JPS6052718B2 - antibacterial agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel synthetic cephalosporin compounds of value as antibacterial agents useful both orally and parenterally for the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria in animals, including poultry and humans. .

The compounds are also valuable as nutritional supplements in animal feed and as therapeutic agents for mastitis in animals. In particular, the present invention uses aldehydes other than formaldehyde and acetaldehyde.
In one position, the benzene nucleus of the α-aminophenylacetamide substituent may be substituted with 1, 2 or 3 groups (preferably para-hydroxy or para-acetoxy groups) which are not reactive towards aldehydes, or The present invention relates to condensation products with 3-thiolated cephalosporins having an α-aminophenylacetamide group, which may be unsubstituted.

゜“3-thiolated cephalosporin” means a derivative of cephalosporanic acid in which the acetoxy group is substituted by a thiol and the 3-acetoxymethyl group is converted to a 3-(substituted)-thiomethyl group. . Preferred thiols are 5-1 or 6-membered heterocyclic rings in which the mercapto group has 1-4 (preferably 3 or 4) NlO, or S atoms (this is an alkyl or alkoxy group having 1 or 4 carbon atoms). 2, which may be substituted with methylthio or trifluoromethyl). The resulting condensation products in the form of sodium and potassium salts exhibit favorable solubility, stability and absorption properties.

The preferred species hydrolyze quickly and completely in the body to regenerate the original amphoteric 3-thiolated cephalosporin, whereas the corresponding condensation products with acetaldehyde, formaldehyde or acetone hydrolyze completely but at an unpleasantly slow rate. is not preferable because it is quite slow. Therefore, the present invention provides (a) an aldehyde other than aormaldehyde or acetaldehyde and (b) an α-substituted monoalpha at the 7-position.
-aminoacetamide group and having an aqueous solubility of less than 125TrL91WL1 in its zwitterionic form, the sodium or potassium salt of an equimolar amount of a condensation product with an amphoteric 3-thiolated cephalosporin, which is preferred according to the present invention. The embodiment is (a) Shikisho-CHO (
However, R2 represents an aliphatic, aromatic or heterocyclic group to which carboxyl or 2-furyl or a strongly acidic group is also attached in the form of its sodium or potassium salt.

) and (b) an amphoteric 3 having an α-substituted mono-α-aminoacetamide group at the 7-position and having a water solubility of 125 m91 m1 or less in its zwitterionic form.
- Provides a sodium or potassium salt of an equimolar amount of the condensation product with a thiolated cephalosporin. In a narrower range of embodiments, the aldehyde with an acidic group is 5-formyl-2-furan sulfonic acid, 0-benzaldehyde sulfonic acid, 4-methoxybenzaldehyde 3-sulfonic acid, 4-hydroxybenzaldehyde 3-sulfonic acid, O- and p-formylphenoxyacetic acid, 5-formylsalicylic acid,
p-formyl-cinnamic acid, glyoxalic acid, phthalaldehydic acid, p-formylbenzoic acid, acetaldehyde sulfonic acid sodium salt or acetaldehyde disulfonic acid sodium salt. Nitro-substituted heterocyclic aldehyde derivatives of various alpha-aminocephalosporins are described in US Pat. No. 3,647,781.

South African Patent No. 72/8 for the reaction products of various α-aminocephalosporins with formaldehyde
475-, reaction products with acetaldehyde in South African Patent 72/8474, and reaction products with various aldehydes and ketones in South African Patent 72/8476. Cephalosporin derivatives having an aldehyde-reacted α-amino group in the acylamide group at the 7-1 position (limited to those having methyl or acetoxymethyl at the 3-1 position) are disclosed in U.S. Patent No. 38808.
No. 42, No. 3887546 and Farm Doc No. 49
It was announced in 807W.

The reaction products of acetone and various α-aminocephalosporins have been published in the following patent documents: (1) Cephaloglycine in U.S. Pat. No. 3,303,193; (2)
What is Cephalexin? U.S. Patent No. 3,714,146, British Patent No. 1,314,758, and U.S. Patent No. 37,800
No. 28, (3) 7-[α-amino(7-thienyl)
What is acetamido]-cephalosporanic acid? U.S. Patent No. 3
(4) Certain ring-substituted cephalosporins are described in U.S. Pat. No. 3,464,985; (5) Certain ring-substituted cephalerxins and cephaloglycins are described in U.S. Pat.
No. 1 and No. 348975.

Furthermore, reactive derivatives of α-amino acids with an α-amino group in which the cephalosporin core, e.g. Although the intermediates produced when acylated with FARMDOC 2285W and 60669
This is illustrated in W. In the field of penicillin, penicillins having an α-amino group in the 7-acylamide substituent, such as ampicillin and ketones and aldehydes, were first introduced by Johnson et al. (US Pat. No. 3,198,804) and Granatec (US Pat. No. 3,198,788). It is clear that it was done.

Similar reaction products of various such penicillins with the same or different aldehydes and ketones were later disclosed in U.S. Pat.
, No. 3325479, (Diketones), No. 34897
No. 46, No. 3549746, No. 3558602, No. 3635953, No. 3641000, No. 36477
No. 81, (including some cephalosporins), No. 372
538 Wani, No. 3780028, No. 378456 Diketone, No. 3886140, No. 3888848,
No. 3,905,955, and No. 3,904,604 and British Patent No. 1,267,936. Pharmaceutically acceptable water-soluble derivatives of amphoteric cephalosporins having the formula: AlRl and R3 are as defined above.

In a preferred embodiment, the carbon attached to the alpha-amino group has the D configuration. They (1) with the addition of water form a true solution suitable for parenteral administration, (2) have adequate thermal stability in the solid state, and (3) aqueous solutions have a service life of several hours or more at room temperature and (4) Derivatives that provide little or no muscle or venous stimulation upon intravenous or intramuscular injection. In particular, the present invention provides alkali metal salts, especially the sodium and potassium salts, of the reaction products of the above-mentioned amphoteric cephalosporins with aldehydes, preferably furpur aldehyde or aldehydes with acidic groups, such as 2-franc sulfonic acid. be. The compounds of the invention exhibit favorable solubility, stability and absorption properties.

Preferred types are the original amphoteric cephalos that rapidly and completely hydrolyze in the body and have the formula: where A represents hydrogen, hydroxy, methyl or methoxy; R1 represents hydrogen, sodium or potassium; represents an aliphatic aromatic or heterocyclic group to which carboxyl or 2-furyl or a strongly acidic group is also attached in its sodium or potassium form and R3 is 1,2,3-triazol-5-yl, tetrazol-5-yl yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiazol-2-yl, 1,3,
4-oxadiazol-3-yl, or 1,2,4-triazol-5-yl, each of these groups being substituted with 1 or 2 lower alkyl groups having 1 to 4 carbon atoms or unsubstituted. It shall be a replacement.

) is provided. In a preferred embodiment, the carbon atom (relative to the hydroxyl group) attached to the benzene ring has the D configuration. Therefore, the present invention has the structural formula: 0-benzaldehyde sulfonic acid, 4-methoxybenzaldehyde 3-sulfonic acid,
4-hydroxybenzaldehyde 3-sulfonic acid,
0- and p-formylphenooxyacetic acid, 5-formylusalicylic acid, 0CH-COOHglyoxalic acid, phthalaldehydic acid, p-formylbenzoic acid, 0HC-CH2SO3Na acetaldehyde sulfonic acid sodium salt and 0H0-CH(SO3Na) 2-acetaldehyde disulfonic acid sodium salt.

A further preferred embodiment of the invention is a formula 1 in which A is hydrogen and R2 is derived from one of the above-mentioned aldehydes, most preferably Kazumasa] or I]-803Na, and R3 is], "卜℃H3or]l-. It is like N/Good.

The compounds of this invention are relatively water-insoluble (125 m9) for intravenous injection, requiring a true solution with a concentration of about 250 m9 in only 1 or 2 ml for BOlus injection.
The present invention solves the problem of formulating amphoteric 3-thiolated cephalosporins (1 ml or less).

Such dosage forms can also be dispensed dry (powder bottle only), which can be reconstituted with sterile water immediately before use, but must be completely dissolved within 2-3 minutes before use. Also, when added to multiple infusions for intravenous infusion (after reconstitution) at a concentration of 91 ml of 10-25Tn, the compound loses more than 10% of its biological activity over the 4-6 hours required for leaching. No.

125m9177 in its bisexual type! Amphoteric 3-thiolated cephalosporins with water solubility below 1 are clearly not suitable and (unlike their non-monoampholytic counterparts such as cephalosin) the required pH is too high for it to separate and at that pH. It cannot normally be converted to the common soluble sodium salt since the free amino groups present are believed to be susceptible to decomposition. The present invention also relates to formula 1: where A.sRl, R2 and R3 are as defined above.

), which method comprises adding a compound having the formula R2CHO (wherein R2 is defined above) to an aqueous suspension of an amphoteric cephalosporin or solvate or hydrate having the formula (1). As expected.

) and the pH of the reaction mixture to about 5.5.
to 8, preferably 6.2-7.2, to form compound 1 in solution and (2) recover compound 1 from solution. be.

Compounds with formula 1 have an asymmetric center at the carbon bonded to two nitrogen atoms.

Therefore, compounds with formula 1 can be prepared in the form of a DL mixture or as individual D
or exists as the L isomer. The cephalosporin starting material used in step (1) of the above method may be any type of amphoteric cephalosporin with a formula that includes the free acid zwitterion or a hydrate or solvate of said zwitterion. The concentration of amphoteric cephalosporin starting material is not critical, but is approximately 25 to 3 ml of cephalosporin starting material per milliliter of solvent.
Good results have been obtained at a concentration of 00m9.

The starting material is preferably ground and sieved into a fine powder, but in order to increase the surface area and reaction rate, it is best to grind the starting material to a particle size of 200 mesh or less. The amphoteric cephalosporin starting material is slurried in water to form an aqueous suspension.

Instead of using an aqueous suspension in step (1), the cephalosporin starting material is (1) a solvent for the alkali metal end product;
(2) is compatible with the aldehyde, (3) is chemically inert to the cephalosporin starting material as well as the final product, and (4) is suspended in an organic solvent that is easily removed from the final product by appropriate drying. It may be muddy. Examples of organic solvents that can be used are dimethyl sulfoxide and dimethyl formamide. However, due to the difficulty of removing residual organic solvent from the alkali metal salt final product, the starting material is preferably an aqueous suspension. After obtaining a suspension of cephalosporin starting material with aldehyde, the pH of the reaction mixture was adjusted to about 5.
A sufficient amount of an alkali metal base, preferably a sodium or potassium base, is added to form the desired alkali metal salt of formula 1 in the solvent.

When the pH rises within this range, an alkali metal salt of the reaction product of the amphoteric cephalosporin and the aldehyde is formed and goes into the liquid. The temperature at which step (1) is carried out does not require precision.

This reaction is carried out at room temperature, and temperatures of 50-60 DEG C. are preferred, although either high or low temperatures can be used. Approximately 1 mole of aldehyde is required per mole of cephalosporin starting material, but the aldehyde may be added in some molar excess over the theoretical amount to ensure complete reaction.

A good ratio of aldehyde to cephalosporin is about 1
．． 3-1.4 often uses 1:1 as well. The alkali metal base (1) creates an alkali metal cation, preferably sodium or potassium ion, and (2) lowers the pH of the reaction mixture to about 5.5 to 8, preferably about 6.275 to 7.
．． Any water-soluble base that can be raised to 2.

Preferred bases in terms of preferred solubility are sodium or potassium hydroxide. Compound 1(7) R3-S moiety leaves at high pH. For this purpose, a base is added in such a way that the pH of the reaction mixture does not rise above about 8. The base is preferably used in the form of an aqueous solution and added gently to the reaction mixture with stirring until the reaction is known to be complete by pH measurement and formation of or near solution. The amount of base used does not require precision, but it is preferable to use about 1 mole of base per mole of cephalosporin. To obtain good results, the solution obtained at the end of step (1) is filtered to remove fixed impurities before the recovery step (2).

The solution may optionally be treated with activated carbon to aid in the removal of colored impurities prior to filtration. The desired product of formula 1 is then recovered from water or a non-mono-aqueous solution by precipitation or lyophilization methods.

Precipitation of the alkali metal salt can be carried out by adding an organic solvent in which the desired salt is insoluble, that is, it does not serve as a solvent. Examples of such non-solvents are isopropanol, n-propanol, t-butanol and acetonitrile. The solvent that can be used in the precipitation step must be one that can be easily removed from the final product under conditions that cause little decomposition of the alkali metal salt.

The best nonsolvent is isoprobal. The nonsolvent may be added to the solution obtained from step (1), or the solution containing the desired alkali metal salt may be added to a large excess of the nonsolvent while stirring. The alkali metal salt of formula 1 is then filtered and washed with a suitable organic solvent, such as isopropanol, and dried in a conventional manner, such as vacuum drying at 50-56 DEG C. for 24 hours or air drying at 60 DEG C. for 24 hours. In addition to the method of recovering the final product by precipitation, the salt having formula 1 can also be recovered by a method of making the liquid produced in step (1) lyophilic. Another method for preparing the compound of formula 1 is as follows: (1) in a suitable inert organic solvent that is a solvent for the triethylamine salt of the aldehyde reaction product of an amphoteric cephalosporin and a non-solvent for the alkali metal salt having formula 1. (2) adding an aldehyde and sufficient triethylamine to the suspension to form a triethylamine salt of the aldehyde reaction product of the amphoteric cephalosporin in solution; and (3) adding a sodium or potassium base soluble in a solvent to the solution to precipitate an alkali metal salt having formula 1.

The starting material is slurried in an inert organic solvent that is a solvent for the triethylamine salt or aldehyde reaction product of the amphoteric cephalosporin, but is a non-solvent for the desired alkali metal salt of Formula 1.

The solvent chosen for step (1) must be one that can be easily removed under conditions that do not cause any decomposition of the final product. Suitable solvents for step (1) can be tested by simple tests. The suspension obtained in step (1) is then treated with preferably a molar excess of aldehyde, best about 1.3 to 1.4 moles per mole of cephalosporin starting material, and the cyclic reaction of the aldehyde with the amphoteric cephalosporin in solution. Add enough triethylamine to form the triethylamine salt of the product.

This reaction mixture is preferably stirred for at least about 3 minutes to complete the reaction. The amount of triethylamine used is not critical, but it is preferred to use about 1 mole per mole of cephalosporin starting material. The temperature in step (2) is usually carried out at room temperature, but higher or lower temperatures can be selected depending on whether the reaction time is desired to be increased or decreased. After producing the solvent or near-solution in step (2), the reaction mixture is treated with activated carbon and filtered as in the first method above. The desired alkali metal salt of formula 1 can then be recovered from the solution in step (2) by adding a sodium or potassium salt soluble in the solvent.

