JPS5921695A - Cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 and R2 are H or lower alkyl; R3 is H, lower alkyl or carbamoyl) and its salt. EXAMPLE:The syn isomer of 7beta-[2-(2-aminothiazol-4-yl)-2-{(pyrazol-3-yl)-methoxyimino}acetamid o]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate. USE:Antibacterial agent. It has antibacterial activity even to Pseudomonas aeruginosa resistant to conventional cephem compounds. PROCESS:The objective compound is prepared by acylating the compound of formula II with the compound of formula III (R4 is H or amino-protecting group used in the synthesis of beta-lactam compound and eliminable by hydrolysis or reduction, e.g. trityl, formyl, tert-butoxycarbonyl, etc.; R5 is H, lower alkyl, or amino-protecting group used in the synthesis of beta-lactam compound and eliminable by hydrolysis or reduction, e.g. trityl, etc.), and if necessary, eliminating the protecting group of the resultant compound of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a cefrorosvorin derivative represented by the following general formula or a salt thereof.

(I) In the formula, R1 represents hydrogen or lower alkyl, Tortoise represents hydrogen or lower argyl, and R3 represents hydrogen, lower alkyl or carbamoyl.

The thiazole moiety which is -m in the structure of the compound of the present invention and its synthetic intermediates is the 2-aminothiazole compound (A) and the 2-
The tautomer of the iminothiazoline compound (B) (though it is thought to have the 11'I structure) is not expressed throughout this specification (in the jq structure or its name as a 2-amino-thiazole compound, but it is limited to does not mean.

(p,) (B) Similarly, when the pyrazole moiety, which is a part of the structure of the compound of the present invention and its synthetic intermediate, is substituted at the 3-position, the tautomeric hlIII structure ( C) and (D), and these will be explained throughout this specification by using the structure (G) as a representative for convenience, but this is not meant to be limiting.

(C) (C1) Furthermore, the compound (I) of the present invention having an oximino group (/c-N-0-) and its synthetic intermediate.

Syn-isomer (E) and anti-isomer (F) exist.

One or a mixture thereof can be obtained. However, in general, the syn isomer is superior in antibacterial activity.

9 In this specification, when the syn isomer and the anti isomer are explained in one expression for convenience, the two-part structure (G)
It is expressed as

In addition, in the one-part structure Ql, methylene is pyrazole (1-1
) Next, the method for producing the compound (1) of the present invention will be described in detail.

formula (R2 is the same as above. R4 is hydrogen or trityl.

Indicates a protecting group for an amine group used in the synthesis of β-lactam compounds, such as formyl, tertiary butoxycarbonyl, or haloalkoxycarbonyl, which can be hydrolyzed and removed by sulfate reduction.

Turtle is hydrogen, lower alkyl, trityl, formyl, tert-butoxycarbonyl or haloalkoxycarbonyl, etc., which can be removed by hydrolysis or halo-reduction.
- Indicates a protecting group for an amino group used in the synthesis of a lactam compound. ) A compound represented by formula 1 is acylated with a compound represented by formula 2 to obtain a compound represented by formula 2. This acylation reaction.

It can be carried out in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide, the so-called Vilsmeier reagent produced from dimethylformamide and phosphorus oxychloride, and the like. Acylation can also be carried out after converting the compound (II) into a reactive derivative, such as an active form such as an acid halide or an active ester. Suitable examples include acid chloride, N
14- such as -hydroxysuccinimide, N-hydroxyphthalimide, ■-hydroxypendutriazole, etc.
Examples include esters with hydroxy compounds. This reaction involves methylene chloride, tetrahydrofuran, and ethyl acetate.

It is carried out in dimethylbormamide or other solvents that do not adversely affect the reaction. Further, these reactions are appropriately selected depending on the 01 (class) of the compound (■) used.

