimethylbenzylamine to the stirred suspension of hydroxyphenyl acetate.

The slurry was cooled to -10°C and cooled to 2.149 (0.
02 mol) of ethyl chloroformate are added. -10
After 20 minutes at °C, 0.02 mol of 7-amino-3-(2
-Methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, 2.8d(
0.02 mol) triethylamine, ]0 d acetonitrile and 40 d pre-heated to 0°C? I? The palm water solution was added all at once and stirred vigorously. After 45 minutes at ℃
The solution is saturated with salt (excess NaCl) for 15 minutes. The organic (top) layer was separated and 40 d of water was added thereto. The resulting solution was concentrated under vacuum at 20° C. to a volume of approximately 50 d. To this solution was added 70 d of methyl isobutyl ketone (MI
BK) and 8 mt of a solution of 90% formic acid are added. The mixture was shaken initially and then stirred at 0° C. for 3 hours. The aqueous layer is then separated and added with fresh 70d0) MIBK.
The mixture was stirred at ℃ for 30 minutes and separated again. The aqueous phase is then 20
It was concentrated under reduced pressure to near dryness at °C. The residual oil is then triturated to a solid with acetonitrile. The solid was collected with P filtration, air-dried, and then vacuum-dried with P2O for 14 hours.
D-α-amino-α-(3'-methoxy-1-hydroxy-phenyl)acetamide]-3-(2-methyl-1
,3,4-thiadiazol-5-ylthiomethyl)-3
- gives Cefem-4-carboxylic acid. This material shows evidence of impurities. Dissolve this substance in 25 d of water, filter with P, adjust to 1.5 with 40% H3PO4, and 1
Add 6 g of Dacro KBL (decolorized carbon), stir for 10 minutes, filter through diatomaceous earth (6'' dicalite) and remove by adjusting with solid NaHCO. Then, a clear white solution of about 15 d The white precipitate was collected by P filtration, air dried, and then vacuum dried over P2O. -1-hydroxyphenyl)acetamide]-3-
(2-Methyl-1,3,4-thiadiazol-5-ylthiomethyl)-13-cephem-4-carboxylic acid shows no evidence of impurities. Example 16 Sodium Jyod-α-amino-α-(3'-methoxy-l-hydroxyphenyl)acetamide]-3-(
2-Methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylate counterion type 7-[D-α-amino-α-(y-methoxy-1-hydroxyphenyl) enyl)-acetamide]-3-
(2-Methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (0.8
To a stirred aqueous suspension of 0 mmol) at room temperature is added 1N aqueous caustic soda solution until a clear solution is obtained.

This solution was directly lyophilized to form an impure solid sodium chloride.
hydroxyphenyl)-acetamio-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylate. Example 17 7-[D-(-)-α-amino-α-(3′-methoxy-4′-hydroxyphenyl)-acetamide]-3-
(2-Methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid 150a
0.05 mol of 7-amino-3 in methylene chloride
-(2-Methyl-1,3,4-thiadiazol-5ylthiomethyl)-3-cephem-4-carboxylic acid was added to a mixed suspension of 13.5 TL (0.092 mono(c) triethylamine, 15 ml (0 .118 mol) of N,N
-dimethylaniline and with cooling (from 7°C to 15°C)
C) 19.1 ml (0.15 mol) of trimethylchlorosilane are added.

After cooling for 15 minutes, the mixture was refluxed for 25 minutes, cooled to 5°C, and 0.061 mol of D-(-)-α-amino-α-(
3'-Methoxy-l-hydroxyphenyl)-acetyl chloride hydrochloride was added.

The mixture was stirred for 1 hour at 10°C to 12°C, then 150 m
1 of water was added, stirred after 15 minutes, the mixture was filtered through P, the two aqueous phases were separated, the pH was adjusted to 2 with 20% NaOH, carbon (109゛Dacro KB'') was added, and after 15 minutes Stir and
The mixture was passed through P. The yellow-green solution is ether (150 m
1) Stratify with 20% NaOH while stirring well.
It was adjusted to The aqueous layer was separated and P. 50m1,
of acetonitrile was added. Crystallization is promoted by rubbing or adding seeds, and the solid 7-[D-(-)-α-amino-
alpha-(3'-methoxy-l-hydroxyphenyl)acetamide]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid is obtained. Example 18 7-[D-α-amino-α-(3′-methoxy-l-hydroxyphenyl)-acetamide]-,3-(2-methyl-1,3,4-thiadiazole-1′) -ylthiomethyl)-3-cephem-4-carboxylic acid
This is obtained by olization and deprotection of 7-[D-α-t-butoxycarbonylmino-α-(3'-methoxy-l-hydroxyphenyl)acetamido]-cephalosporanic acid.