Preferred salts are the sodium or potassium salts of organic acids having about 2 to 18 carbon atoms, such as 2-ethylcaproic acid, oleic acid, glycolic acid, propionic acid, acetic acid, etc. The preferred salts for methanol solvent systems are sodium or potassium 2-ethylcaproate, and the best solution for this salt is in an organic solvent that is miscible with methanol, such as isopropanol.The most preferred alkali metal salts are - Sodium or potassium 2-ethylcaproate solution in isopropanol.The alkali metal salt should be added gently with stirring in sufficient quantity to precipitate the maximum amount from the solution. The precipitate is stirred for about 1 hour and then filtered. The precipitate is washed with a suitable organic solvent, e.g. methanol, and heated in a conventional manner, e.g.
Vacuum dry for 1 hour or air dry at 60°C for 4 hours. Second
The method can be carried out without using trimethylamine in step (2). In this variant, an amphoteric cephalosporin or a solvate or hydrate thereof, preferably in methanol or propylene glycol solvate or hydrate form,
It is best to make a suspension of the methanol solvate in an inert organic solvent (preferably methanol) which is a non-monosolvent of the product of formula 1, followed by a molar excess of the aldehyde and the reaction. A sufficient amount of solvent soluble sodium or potassium base is added to raise the pH of the product to about 5.5-8. As bases it is preferred to use the sodium or potassium salts mentioned as preferred for the second method. In this variant, the cephalosporin starting material passes into the solvent and the insoluble alkali metal salt precipitates almost instantaneously. Since no solvent is available upon completion of the reaction, it is advisable to heat and stir the reaction mixture at about 45-50 DEG C. for up to several hours to obtain maximum yield of final product. The solid product is washed and dried separately to obtain the desired salt of formula 1. The alkali metal salts of the present invention are solid and have moderate thermal stability, high solubility in water, satisfactory water stability, no muscle or venous irritation upon intravenous or intramuscular injection, and are compatible with various Gram-positive and Gram-negative bacteria. It can be used to produce pharmaceutical compositions of amphoteric cephalosporins with excellent in vivo and in vitro antibacterial activity against cephalosporins.

Sodium and potassium salts of formula 1 can be dissolved in water to produce relatively concentrated solutions with an activity of at least 250 m91 m1.

The activity of this salt is 250m91m1 concentration (PH5.7-6
．． 8) has moderate water stability. The compounds of the present invention are hydrolyzed in dilute solution to the parent amphoteric cephalosporin of formula 1. The compounds of the present invention are rapidly hydrolyzed to the parent cephalosporin at any concentration in acidic aqueous solution.
This property makes the compounds of the present invention useful for the purpose of purifying parent amphoteric antibiotics, for example, after washing the solid-state compound with a non-monohydrous solvent to remove solvent-soluble impurities, it becomes easily amphiphilic. It can be reconverted into antibiotics. The activity of compounds having formula 1 is substantially equivalent to that of amphiphilic cephalosporins.

Another feature of the invention is a compound having formula 1 suitable for constitution with water for use as an antibiotic composition suitable for parenteral administration and a pH of the composition on reconstitution with water of about 5. It is an object of the present invention to provide a pharmaceutical composition comprising a solid pharmaceutically acceptable water-soluble organic acid present in an amount such that the amount is between 5 and 7.5.

The dry mixture in the above composition of the salt having formula 1 and the organic acid has a high concentration suitable for parenteral administration, i.e. at least 250m91m
It can be reconstituted with water to make up to 1 solution.

Compositions made in accordance with the present invention are mixed with a sufficient amount of a pharmaceutically acceptable water-soluble solid organic acid such that when reconstituted with the compound having formula 1, the pH of the composition is about 5 to 6. It can be manufactured by The organic acid used in the composition can be any non-toxic water-soluble solid organic acid.

Examples of suitable acids include citric acid, tartaric acid, glycine hydrochloride, ascorbic acid, succinic acid, and the like. The best acid to use in the compositions of this invention is citric acid. The exact proportions of compound of formula 1 and solid organic acid will depend on the physical and chemical properties of the chosen acid, such as acidity, solubility, etc.

It has been found that generally the desired pH range of 5-6 upon reconstitution with water is achieved when the solid organic acid is used in an amount of about 4-6% by weight of the compound having Formula 1. In addition to the above composition, formula 1
Compounds with 100 gram-positive and gram-negative bacteria are potent antibacterial agents useful for both oral and parenteral administration in the treatment of infectious diseases in animals, including poultry and humans, caused by many Gram-positive and Gram-negative bacteria.

The compounds and compositions are also valuable as animal feed supplements and mastitis treatments in cattle. The salts and salt-organic acid mixtures of the present invention can be formulated as pharmaceutical compositions containing, in addition to the active ingredient, a pharmaceutically acceptable carrier or diluent.

Although the compounds can be administered either orally or parenterally, their high aqueous solubility makes them particularly useful for parenteral administration. For the treatment of bacterial infectious diseases in humans, the compounds and compositions may be administered in divided doses, e.g., approximately 5 to 20 Tn9 divided into 3 or 4 doses per day.
/K9/day can be administered. These are the active ingredients 12
It is administered in dosage units of 5.250 or 500 mg. Preparation of starting material 7-[D-α-amino-α-(p-hydroxyphenyl)-acetamide]-3-(1,)2,3-triazol-5-ylthiomethyl-3-cefemu-4-carboxylic acid methanol solvate Preparation of D-(-)-p-hydroxyphenyl-glycine 8.36y1 (4). A mixture of 0.05 mol) and 3.20 y (0.075 mol) of magnesium oxide was mixed well and added.

After stirring the mixture for 1 hour, 10.74y (0.075 fmol) of t-butoxycarbonyl azide was added. The mixture was heated and stirred at 45-50° C. for 17 hours under nitrogen. Dilute the solution with 400ml of water and add 300ml of ethyl acetate.
Extracted twice with m1. pH the aqueous phase with 10% citric acid solution.
4 acidified and saturated with NaCl. The aqueous mixture was extracted with 3 x 400 ml of ethyl acetate, the liquid was dried over Na2sO4 and the solvent was evaporated. The residue was triturated with 6° Skelesolve B to give 10.49 (78.5%) of D-α-t-butoxycarbonylamino-α-(p-hydroxyphenyl)monoacetic acid as a solid. 7-Amino-3-(1,2,3
-Triazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid 6.0f (19.0 mmol) in a suspension of 1,1,1,3,3,3-hexamethyluzine lazan 8.5ml ( 40.9 mmol) was added.

The mixture was stirred and distilled under reflux for 4 hours to form a clear liquid.
The solvent was evaporated and the residual oil was pulled under high vacuum at room temperature overnight. The foamy residue was dissolved in 85 ml of dry THF (tetrahydrofuran) and cooled to about -15F for the next reaction. D-α-
t-Butoxycarbonylamino-alpha-(4-hydroxy)acetic acid 4.4y (16.5 mmol) was dried in THF.
Dissolved to 145 ml.

This liquid was cooled to -20°C and stirred. The temperature of this liquid is about -10
1.6 f (16 mmol) of N-methyl morpholine and 3.3 I1 (16.8 mmol) of isobutyl chloroformate were added one after another at such a rate that the mixture did not rise above zero.
Next, after stirring this mixture at -12 to -15°C,
Cooled to 20°C and silylated 7-amino-3-(1,2
,3-triazol-5-ylthiomethyl)-3-cephemu-4-carboxylic acid solution in THF was added in one portion. The temperature increased by about -1. External cooling was discontinued until the temperature reached 0°C. Now heat the mixture at 2-3℃ using an ice-water bath for 30 minutes.
Stir for hours. Then, cooling was stopped for 1 hour and the temperature remained at 20 minutes. A total of 30 mt of methanol was added and the mixture was stirred at room temperature. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate (30%).
After suspending the suspension in a volume of 0 ml, the suspended solid was separated. (11.8 Da) The ethyl acetate solution was extracted three times with 5% NaHCO3 solution.
The extracted NaHCO3 solutions were combined and cooled in an ice bath, and methyl acetate was added to make the pH pH2 acidic with 42.5% H3PO4. The liquid was shaken and then separated. Then, after drying the ethyl acetate solution over sodium sulfate, about 15-20 ml
It evaporated until. This liquid was then added to stirring cyclohexane (~400ml) in an ethylene Meyer flask.

After stirring for three times, the precipitate was collected by filtration. Air-dried solid 7
-[D-α-t-butoxy a carbonylamino-α-
(p-hydroxyphenyl)acetamide]-3-(
1,2,3-triazol-5-ylthiomethyl)-3-
Cefhemu 4-carboxylic acid was 1.75y. 71 [
D-α-t-butoxycarbonylaminoα-(p-
hydroxyphenyl)acetamide]-3-(1,2
, 3-triazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid 3.5f in 98-100% HCOO
The mixture was dissolved in 80 mL of H and stirred at room temperature for 2 hours.

HCOOH was evaporated under reduced pressure (aspirator bath temperature was 40° C. or less) and finally azeotroped with 30 ml of toluene three times.
The solid was dried under high vacuum over P2O5 overnight. Foamy substance 3.
I got 5J. This 2I1 is converted into 300ml of H2O:CH3
After stirring with OH (8:2), it was filtered to remove 0.3 y of solid matter, and charcoal-treated diatomaceous earth (
Celite) and freeze-dried to produce crude 7-[D-α-amino-α-(p-hydroxyphenyl)aldehyde]-
3-(1,2,3 triazol-5-ylthiomethyl)
0.9y of -3-cefemu-4-carboxylic acid was obtained. It was crystallized by the following method. 6 ml of 99% methanol was placed in a test tube, 0.2 y of the crude material was suspended, and the mixture was heated and boiled.

Heating was immediately stopped and the molten material was ground with the seeds. The melt crystallized. In this way, the total amount of 0.211y 71 [D-
α-Amino-α-(p-hydroxyphenyl)-acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid was obtained from 0.400 da of crude material. This material was dissolved on P2O5 at 560
/0.1 size. Melting point>200℃. IRI:. N
The MR results showed that the structures were consistent. NMR shows 113 moles of H3
Indicated the presence of OH. ClRHl8N6O5S2,H2
Analytical value for O,ll3CH3OH: Calculated value: Cl4
4.83; Hl4.38: Nll7. lO; Sll3
．． O9 measurement value: Cl43.97; H14.36:Nll
5.84; S,. 6. 18O bean paste - 100% formic acid 175
m1 under anhydrous conditions 7-[D-α-t-butoxycarbonylamino-α-(p-hydroxyphenyl)acetamide]-3-(1,2,3-triazole 5
-ylthiomethyl)-3-cefemu-4-carboxylic acid 6
．． 5y (11.55 mmol) was dissolved.

2. Stir the mixture at room temperature. Stir for hours. Part of the liquid 125ml
was evaporated under reduced pressure to give an amber oil. The oil was then vacuum azeotroped three times with 70 mt of toluene. Residue 80:20H2
0: Suspended in 700 ml of CH3OH solution and stirred, most of the treated solid was dissolved, so it was filtered and the filtrate was mixed with 1° Dalgo charcoal.
．． 5y and 2 conflicts were processed. It was filtered through a layer of charcoal ceride. The liquid was then freeze-dried in nine 100ml round bottom flasks. The freeze-dried material was 2.415y. This was crystallized every 0.200 f as described above. Thus, the total amount of 71 [D-α-amino-α-(p-
hydroxyphenyl)acetamide]-3-(1,2
, 3-triazol-5-ylthiomethyl)-3-cephemu-4-carboxylic acid was obtained.

NMR was consistent and showed the presence of 1-3 moles of CH3OH. Cl8Hl8N6O5S2, H2O, ll3CH3O
Analysis of H! Value: Calculated value: Cl44.83; Hl4
．． 38;Nll7. lO;Sll3. O9 measurement value: Cl
45.77; Hl4.44; Nll6.6lCl44.
36; Hl4.34; Nll6.52; Sll3. Ol
, 13.017-[D-α-amino-α-(p-hydroxyphenyl)-acetamide]-3-(1,2,3
-Crystalline methanol solvation of triazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid. Manufacture of things 1
7-[D-α-amino-α-(p-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid 50f as n-25. 95% V/V methanol/water (
A slurry was made in 250 ml of 95% methanol.

2 Add concentrated hydrochloric acid while stirring vigorously and add PHL. 3-1.5
A solution or something close to it was obtained.

: PHL. with triethylamine. It was set at 7.

7.5y of activated carbon ("Gluco G-60") was added and slurried for 30 minutes.

) The charcoal was filtered off and washed with 75 ml of methanol, which was added to the filtrate.

Steps 2, 3 and 4 must be completed within 5 hours. The filtrate and washing solution from Step i were stirred vigorously and triethylamine was added over 5 minutes to adjust the pH to 4.5.

Crystallization began in about 1-3 minutes and the mixture was slurried for 1 hour. Collect the crystals by filtration and wash with 100ml of methanol56
It was vacuum dried at ℃ for 24 hours.

Yield 75-90%, bioanalysis = 850-900 rI
1CgITn9, NMR<51R consistent with 1 mol methanol; %H2O. ．． KF=2-4.0'-[D-
Crystalline 1,2-propynone glycol of α-amino-α-(p-hydroxyl-enyl)-acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-selemu-4-carboxylic acid Method for producing solvates 17-
[D-α-amino-α-(p-hydroxyphenyl)
-acetamide]-3-(1,2,3-triazol-5
-ylthiomethyl)-3-cefemu-4-carboxylic acid 2
Slurry 5q in 150-200 mt of 75% V/V propylene glycol-water solution at 20-25 C.

(ii) Add concentrated hydrochloric acid to bring the pH to 1.2, making it a solution or something close to a liquid.

3 While stirring vigorously, gently add triethylamine (TEA) to the PHL. 7-1.8.

Add 15y of ゜゜゜゜゜゜゜゜゜゜゜゜゜゜゜゛゛ to make the mixture into a three-powder slurry.

Filter out the charcoal. (filtration is slow, 18.5C1n,.S
SN0.57ea paper is good. ) Wash the filter cake with 40 ml of 75% propylene glycol-water solution and combine the washings with the filtrate. Steps 2, 3 and 4 must be completed within 5 hours. ) While vigorously stirring the mixture in step 4, add triethylamine in one portion to adjust the pH to 4.5.

Crystals form in about 1-3 minutes. Slurry the mixture for 1 hour. S7-[D-α-amino-α-(p-hydroxyphenyl)-acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cefemu 4-
The propylene glycol solvate crystals of carboxylic acid are filtered off.