From the compound (■) thus obtained, the compound represented by formula (1) can be obtained by removing the protecting group, if necessary. The elimination reaction of the protecting group is hydrolysis,
This can be done by reduction etc. Hydrolysis with acid is one of the most common methods and is the preferred method for removal of protecting groups such as trityl, polmyl, and tert-butoxycarbonyl. As the acid used.

Examples include organic acids such as formic acid and trifluoroacetic acid, and inorganic acids such as hydrochloric acid. In this case, a solvent that does not adversely affect the reaction may be used, and the reaction may be carried out in the presence of a scavenger such as anisole or thioanisole.

Hydrolysis with a base is used to remove an acyl group, and an inorganic base such as sodium hydroxide or an organic base such as triethylamine is used. Further, in the case of a haloalkoxycarbonyl group such as trichloroethoxycarbonyl, the protecting group can be removed by a reduction reaction.

Alternatively, using the above-mentioned compound (II).

By acylating a compound represented by the formula 0 (X represents a halogen such as chloro or bromine, and R6 represents a protecting group for carboxylic acid used in the synthesis of β-lactam compounds such as tertiary butyl or benzhydryl). An intermediate represented by formula (2) is obtained. The acylation reaction is performed on the compound (n
) can be carried out in the same manner as when compound Oil) is acylated.

Next, one set of intermediate side) ] When reacted with the compound represented by, formula 1♀ The compound is obtained. This reaction is acetone.

Dichloromethane and acetonitrile can be used in solvents that do not adversely affect the reaction.

Next, compound (I) can be obtained by converting the sulfoxide (/S→O) of intermediate 611) into sulfide <:S) and then removing the protecting group. The reaction of deoxidizing sulfoxide to form a sulfide compound can be carried out using reagents such as phosphorus trichloride, phosphorus tribromide, acetyl chloride and stannous chloride, and acetyl chloride and potassium iodide.

Further, the reaction for removing the protecting group can be carried out under the same conditions as in the case of removing the protecting group from compound (IV).

Furthermore, if a compound represented by formula 2 () (R7 represents lower alkyl) is acylated using compound (II) to obtain a compound represented by formula 1, then the protecting group is removed. A compound represented by formula 5 can be obtained. This compound (2
) and the above-mentioned compound (4) can also be reacted to obtain the compound represented by formula (I). this(
The reactions of 9) and (4) may be carried out in the presence of potassium iodide, potassium thiocyanate, or the like. It is also advantageous to carry out the reaction in an aqueous solvent with a pH of 5 to 8.

The compound of formula (1) is an alkali metal, an alkaline earth metal or a core conductor thereof, such as a hydroxide.

It is also possible to obtain a form in which the 4-position carboxylate becomes an alkali metal or alkaline earth metal salt by reacting with a carbonate or the like by a conventional method.

Furthermore, the compound of formula (1) can be obtained as a suitable acid addition salt, such as -iiL acid salt or bicyclic salt, or as a salt with an organic acid such as formic acid or maleic acid. You can get it.

Compound (l[) used in the synthesis of compound (I) can be obtained by, for example, reacting a compound represented by formula 1 with a compound represented by formula 1. Reaction solvents include water, ethanol, etc.
Any solvent that does not affect the reaction can be used.

The above compound (xi) can be prepared by reacting a compound represented by formula (1) with +9-hydroxyphthalimide, or by reacting a compound represented by formula (2) with a reagent such as triphenylphosphine and ethyl azodicarboxylate. React using 2
After obtaining the compound represented by the formula, it can be obtained by treating this compound with hydrazine or hydrochloric acid.

Further, after performing a reaction to introduce a captive group into a compound (XM) in which R5 is hydrogen.

For example, by treatment with hydrazine or the like, the corresponding compound (Xlll) in which ns is trityl, formyl, tertiary butoxycarboxyl, etc. can be obtained.

Compound of the present invention 11. P exhibits a broad antibacterial spectrum and high antibacterial activity, but is particularly resistant to conventional cephem compounds.
It also has antibacterial activity against S. and Aeruginosa.