1.7-[α-(3'-methoxy-4'-hydroxyphenyl)-α-D-(t-butoxycarbonylamino)
Acetamide]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cepheme-4
- 0.27 mol of carboxylic acid sodium J
'-Methoxy-1-hydroxyphenyl)-α-D-(
-)-(t-Butoxycarbonylamino)-acetamido]-cephalosboranate [6 acylated above for starting material 1, 7-amino-3-(2-methyl-1,3
, 4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid with an equimolar amount of 7-aminocephalosporanic acid] was synthesized by substituting 10
00d in 0.1M phosphate buffer H64 and then 4.3f1 (0.31 mol) of 5-mercapto-1,2,3-triazole potassium salt is added.

The solution is heated to 55° C. for 5 hours under nitrogen. 1 hour later, P
H is adjusted to 6.4 by adding a small amount of 40% H3PO4.

After heating for 5 hours, the solution is cooled to 23° C. and the pH is adjusted to 2 by adding 3N-HCI under the ethyl acetate layer.

The product was extracted into ethyl acetate and stirred for 15 minutes at 23° C. with 2 g (1 Dacro KB) decolorizing charcoal. The mixture is then passed through 6 parts of Celite and the ethyl acetate is removed under vacuum. The residue was triturated with ethyl ether until solid, collected by filtration and dried under vacuum over P2O5. to. 7-[α-D-(3'-methoxy-l-hydroxyphenyl)acetamide]-3-(2-methyl-1,3
, 4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid 0.105 mol of 71[α-(
3'-Methoxy-l-hydroxypheno(c)-α-
D-(t-butoxycarbonylamino)-acetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was added to 30 ml of trifluoroacetic acid at 5°C. Solution.

The temperature was raised to 23°C and further stirred for 30 minutes.

This solution is slowly poured into 1000 Tf11 of anhydrous ethyl ether with vigorous stirring.

The precipitate was collected by P filtration, washed with 100 d of ethyl ether,
Dry for 1 hour under P,O, top vacuum. Next 75m1H,
After stirring at 23°C for 30 minutes, the solid was separated. 29
(''Dacro KBl) decolorizing charcoal was added to the P filter and after stirring at 23° C. for 10 minutes, the slurry was P filtered through 1 Celite.

The P content was adjusted to 4 by adding triethylamine.
Solids are classified by P. The P residue is distilled off in a high vacuum to form an oil. Knead this with acetonitrile. Product 71 [D-
α-amino-α-(3'-methoxy-4'-hydroxyphenyl)acetamide]-3-(2-methyl-1,3
, 4-thiadiazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid was collected by P filtration and air-dried. Example 19 7-[D-α-amino-α-(j-methoxy-4′-hydroxyphenyl)acetamide]-3-(2-methyl-1,3,4-thiadiazole) via enamine mixed anhydride Synthesis of -3i Cefem-4-Carbon brewing of 5-ylthiomethino, -1''5◆- dry fermented acetonitrile -1
Stir at 9°C and add 5 wt < 0.05 mol) of ethyl chloroformate, then 7.5 d of 1% N-methylmorpholine in acetonitrile, then 0.05 mol of sodium D-(1)-N. -(2-methoxycarbonyl-
Add 1-methylvinyl)-α-amino-α-(3'-methoxy-4'-hydroxyphenyl) acetate.

The mixture is stirred for 1 hour at -18°C to -20°C. At the same time, while performing this operation, 6.269 (0.02 mol) of 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carvone 11II! 150wi1 dry CH, Cl
2 and suspended therein, 5.6d (0.04 mol) of triethylamine and 2.5d (>0.02 mol) of N,N-
Dimethylaniline was added. After stirring for 10 minutes, 7.62
mt (0.0 (0.06 mol)) of trimethylchlorosilane is added dropwise over 20 minutes.