Filtration is slow. (12.5-15.0c71SSN0.
60 bridge paper is good) Crystals in 75% propylene glycol 5
0ml, methanol 50ml, and acetone 50ml sequentially and vacuum dried at 56°C for 2$f. Biological yield 80
-95%. 7-[D-α-amino-α-(p-hydroxyphenyl)-acetamide]-3-(1,2,3 triazol-5-ylthiomethyl)-3-cefemu 4
- Properties of carboxylic acid propylene glycol solvate a Biological analysis = 850-900rncgIm9bIR-N
Consistent with the MR structure containing 1.0-1.5 moles of propylene glycol (14-19% propylene glycol).

It is clear that there is no loss of the 3-triazole side chain.

c %H2O. ．． K. F=1-3.00d crystal form=1
00% crystallinity (microcrystalline triangle) e melting point 182-184℃
(D1 hot stage) f [α]t (C=1%; 1
N-HCl) = +53g Water solubility = approx. 10 in water at 23°C
Loss of biological activity when stored at 100°C for 24 hours = <6%; Time = 12%; 1 month at 56°C = <10
71 [D-α-amino-α-(p-hydroxyphenyl)acetamide] prepared in the production of crystalline methanol solvate from crystalline propylene glycol solvate
-3-(1,2,3-triazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid propylene glycol solvate 50' was slurried in 250 ml of 95% V/V methanol-water solution at 22-25°C. did.

PHL. with concentrated hydrochloric acid while stirring vigorously. A treatment solution or something similar to a solution with a concentration of l-1.5 was obtained. Add triethylamine to adjust the pH to 1.7, add 7.5 Da of activated carbon,
It turned into a slurry. The charcoal was filtered off and washed with 75 ml of methanol. The washings were combined with the filtrate. (This step must be completed within 5 hours from HCl addition.) The combined solution was stirred vigorously and triethylamine was added over 5 minutes to bring the pH to 4.
．． I gave it a 5. Crystallization started in about 1-3 minutes. 1 of the mixture
The crystals were made into a slurry and separated by filtration, washed with 100 mL of methanol, and dried under vacuum at 56° C. for 24 hours. Biological yield 75-
90%, biological analysis = 850-900rr1CgIm
9, NMR- was consistent at 1 mole of methanol.
%H2O,. K. F. =2-4.0. Crystallinity 71 [D-
Preparation of α-amino-α-1(hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid sesquihydrate 71 [D-α-amino-α -(p-hydroxyphenyl)-acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cefemu 4-carboxylic acid methanol solvate (15 g) was slurried in 60 ml of water.

Increase the pH of the mixture to 6.5 by adding 4N NaOH to 20
Passed through 0 mesh steel.

The reaction product was slurried at room temperature for 2 hours, during which time the pH was maintained at 6.
I kept it at 5. The crystals were filtered and washed with 20ml of water at 3rC for 2 hours.
Hashirama air drying gave the title crystal 11.5y. Biological analysis = 924mcgIm9 (average %H2O..K.F. =
5.26). NMF. 15lR matched the desired structure and showed that the product was free of methanol but had traces of propylene glycol. Crystalline 71 [D-α-amino-α-(p-hydroxyphenyl)acetamide]-3
-(1,2,3-triazol-5-ylthiomethyl)-
Preparation of 3-cephemu-4-carboxylic acid sesquihydrate and production of other crystalline hydrates Substantially free of propylene glycol 7-[D-α-amino-α-(p-hydroxyphenyl)acetamide]- 3-(1,2,3-triazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid methanol hydrate (200 mesh, 10.0
y) at room temperature (20-252C) with deionized water 30-4
The slurry was slurried in 0 ml to create an aqueous suspension with a pH of 3-4.

Gently add 40% NaOH while stirring vigorously.
H was set to 6.3-6.7. The mixture was adjusted to pH 6.3-6.
7 for 2 hours. Separate the crystals by filtration, wash with water, and store at room temperature for 2
4J! II air-dry to obtain crystalline 71 [D-α-amino-α
-(p-hydroxyphenyl)acetamide]-3-
(1,2,3-triazol-5-ylthiomethyl)-3
-cefemu 4-carboxylic acid dihydrate (950-100
A yield of 75-80% by weight of 0mcg1m9) was obtained. IR
and NMR analysis were consistent with the desired structure and showed the product to be free of methanol but with traces of propylene glycol. H2O, K. F. = 6.560 A sample of crystalline dihydrate was air-dried at 3rC for 2 hours to obtain crystalline 7-[D-
α-Amino-α-(p-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephemu-4-carboxylic acid sesquihydrate was obtained.

H2O. ．． K. F. =4.260 A second sample of the dihydrate was air-dried for two hours at 45°C to obtain a crystalline sesquihydrate. H
2O,. K. F. =5.5.56 another sample of dihydrate
Air-dry for 24 hours at ℃ to obtain crystalline 7-[D-α-amino-α
-(p-hydroxyphenyl)acetamide]-3-
(1,2,3-triazol-5-ylthiomethyl)-3
-Cefemu 4-carboxylic acid monohydrate was obtained. H2O,
K. F. = 4.38 (theoretical monohydrate H2O% = 3.
75) Another sample of the dihydrate was vacuum dried over P2O5 at room temperature for two hours to obtain crystalline 71[D-α-amino-α-(p-
hydroxyphenyl)acetamide]-3-(1,2
, 3-triazol-5-ylthiomethyl)-3-cefemu 4-carboxylic acid hemihydrate was obtained. H2O. K. F
．． = 2.63 (theoretical H2O% of hemihydrate = 1.91
) A sample of the dihydrate was vacuum dried at 56° C. for 24 Tf to obtain a crystalline hemihydrate.

H2O. ．． K. F. =1.6-2.00 D- in the following way
(-)-2-(3″-methyl-4″-hydroxyphenyl)glycyl chloride hydrochloride was produced with high purity and high yield; about 0.06 mol of D-(-)-2-(3″ -Methyl-4″-hydroxyphenyl)glycine to dioxane 1
It was made into a slurry in 00m1.

COCI2 (
phosgene). After a total of 3.5 hours, a yellow liquid was obtained. Excess phosgene was added to the solution by passing nitrogen through it. 2. Add HCl gas to the liquid. Ichima bubbled. The liquid was stirred and a small amount was diluted with ether to form crystals, which were added to the batch as seeds. The solution was stirred for one hour at 20-25°C. The resulting crystalline D-(-)-2-(3''-methyl-4''-hydroxyphenyl)-glycyl chloride hydrochloride slurry was filtered to collect the product. After washing the filter cake with dioxane and methylene chloride, vacuum desiccator
D-(-)-2- of about 7y was dried on top to P2 in a
(3″-Methyl-4″-hydroxyphenyl)-glycyl chloride hydrochloride was obtained. 2-(3″-methyl-4″-
Hydroxyphenyl)glycine 75 in 100ml of water
A solution containing 59.02f (0.6 mol) of 2-methylphenol was added to 400ml of water at room temperature.
y (0.5 mol) and 140 ml of concentrated ammonium hydroxide.

The temperature of the mixture rose to 37°C. The mixture was stirred at room temperature for 6 hours. Initially PHLO. The pH of the heated solution is 6NH.
Crystals adjusted to 6.8 with C1 were formed. The product was collected by filtration, washed with water and dried under vacuum over P2O5 to obtain 2-(3"-
Methyl-4″-hydroxyphenyl)-glycine 31
．． 5y (34.8%) was obtained. Decompose at 196-199°C.

IR and NMR spectra were consistent with the desired product.
[Reference: Belky Patent No. 7740 (Farmdoc 27, 12 liver) of Beachyam Group Co., Ltd. in 2019 has a melting point of 205-20 rC]. Analytical values for C9HllNO3: Calculated values: Cl59.66; Hl6. l3;Nl7.73
Measured value: Cl57.68; Hl6.23; Nl7.43
; H2Ol2.342.34% Correction value for H2O: Cl59. O6; Hl6. l2;Nl7.67
.

D,L-N-chloroacetyl-2-(3″-methyl-4
″-hydroxyphenyl)glycine 20% sodium hydroxide was added to a suspension of 20.2 f (0.112 mol) of D,L-2-(3″-methyl-4″-hydroxyphenyl)glycine in 175 ml of water. In addition, the treatment solution was adjusted to PHlO.3.

The liquid was cooled in an ice bath and 38.2q (0.2q) of chloroacetic anhydride was added.
24 mol) was added at once, and 20% sodium hydroxide was added to maintain the pH at 10 until the pH of the reaction mixture did not change. The reaction mixture was cooled and stirred for an additional hour. The reaction mixture was then adjusted to pH 2.0 with 6N HCl. Drilling crystals were formed. The product was collected by filtration, washed with water, and air-dried. hot water 200
Recrystallize from m1 to obtain D,L-N-chloroacetyl-2
-(35-Methyl-4'-hydroxyphenyl)-glycine 13.7y (47.4%) was obtained. IR and NMR
The spectrum was consistent with the desired product. CllHl2NO
Analysis value for 4Cl, H2O: Calculated value: Cl47.9
2; Hl5. ll8:Nl5. O8l measurement value: Cl48
．． ll; Hl5. l6; Nl5. l5゛D-(-)-N
-chloroacetyl-2-(3″-methyl-4″-hydroxyphenyl)glycine isopropyl alcohol 50
D, L-N-j chloroacetyl-2-(3″-
Methyl-4″-hydroxyphenyl)glycine 5.0
y (0.0194 mol) and L-ephenamine acetate 6.1y (0.0213 mol) were added and dissolved by heating on a steam bath.

When 50 mt of water was added and the mixture was cooled, L-ephenamine salt crystallized. This salt was collected by filtration and air dried. Add this salt to 30 m of water.
1 and suspended in methylene chloride at a pH of 20.
% NaOH to 10.0.

The phases were separated and the aqueous phase was extracted two more times with methylene chloride. Then, the aqueous solution was adjusted to pH 2. with 6N HCl. A product obtained by converting the mixture to O was crystallized. The product was collected by filtration and dried in vacuo over P2O5 to yield 0.9y (3''-methyl-4''-hydroxyphenyl)glycine of D-(-)-N-chloroacetyl-2-(3''-methyl-4''-hydroxyphenyl).
6.1%). Melting point 170-172°C. [α]KO
=185.9 (C1, 95% EtOH), IRI: d.
NMR spectrum was consistent with the desired product. CllH,
Analytical value for 2NO4Cl: Calculated value: Cl5l. 27
: Hl4.696; Nl5.436 Measured value: Cl5l.
2l; Hl 4.77; Nl 5.29l, 2-diphenyl-2-methylaminoethanol is normally efenamine (1
Registered in the United States on June 7, 951) and has the structure:

This compound is also N-methyl-1,2-diphenyl-2
-hydroxyethylamine or α,β-diphenyl-β-hydroxy-N-methylethylamine or 1,2
-Diphenyl-2-methylamino-1-ethanol.

This method utilizes only the rebo erythro isomer.

This manufacturing method and the reaction with penicillin G are described in US Patent No. 2645.
No. 638 (V.J. Young) and No. 2768081 (F.H. Book Walter). The latter is W. B. Wheatley et al., J. Or-G. Chem. ,
Rev. of the previous literature in Japan 0D11564-1571 (1953). It's Iyuni. It is based on Sheehan et al. (J.Am.
Chem. , S.O.C. ,? , 3089-3094 (19
59); see especially page 3091) to degrade racemic phenooxy-methylpenicillin. D
-(-)-2-(3''-methyl-4''-hydroxyphenyl)-glycine D-(-)-N-chloroacetyl-2-(3''-methyl-4''-hydroxyphenyl)
100ml of glycine 11.1f (0.0431mol)
2NHC1 and add it to 1. Distilled under reflux for hours.

The solution was cooled and the pH of the solution was adjusted to 5.0 with 20% NaOH to crystallize the treated product. The product is collected by filtration, washed with water, and P2O
．． D-(-)-2-(3″-methyl-4″-hydroxyphenyl)glycine 7.4y (94
．． 7%). Decomposes at 205-209°C.

[α] 4 = 152.61 (C1, INHCl). IR
and NMR spectra were consistent with the desired product. C9Hl
Analytical values for lNO3: Calculated values: Cl59.66; Hl6. l3;Nl7.33
Measured value: C,. 58.62: Hl5.49; Nl7.7
8; H, Oll. 46Ol. Correction value for 46% H2O; Cl59.48; Hl5.4l; Nl7.84
.

D-(1)-Nt-butoxycarbonyl-2-(3″
-methyl-4″-hydroxyphenyl)glycine H2
D-(-)- in 200 ml of O-dioxane (1:1)
2-(3″-methyl-4″-hydroxyphenyl)-
A suspension of 7.2y (0.0397 mol) of glycine and 3.2y (0.08 mol) of magnesium oxide powder was stirred at room temperature, and to this was added 9.7 y of t-butoxycarbonyl azide.
y (0.068 mol) was added dropwise.

The reaction mixture was then heated to 1 Cj at 42-45°C under nitrogen.
After heating for 1 hour, the mixture was diluted with 100 ml of ice water. The liquid was covered with ethyl acetate and the separated impurities were filtered off. The aqueous phase of the filtrate was separated and extracted twice more with ethyl acetate. The aqueous solution was then adjusted to pH5. with 42% phosphoric acid. The mixture was extracted with ethyl acetate five times. The combined organic extracts were washed three times with water, dried over sodium sulfate, and the solvent was removed in vacuo, leaving an oil. The oil was dried under vacuum over P2O5 to yield D-(-)-Nt-butoxycarbonyl-2-(3''-methyl-4''-hydroxyphenyl)glycine 10.6y (95%). The IR spectrum was consistent with the desired structure. 71 [D-2
-t-butoxycarbonylamino(3″-methyl4
″-hydroxyphenyl)acetamide]-3-(1
,2,3-triazol-5-ylthiomethyl)-3-cepheme-4-carboxylic acid A mixed anhydride D-(-)-Nt-butoxycarbonyl-2-(3''-methyl4''-hydro) in 0 ml of tetrahydrofuran. oxyphenyl)glycine 2.8f(a). 01 mole)
The solution containing was cooled to -15°C in an ice salt-acetone bath.

This was followed by 1.01 y (0.01 mol) of N-methylmorpholine and then 1.37 y of isobutyl chloroformate.
(0.01 mol) and the reaction mixture was heated to -15°C to -2
The mixture was stirred at 0°C for 8 minutes. Immediately N-methylmorpholine hydrochloride was precipitated and separated. B Coupling 3.1f (0.01) of 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid was suspended in 100 mL of water and N-methylmorpholin 1. 01g(a). 01 mol) was added, but it did not become a complete solution.