The following table compares the antibacterial activity of some compounds of the present invention with that of cefotaxime.

Antibacterial spectrum Minimum inhibitory concentration (M I Ci p9 /lnl, bacterium ffi 1 o6
/vat) Compound AI7β-(2-(2-aminothiazol-4-yl)-2-((pyrazol-3-yl)
methoxyimino)acetamide), -5-(1-pyridinio)methyl-3-cephem-4-carboxylad (syn isomer) Compound B nia β-(2-(2-aminothiazole-4-
yl)-2-((pyrazol-4-yl)methoxyimi/)acetamido)-a-(1-pyridinio)methyl-3
-Cephem-4-carboxilade (syn isomer) Example 1; 7β-(2-(2-aminothiazole-4-
yl)-2-((pyrazol-3-yl)methoxyimino)acetamide)-L-(1-viridinio)methyl-8
-Cephem-4-rupoxylate (syn isomer) [Step I] Ethanol solution 2 in which 0.289% of sodium 3-(7talimidoxymethyl)pyrazole metal was dissolved
0+111, N-hydroxyphthalimide 1 under water cooling
．． 969. Then, 3] 7dezole hydrochloride 765 +
After adding ug, stir at room temperature for 2.5 hours. After evaporation of the solvent, water was added to the residue and extracted with chloroform. The chloroform layer was washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is washed with ether to obtain the title compound having a melting point of 166-168°C.

Elemental analysis CI 211cr Calculated value for Ha Os Ci 59.2+3. II 8.73. N
17.28 actual measurement value C58,91,H3,84,N
17.21 (Engineering ml [)] 0.589 of the compound obtained in 8'-(phthalimidoxymethyl-N-tritylpyrazole [Process]) was dissolved in 20 methylene chloride.
Suspend in triphenylmethyl chloride 0.019
and 0.85 m of triethylamine (!) at room temperature,
Stir for hours. The reaction solution was washed with a 10% citric solution #1 and then with saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent and washing the residue with ether, the melting point is 177-179°.
The title compound o, so9 of C is obtained.

IRνKBrcnr': 1790.1735ax aw-uyn (aDats, ppm) 5-25 (2
H+ 81uoci(z)6.52 ([1,6,
J・-211z, pyrazole 4th position 11) 7.0 to 7.
3 (1(3H, [11,) lytyl and H at the 5-position of pyrazole) 7.72 (4H, s, phthalimide) [Step m]
0.869 of the compound obtained in 3-(aminooxymethyl)-N-tritylpyrazole [Step 1] was dissolved in ethanol 201
1, add 90 m9 of hydrazine hydrogen,
Heat and stir at 70°C for 1 hour. After filtering off the precipitated insoluble matter, the solvent is distilled off. Ethyl acetate was added to the residue, and insoluble matter was filtered off again.

The filtrate was washed with saturated saline and dried with anhydrous sodium hydroxide. After distilling off the solvent, washing the residue with ether gives a melting point of 1.
The title compound 0664 is obtained at 05-110°C.

IRy can, 3400.1?20,1485
゜ax ■440 GW-NMR (C11Gj3+ ppm) 4.72 (
2H,s, No-C1H2-)6.27 (I H,
eI, J-2H7,, H at position 4 of pyrazole) 7.1~
7.4 (16H, m, ) lytyl and H at position 5 of birazole) [Step ■) 2-(2-tritylaminothiazol-4-yl)-2-((N-)ditylpyrazole-
0.629 of the compound obtained in 3-yl)methoxyimino)acetic acid [Step 1] was suspended in 20 tl of ethanol, (
2-) Dithylami/thiazol-4-yl)glyoxyl f3J, 0.759 is added and stirred at room temperature for 3 hours. After removing the solvent, add ethyl acetate to the residue, wash with brine containing dilute salt M, then wash with saturated brine, and dry with IJum. After washing the residue with ether, the title compound 1 having a melting point of 143-14.6°C is obtained.
．． Get 289.