The mixture was then refluxed for 35 minutes, cooled, evaporated to an oil under reduced pressure, reslurried in 80ml of dry acetonitrile and cooled to -20°C, II. Add the stirred mixture to the aqueous solution. The temperature is maintained at -20 to -15°C for 30 minutes, -15 to 0°C for 30 minutes, and then allowed to reach room temperature (22°C) for 1 hour. Then stir for an additional hour. The salt is then separated from the P, washed twice with 25 d of acetonitrile, and the combined P filtrate is stirred with 20 d of methanol for 30 minutes. Finally, 20 Tnt of water is added and then stirring is continued for 3 hours at 22°C and left overnight (15 hours) in a cold room at about 10°C. Crystallization begins after 10-15 minutes.

The initial value is approximately 2.8 and the final value is approximately 4.5. The product was collected by P filtration, washed thoroughly with acetonitrile, air-dried, and P2
The product was dried under vacuum, then finely pulverized using a motor, suspended in 200 d of methylene chloride for 30 minutes, and stirred. It was collected by P filtration and air-dried to form a solid 7-[D-α-amino-α-(
3'-methoxy-4'-phenyl)acetamide]-3
-(2-Methyl-1,3,4-thiadiazole-5-ylthiomethyl)-3-cephem-4-carboxylic acid is obtained. Example 20 Acetoxymethyl JyokD-α-amino-(3'-methoxy-l-hydroxyphenyl)acetamide]-3
-(2-Methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylate acetoxymethyl J me[amino-3-(2-methyl-1,
3,4-Thiadiazol-5-ylthiomethyl)-3-
In a 30a solution of Cefem-4-carboxylate (regenerated from 0.009 mol of hydrochloride) in ethyl acetate,
．． The mixture with 020 mol of pyridine is cooled on ice;
While stirring, 0.0, 1.0 mol D-(-)-2-(3
'-Methoxy-C→[-Droxyphenyl)glycine
A solution of chloride salt 301 in ethyl acetate was added between 105+ KO and after cooling for a further 20 minutes, the stirring was continued at room temperature for 1 hour.
The time continued.

The mixture is then sequentially treated with an aqueous solution of sodium carbonate, 0.
Washed with 1N hydrochloric acid and water, dried and evaporated under vacuum to give the desired acetoxymethyl
Methoxy-l-hydroxyphenyl)acetamide]-
3-(2-methyl-1,3,4-thiadiazole-5-
ylthionotyl)-3-secoem-4-carboxylate is given as an oil which crystallizes on trituration in cyclohexane. The pivaloxymethyl, methoxymethyl, acetonyl and phenacyl esters corresponding to the above acetoxymethyl esters are the acetoxymethyl J me[amino 3-(2-methyl-1
,3,4-thiadiazol-5-ylthiomethyl)-3
- Cefem-4-carboxylate hydrochloride at 0 each
．． 009 moles of 7-amino-3-(2-methyl-1,3
, 4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid by replacing it with the hydrochloride of bivaloyloxymethyl, methoxymethyl, acetonyl and phenacyl esters.

Example 217-[D-α-amino-α-(y-methoxy-4'-hydroxyphenyl)acetamide]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3- Conversion of Cefem-4-carboxylic acid to its hydrochloride 7-[D-α-amino-α-(31-methoxy-l-hydroxyphenyl)-acetamide]-3
-(2-Methyl-1,3,4-thiadiazol-5-ylthiometal)-3-cephem-4-carboxylic acid (20
0η) in 10 d of distilled water and stirred with a magnetic stirrer.

Concentrated HCI was added dropwise and a clear solution was obtained in 6-7 drops with a... of about 0.8. The solution is then freeze-dried to approximately 205mf
Solid 7-[D-α-amino-α-(3′-methoxy-l-hydroxyphenyl)acetamide]-3-(2
-Methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic hydrochloride. Example 22 7-[D-α-amino-(3'-methoxy-1-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4
-carboxylic acid 4.279 (0.01365 mol) of 7-amino-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid, 6.64
A mixture of f1 (0.041 mol) 1,1,1,3,3,3-hexamethyl-disilazane and 200d methylene chloride was heated at reflux for 4 hours to give a clear solution.

After storage at room temperature overnight, the solvent was removed under reduced pressure. The residue was dissolved in 150 d of tetrahydrofuran and the solution was cooled to 0 to 5°C before use. N-methylmorpholine (
3.06d, 0.0273 mol) and 3.48d (0
．． 0273 mol) of isobutyl chloroformate to 8.19 (0.0273 mol) of D-(-)-N-(t
-Butoxycarbonyl)-2-(y-methoxy-1-hydroxyphenyl)glycine was added to a 300ml solution of tetrahydrofuran at -15°C.