Then, 1,1,3,3-tetramethylguanidine was added dropwise until the suspension became a transparent liquid. The solution was then placed in an ice bath at 4°C.
The mixture was cooled to -15°C and added to the mixed anhydrous solution. Remove the cooling bath and mix 1. Stir for hours. The tetrahydrofuran was then removed under reduced pressure and the aqueous concentrate was covered with ethyl acetate. The aqueous phase was diluted with 42% phosphoric acid to pH 2. When the mixture was exposed to O, insoluble matter was separated. The solids were filtered off and the aqueous phase of the filtrate was extracted two more times with ethyl acetate. The combined extracts were washed twice with water, dried over sodium sulfate, and the solvent was removed under reduced pressure, leaving a sticky oil. This oil was triturated with Skelsorb B (containing a small amount of diethyl ether) to obtain a solid product. This solid product was collected by filtration, washed with Skelsorb B, and air-dried. Analysis of the product (silica gel disol, 97:3 acetone-acetic acid) revealed that this material was a mixture of the desired product and side chain acid. This material was then stirred for 1 hour with 100ml of anhydrous diethyl ether. Insoluble solids were collected by filtration and air-dried.
-2-t-butoxycarbonylamino(3″-methyl4″-hydroxyphenyl)acetamide]-3-
(1,2,3-triazol-5-ylthiomethyl)-3
-Cefemu 4-carboxylic acid 0.95y (16.4%)
I got it. TLC (97:3 acetone-acetic acid on silica gel) showed that the sample contained only traces of side chain acids. The infrared spectrum was consistent with the desired product. 71 [
D-2-t-butoxycarbonylamino(3″-methyl 4″-hydroxyphenyl)acetamide]-3
-(1,2,3-triazol-5-ylthiomethyl)-
3-Cefemu 4-carboxylic acid mixed anhydride D-(-)-N-t in 500 mt of tetrahydrofuran
-butoxycarbonyl-2-(3″-methyl-4″-
hydroxyphenyl)glycine 14.069 (0.0
A solution of 5 mol) was cooled to -15°C in an ice salt-acetone bath.

This was followed by 5.06f (0.05 mol) of N-methylmorpholine and then 6.83y of isobutyl chloroformate.
(0.05 mol) and the reaction mixture was adjusted to -13 to -17
The mixture was stirred at ℃. Immediately N-methylmorpholine hydrochloride was precipitated and separated. Silyl ester J amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephemu-4 monocarboxylic acid 8.0
y (0.025 mol), triethylamine 7.0 ml (
0.05 mol), N,N-dimethylaniline 6.9 ml
(0.0545 mol), chlorotrimethylsilane 9.5
m1 (0.075 mol) and methylene chloride 650 mL
The mixture was heated to reflux for 3 hours.

After the first hour of heating under reflux, chlorotrimethylsilane 1.
Added 6m1. The hazy liquid was cooled and methylene chloride was removed under reduced pressure. Dilute the residue with 500ml of tetrahydrofuran.
It reached 1. The coupled siliester solution was cooled to 10-15°C in an ice bath and the mixed anhydride solution was added at once to -15°C.

The cooling bath was removed and the reaction mixture was stirred for 2 hours. water 50
After adding 0 ml of tetrahydrofuran and removing tetrahydrofuran under reduced pressure, a gummy oil was separated. The oil was extracted into ethyl acetate and the phases were separated. When the aqueous phase (PH 3.8) was covered with ethyl acetate, some solid separated. This precipitate was filtered off, and the aqueous phase of the filtrate was separated. The aqueous solution was adjusted to pH 2.3 with 42% phosphoric acid and extracted again with ethyl acetate. The combined extracts were washed three times with water, dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain a sticky oil. The oil was dissolved in anhydrous diethyl ether 100TrLt. 151.5m
A solid formed after stirring for 1 hour. The product was filtered, washed briefly with anhydrous diethyl ether, and air dried. Product Tl
f:. (silica gel disol 99:1 acetone-acetic acid) showed this material to be a mixture of the desired product, a side chain acid, and a third unknown component. This substance was mixed again with 100ml of anhydrous diethyl ether and 1.5F! Stirred for 8 hours. The insoluble solid was collected by filtration and air-dried to give 71[D-2-t-butoxycarbonylamino(3″-methyl-4″-hydroxyphenyl)-acetamide]-31(1,2,3- 10.7y (74.4%) of triazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid was obtained.

TLC (silica gel disol 99:1 acetone-acetic acid) showed that the sample contained only traces of side chain acids and an unknown third component. The IR spectrum was consistent with the desired product. 7-[D-2-t-butoxycarbonylamino(3″-methyl-4″-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cefemu-4-carvone Acid A mixed anhydride D-(-)-N-t in 425 ml of tetrahydrofuran
-butoxycarbonyl-2-(3''-methyl-4゛-
hydroxyphenyl) glycine 12.2y (0.04
34 mol) in an ice monosalt-acetone bath at -15°C.
It was cooled to

This was added with 4.35y (0.04y) of N-methyl-morpholin.
34 mol) and isobutyl chloroformate 5.87y
(0.0434 mol) was added to the reaction mixture at -15°C.
The mixture was stirred once. N-methylmorpholine hydrochloride was immediately precipitated. B silyl ester J amino-3-(1,2,3-triazol-5-ylthiomethyl)-cefemu-4-carboxylic acid 6.8y(
0.0217 mol), triethylamine 6.02 ml (
0.043 mol), N,N-dimethylaniline 6.0 m
1 (0.0473 mol), chlorotrimethylsilane8.
26 ml (0.0651 mol) and methylene chloride 55
0ml of the mixture was heated to reflux for 2 hours.

The hazy liquid was cooled, methylene chloride was removed under reduced pressure, and the residue was taken up in 425 mt of tetrahydrofuran. C. The coupled silyl ester solution was cooled to 10°C in an ice bath and once added to the mixed anhydride solution at -15°C.

After removing the cooling bath and stirring the reaction mixture for 2 hours, water
5ml was added and stirred for 5 minutes. Tetrahydrofuran was removed under reduced pressure to produce a gummy oil. This oil was extracted into ethyl acetate and a small amount of undissolved solid was filtered off. The aqueous phase of the filtrate was separated and adjusted to pH 2 with 42% phosphoric acid. The mixture was extracted with ethyl acetate twice or more. The combined extracts were washed three times with water, dried over sodium sulfate, and the solution was removed under reduced pressure to yield a sticky oil. This oil was dissolved in 30 ml of acetone and this solution was added dropwise to a well-stirred 300 mt volume of anhydrous diethyl ether. Add this mixture to 2. Stir for hours. The separated insoluble solid was collected by filtration and air-dried. TLC of the product (99:1 acetone-acetic acid on silica gel) showed the material to be a mixture of the desired product, a side chain acid, and a third unknown component. This solid was again stirred with 80 ml of anhydrous diethyl ether for 1 hour. The insoluble solid was collected by filtration, briefly washed with anhydrous diethyl ether, and air-dried to obtain 71 [D-2
-t-butoxycarbonylamino(3″-methyl-4″-hydroxyphenyl)acetamide]-3-(
1,2,3-triazol-5-ylthiomethyl)-3-
5.8f (46.5%) of cefhemu 4-carboxylic acid was obtained.

L°C (silica gel disol 99:1 acetone-acetic acid) showed that the sample contained slight side chain acids and traces of a third unknown component. The IR spectrum was consistent with the desired product. 7
-[D-2-amino(3″-methyl-4″-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cefemu 4-
Carboxylic acid Cold trifluoroacetic acid 15ml to 7-[D-2
-t-butoxycarbonylamino(3″-methyl-4″-hydroxyphenyl)acetamide]-3-(
1,2,3-triazol-5-ylthiomethyl)-3-
Cefemu 4-carboxylic acid 0.95y (a). 002 mol) was added and the solution was stirred for 1 minute.

This solution was then poured into 200 ml of a 2:1 "D-2-amino(3"-methyl-4) solution and the mixture was cooled.
″-hydroxyphenyl)acetamide]-3-(1
, 2,3-triazol-5-ylthiomethyl)-3-cephemu-4-carboxylic acid precipitated trifluoroacetate was collected by filtration, washed with 2:1 "Skellysorb B8 monoanhydrous diethyl ether, and dried under vacuum over P2O. substance 0.75
I got y. Add 0.75 y of this salt to 250 ml of water, 25 ml of Amperlite LA-1 acetate type resin (25% in methyl isobutyl ketone) and 25 ml of methyl isobutyl ketone.
ml and stirred at room temperature for 2 hours. The phases were separated and the methyl isobutyl ketone layer was extracted once with water. The aqueous phases were combined and extracted eight times with diethyl ether. The aqueous phase was filtered and the solution was removed under reduced pressure to produce a treated solid which was triturated with methyl isobutyl ketone. This substance. was collected by filtration, washed with methyl isobutyl ketone and acetone, and dried under vacuum at 65°C over PO to obtain 7-[D-2-amino(3″-methyl-4″-hydroxyphenyl)acetamide]-3-(
1,2,3-triazol-5-ylthiomethyl)-3-
0.36y (59%) of cefem l-4-carboxylic acid was obtained. 〉Decomposes at 150°C. IR and NMR spectra were consistent with the desired product. LA-1 resin is a mixture of secondary amines, each secondary amine having the formula:
2 and R3 shall have 11 to 14 carbon atoms therein.

). This particular mixture of secondary amines, also referred to herein as "Liquid Amine Mixture NO.", is a clear amber liquid with the following physical properties: a viscosity of 70 Cpd at 25 C; Specific gravity at 20℃ 0.826
:Refractive index at 25℃ 1.4554:1077!77! Fractional distillation range up to 170℃ -0.5%, 170-220
-3% at 220-230°C, -90% above 230°C and -6.5% above 230°C. 7-[D-2-amino(3″-methyl-4″-hydroxyphenyl)acetamide]-
3-(1,2,3-triazol-5-ylthiomethyl)
-3-cefemu 4-carboxylic acid is also BL-S638
Also called.

2-(3″-methoxy-4″-hydroxyphenyl)glycine 75% glyoxylic acid in 100 ml of water
A solution containing 9.2y (0.6 mol) was mixed with 400 mt of water at room temperature.
There is 62.07 da(a) of 2-methoxyphenol in it. 5
mol) and 140 ml of concentrated ammonium hydroxide.

The temperature of the mixture reached 35°C. The mixture was stirred at room temperature for an hour. The crystalline product was collected by filtration, washed with water, and then with acetone. 2-(3″-methoxy-4″-hydroxyphenyl)glycine 7.4
g (58.2%) was obtained. Decomposes at 218-220°C.

(240°C) IR and NMR spectra show the desired product -
-I got it. ; Analysis value for 9H11N04: Calculated value: Cl54.82:Hl5.62;Nl7. lO
.

Measured value: Cl53.77; Hl5.9l; Nl6.97
. ll2Oll. Correct with 1.13% H2O.
Cl54.38; H15.85; Nl7. O5; Thoughts:
B1 block, Z. ．． PhysiOlChem. , vertical,
226 (1917). 2-(3″-methoxy-4″-
Hydroxyphenylene) Decomposition of glycine ~ Methyl 2-
(3″-methoxy-4″-hydroxyphenyl)-
Glycinate 2-(3') in 500 ml of absolute methanol
-Methoxy-4''-hydroxyphenyl)glycine 94y (0.476 mol) was cooled and HCl gas was bubbled through it vigorously.

At first it was a clear liquid, but gradually a large amount of crystalline product separated. After 2 hours, the methyl ester hydrochloride was filtered off, briefly washed with methanol, and air-dried to obtain a voltage of 99.6V.

A cold solution of hydrochloride in 800 mt of water was adjusted to pH 8 (Na
OH) to give a crystalline precipitate of the ester free base. (8
1.3y), the IR and NMR spectra matched. Cl
Analytical values for OHl3NO4: Calculated values: Cl56.86; Hl6.2O; Nl6.63
Measured value: Cl56.46: Hl6.28: Nl6.55
; 1120. ．． 0.59BD-(-)-2-(3″-
Methoxy-4″-hydroxyphenyl)glycine methyl 2-(3″-methoxy-4″-hydroxyphenyl)-glycinate 50y (0.237 mol), acetic acid 19ml (0.333 mol) and i-PrOT (isopropyl alcohol) A partial solution was obtained by heating the mixture of 11 to boiling.

Dibenzoyl-d monotartaric acid/hydrate (89.2y0.2
77 mol) was added with thorough stirring, and the mixture was distilled under reflux. Salt soon began to crystallize. Heating was discontinued and the flask was allowed to gradually cool to room temperature. Precipitate after cooling in an ice bath?
Over-collected. Concentration of the furnace liquor to the first third yielded a small amount of second salt. The total yield for both was 54.1y after air drying. (Contains solids, see below) The p solution was concentrated to remove the solvent.

Mix the sticky residue with 1300ml of 1N HC and convert the mixture to CH
Extracted with CI34OOml. This CHCl2 phase is
Extracted twice with 0 ml of 1N HCL. Combined HCl
The extract was briefly concentrated to remove remaining CHCl3, and then distilled under reflux for 1 hour. When the liquid is concentrated to a small amount, the amino acid HCl
Salt crystallized. The product was filtered and collected with 1NHC150m
Recrystallized from 1. The product solution in 200ml of water was adjusted to PH
It was adjusted to 4.5 (NaOH). The mixture was heated to near boiling and cooled to precipitate D-(-)-2-(3''-methoxy-4''-hydroxy-phenyl)glycine as hair-like needle crystals. After cooling overnight, the product was collected by filtration, briefly washed with water, washed with methanol, and dried at 40°C to obtain &7y. [α]? 0=-136.5 (C1, 1
NHC1), and the NMR spectra were in good agreement. C
Analysis value for 9HllNO4, H2O: Calculated value: Cl
5O. 23; Hl6. O9; Nl6.5l; H2Ol
8.37 Measured value: Cl5O. 43; Hl6.23:Nl
6.5l; H2Ol8.95CL-(+)-2-(3
Solid A (54.1y) on -methoxy-4''-hydroxy-phenyl)glycine was stirred well and suspended in 1300 ml of 1N HCl and 3500 ml of CHCl.

Since the salt did not decompose in this solution, as much CHCl3 as possible was separated, 00 ml of MIBK3 was added, and the mixture was thoroughly stirred. This MIBK phase was further extracted three times with 200 ml of 1N HCl. The combined HCl extract was simply concentrated to remove the acid distilling solvent and heated under reflux for 1 hour to hydrolyze the ester. The reaction mixture was concentrated to a small volume, cooled in an ice bath, and the crystalline amino acid HCl salt was collected by filtration. 1N of this salt
Recrystallize from 175 nL of HC, warm 500 ml of water, dissolve the solution, quickly filter the solution, adjust the pH to 4.5 (NaOH), and add amphoteric iodine. crystallized. Heat the mixture to a boil? Filter and leave in a cool place to form a crystalline product, L-(+)
-2-(3''-methoxy-4''-hydroxyphenyl)glycine was precipitated. The product was collected by filtration, briefly washed with water, washed with methanol, and dried at 40°C to obtain 9.6y. [α]? 0 = +127.2 (C1, 1NHC
Therefore, the R and NMR spectra matched.