IRνKBr(Ill-': 1720.1520[
IIax CW-NMrl (GDC13*ppm)5.42
(211,s, -N-0-CII2)6.05
(1)1. d, J-211z, H at position 4 of pyrazole) 6.53 (IH, s, H at position 5 of thiazole) 7.
0-7.4 (m,) lytyl and pyrazole 5) 1)
[Step V) 7β-(2-(2-aminothiazole-
4-yl)-2-((pyrazol-8-yl)methoxyimino)acetamide]-8-(1-pyridinio)methyl-3-cephem-4-carboxilade (syn isomer) Dimethyl dimethyl acetate under water cooling Formamide 0.77-
and 0.01 - of phosphorus oxychloride to prepare a reaction mixture of 1:811 O -. Compound bag obtained in [Step ■]) 1.
20G' was dissolved in 5 ml of ethyl acetate, and the reaction mixture 3.0- was added under water cooling.

Stir for 50 minutes. This reaction solution was mixed with 7β-amino~・3
-(1-Pyridinio)methyl-3-1hi7emu 4-carboxilade dihydrochloride 1.19 and bis(trimethylsilyl)acetamide 1.2 ml acetonitrile 8-
It is added to the solution under ice cooling, and after 15 minutes, the mixture is returned to room temperature and stirred for 2 hours. Brine was added to the reaction solution, ethyl acetate was distilled off under reduced pressure, and the mixture was extracted with chloroporm. Dry over anhydrous sodium sulfate, evaporate the solvent, and wash the residue with ether.

1.659 of a light brown powder is obtained. 98% formic acid 2QflIt and concentrated hydrochloric acid 1- are added to this powder, and the mixture is stirred at room temperature for 45 minutes. Remove the precipitated solid by filtration.

Concentrate the filtrate under reduced pressure. The aqueous solution of the residue was diluted with Diaion I.
Column chromatography using P-20 as a carrier (
I
If purified with N: 10% methanol), the title compound 1
Obtain 20 m9. Melting point 150-170°C (min M) Elemental analysis Calculated value for 0zzllzo+IaOsS2 bow i20 Ci, 30. Ha, (17, N 20.
06 Actual value Ci 47.25. 114.32.
N10.64IRvKI3rcm-': 3400
〜2800.1770゜IllIll660.1(ilO,1525 F T -NMR(D20.ppm, 200M
Hz) 3.12 (IH, (1, J-18Hz, C
2-+1)3,Q O(111,d, J=18Hz
, 02-II) 5.28 (IH, d, J-5H
z, CaH)5.26 (2H,s, N-0-
0112)5.8 (3(ill, d, J-14H
z, coz◎) 5.57 (Ill, d, J-1
411z, an, r-◎)5.88 (1)(; d
, J-5H2, C7-+1 )6A 7 (IH, (
1, J-211z, H at position 4 of pyrazole) 6.98 (
IH,s, H at the 5th position of thiazole)? , f13 (monthly 1.
d, J-2Hz, H at position 5 of pyrazole) 8.10 (
2+1. t, J-7111, II at the 3.5-position of pyridine) 8.59 (1) [, t, J-711z, H at the 4-position of pyridine) 8.96 (2H, d, J-711
z, H at the 2,6-position of pyridine) Example 2 near β-(2-
(2-aminothiazol-4-yl)-2-((pyrazol-3-yl)methoxyyl/)acetamide)-3-
(1-Pyridinio)methyl-8-cephem-4-carposilad (syn isomer) [FUI] Tertiary butyl 7β-(2-(2-tritylaminothiazol-4-yl)-2-((N- Tritylpyrazol-8-yl)methoxyimino)acetamido-8-bromomethyl-1-oxide-3-cephem-4,-carboxylad (syn isomer) Phosphorus pentachloride 42ofn9't=m in chloroform 70-, -25 Cooled to ~-80°C. Added compound 1.1i19 obtained in step ① of Example 1, and stirred at the same temperature for 3012 minutes. Triethylamine Q, 5w4 was added and 8 minutes later, 7β-
Hydrochloric acid IM of amino-3-bromomethyl-1-oxide-3-7femu-4-carboxylic acid tertiary butyl ester
Aio■ and triethylamine 0.28+i7 dichloromethane solution were added and stirred at the same temperature for 40 minutes. After adding ice-cooled chloroborum 50I+It, wash with water. Then 3
% sodium bicarbonate vesicles sequentially washed with saturated salt water. After drying with anhydrous sodium sulfate, dry. The residue was purified by column chromatography (silica gel '459, solvent: chloroform 2, then chloroform:acetic acid ethyl ester - 4:1) to obtain the title compound 1.929.