The mixture was stirred at −15° C. for 6 minutes to form a mixed anhydride. A solution of the silyl ester in tetrahydrofuran at 0°C to 5°C was added to the mixed anhydride at -15°C.

After 10 minutes, the cooling bath was removed and the mixture was stirred for 2.5 more hours.

Water (250w11,) was added to the reaction mixture. The mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran.
The aqueous solution of the concentrate was acidified with 42% phosphoric acid and extracted three times with ethyl acetate. The mixture was P-filtered during the first extraction to remove a small amount of insoluble material. The combined ethyl acetate extracts were washed once with water, dried (Na2SO4), and concentrated to dryness. Knead the residue with anhydrous ether and
．． Yielded 89 solids. Solid (2.89) and 9 of 50d
The 7% formic acid solution was stirred at room temperature for 2 hours.

Formic acid was distilled off under reduced pressure. The residue was azeotroped with toluene to completely remove formic acid. The residue was triturated with water-containing ethyl acetate (dried over phosphorous pentoxide at 65°C under vacuum for 2 hours) to obtain 1.429 7-[D-α-amino-(3'-methoxy-l-hydroxyphenyl)]. enyl)acetamide]-3-(
1,2,3-triazol-4-ylthiomethyl)-3
- gave Cefem-4-carboxylic acid. Slowly decomposes at approximately 165℃. IR<5 NMR spectra were consistent. Biological Data 71[D-α-amino-(3'-methoxy-1-hydroxyphenyl)-acetamide)]-31(1,2 ,3-triazol-5-ylthiomethyl)-3-cephem-4
- Samples prepared by dissolving carboxylic acid in water and diluting with Nutrient Pross were heated at 37°C in a tube dilution chamber.
I decided to culture it overnight.

The following minimum prohibited concentrations (M.I.C.
) was found to be expressed in units of Mcg/d. Contains zephalexin. *1 for each of 8 mice
Oral administration of 00r11f/Kg.
It was formulated as a solution in mg river/d. This diluent has the formula: Example 23 7-[D-α-amino-α-(3'-methoxy-l-hydroxyphenyl)acetamide]-3-(1,2,3
-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid 93.

99 (0.3 mol) of 7-amino-3-(1,2,3-
To a stirred suspension of triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in 1400 WLI of dry CH2CZ, was added 81d (0.58 mol) of triethylamine, then 50 TILI! C. O. 39 mol) of N
, N-dimethylaniline.

After cooling to 12° C., 76.2 d (0.6 mol) of trimethylchlorosilane are added over 15 minutes.

The mixture was allowed to slowly reach reflux for an additional 15 minutes,
After refluxing for 45 minutes, the almost clear solution was cooled to 5°C and 0.354 mol of D1(1)! a-Amino-α-(3'-methoxy-l-hydroxyphenyl)-
Acetyl chloride hydrochloride is added in portions over 3Q minutes. The mixture was stirred for 1 WWIJ at 5°C, and the ice bath was removed for 1
Stir for an hour (maximum temperature 18°C). Add the water from step 11 while stirring well, and slowly add 2.2 with 20% NaOH.
Adjust the horse mackerel.

The aqueous phase is separated and the CH2Cl2 layer and gummy precipitate are discarded.
Under a layer of ether (11) adjust the volume of the solution to 2 with good stirring. The aqueous phase is stirred with 20 fI0)6 Daclo KB'' (carbon) for 15 min, filtered and adjusted to 4... under a fresh layer of ether (11).
After stirring for 1 hour, the crystals were separated from P, washed well with water, then washed with acetone, and air-dried. After vacuum drying over P,O5, solid 7-[D-α-amino-α-(3'-methoxy-1-hydroxyphenyl)acetamide]-3-(
1,2,3-triazol-5-ylthiomethyl)-3
-Cefem-4-carboxylic acid is obtained. Example 24 7-[D-α-amino-α-(y-methoxy-l-hydroxyphenyl)acetamide]-3-[S-(1,2
,3-triazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid 50111t in acetonitrile with 0.02 mol of sodium D-α-(1-carbomethoxypropen-2-yl)-amino-3'- Methoxy
Two drops of N,N-dimethylbenzylamine are added to the stirred suspension of 1-hydroxyphenyl acetate.