Analysis value for C9HllNO4, H2O: Calculated value: C
l5O. 23; Hl6. O9; Nl6.5l; H2
Ol8.37 measurement value: Cl5O. 53; Hl6. O6;
Nl6.62; H2Ol7.46OD-N-(2-
Sodium methoxycarbonyl-1-methylvinyl)-α-amino-α-(3″-methoxy-4″-hydroxy-phenyl)acetate in 320 ml of methanol
OH3. O2fl(a). 078 mol)) is stirred to give a solution containing (-)-21≧(3″-methoxy-4″).
-Hydroxyphenyl)glycine (0.08 mol) was added, and the mixture was heated under reflux to dissolve 9.6 ml (a) of methyl acetoacetate in 80 ml of methanol. 088 mol) was added over 30 minutes.

After three more reflux distillations, toluene was added at the same rate while methanol was being distilled off to keep the content approximately the same. When the internal temperature reached 100°C, the suspension was placed in an ice-water bath, cooled for 4 hours, filtered, thoroughly washed with toluene, air-dried, and vacuum-dried over P2O5 until a constant weight was obtained. Sodium oxycarbonyl-1-methylvinyl)-α-amino-α-(3″-methoxy-4″-hydroxyphenyl)acetate was obtained. D-(-)-(3-methoxy-4-hydroxyphenyl)-glycine was produced with high purity and high yield by the following method: about 0.06 mol of D-(-
)-2-(3''-methoxy-4''-hydroxyphenyl)glycine was slurried in 100 ml of dioxane.

COCl2 (Phosgene) was passed through the slurry while stirring and maintaining the temperature at 50°C. The total time spent was 3.5 hours. A yellow liquid was obtained. Excess phosgene was purged by passing nitrogen through the solution. Next, add 2 HCl gas to this liquid.
．． Time passed. This liquid was stirred and a small amount of it was diluted with a small amount of ether to form a small amount of crystals, which were added to the liquid as seeds. This solution was stirred for 11 minutes at 20-25°C. The obtained crystalline D-(-)-2-(3″-methoxy-4″-
The product was collected by filtering the slurry of (hydroxyphenyl)-glycine chloride hydrochloride. This filter cake was washed with dioxane and methylene chloride and P2O5 was washed in a vacuum desiccator.
D-(-)-2-(3″-methoxy-4
About 7y of D-(-)-N-(t-butoxycarbonyl)-2-(3"-methoxy-4"-hydroxyphenyl)glycine D was obtained. -(-)-2-(3″-methoxy-4″-hydroxyphenyl)glycine 8.6y(
0.04 mol), magnesium oxide 3.2y (0.08
mol), t-butoxycarbonyl azide 9.7y (
0.068 mol) and 1:1 dioxane-water 240 m
The mixture of Example 1 was heated and stirred at 45-50°C for 2 hours under a nitrogen atmosphere.

The reaction mixture was cooled, diluted with 240 ml of ice water, filtered, and extracted once with tyl acetate. The aqueous phase was acidified to pH 2 and extracted five times with ethyl acetate. Combine the ethyl acetate extracts and add Na2
Drying over sO4 and concentration in vacuo until free of solvent gave 6.3 dt of product as a sticky oil. Decomposition A of 2-(3-methoxy-4-hydroxyphenyl)-glycine (
-)-2-(3-methoxy-4-hydroxyphenyl)-glycine d-10 birch sulfonate 2-(3
-methoxy-4-hydroxyphenyl)glycine 5
．． A mixture of 50 ml of Oy1 glacial acetic acid and 2.5 ml of water was heated to a solution.

Quickly strain the hot liquid and leave it at room temperature for 1 turbidity to remove 1.78y of salt.
was crystallized. It was recrystallized from 15ml of acetic acid and dried at 40°C to obtain 1.54y of (-)-2-(3-methoxy-4-hydroxyphenyl)glycine d-10 monocamphor sulfonate. After partial decomposition at 164-170℃, decomposition 175-180'CO[α]KO=-35.31(
(ClH2O) The combined acetic acid solution was concentrated under reduced pressure to a small volume.

The crystalline solid was filtered and recrystallized from 15 ml of acetic acid.
A second recovery amount of 2.48y was obtained by drying at -. 164-
Decomposes at 170℃.

[α]KO=-32.7 (ClH2O).

B (-)-2-(3-methoxy-4-hydroxyphenyl)glycine(-)-2-(3-methoxy-4
A portion (1.2y) of the first recovered amount of -hydroxyphenyl)-glycine d-10-camphor sulfonate was dissolved in 12ml of water, and the pH of the solution was adjusted to 4.5 with a dilute aqueous NH4OH solution.

The mixture was heated into solution. The solution was cooled first to room temperature and then to 5°C to crystallize the amino acids. The product was filtered, washed briefly with a few drops of water and methanol, and dried at 40°C to obtain 0.37y of (-)-2-(3-methoxy-4-hydroxyphenyl)glycine. 210-21
Decomposes at 2°C.

[α]KO=-137.6(CllNHCl)C9H
Analytical values for 11NO4: Calculated values: Cl54.82; H15.62; N17. lO
Measured value: Cl54.37; H15.9O; Nl7.2l
; H2OlO. 7l.

C(-)-2-(3-methoxy-4-hydroxyphenyl)glycine 2-(3-methoxy-4-hydroxyphenyl)-glycine hydrate 200y,. d-10
- A mixture of 260 y of camphor sulfonate, 21 ml of glacial acetic acid and 100 ml of water was heated to a solution and quickly filtered.

Seeds were added to this solution and allowed to stand at room temperature for 3 days to crystallize salt 76f. This salt was recrystallized from 400ml of acetic acid71
．． It became 0y. During the first recovery of salt? The liquid was concentrated to half and crystallized to obtain 118.5f1.

The product was recrystallized from 500 ml of acetic acid and air-dried (-).
-2-(3-methoxy-4-hydroxyphenyl)
105.2y of glycine d-10 monocamphor sulfonate was obtained. Concentrated NH4OH was added to a solution of the above salt 71y added to a total of 150 ml of water and 150 ml of methanol while stirring.

The mixture soon became thick, but it was heated to 50°C and the NH4
OH was continued to be added dropwise until the pH was 4.5. After cooling the liquid on ice, it was briefly washed with filtered cold 1:1 Me0H and water, washed with cold methanol, and dried under vacuum at 40°C to obtain (-)-2-(3-
Methoxy-4-hydroxyphenyl)glycine 34
．． 5g was obtained. Decomposes at 204-206℃, [α]FO=
-132.4(CllNHCl)C9HllNO4,H
Analytical value for 2O: Calculated value: Cl5O. 23; Hl6
．． O9; Nl6.5l Measured value: Cl49.96; Hl6
．． l2; Nl6.6l.

A mixture of (-)-2-(3-methoxy-4-hydroxyphenyl)glycine (-)-2-(3-methoxy-4-hydroxyphenyl)glycine 9.2f and 50ml of 48% hydrobromic acid for 4 hours. Heat to reflux.

When the solution was cooled, crystals precipitated, so they were collected by filtration and heated to 40°C.
It was dried to obtain 1.8 Da. melting point 248-250'C,
At temperatures above 0°C, it first darkens and decomposes. [α]? 0=-42
．． 1.

(ClH2O)C8Fl9NO4, HBr, ll2H2
Analytical value for O: Calculated value: Cl35. l8; Hl4.
O6;Nl5. l3: FI2Ol3.3O measurement value: C
l35.26; Hl4. Ol;Nl5.32;H2O
It was concluded that this material was a 3:1 composition of the (-) and (+) isomers of 2-(3,4-dihydroxyphenyl)-glycine HBr.

This p liquid was concentrated to a small amount.

Separated crystals? I over-collected the liquor and kept it aside. The crude product was recrystallized from 20 ml of acetic acid, filtered, and washed with methyl isobutyl ketone and anhydrous ether to give white crystalline (-)-2.
3.0y of mono(3,4-dihydroxyphenyl)glycine hydrobromide was obtained. Melting point 106-10g'CO [α
] Pi0=-85.0y(ClH2O)C8l(9N04
, I(Br, Analysis value for H2O: Calculated value: Cl34
．． O6; Hl4.29; Nl4.97; H2Ol6.
37 measurement value: Cl43. O7; Hl4. l7;Nl4.
99; H2Ol6.8O.

The acetic acid solution was concentrated to remove the solvent.

To the oily residue was added 75 ml of methyl isobutyl ketone, and the solution was crystallized initially at room temperature and then in an ice bath. The product was filtered and washed with methyl isobutyl ketone and anhydrous ether to give a white crystalline (-)-2-(3 , 4-dihydroxyphenyl)-glycine hydrobromide (1.5y) was obtained. Melting point 106
-108℃, [α]CO=-84.5H20)C8H9
Analytical values for NO4, lIBr, H2O: Calculated values: C
l34. O6; Hl4.29; Nl4.97; H2O
l6.39 measurement value: Cl33.79; Hl4.3l; N
14.94; H2O, 7.080 The concentrate from the crude HBr salt was concentrated until free of solvent.

Dissolve the crystalline residue in 8 ml of water and adjust the pH of the solution to concentrated NH4O.
When the value was adjusted to 4.5 with an aqueous H solution, zwitterions crystallized.
This mixture was cooled with an equal volume of methanol and diluted ice for 3 minutes. The generated (-)-2-(3,4-dihydroxyphenyl)glycine was filtered, washed briefly with 1:1 Me0H, water and methanol, and dried at 40°C for 2 hours to give 0.53
I got 6y. At temperatures above 220°C, the color first becomes dark and decomposes (indistinct) 234-238°C0 [α]? 0=-158.2
Light (CllNHCl) Analysis value for C8ll9NO4; Calculated value: Cl52.46; Hl4.95; Nl7.6
5 measured value: Cl5l. 82; Hl5. O3;Nl7.7
57-[D-α-amino(3″-methoxy-4″-hydroxyphenyl)acetamide]-3-(1,2
, 3-triazol-5-ylthiomethyl)-. 3-cefemu-4-carboxylic acid 7-amino-3-(1,2,3-
Triazol-4-ylthiomethyl)-3-cefemu 4
-carboxylic acid 4.27f (0.01365 mol), 1,
1,1,3,3,3-hexamethyldisilazane 6.64
f (0.041 mol) and methylene chloride 2007 rL
The mixture was heated under reflux for 4 hours to obtain a clear liquid.

After standing overnight at room temperature, the solution was removed under reduced pressure. Dissolve the residue in 150mt of tetrahydrofuran and keep the solution at 0-5°C before use.
It was cooled to N-methylmorpholine 3.06ml (0
．． 0273 mol) and isobutyl chloroformate3.
48 mt (0.0273 mol) in tetrahydrofuran 3
D-(-)-N-(t-butoxycarbonyl)-2"-(3"-methoxy-4"-hydroxyphenyl)glycine 8.1f1 (0.0273 mol) in 00ml
was added to a -15°C solution containing

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

After 1 serving, remove the cooling bath and pour the mixture into 2 servings. Stirred for more than an hour.

250 ml of water was added to the reaction mixture, and the mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. 42% concentrated aqueous liquid
The mixture was acidified with phosphoric acid and extracted three times with ethyl acetate. During the first extraction, the mixture was filtered through P to remove insoluble materials. The combined ethyl acetate extracts were washed once with water, dried over Na2sO4, and concentrated to dryness. The residue was triturated with anhydrous ether to give a solid 2.8y. A solution of 2.8 g of solid and 50 ml of 97% formic acid was stirred at room temperature for 2 hours, and then the formic acid was distilled off under reduced pressure.
The residue was azeotroped with toluene to completely remove formic acid. The residue was triturated with wet ethyl acetate and triturated over P2O5 at 65°C.
Vacuum dry for 7 hours [D-α-amino(3″-methoxy-4″-hydroxyphenyl)acetamide]-
1.42V of 3-(1,2,3-triazol-4-ylthiomethyl)-3-cefemu-4-carboxylic acid was obtained.
Gradually decomposes at temperatures above approximately 165℃. IR and NMR spectra matched. 71 [-D-α-amino(3″-methoxy-4″-hydroxyphenyl)acetamide]-
3-(1,2,3-triazol-4-ylthiomethyl)
-3-cefemu-4-carboxylic acid is also called BL-Sf)89.

Compounds of the present invention combine aldehydes with the structure: R2-CHO, where R2 is as previously defined, and with the formula: (
In the formula A, . R1 and R3 are as defined above.

) is produced by reaction with cephalosporin. In a preferred embodiment, the carbon bearing the α-amino group is D
Has a configuration. The latter compounds having the formula are prepared by general and sometimes special methods published in the following patents:
US Patent No. 3641021, No. 3899394 US Patent No. 3855213, No. 386738 South African Patent No. 73/4055 No. No. 2500386 (Farm Doc 49692W) Belky Patent No. 814
No. 727 (Farmdoc 82562V) West German Patent No. 2
No. 404,592 (Farmdoc 57268) An alternative method for making the amphoteric cephalosporins used herein as starting materials is to replace the side chain acid with the appropriate p-hydroxy-2-
Phenylglycine (which may bear further substituents and the α-amino group therein is suitably protected upon acylation in the conventional manner), for example as previously described in U.S. Pat. No. 3759904 and No. 3
Either make 3-thiolated cephalosporins using 2-phenylglycine or tetrazol-acetic acid as in No. 850,916, or make 7-monosubstituted cephalosporin acids and then replace the 3-acetoxy group with the desired thiol. This is the method.

Examples include U.S. Pat. Nos. 375,701 and 3757.
Please refer to No. 015. The following BL-S64O is 7-[D-α-amino-α-(p-hydroxyphenyl)
Acetamide]-3-(1,2,3-triazol-5-
It is also called cephatridine.

Regarding those propylene glycates, see 1 and 2 above.
- Refers to propylene glycol solvate. BL-S64
3 is 7-[D-α-amino-α-(p-hydroxyfninyl)acetamide]-3-(2-methyl-1,3,
It refers to 4-thiadiazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid and is also known as cefaparol. l The following examples are intended to illustrate and not limit the invention.

Example 1 BL-SlO52: 2-fulpuraldehyde and BL-
Manufacturing structure of sodium salt of reaction product of S64O: BL
-SlO52 method (1) 2.7 ml of 2-fulpur aldehyde (3.13 V; 1
．． 1 equivalent).

(2) Add 15y of BL-S64O methanol adduct and add 40% sodium hydroxide at the same time.
Keep H between 5.5 and 6.0.

(Do not raise the pH above 6.5.) A pale orange solution or near liquid is obtained. (3) Remove particles, pyrogens, and bacteria by passing the solution through a suitable material.

It is necessary to complete steps 1 and 2 within 2 hours. (4) After making the solid lyophilic for a long time, keep the solid at 50-56°C under a two-bridge vacuum.