I RyKBrc+n-': I B 00ax F T -tJ M R (G D C1s T ppm
+ 200 MHz) 1.58 (9H,s, tertiary butyl) 2.13? , 8.31 (respectively IH
, (1, J-1811z, (4-H)4.89 (I
H, (1, J-6H2, 06-H15,441 (2IT
, s, -0-0) (2) 6.10 (LH, dd,
J-8Hz, 6Hz, c, -111 [Process ■]
Tertiary butyl 7β-(2-(2-aminothiazole-
4-yl)-2-((N-tritylpyrazol-3-yl)methoxyimino)acetamide)-3-(1-pyridinio)methyl-1-oxide-3-cephem-4-carboxilade bromide (syn isomer ) Compound 1.907 obtained in [Step 1] was dissolved in 5Qmt of acetone, and pyridine 1.907 was dissolved in 5Qmt of acetone under water cooling. After adding 7 tnl, 1 at room temperature.
Stir for 4 hours. The solvent was distilled off and the residue was dissolved in acetone 3-. After adding about 40 ml of ether with stirring, the precipitate was triturated to give 1.539 ml of the title compound.

FT-NMFI (cDc13.ppm, 200M
Hz) 1.57 ('J H,s, tertiary butyl)3.
70.4.13 (I H, d, J-18H respectively
z, □ a2-H)5.40 (2H,s, -001
12-)6.25 ([1, dd, J-8Hz, 8
Hz, 07 H) [Step 1 [) 7β-(2-(2
-aminothiazol-4-yl)-24(pyrazole-
3-yl)methoxyimino)acetamide]-3-(1-
Pyridinio)methyl-3-cephem-4-carboxilade (synh (pillar)) Compound 1.1 (1' obtained in Step II) was dissolved in 15 ml of dimethylformamide and cooled to 5F1~GooC. Under stirring, the bicyclic ratio Add the neighbor 0.2117, -4,0
Stir for 30 minutes at ~-50°C. -50 to -60 again
Then, add chloroform to 50°C.

Wash twice with saturated saline and then with water. After drying organic J.5'r with anhydrous sulfuric acid → -thorium, the solvent was distilled off. The residue was suspended in 9 ml of Adisol and stirred at -30 to -40°.
Add 6♂l of trifluoroacetic acid at C. Then, the mixture was stirred at room temperature for 30 minutes under water cooling for 3:11 J J'B. The reaction solution was poured into cooled isopropyl ether 3Qud, and the precipitate was collected by filtration. Powder obtained in this way (5s o rn9)
Dissolved in water 18-, add 3% sodium bicarbonate water under water cooling,
Adjusted to p+17-8. It is placed on a column of HP-2070τLt and adsorbed.

Powder obtained from 5% tetrahydrofuran eluate (3422
119) by high-speed liquid pomatography (carrier: Micro Bonder Pack eta (manufactured by Waters), solvent = 1
Purification with 5% methanol) yielded 100 m9 of the title compound.
get. TLC and FT-NMR of this product were consistent with the compound obtained in Example 1.