The slurry is cooled and stirred at -10°C. here 2.1
49 (0.02 mol) of ethyl chloroformide is added. After 20 minutes at -10°C, 6.269 (0.02 mol) of 7-amino-3-[S-(1,2,3-triazol-5-yl)-thiomethyl]-3-cepheme-4-carvone A solution consisting of acid, 2.8 d (0.02 mol) of triethylamine, 40 ml of acetonitrile and 40 d of water, precooled at 0° C., is added all at once with vigorous stirring. After 45 minutes at 0° C., the solution is saturated with salt (excess NaCl) for 15 minutes.

The organic CD layer is separated and 40 d of water is added thereto. The resulting solution is concentrated under vacuum at 20° C. to a volume of approximately 50 d. To this solution was added 70 ml of methyl isobutyl ketone (M
IBK) and 8d of 90% formic acid. The mixture is first shaken and then stirred for 3 hours at 0°C. The aqueous phase is then separated, stirred with fresh 70 wL1 MIBK at 0° C. for 30 minutes and separated again. The aqueous phase is then concentrated to near dryness under reduced pressure at 20°C. The residual oil is then triturated to a solid with acetonitrile. The solid was collected by P filtration and air-dried.
Vacuum drying over O5 for 14 hours yielded a solid 7-[D-α-amino-α-(3'-methoxy-l-hydroxyphenyl)acetamide-3-[S-(1,2,3triazole-5 -yl)-thiomethyl]-3-cephem-4-carboxylic acid. This substance) shows evidence of impurities.

These are as follows: dissolve this substance in 25 d of water and pass through the P...
Adjust to 1.5 with 0% H, PO4, 19 6 Daclo KB
Add decolorizing carbon, stir for 10 minutes, filter through diatomaceous earth (6 dicalite) and 3.
It is removed by adjusting to 5. The clear white solution is then concentrated to a volume of about 15 mt, and the white precipitate is collected by P filtration and air dried, then vacuum dried over P2O5. The amorphous water-soluble product 7-[D-α-amino-α-(3'-methoxy-l hydroxyphenyl)acetamide]-3-
[S-(1,2,3-triazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid shows no evidence of any significant impurities. Example 25 Sodium JyokD-(α-amino-α-(3'-methoxy-l-hydroxypheno(c)-acetamide)
]-3-[S-(1,2,3-triazol-5-yl)-thiomethyl]-3-cephemu-4-carboxylate, vol.

The zwitterionic form of 71[D-α-amino-α-(3'-methoxy-4'
-Hydroxyphenyl)-acetamide]-3-[S-
To a stirred aqueous suspension of 0.8 mmol of (1,2,3-triazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid is added 1N aqueous sodium hydroxide at room temperature.

Immediately freeze-dry this solution to obtain impure solid sodium J.
yo■■ droxyphenyl)acetamide]-3-[S-(1,
2,3-triazol-5-yl)thiomethyl]-3-
Cefem-4-carboxylate is obtained.

Example 26 7-[D-(-)-α-amino-α-(y-methoxy-
4-hydroxyphenyl)-acetamide]-3-[S
-(1,2,3-triazol-5-yl)-thiomethyl]-3-cefemu-4-carboxylic acid 7-amino-3-
[S-(1,2,3-triazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid 169 (0.
13.5 T of triethylamine in a stirred suspension of 0.05 mol)
n1 (0.092 mol), N,N-ditylaniline 15
Add WLt (0.118 mol) and trimethylchlorosilane 19.1d (0.15 mol).

After cooling for 15 minutes, the mixture was refluxed for 25 minutes, cooled to 5°C, and converted to D-(1)-α-amino-α-(3′-methoxy-
0.061 mol of l-hydroxyphenyl)-acetyl chloride hydrochloride is added.

The mixture was stirred for 1 hour at 10-12°C, then 150% water
d was added, after stirring for 15 minutes, the mixture was filtered, the aqueous phase was separated, - was adjusted to -2 with 20% NaOH, carbon (DarcOKB) 109 was added, and after stirring for 15 minutes,
The mixture is filtered through P. Ether (150d) to pale yellow solution
Add and stir well... with 20% NaOH =
Adjust to 4. The aqueous phase is separated off, filtered and 50 ml of acetonitrile are added. Attracted or crystallized as seeds, 7-[D-(1)-α-amino-α-(gymethoxy-l-hydroxyphenyl)-acetamide]-3
-[S-(1,2,S-triazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid solid is obtained. Actual example 27 7-[D-α-t-butoxycarbonylamino 1α−(
Thiol of 3'-methoxy-1-hydroxyphenyl)acetamido]-cephalosporanic acid.