The obtained solid is Kanichi-SlO52. (BL-SlO5
The solution of step 2 or step 3 can be precipitated from 15-20 volumes of sterile isopropanol. )BL-
Properties of SlO52 (1) Biological analysis = 775-800n1cgh9 (2
) IR-NMR2 (a) Well determined and consistent.

(b) Two products, 40% cycloadduct, 60% acyclic adduct, are poured in about 60m91ml of D2O.

(c) β-lactam and 3-triazole remain intact.

(3) Solubility 400mgIm1 or more (4) Paper strilp chromatography method BL-S6
Single zone in Rf of 4O (concentration 0.2m91m1)
3(5) Liquid chromatography method (
Concentration: 1m91ml) Time: 012 Free BL-S64 %: 69.274.294.5 (6) Analysis results*.
AAB 45% 10 serum + Protus 50%** Dilution rate of overnight Protus culture (1) 79.5% of BL-S64O
The content was adjusted.

In other words, the numbers are lower, ie improved. This adjustment was also made in the tests described below. Alternatively, a higher dose was used to obtain an equivalent dose. Compounds were made up in 0.01% phosphate buffer.

BL-S64O was used as a standard for all compounds. The compounds were prepared in Tween-CMC.

Ran-S64O was used as a standard for all compounds. FO manufacturing method (1) Add 5-formyl 2 to 75 ml of water (6 times)
-Add 9.0f of French sulfonic acid sodium salt (Fiπ1stop?1-S)''31'4a) and the compound is 0.0
in 1% phosphate buffer.

BL-S64O was used as a standard for all compounds. System No. BL-SlO52 and Ran-S64O's I
Vapor chromatograms were examined on mouse urine collected 0-2 hours and 2-4 hours after M administration. Two identically located spots were observed in all cases except that of the standard (which was not administered to mice, giving a single identical spot for each of BL-S64O and BL-SlO52). Ta. This means that the derivative is completely derived from the parent compound B.
It showed hydrolysis to L-S64O and the expected metabolites. Example 2 Reaction product of BL-S64O and 5-formyl-2-furan sulfonic acid sodium salt (BL-SlO27)
Formula (BL.-SlO27) (2) Stir the solution vigorously and sprinkle 20f (1 equivalent) of 1,2-propylene glycol adduct into BL-S64 over 1 liter while adjusting the pH to 6-7.0. adjust.

A liquid or something close to a liquid. (3) Adjust the liquid to pH6-7. The mixture was stirred at 55-60°C for 10 minutes and then cooled to 4-8°C. A small amount of starch is produced. (4) The mixture is stirred once at 4-8°C and then filtered. (5) While vigorously stirring the isopropanol 1e, add the licorice solution over a period of 5 minutes.

A large amount of starch is produced. Stir the mixture for 5 minutes. (6)
Filter the solid and wash with 200ml of isopropanol.56
Vacuum dry for 2 hours at ℃.

(7) Dissolve the solid in 60 ml of water at 4-6°C (remove a small amount of insoluble material by filtration.

) Make the deep water lyophilic for 24 hours. Yield 23y: Biological yield = 89% Properties of BL-SlO27 (1) Biological analysis as BL-S64O = 724m
cg1m9 (theoretical value = 750rT1Cg1m9) (2)
Solubility=>500mgImt (3) IR-NMR: Consistent with structure.

In 70m91ml the compound is present as 80% cyclic derivatives and 20% acyclic derivatives.

(4) Vapor strip and liquid chromatography methods show that the product exists as free BL-S64O in 0.2 and 1.0 m91 ml aqueous solutions.

(5) MIC bacterial spectrum is the same as that of BL-S64O.

(6) Mouse blood concentration after oral and intramuscular administration is immediately -S
It is the same as that of 64O.

(7) Concentration of this product: 250007TL, Cg1ml
The aqueous solution should be kept at room temperature for at least 3 days or at 6°C (freezer).
It is stable (retains sufficient biological activity) for 14 days, making the solution suitable for oral use.

(8) Analysis results (9) Melting point > 130°C (gradual decomposition) ** Dilution rate of overnight Protus culture (1) This value was recalculated because BL-S64O in the sample was only 65%: i.e. The numbers were lower, ie improved.

(2) BL-S64O=71 [D-α-amino-α1 (
p-hydroxyphenyl)acetamide]-3-(1
,2,3-triazol-5-ylthiomethyl)-3-cephemu-4-carboxylic acid.

Compounds were made in Tween-carboxymethylcellulose and eight mice were used for each compound.

1BL-S64-JyokD-α-amino-α-(p-hydroxyphenyl)acetamide]-3-(1,2,
Preparation method for 3-triazolyl-5-isothiomethyl)-3-cepheme-4-carboxylic acid (1) o-Folmylphenooxyacetic acid (/?, ℃H2COONa3757yl9) in 10 ml of water
Make a slurry in 1 and add 4N NaOH with vigorous stirring to pH 7. Let it be a solution of O.

It was used as the third standard.

BL-SlO27 is a water-soluble derivative produced when BL-S64O is reacted with sodium furfuralsulfonate.

The production potency is 724mcgIm9 with BL-S64 talk. 250, 25 and 107 as BL-SlO27
7!9, Aqueous solutions containing BL-S64 talk/ml should be frozen (
4° C.) or at room temperature without appreciable loss of at least two bridge activity.

1BL-S4O-JyokD-α-amino-α-(p-hydroxyphenyl)acetamide]-31(1,2,
3-Triazol-5-ylthiomethyl)-3-cefemu-4-carboxylic acid was used as a standard.

Compounds were dissolved in 0.01 phosphate buffer.

Example 3 BL-S64O methanol adduct 2y(
4NNa0 at the same time while adding 1 equivalent of
Add H to maintain pH at 6-6.5.

It becomes liquid or something close to liquid. Filter the J(3) solution and leave it at room temperature.

(4) The liquid is made lyophilic for 2 $f to obtain the product as a solid.

Properties of solid products (1) IR-NMR (70mgIm1) is consistent with the structure.

Triazolyl and β-lactam remain the same). (2) Vapor strip and liquid chromatography methods show that BL-S64O does not contain any aldehydes at 0.2 and 1 m91 ml.

(3) Water solubility > 400m91mt (4) Melting point > 145°C (decomposed) * AAB 45%, serum 5% + Protus 50% ** Dilution rate of overnight Protus culture (1) BL-S64O (:1)
The content was adjusted to 68%.

(2) The content of BL-S4O was adjusted to 67%. That is, the numerical value is lower, ie improved. This adjustment or the test described below was also performed. Alternatively, a higher dose was used to give an equivalent dose. Compounds were made up in 0.01 phosphate buffer.

BL-S64O was used as a standard for all compounds. The compounds were prepared in Tween-CMC. BL-S64O was used as a standard for all compounds. Compounds were made up in 0.01 phosphate buffer. BL-S4O was used as a standard for all compounds. BL-SlO27, 1048 and 6
40 IM administrations (10m91k9 and 50m91k9
) System NO. 9 (butyl acetate, n-butanol, diglacial acetic acid: water = 80:15:40:24) using a descending chromatography method. Two identical spots were observed in all cases except for the standard (not mouse or mouse) which showed a single similar spot. This shows that the two derivatives are the parent compound (BL-S6
4O) was completely hydrolyzed. Example 4 Process for producing the reaction product of 5BL-S64O and O-benzaldehyde sulfonic acid (BL-SlO55) (1) Add O-benzaldehyde sulfone r to 10 ml of water.
Dissolve 87m9 of sodium salt.

(2) While stirring the solution vigorously, add 2y of BL-S64O methanol adduct (1 equivalent) to 4N at the same time.
Suspend the solution while keeping the pH of Na0H'8 at 6.5.

(3) The liquid is filtered, left at room temperature for 1 hour, and then liquefied for 2 hours to obtain the desired product as a solid.

Product properties (1) IR-M interpretation = consistent with well-determined structure.

(2) Water solubility=>400mg/Ml. (3) Analysis results (4) Star i-1 analysis = 800n1cg1mg (5) IR-
NMR = (a) β-lactam and triazole moieties remain intact.

(b) The compound is not recognized as a cycloadduct.

(6) Vapor strip chromatography method: BL-S
A double zone is recognized at Rf of 64O. (7) Liquid chromatography method: (8) Water solubility 400 m91 mt or more (9) Numberni This product is called BL-SlO55.

(10 Melting point> 150°C (decomposition) * AtSB 45% 10 Serum 5% 10 Protus mentioned above 50% ** Dilution rate of overnight Protus culture (1) Adjusted to 65% content of BL-S64O.

That is, the numerical value is lower, ie improved. This adjustment was also performed in the following test. Alternatively, a larger amount was used to obtain an equivalent dose. Compounds were made up in 0.01% phosphate buffer.

Values are the average of three tests. (1) BL-S64O was used as a standard.

The compound was created in Tween-CMC. Values are the average of two tests. (1) BL. -S64O was used as standard.

Compounds were made up in 0.01% phosphate buffer. (
1) BL-S64O was used as a standard.

0-2 hours and 2 hours after administration of BL-SlO55 and 640
- System No. for mouse urine collected in 4 hours. 9
(Butyl acetate di-n-butanol diglacial acetic acid: water = 8
Superchromatograms were performed to examine antibiotically active metabolites using the descending chromatography method (0:15:40:24). A single identical spot was observed in all cases. This indicates that this derivative is completely hydrolyzed to the parent compound (BL-S64O).
*Example 5BL-SlO27:BL-S6
Preparation of reaction product of 4O and 5-formyl-2-furansulfonic acid: BL-SlO27 Production method of BL-SlO27 (1) 5-formyl-2-furansulfonic acid sodium salt (0HC-7, LSO3Na) 9v to 60
When mixed vigorously with water at -65°C, most of it dissolves.

(2) While stirring the liquid vigorously, sprinkle 20y of BL-S64O propylene glycol adduct over 1 particle and add 40% NaOH at the same time to make the liquid pH 6.5-7.
．． Keep it at 0.

(Do not raise the pH above 7.2.) It becomes a liquid or something close to a liquid. (3) 55% of solution with pH 6.5-7.0
After stirring for 1 time at -60°C, cool and stir for 1 time at 4-8°C.

(4) Remove a small amount of insoluble matter by filtration.

(5) Add the mustard liquid* (see Note 1) to the isopropanol in 1e while stirring vigorously.

An amorphous precipitate forms. Continue stirring for 5 minutes.

(6) Filter the precipitate, wash with 100ml of isopropanol, and vacuum dry at 50-56°C for 1 hour.

(7) Dissolve this solid in 60 ml of water and cool to 4-6°C.

If there is a very small amount of precipitate, separate it. (8) Pass the solution at room temperature through a suitable mesh to remove particles, pyrogens and bacteria.

Steps 7 and 8 must be completed within 4 hours. (9) After lyophilization under sterile conditions, 18-2 times 5
Heat under vacuum to 0-56°C.

The yield of BL-SIO27 is about 22-24 g.

*Note 1 (Step 5) Random-S64O methanol adduct 18.7 instead of BL-S64O propylene glycol adduct
If y is used, the solution can be cooled to 4-6° C. and filtered with P to directly make it lyophilic as described in Step 8-9. Characteristics of disorder-SlO27 (1) Biological analysis = 724 mcg/M9 (2) Biological yield = 85-95% (3) 1R-NMR (a) Consistency regarding structure.

(b) about 80% cyclic in D2O in 70m91m1;
20% acyclic.

(C) Isopropanol approximately 0.05 mol (4) Vapor strip chromatography method (0.2m91Tnt)
No evidence of derivatives at 100% BL-S64O.

(5) Liquid chromatography method 0'91mtpH7 in phosphate buffer) (6) Water solubility >400m91m1 (7) Analysis results: (8) Mouse blood concentration = Oral and intramuscular concentration are approximately B
Same as L-S64O propylene glycol adduct.

BL-S64O appeared in the urine, but no derivatives were present. (9
) (a) Solid stability = 10% loss or less at 56°C for 1 month.

(b) Liquid stability = 2 between at least two bridges at room temperature
50125 and 10W! Less than 10% loss of activity of 91ml BL-S64O. QO melting point> 130°C (gradual decomposition) Example 6 Material: 1f (A). 00217 mol) BL-S64O,
429 mg (a). 0217 mol) 5-furfuralsulfonic acid sodium salt 217 mg (4). 0434 mol) triethylamine, 1.2y (0.0434 mol)
Potassium 2-Ethylcaproate (KEH) Method To a suspension of BL-S64Oly in 8 mt of methanol was added 217 m9 of triethylamine (TEA) and 429 mg of 5-furfuralsulfonic acid.

When the mixture was heated to reflux, all the solids immediately dissolved. 3 liquid
Heat for KEHl. Added 2y. The separated yellow salt was collected and washed with methanol. Salt in desiccator P2C
! ，Dried on top. Yield 800T19. C23H17H
Analysis value for 608S2NaK4H20: Calculated value: C
l37.54; Hl3.4l; Nlll. 42 measurements:
Cl37.3O; H13.3l; NllO. l8 melting point>
The reaction was carried out as above using sodium 2-ethylcaproate in place of the decomposed KEH at 140°C.

This salt did not precipitate from methanol, so the liquid was filtered! The solution was diluted with isopropyl alcohol. The precipitated solid was collected and washed with isopropyl alcohol. Since this salt is hygroscopic, it was vacuum dried over P2O5 to obtain 800 mg. Decomposes at melting point of 140℃ or above. C23Hl7N6O8s
Analysis value for 3Na2: Calculated value: Cl42.65:H
l2.78; Nll3.65. Measured value: Cl4l. O3
;Hl3.94;NllO. 54. The pH of the solution prepared by dissolving this sample in water was 6.5. Vapor strip analysis in buffer and human serum was performed.

The sample showed only one point corresponding to BL-S64O. Both samples showed a water solubility of 1 ml or more at pH 6.5. The vapor strip chromatography method uses human serum at pH 7 and human serum at pH 7.
It was shown to be completely hydrolyzed to -S64O in a mixture of 1 molar phosphate buffer.

Vapor strip biographs were performed in the following manner. Samples were added to 0.1 MPH7 phosphate buffer and 50
500γIm in PH7 mixed human serum at 0γIml
It was dissolved to a concentration of 1. A 10μ' sample of BL-S64O and the above product was added to White NO. Spotted on a 112 inch strip of l vapor, this was mixed with 80% butyl acetate and 15% n-butanol. Developed in acetic acid 4 and water 24 system at 2rC for 16 hours. Air dry the strip B. subtilis A. T. C. C. 6633 on an agar plate planted with seeds. RfO. in all samples after 3 hours, 1 hour, 3 hours and 6 hours. 3 single zones were shown.

High pressure liquid chromatography at a concentration of 1 mg ImL showed complete hydrolysis to parent BL-S64O after 3 cycles. 0.

01M sodium acetate PH4L-methanol 8 volumes Flow rate 0
．． μ bonderback (BO) using a fluid phase of 52 mt/min
ndapack) Cl8 (Waters Associates)
The sample was chromatographed on the column.