Example 8 Near β-(2-(2-aminothiazole-4-
yl)-2-((pyrazol-4-yl)methoxyimino)acetamide)'-'3-(1-pyridinio)methyl-3-cephem-4-rupoxylate (syn isomer) [Step 1) 1-) Ethyl dithylvirazole-4-carboxylate 0.789 ethyl pyrazole-4-carboxylate was dissolved in 15-methylene chloride and iM triphenylmethyl 1.
569 and triethylamine 0.86- are added, and the mixture is stirred at room temperature for 1.5 hours. The reaction solution was washed with lθ% citric acid, then saturated saline, and anhydrous sulfuric acid. After drying with IJum,
Evaporation of the solvent yields the title compound 2,459 as an oil.

CW-NMR (GDC131ppm)], 80 (311,t, J-7Hz, -cH2
C1!3)4.26 (2H,q, J-7Hz,
-CI2GII3) 7.1 to 7.4 (15H, m,
) lythyl) 7.92 (IH,s, 1 at the 3rd position of pyrazole)
1) 8.08 (H(,s, 1 at the 5th position of pyrazole]) [
Process■]4. -Hydroxymethyl-1-tritylpyrazole Lithium aluminum hydride 0.4.29 was suspended in tetrahydrofuran 3Q+nt, and under water cooling, a tetrahydrofuran solution of compound 2.459 obtained in Step I was added.
Heat to reflux at ℃ for 1 hour. from now on.

Sex with water. Solvent evaporation. The residue was dissolved in ethyl acetate and washed with brine. After drying with sulfuric acid (anhydrous sulfuric acid), the solvent is distilled off, and the residue is washed with ether to give a melting point of 181-184°C.
(7) Prepare the title compound 1,539.

(3W-NMR (cncla, ppm) 4.51 (2
H, s, QC; H7-)7, '1~7.4 (16
H, rn, trityl and pyrazole 3rd position (1) + 1) 7
．． 63 (Ill, S, pyrazole 5th position (7)H) [
]2L[)4-(phthalimidoxymethyl)-
With 1-tritylpyrazole [Step ■]? Compound 1.519 was dissolved in 3 Qmt of tetrahydrofuran to give 0.789 of N-hydroxyphthalimide. ) 1.26 ml of liphenylphosphine and 0.849 ml of ethyl azodicarbonate were sequentially added at room temperature,
Stir for 30 minutes. After evaporation of the solvent, the residue is purified by column chromatography using silica gel as a carrier (Fl/Ethyl:Benzene-1:4) to yield the title compound 1.842 having a melting point of 186-188°C.

Elemental analysis Calculated value for G3rII2sN303 G
76.68. H4, 78, N 8.66 actual value
C76,90,! (4,1)4. N 8.64IR
v""c+n-': 1780.1720ax GW-NMR (cDcJ3.ppm) 5.12 (2H, 3, NOCiH2) 7.0-7.3
(1511, m, ) 7.51 (Ill,
s, H at position 3 of pyrazole) 7.70 (III, s
, I()7.78 (41i, S, phthalimide) at the 5th position of pyrazole [Step ■] 4-amineoxymethy; v
-1-) 0.869 of the compound obtained in lytylpyrazole [Step
FurdJ saze to nl, hydrazine hydra-1 90
(2) was added and stirred at 70''C for 1 hour. The precipitated crystals were removed by filtration, and the solvent was distilled off. Chloroporm was added to the residue, and insoluble matter was removed by filtration again.

Wash the filtrate with saturated saline. Anhydrous sulfuric acid) If dried over IJum and distilled off the solvent, the melting point is 138-18.6°C.
0.71 g of the title compound is obtained.