Then, by deblocking, 71[D-α-mono-amino-α-(3′
-methoxy-4'-hydroxyphenyl)-acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid A. 7- [
α-(y-methoxy-l-hydroxyphenyl)-α-
D-(t-butoxycarbonylZ・noreamitsu)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid sodium Jyorokα-(y-methoxy- 4I-monohydroxyphenyl)-α-D-(-)-(t-butoxycarbonylamino)-acetamido]-cephalosporanate (starting material, above-acylated 7-amino-3-[S-(
1,2,3-triazol-5-ylthiomethyl]1-3-cephem-14-carboxylic acid prepared using an equimolar amount of 7-aminocephalosporanic acid)0.
27 mol of 0.1M phosphate buffer (PFl6.4) 1
00011t, then 5-mercapto-1,
4.39 (0.31 mol) of 2,3-triazole potassium salt are added.

Heat the solution at 55° C. for 5 hours under nitrogen atmosphere. After 1 hour, the pH is adjusted to 6.4 by adding a small amount of 40% H, PO4.

After heating for 5 hours, the solution was cooled to 23° C. and 3N HCI was added to the ethyl acetate layer. Adjust to 2.

The product was extracted into ethyl acetate and saturated with decolorized charcoal (DarcO
KB) 29 is added and then stirred for 15 minutes at 23°C. It is then filtered through a pad of Celite and the ethyl acetate removed under vacuum. The solid is triturated with ethyl ether, collected by Pfiltration and dried over P2O5 under vacuum. B. 7
-[α-D-(3'-methoxy-1-hydroxyphenyl)acetamide]-3-(1,23-triazole-
5-ylthiomethyl)-3-cephem-4-carboxylic acid 7-[α-(3'-methoxy-4'-hydroxyphenyl)-α-D-(t-butoxycarbonylaminoacetamide]-3-(1 ,2,3-triazole-5-
ilthiomethyl)-3-cephem-4-carboxylic acid 0
．． 105M (mol) in 30d of trifluoroacetic acid at 5°C
Dissolve with.

Bring to 20°C and stir for an additional 30 minutes.

While stirring vigorously, dissolve the solution in 100% anhydrous ethyl ether.
The precipitate is collected by filtration, washed with 100 ml of ethyl ether, and dried under vacuum over 100 ml of P.O. Then dissolved in 75 d of water;
After stirring for 0 minutes, filter the solid. Decolorizing charcoal (DarcOK
B) Add 29 to the p liquid, stir for 10 minutes at 21 V, and then pass the slurry through a Celite pass S. To add triethylamine, adjust the above-1 > Tp liquid to 4 to remove the solid. PVII. is evaporated under high vacuum to an oil and triturated with 1 liter of acetonide. F amide]-3-(1,2,3-triazo≦l-5-ylthiomethyl)-3-cepheme=4-carboxylic acid The product was recovered by P filtration and evaporated.6.

2゛L rumors - 2゛8 Enamine mixed anhydride method 71 [D-α-amino-
α-(3'-methoxy-1-hydroxyphenyl)acetamide]-3-(1,2,3-triazole-5-
Preparation of ethyl chloroformate (5d) (0.05 mono(c)), then 7.5 ml of 1% N-methylmorpholine in acetonitrile, then sodium D- (→−α
150 ml of dry acetonitrile are stirred at -19 DEG C. while adding 0.05 mol of -(2-methoxycarbonyl-1-methylvinyl)-amino-.alpha.-(3'-methoxy-1-hydroxyphenyl) acetate.

The mixture is stirred at -18°C to -20°C for 1 hour. At the same time, while performing this operation, 7-amino-3-(1,2
,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (6.26 g (0.02 mol) suspended in dry CH2Cl2l5Od {-, triethylamine 5.6〃d (0.04 mol) and 2.5 mi (>0.02 mol) of N,N-dimethylaniline are added. 1
After stirring for 0 minutes, 7.62 ml of trimethylchlorosilane (0
．． 06 mol) was added dropwise over a period of 20 minutes.