Detection was by U in 354 μml. The sample was dissolved in the fluid phase at a concentration of 1 m9 Mt, and 2μ was injected into BL-S6.
4O eluted at 18 minutes and aldehyde at 6 minutes. Quantification of BL-S64O and 5-fluoromylfuran sulfonic acid was performed using p-toluenesulfonic acid as an internal standard. Example 7 BL-SlO57:B
Formula for producing sodium salt of the reaction product of L-S643 and 2-furaldehyde: BL-SlO57 Method (1) BL-S643,3Fl2Oly at 40-45°C
Make a slurry in 10ml of water.

(2) 2-furaldehyde 0.25y (1.25 equivalent)
Add.

(3) While vigorously stirring the liquid, add 1N sodium hydroxide to adjust the pH to 7.5, and it will become a solution or something close to a liquid in 5 minutes.

(4) Cool the liquid to 22-24°C to remove particles, pyrogens, and bacteria. pass the time.

(5) Under sterile conditions, it is made lyophilic for an extended period of time to obtain disordered -SIO57.

(BL-SlO57 can also be obtained by precipitating the sterile solution of step 4 with 15 to 2 volumes of sterile isopropanol.) Properties of BL-SlO57 (a) Bioanalysis (with cefatridine as standard) = 7
59rncg1m9.

(b) IR=β-lactam as is, well determined.

(c) NMR= (1) Well determined and consistent.

(2) Approximately 75% cycloadduct *B
Production method of L-SlO58 (1) 10ml of water at 40-45℃
First, 5-formyl-2-furanyl sulfonic acid sodium salt is slurried to form a solution or something close to a liquid.

(2) BL-S643,3H2 while stirring the liquid vigorously.
Ol(d) Solubility in water 400m9'ml or more.

(e) Vapor strip chromatography = 0 and 1 hour, mainly 1 zone at Rf of BL-S643 at 3rC. (Concentration = 0.2Tngem1) (f
) Liquid chromatography = PH6 within 1 hour at room temperature. 100% hydrolysis in l buffer. (Concentration 1TfL
91ml) (g) MP = 180°C (shrinkage) Decomposed at 200°C (5) Analysis results: Example 8 BL-SlO58: Reaction product of BL-S643 and sodium 5-formyl-2-furan sulfonate Formula: B
Sprinkle one drop of L-SlO58y into the solution, and at the same time add 1N sodium hydroxide to maintain the pH of the solution at 7-7.5.

It becomes a solution or something close to it within 5 minutes.

(3) Cool the liquid to 20-23°C and pass through a suitable material to remove particles, bacteria and pyrogens.

(4) Make the liquid lyophilic for 48 hours.

The obtained powder is 58% of Ranichi SlO. (Sterile BL-SIO
58 can also be obtained by precipitating the solution from step 3 from 15-2 volumes of sterile isopropanol. ) Properties of BL-SlO58 (a) Biological analysis (cefatridine as standard) = 6
85mcg1m9.

(b) IR-NMR (1) Well determined and consistent.

(2) β-lactam and 3 side chain intact.

(3) Cycloadduct 90% (approximately 600 m91 m1 in D2O
(c) Vapor strip chromatography = BL-S-643 at 37 mC and 1 h.
Mainly 1 zone in Rf.

(d) Liquid chromatography (1 mg I in PH6 buffer)
m1) (e) Analysis results: (f) Melting point 180-200°C (decomposition) *, AAB 45% serum + Protus 50%**
Dilution rate of overnight Protus culture (1) 8 of BL-S643
The content was adjusted to 0%.

(2) The content was adjusted to 59% of BL-S643. That is, the numerical value is lower, ie improved. This adjustment was also made in the following test. Alternatively, a larger amount was used to obtain the desired dose. System No. 1 for descending chromatography method. 9 (butyl acetate, di-n-butanol, diglacial acetic acid: water = 80:15:40:24) to detect antibiotically active metabolites using BL-SIO.
Vapor chromatograms were examined on mouse urine collected 0-2 hours and 2-4 hours after LM administration of 57, 1058, and 643.

Claims (1)