The mixture was then refluxed for 35 minutes, cooled, evaporated under reduced pressure to an oil, reslurried in dry acetonitrile 80d, cooled to -20°C and added in one portion to the mixed anhydrides with vigorous stirring. do. Temperature -20℃~-15℃
maintained at -15°C to 0°C for 30 minutes,
Allow to come to room temperature (22°C) for 1 hour and stir for a further 1 hour. Then, filter the salt and add 25 ml of acetonitrile.
207n1 of methanol is added, and the combined P solution is stirred for 30 minutes. Finally, add 20 d of water,
Stirring was continued for 3 hours at 22°C, then overnight at approximately 10°C (in a cold room).
15 hours). Crystallization begins after about 10-15 minutes. The first one is about 2.8 and the last one is about 4.5. The product was collected by P filtration, washed thoroughly with acetonitrile, air dried, vacuum dried over PO, then ground in a milk needle, suspended in 200 d of methylene chloride, stirred for 30 minutes and filtrated with P filtration. 71 [D-α-amino-
A solid α-(methoxy-1-hydroxyphenyl)acetamide)-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid is obtained. Example 29 Acetoxymethyl-Jyo-kD-α-amino-4(3'-
Methoxy-l-hydroxyphenyl)acetamide]-
3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylate Acetoxymethyl-J-amino-3-(1,
2,3-triazo-1-5-ylthiomethyl)3-
Cefem-4-carboxylate (its hydrochloride 0.00
0.020 mol of pyridine is added to a solution of 9 mol (regenerated from 9 mol).

D-(-)-2-(y-methoxy-
l-Hydroxyphenyl)glycine chloride hydrochloride 0
．． The mixture is ice-cooled and stirred while adding 0.010 mol over 10 minutes. After cooling and stirring on ice for an additional 20 minutes, stirring is continued for 1 hour at room temperature. The mixture was then washed with aqueous sodium bicarbonate, 0.1N hydrochloric acid, water, dried and evaporated under vacuum to give the desired acetoxymethyl-J-α-amino-(3 '-Methoxy-1-hydroxypheno(c)acetamide]-3-
(1,2,3-triazol-5-ylthiomethyl)
-3-cephem -4-carboxylate is obtained. This crystallizes when milled in cyclohexane. Hydroloxymethyl ester, methoxymethyl ester, acetonyl ester and phenacyl ester corresponding to the above acetoxymethyl ester are the acetoxymethyl-
(1,2,3-triazol-5-ylthiomethyl)
pivaloyloxymethyl, methoxymethyl of 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid instead of -3-cephem-4-carboxylic acid hydrochloride; It is prepared by using 0.009 mol of acetonyl and phenacyl ester hydrochloride. Example 307-[D-α-amino-α-(gimethoxy-l-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cepheme-14-carboxylic acid Conversion to its hydrochloride 71 [D-α-amino-α-(3′
-methoxy-l-hydroxyphenyl)acetamide]
-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem 4-carboxylic acid 200wL1! ，
is suspended in 10 d of distilled water and stirred with a magnetic stirrer.

Concentrated hydrochloric acid is added dropwise and a clear liquid is obtained after adding 6-7 drops. ... is approximately 0.8. The solution is then lyophilized and
7-[D-α-amino-α-(3'-methoxy-l-hydroxyphenyl)acetamide]-3-(1,2,3
-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic hydrochloride hydrochloride solid approximately 205 mf7 is obtained.
Example 31 7-[D-α-amino-α-(3'-methyl-l-hydroxyphenyl)-acetamide]-31(2-methyl-
1,3,4-oxadiazol-5-ylthiomethyl)
-3-Cefem-4-carboxylic acid The general procedure of Example 13 is repeated.

However, D-(-)-N-(t
-butoxycarbonyl)-2-(3'-methoxy-45
-hydroxyphenyl)glycine and 7-amino-3
-(2-Methyl-1,3,4-triazo;ru;5-tone ylthiomethyl)-3-cephem-14-carbonyl instead of D-(-)-N-(t-butoxycarbonyl)-2- (3'-methyl-l-hydroxyphenyl)glycine and 7-amino-3-(2-methyl-1,3,
4-Oxadiazole-5-ylthiomethyl)-3-
Cefem-4-carboxylic acid is used. It has been found that the product thus produced gradually decomposes at temperatures above 145°C. NMR and IR analysis were consistent with the product of the proposed structure. C2OH2lN5O5S2: Actual value: C46.97eH4.73Nll. 9OH, O
(by Karl Fischer method) 5,・[・2・
? 3.25% theoretical value: C48
．． 87H4.3lNl4.25 According to in vitro tests, the above compound is D. pneumOniaeA9585
For 0.08mc 1st, St. py0gene
0.08 mcg/d1 and S for sA9604
．． 0.6 mcg/d for aureus A9537
It can be seen that it has a minimum inhibitory concentration (MIC) of .

Example 32 7-[D-α-amino-α-(3′-methyl-l-hydroxyphenyl)acetamide]-31(2-methyl-
1,3,4-thiadiazol-5-ylthiomethyl)-
3-cephem-4-carboxylic acid The general procedure of Example 12 is repeated.

However, D-(-)-N-(t-butoxycarbonyl)-
In place of 2-(3'-methoxy-l-hydroxyphenyl)glycine, an equivalent amount of D-(-)-N-(t-butoxycarbonyl)-2-(3'-methyl-l-hydroxyphenyl) Use glycine. After removing the amino blocking group with trifluoroacetic acid, the product is prepared. The product decomposes to removal at temperatures above about 110°C. IR and NM
R analysis is consistent with the proposed structure. C2OH2lN3
O5SS: Theoretical value: C47.32H4. l7Nl3.8O actual measurement value:
C49. llH5.9ONll. O7H2O(Karl
Fischer method) = 5.98% According to in vitro tests, the above compound has a D. pneu
0.02mcg/D for mOniaeA9585
, Sal. 1mcg for enteritidis
/d and Kl. It was found to have a minimum inhibitory concentration (MIC) of 2 mcg/Tnl against pneum Oniae A9977.

Example 33 7-[DL-α-temino-α-(3′-ethoxy-l-
hydroxyphenyl)tesetotemide]-3-(1,2,
Repeat the general procedure for 3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, TIIS13.

However, D-(-)- used in Implementation 1P1J13
N-(t-ptoxycarbonyl)-2-(35-methoxy-4I-xyphenyl)glycine and 7-temino-3-(2-methyl-1,3,4-triazole-S'←ilthiomethyl) DL-N-(t-butoxycarbonyl)-2-(3'-ethoxy-41-xyphenyl)glycine and 7-amino-3-(1,2 ,3
-Triazol-5-yl thiomethyl)-3-cephem-4-carboxylic acid is used. The product dried overnight over P2O5 under vacuum is seen to gradually decompose at temperatures above about 165°C. IR and NMR spectra are consistent with the proposed structure. C child 0H22N606S2: Theoretical value: C47.42H4.379Nll. O6 actual value: C46.96H5. l5Nl3.32H,O(Kar
(by Fischer method) = 4.25% From in vitro tests, the above compound has a D. pneumOniaeA9
0.02 mcg/TfLl for St. 585. p
0.04 mCg/for yOgenesA96O4
TlLtl and Sal. enteritidis A9
1.3mcg/7nI for 53l! It was found to have a minimum inhibitory concentration of .

Claims (1)

[Claims] 1. 1st term formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ I (However, in the formula, R is C_1 to C_4 alkyl or C_1
~C_4 alkoxy and Het is the residue of a triazole, alkylthiazole, or alkyloxadiazole)
There are chemical formulas, tables, etc. ▼ II (Het in the formula is as defined above) or easily cleavable esters or salts thereof. ▲ Numerical formulas, chemical formulas, tables, etc. in which R is as defined above and B is an amino protecting group) to remove the amino protecting group and form the desired compound of formula I or its readily cleavable compound. The ester or pharmaceutically usable salt is prepared and, if desired, before or after the removal of B (a) the corresponding readily cleaved product in the form of the free acid or its salt by methods known per se. (b) converting the product in the form of an ester or a salt thereof which can be easily cleaved by methods known per se into the corresponding free acid compound or a pharmaceutically acceptable salt thereof; A method characterized in that it is converted into a usable salt. 2nd term formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ I (However, in the formula, R is C_1 to C_4 alkyl or C_1
~ C_4 alkoxy and Het is the residue of triazole, alkylthiadiazole, or alkyloxadiazole) In the production of compounds having the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ IV (wherein R is above or a readily cleavable ester or salt thereof with the formula HS
-HetV (where Het is as defined above) with a thiol or salt thereof to form a compound of formula I or a readily cleavable ester or pharmaceutically usable salt thereof to form the desired (a) converting the free acid or the product in its salt form into the corresponding easily cleavable ester or its pharmaceutically usable salt by methods known per se; A process characterized in that the products in the form of easily cleavable esters or their salts are converted into the corresponding free acid compounds or their pharmaceutically usable salts by methods known per se.