[Claims] 1 Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A represents hydrogen, hydroxy, methyl or methoxy, R^1 represents hydrogen, sodium or potassium, and R^2 represents carboxyl, 2-furyl, or an aliphatic, aromatic or heterocyclic group to which a strongly acidic group is also attached in the form of its sodium or potassium salt, and R^3
is 1,2,3-triazol-5-yl, tetrazol-5
-yl, 1,2,4-thiadiazol-5-yl, 1,3
, 4-thiadiazol-2-yl, 1,3,4-oxadiazol-3-yl, or 1,2,4-triazol-5-yl
yl, each of which is substituted with 1 or 2 lower alkyl groups having 1 to 4 carbon atoms, or unsubstituted. ) A compound characterized by the following. 2 R^2 is 2
-furyl, 2-furan-5-sulfonic acid, phenyl-
2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy- 4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxyphenyl,
The compound according to claim 1, which is 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 3. The compound according to claim 1, wherein R^2 is 2-furyl. 4. The compound according to claim 1, wherein R^2 is 2-furan-5-sulfonic acid. 5 Claims 1 and 2 in which R^1 is sodium
, 3 or 4. 6 Claims 1, 2, wherein R^1 is potassium
A compound according to any one of Items 3 and 4. 7. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A represents hydrogen, hydroxy or methoxy, R^1 represents hydrogen, sodium or potassium,
and R^2 represents an aliphatic, aromatic or heterocyclic group to which a carboxyl or 2-furyl or strongly acidic group is attached in the form of its sodium or potassium salt. ) The compound according to claim 1, which is represented by: 8
R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-3
-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxyphenyl, 8. The compound according to claim 7, which is 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 9. The compound according to claim 7, wherein R^2 is 2-furyl. 10. The compound according to claim 7, wherein R^2 is 2-furan-5-sulfonic acid. 11 Claim 7, in which R^1 is sodium,
A compound according to any one of Items 8, 9, or 10. 12 Claims 7 and 8 in which R^1 is potassium
, 9 or 10. Compound 13. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents hydrogen, sodium or potassium, and R^2 represents carboxyl or 2-furyl, or the strong acid group is in the form of its sodium or potassium salt. represents an aliphatic, aromatic or heterocyclic group bonded with ). 1
4 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxy-methoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxy 14. The compound according to claim 13, which is phenyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 15 Claim 13 in which R^2 is 2-frills
Compounds described in Section. 16. The compound according to claim 13, wherein R^2 is 2-furan-5-sulfonic acid. 17 Claim 15 in which R^1 is sodium
or a compound according to item 16. 18. The compound according to claim 15 or 16, wherein R^1 is potassium. 19 Claim 15 or 1 in which R^1 is hydrogen
Compound according to item 6. 20. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A represents hydrogen, hydroxyl, methyl or methoxy, R^1 represents hydrogen, sodium or potassium, and R^2 is carboxyl or 2-furyl. or represents an aliphatic, aromatic or heterocyclic group to which a strong acid group is bonded in the form of its sodium or potassium salt. 2
1 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxyphenyl 21. The compound according to claim 20, which is enyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 22 Claim 20 in which R^2 is 2-frills
Compounds described in Section. 23. The compound according to claim 20, wherein R^2 is 2-furan-5-sulfonic acid. 24 Claim 20 in which R^1 is sodium
, 21, 22 or 23. 25 Claim 20, in which R^1 is potassium,
A compound according to any one of Items 21, 22, or 23. 26. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents hydrogen, sodium or potassium, and R^2 represents carboxyl or 2-furyl or a strong acidic group as well as its sodium or potassium salt form. represents an aliphatic, aromatic or heterocyclic group bonded with ). 2
7 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxy 27. The compound according to claim 26, which is phenyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 28 Claim 26 in which R^2 is 2-frills
Compounds described in Section. 29. The compound according to claim 26, wherein R^2 is 2-furan-5-sulfonic acid. 30. The compound according to claim 26 or 27, wherein R^1 is sodium and has the D configuration. 31. The compound according to claim 26 or 27, wherein R^1 is potassium and has the D configuration. 32. The compound according to claim 26 or 27, wherein R^1 is hydrogen and has a D configuration. 33. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A represents hydrogen, hydroxy or methoxy, R^1 represents hydrogen, sodium or potassium,
and R^2 represents an aliphatic, aromatic or heterocyclic group to which a carboxyl or 2-furyl or strongly acidic group is attached in the form of its sodium or potassium salt. ) The compound according to claim 1, which is represented by: 3
4 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxy 34. The compound according to claim 33, which is phenyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 35 Claim 33 in which R^2 is 2-frills
Compounds described in Section. 36. The compound according to claim 33, wherein R^2 is 2-furan-5-sulfonic acid. 37 Claim 33 in which R^1 is sodium
, 34, 35 or 36. 38 Claim 33, in which R^1 is potassium,
A compound according to any one of Items 34, 35, or 36. 39. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents hydrogen, sodium or potassium, and R^2 represents carboxyl or 2-furyl or a strong acid group in the form of its sodium or potassium salt. The compound according to claim 1, which represents a bonded aliphatic, aromatic or heterocyclic group. 4
0 R2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-3
-Sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxyphenyl , 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 41 Claim 39, in which R^2 is 2-frills
Compounds described in Section. 42. The compound according to claim 39, wherein R^2 is 2-furan-5-sulfonic acid. 43. The compound according to claim 41 or 42, wherein R^1 is sodium and has the D configuration. 44. The compound according to claim 41 or 42, wherein R^1 is potassium and has the D configuration. 4
5. The compound according to claim 41 or 42, wherein R^1 is hydrogen and has a D configuration. 46. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A represents hydrogen, hydroxyl, methyl or methoxy, R^1 represents hydrogen, sodium or potassium, and R^2 is carboxyl or 2-furyl. or an aliphatic, aromatic or heterocyclic group to which the strongly acidic group is also attached in the form of its sodium or potassium salt. 4
7 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxylphenyl 47. The compound according to claim 46, which is oxyphenyl, 3-carboxyphenyl, methanesulfonic acid, or methanedisulfonic acid. 48 Claim 46 in which R^2 is 2-frills
Compounds described in Section. 49. The compound according to claim 46, wherein R^2 is 2-furan-5-sulfonic acid. 50 Claim 46 in which R^1 is sodium
, 47, 48 or 49. 51 Claim 46, wherein R^1 is potassium,
Compound 052 according to any one of Items 47, 48 or 49
．． Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents hydrogen, sodium or potassium, and R^2 represents carboxyl or 2-furyl or a strong acidic group as well as its sodium or potassium salt form. represents an aliphatic, aromatic or heterocyclic group bonded with ). 5
3 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)-vinylphenyl, carboxyl, 2-carboxylphenyl 53. A compound according to claim 52 which is oxyphenyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 54 Claim 52 in which R^2 is 2-frills
Compounds described in Section. 55. The compound according to claim 52, wherein R^2 is 2-furan-5-sulfonic acid. 56. The compound according to claim 54 or 55, wherein R^1 is sodium and has the D configuration. 57. The compound according to claim 54 or 55, wherein R^1 is potassium and has the D configuration. 58. The compound according to claim 54 or 55, wherein R^1 is hydrogen and has a D configuration. 59. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A represents hydrogen, hydroxyl, methyl or methoxy, R^1 represents hydrogen, sodium or potassium, and R^2 is carboxyl or 2-furyl. or an aliphatic, aromatic or heterocyclic group to which the strongly acidic group is also attached in the form of its sodium or potassium salt. 6
0 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxy 59. A compound according to claim 59 which is phenyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 61 Claim 59 in which R^2 is 2-frills
Compounds described in Section. 62. The compound according to claim 59, wherein R^2 is 2-furan-5-sulfonic acid. 63 Claim 59 in which R^1 is sodium
, 60, 61 or 62. 64 Claim 59, in which R^1 is potassium,
60, 61 or 62. 65. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents hydrogen, sodium or potassium, and R^2 represents carboxyl or 2-furyl or a strong acidic group as well as its sodium or potassium salt form. represents an aliphatic, aromatic or heterocyclic group bonded with ). 6
6 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxy 66. The compound of claim 65 which is phenyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 67 Claim 65 in which R^2 is 2-frills
Compounds described in Section. 68. The compound according to claim 65, wherein R^2 is 2-furan-5-sulfonic acid. 69. The compound according to claim 67 or 68, wherein R^1 is sodium and has the D configuration. 70. The compound according to claim 67 or 68, wherein R^1 is potassium and has the D configuration. 71. The compound according to claim 67 or 68, wherein R^1 is hydrogen and has a D configuration. 72. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A represents hydrogen, hydroxyl, methyl or methoxy, R^1 represents hydrogen, sodium or potassium, and R^2 is carboxyl or 2-furyl. or an aliphatic, aromatic or heterocyclic group to which the strongly acidic group is also attached in the form of its sodium or potassium salt. 7
3 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxylphenyl 73. The compound according to claim 72, which is oxyphenyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 74 Claim 72 in which R^2 is 2-frills
Compounds described in Section. 75. The compound according to claim 72, wherein R^2 is 2-furan-5-sulfonic acid. 76 Claim 72 in which R^1 is sodium
, 73, 74 or 75. 77 Claim 752 in which R^1 is potassium
, 73, 74 or 75. 78. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents hydrogen, sodium or potassium, and R^2 represents carboxyl or 2-furyl or a strong acidic group as well as its sodium or potassium salt form. represents an aliphatic, aromatic or heterocyclic group bonded with ). 7
9 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)-vinylphenyl, -carboxyphenyl , 3-carboxyphenyl, carboxyl, methanesulfonic acid or methanedisulfonic acid. 80 Claim 78 in which R^2 is 2-frills
Compounds described in Section. 81. The compound according to claim 78, wherein R^2 is 2-furan-5-sulfonic acid. 82. The compound according to claim 80 or 81, wherein R^1 is sodium and has the D configuration. 83. The compound according to claim 80 or 81, wherein R^1 is potassium and has the D configuration. 84. The compound according to claim 80 or 81, wherein R^1 is hydrogen and has a D configuration. 85. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A represents hydrogen, hydroxyl, methyl or methoxy, R^1 represents hydrogen, sodium or potassium, and R^2 is carboxyl or 2-furyl. or an aliphatic, aromatic or heterocyclic group to which the strongly acidic group is also attached in the form of its sodium or potassium salt. 8
6 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxy 86. The compound of claim 85 which is phenyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 87 Claim 85 in which R^2 is 2-frills
Compounds described in Section. 88. The compound according to claim 85, wherein R^2 is 2-furan-5-sulfonic acid. 89 Claim 85 in which R^1 is sodium
, 86, 87 or 88. 90 Claim 85, wherein R^1 is potassium;
86, 87 or 88. 91. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents hydrogen, sodium or potassium, and R^2 is a fatty acid to which a strong acidic group is also bound in the form of its sodium or potassium salt. The compound according to claim 1, which represents a group group, an aromatic or heterocyclic group, or a carboxyl or 2-furyl group. 9
2 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxyphenyl, 3-hydroxy-4
-carboxyphenyl, 4-(2'-carboxy)
Claim 91: Vinylphenyl, carboxyl, 2-carboxyphenyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid
Compounds described in Section. 93 Claim 91 in which R^2 is 2-furil
Compounds described in Section. 94. The compound according to claim 91, wherein R^2 is 2-furan-5-sulfonic acid. 95. The compound according to claim 93 or 94, wherein R^1 is sodium and has the D configuration. 96. The compound according to claim 93 or 94, wherein R^1 is potassium and has the D configuration. 97. The compound according to claim 93 or 94, wherein R^1 is hydrogen and has a D configuration. 98. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A represents hydrogen, hydroxyl, methyl or methoxy, R^1 represents hydrogen, sodium or potassium, and R^2 is carboxyl or 2-furyl. or an aliphatic, aromatic or heterocyclic group to which the strongly acidic group is also attached in the form of its sodium or potassium salt. 9
9 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-
3-sulfonic acid, 2-carboxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxy 99. The compound of claim 98 which is phenyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. Claim 9 in which 100 R^2 is 2-frills
Compound according to item 8. 99. The compound of claim 98, wherein 101 R^2 is 2-furan-5-sulfonic acid. 102 Claim 9 in which R^1 is sodium
8, 99, 100 or 101. 103 Claim 98 in which R^1 is potassium
, 99, 100 or 101. 104 ・Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents hydrogen, hydroxyl, methyl, or methoxy, and R^2 represents carboxyl or 2-furyl or the strong acid group also represents its sodium or The compound according to claim 1, which represents an aliphatic, aromatic or heterocyclic group bonded in the form of a potassium salt. 1
05 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-3-sulfonic acid, 2-carbo Oxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxyphenyl, 3-carboxyphenyl, methanesulfone 105. The compound of claim 104 which is an acid or methanedisulfonic acid. 106 R^2 is 2
- A compound according to claim 104 which is furyl. 107 The compound according to claim 104, wherein R^2 is 2-furan-5-sulfonic acid. 108 A compound according to claim 106 or 107, wherein R^1 is sodium and has the D configuration. 109 The compound according to claim 106 or 101, wherein R^1 is potassium and has the D configuration. 110 The compound according to claim 106 or 107, wherein R^1 is hydrogen and has a D configuration. 111 ・Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A represents hydrogen, hydroxy, methyl, or methoxy, R^1 represents hydrogen, sodium, or potassium, and R^2 represents carboxyl or 2 - represents an aliphatic, aromatic or heterocyclic group to which furyl or a strongly acidic group is also attached in the form of its sodium or potassium salt. 1
12 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-3-sulfonic acid, 2-carboxylic acid Oxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxyphenyl, 3-carboxyphenyl, methanesulfone 112. The compound of claim 111 which is an acid or methanedisulfonic acid. 113 Claim 1 in which R^2 is 2-furil
A compound according to item 11. 114. The compound of claim 111, wherein R^2 is 2-furan-5-sulfonic acid. 115 Claim 1 in which R^1 is sodium
11, 112, 113 or 114. 116 Claim 11 in which R^1 is potassium
1, 112, 113 or 114. 117・Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents hydrogen, sodium or potassium, and R^2 represents carboxyl or 2-furyl or a strong acidic group as well as its sodium or potassium salt. The compound according to claim 1, which represents an aliphatic, aromatic or heterocyclic group bonded in the form of. 1
18 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-3-sulfonic acid, 2-carbo Claims that are oxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, methanesulfonic acid or methanedisulfonic acid A compound according to paragraph 117. 119 Claim 1 in which R^2 is 2-furil
A compound according to item 17. 120. The compound of claim 117, wherein R^2 is 2-furan-5-sulfonic acid. 121. The compound according to claim 119 or 120, wherein R^1 is sodium and has the D configuration. 122. A compound according to claim 119 or 120, wherein R^1 is potassium and has the D configuration. 123. The compound according to claim 119 or 120, wherein R^1 is hydrogen and has a D configuration. 124 (a) R^2-CHO, where R^2 represents carboxyl, 2-furyl, or an aliphatic, aromatic or heterocyclic group to which a strongly acidic group is also attached in the form of its sodium or potassium salt ) and (b) -CH_2-S- at the 3-position.
R^3 group (where R^3 is substituted with 1 or 2 lower alkyl groups having 1 to 4 carbon atoms or unsubstituted 1,
Represents 2,3-triazol-5-yl. ) with 7-
Equimolar condensation product with a 3-thiolated amphoteric cephalosporin having an α-substituted -α-amino-aceto-amide group in position and having a water solubility of less than 125 mg/1 ml in the zwitterionic form. The compound according to claim 1, which is 125 (a) Formula R^2-CH
(b )3-position-CH_2-
S-R^3 group (where R^3 represents 1,2,3-triazol-5-yl substituted with 1 or 2 lower alkyl groups having 1 to 4 carbon atoms or unsubstituted) 125 mg/ml in its zwitterionic form with an α-substituted -α-amino-acetamido group in the 7-position.
A compound according to claim 1 which is an equimolar condensation product of sodium or potassium with a 3-thiolated amphoteric cephalosporin having a water solubility of: 1
125. The compound according to claim 125, wherein 26 R^2 is 2-furan-5-sulfonic acid. 127 (a) Formula R^2-CHO, where R^2 represents an aliphatic, aromatic or heterocyclic group to which 2-furyl, carboxyl or a strongly acidic group is also attached in the form of its sodium or potassium salt ) and 5-formyl-2-furan sulfonic acid, o-benzaldehyde sulfonic acid, 4-methoxybenzaldehyde-3-sulfonic acid, 4-hydroxybenzaldehyde-3-sulfonic acid, o- and p-formyl Milphenooxyacetic acid, 5-formylsalicylic acid, p-formylcinnamic acid, grilloxalic acid,
an aldehyde with an acidic group which is phthalaldehydic acid, p-formylbenzoic acid, acetaldehyde sulfonic acid sodium salt or acetaldehyde disulfonic acid sodium salt; (b) -CH_2-S-R^3 at the 3-position;
group (where R^3 is substituted with 1 or 2 lower alkyl groups having 1 to 4 carbon atoms, or unsubstituted 1, 2,
Represents 3-triazol-5-yl. in an equimolar amount with a 3-thiolated amphoteric cephalosporin having an α-substituted -α-amino-acetamido group in the 7-position and having a water solubility of not more than 125 mg/ml in its zwitterionic form. A compound according to claim 1 which is a sodium or potassium salt of the condensation product. 128. The compound of claim 127, wherein the aldehyde is 5-formyl-2-furansulfonic acid. 129. (1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼II (In the formula, A represents hydrogen, hydroxyl, methyl or methoxy, R^1 represents hydrogen, sodium or potassium, and R^3 is 1 , 2,3-triazol-5-yl, tetrazol-5-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1
,3,4-oxadiazol-3-yl or 1,2,4-
Triazol-5-yl, each of which groups may be substituted with 1 or 2 lower alkyl groups having 1 to 4 carbon atoms or may be unsubstituted. ) An aqueous suspension of an amphoteric cephalosporin or its solvate or hydrate represented by the formula: R^2-CHO (where R^2
represents an aliphatic, aromatic or heterocyclic group to which carboxyl or 2-furyl or a strongly acidic group is also attached in the form of its sodium or potassium salt. ) and the desired formula in the solvent by treatment with enough water-soluble sodium or potassium base to raise the pH of the reaction mixture between 5.5 and 8: ▲ Mathematical formulas, chemical formulas, tables, etc. ▼ I ( where A, R^1, R^2 and R^3 are as defined above.) and (2) recovering said salt from solution. A method for producing a compound represented by the above formula I. 130 Claim 1 wherein the amphoteric cephalosporin starting material of formula II is in the form of a methanol or propylene glycol solvate or sesquihydrate
The method described in Section 29. 131. The method of claim 129 or 130, wherein the base is sodium or potassium hydroxide. 132. The method of any of claims 129, 130, or 131, wherein the desired compound is recovered from the solvent by a philophilization method. 133. The method of any of claims 129, 130 or 131, wherein in step (2) the desired compound is precipitated by adding to solution an organic solvent in which the salt thereof is insoluble. 134. The method of claim 133, wherein the organic solvent is isopropanol. 135 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-3-sulfonic acid, 2-carbo Oxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-
135. The method according to any one of claims 129 to 134, which is carboxy)vinylphenyl, carboxyl, 2-carboxyphenyl, 3-carboxyphenyl, methanesulfonic acid or methanedisulfonic acid. 136 Claim 1 in which R^2 is 2-frills
The method according to any one of Items 29 to 135. 137. The method of claims 129 to 135, wherein R^2 is 2-furan-5-sulfonic acid. 138. The method according to any of claims 129 to 137, wherein R^3 is 1,2,3-triazol-5-yl. 139 (1) 7-[D-α-amino-α-(p-hydroxyphenyl)acetamide]-3-(1,2,3
-triazol-5-ylthiomethyl)-3-cephem-
It is a solvent for triethylamine salt, a furfural reaction product of 4-carboxylic acid, and is an alkali metal represented by the formula IV: ▲ Numerical formula, chemical formula, table, etc. ▼IV (In the formula, R^1 represents sodium or potassium.) 7-[D-α-amino-α-(p-hydroxyphenyl)acetamide]-3-(1,2,
A suspension of 3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid or its solvate or hydrate is prepared, and (2) furfural and sufficient triethylamine are added to the suspension. 7-[D-α-amino-α-
(p-hydroxyphenyl)acetamide]-3-(
1,2,3-triazol-5-ylthiomethyl)3-cephem-4-carboxylic acid to form a triethylamine salt of the furfural reaction product, and (3) add a sodium or potassium base soluble in the solvent to form a solution. expression desired from
Formula I characterized in that it precipitates an alkali metal salt of I
Method for producing compounds with V. 140 7-[D-α-amino-α-(p-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid starting material in methanol or in the form of a propylene glycol solvate or sesquihydrate. 141. The method according to claim 140, wherein the solvent in step (1) is methanol. 142. The method of claim 141, wherein the sodium or potassium salt in step (3) is sodium 2-ethylcaproate or potassium 2-ethylcaproate. 143 7-[D-α-amino-α-(
p-hydroxyphenyl)acetamide]-3-(1
,2,3-triazol-5-ylthiomethyl)-3-
A suspension of cefem-4-carboxylic acid methanol solvate is formed and (2) a molar excess of furfural and sufficient triethylamine are added to the suspension to form a suspension of 7-[D-α-amino-α-(p -Hydroxyphenyl)acetamide]-
forming the triethylamine salt of the furfural reaction product of 3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, and (3) sodium or potassium 2-ethylcaproate in isopropanol. Formula IV is characterized in that the desired alkali metal salt of Formula I is precipitated from the solution by adding a solution of ▲Mathematical formulas, chemical formulas, tables, etc.▼IV (In the formula, R^1 represents sodium or potassium. ) A method for producing the compound shown in 144. The method of claim 143, wherein the solution obtained in step (2) is filtered before the precipitation in step (3). 145. The method according to claim 144, wherein the solution obtained in step (2) is treated with activated carbon before the filtration step. 146 (1) 7-[D-α-amino-α
-(p-hydroxyphenyl)acetamide]-3-
(1,2,3-triazol-5-ylthiomethyl)-3
- making a suspension of cefem-4-carboxylic acid or its solvate or hydrate; (2) adding furfural to the suspension and sufficient amount to raise the pH of the reaction mixture to between about 5.5 and 8; Add a soluble sodium or potassium base to an appropriate amount of the solvent and (3) form the reaction mixture into formula IV: ▲Mathematical formula, chemical formula, table, etc. ▼IV (In the formula, R^1 represents sodium or potassium.) A method for producing a compound represented by the above formula IV, characterized in that a desired product represented by the formula IV is recovered. 147 7-[D
-α-amino-α-(p-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid starting material solvated with methanol or propylene glycol 147. The method of claim 146, in the form of a compound or a sesquihydrate. 148. The method of claim 147, wherein the inert organic solvent is methanol. 149 Claim 14, wherein the base used in step (2) is sodium or potassium 2-ethylcaproate.
The method described in Section 8. 150 (1) 7-[D-α-amino-
α-(p-hydroxyphenyl)acetamide]-3
-(1,2,3-triazol-5-ylthiomethyl)-
forming a suspension of 3-cephem-4-carboxylic acid methanol solvate; (2) adding a molar excess of furfural to the suspension and a sufficient amount of a solution of sodium or potassium 2-ethylcaproate in isopropanol; 147. The method of claim 146, wherein the pH of the reaction mixture is brought up to between about 5.5 and 8, and (3) the desired product of formula IV is recovered by filtration. 151. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (In the formula, A represents hydrogen, hydroxy, methyl, or methoxy, R^1 represents hydrogen, sodium, or potassium, and R^2 represents carboxyl or 2-furyl. or an aliphatic, aromatic or heterocyclic group in which the strongly acidic group is also in the form of its sodium or potassium salt, and R^3
is 1,2,3-triazol-5-yl, tetrazol-5
-yl, 1,2,4-triazol-5-yl, 1,3,
4-thiadiazol-2-yl, 1,3,4-oxadiazol-3-yl or 1,2,4-triazol-5-yl, each of which has 1 to 4 carbon atoms, a lower alkyl group; Substituted with 1 or 2 or unsubstituted. ) and a pharmaceutically acceptable solid, water-soluble organic acid in an amount such that the pH of the formulation when reconstituted with water is between about 5 and 6. An antibacterial agent suitable for reconstitution with water for use as a parenterally administrable antibiotic formulation, characterized in that it is present. 1
52 R^2 is 2-furyl, 2-furan-5-sulfonic acid, phenyl-2-sulfonic acid, 4-methoxyphenyl-3-sulfonic acid, 4-hydroxyphenyl-3-sulfonic acid, 2-carbo Oxymethoxyphenyl, 4-carboxymethoxyphenyl, 3-hydroxy-4-carboxyphenyl, 4-(2'-carboxy)vinylphenyl, carboxyl, 2-carboxyphenyl, 3-carboxyphenyl, methanesulfone The antibacterial agent according to claim 151, which is an acid or methanedisulfonic acid. 153 Claim 1 in which R^2 is 2-frills
The antibacterial agent according to item 51. 154 The antibacterial agent according to claim 151, wherein R^2 is 2-furan-5-sulfonic acid. 155 Claims 151-154 wherein the solid organic acid is present in an amount of about 4-6% by weight of the compound having formula I
The antibacterial agent described in any of the sections. 156. The antibacterial agent according to any one of claims 151 to 154, wherein the solid organic acid is citric acid.