GW-NMR (CDC13, ppm) 4.58 (2H, s, N0GH2-7, (1-7.
4 (161-1,rn, )rityl pyrazole 8th position 11)7167 (1)1. S, pyrazole 5th position σ
Month I) (Engineering 11V) Compound obtained in 2-(2-)ditylaminothiazol-4-yl)-2-((1-)ditylpyrazol-4-yl)methoxyimino)acetic acid [Step 1] 0. 719 was suspended in 20 ethanol and 1 nail, (2
-) 0.75 g of dithylaminothiazol-4-yl)glyoxyl fi is added in small portions over a period of 4 hours. After removing the solvent, the residue was dissolved in chloroform and dried over anhydrous sodium sulfate. After evaporating the solvent, wash the residue with ether.
0.829 of the title compound is obtained, melting point 130-135°C.

IRvKBrcm-': 1720.1505ay CW-NMR(GDC;Isrpp"
)4.98 (2II, s, N0O112-)6.
40 ([1,s, thiazole 5th position II) 7.1~
7. a (m, )rityl) 7.36 (s, H at the 3rd position of pyrazole) 7.61 (1
) Iy sr H at position 5 of pyrazole) [Step M) 7β
-(2-(2-amithiazol-4-yl)-2-(
(pyrazol-4-yl)methoxyimino)acetamide)-8-(l-pyridinio)methyl-8-cephem-4
-Carboxilald (syn isomer) Compound 0.80 mg obtained by suspending 280 mg of phosphorus pentachloride in 20- of methylene chloride and cooling to -30°C [Step V]
Add a methylene chloride solution of G+, sonomama (7)fEr
Stir for 20 minutes at 1 degree. This reaction solution was cooled on ice.
β-amino-3-(l-pyridinio)methyl-3-cephem-di-carboxylade dihydrochloride 0.759.
Bis(trimethylsilyl)acetamide 1.2 vnl
and acetonitrile, and stirred for 8 hours.

Dilute the reaction solution with chloroform and wash with saturated saline. #
After drying with lu sodium sulfate, the solvent was distilled off and the residue was washed with ether to obtain light brown powder 1.129. 98%
Add to a mixture of formic acid 12- and concentrated hydrochloric acid Q, Q ml under water cooling.
Add the above powder, return to room temperature, and stir for 1 hour. Precipitated crystals are removed by filtration and concentrated under reduced pressure. aqueous solution of the residue.

High performance liquid chromatography using Diaion HP-20 (100 m7) as a carrier (Jr% tetrahydrofuran) followed by high performance liquid chromatography (carrier: Partsil (Wara) manufactured by Yon Co., Ltd.).

Purification using 15% methanol (solvent: 15% methanol) yields the title compound. Melting point 150-165°C (decomposition) Elemental analysis C2
2 Horse ONB 0S 82・2-) Calculated value for lI20 C45, 12, H4, 30, N 19.14 Actual measurement value C45, 29, H41, 22, N 10.25KB
r −1 rnν cm: 340 Q~3100.1110
゜ax 1660, 1605 F T -N M n (D20 + ppm + 2
00 MHz) 8.1.5 (IH, d, J=11
HIz, 02H) 3.60 (L H, d, J-1
8Hz, C2If )5.21 (211,B, -
NOC112) 5.22 (Ill, d, J-51
1z, 06-H) 5.39 (111, d, J-1
4Hz, 0j32 @ )5.58 (1)(,d,
J-14112,C! ! 2-@)5.84 (Il
l, 6. J-5H2,0711) 7.01 (Il
l, 8. H at position 5 of thiazole) 7.78 (2H,s
, H at position 3.5 of pyrazole)8.14 (2)1. t
, J-711z, H at pyridine 3.5 position) 8.62
(LH, t, J-7Hz, H at position 4 of pyridine) 8.9
1 (2H, d, J-'H1z, H at the 2,6 position of pyridine) Example 4 near β-(2-(2-aminothiazole-
4! -yl)-2-(Cpyrazol-3-y/I/)methoxyimino)acetamide)-3-(4-rubamoyl-1-pyridinio)methyl-8-cephem-4-carboxilade (syn isomer) [Step ■] Tertiary butyl 7β-(2-(2-ami/
thiazol-4-yl)-2-((N-tritylpyrazol-8-yl)methoxyimino)acetamide)-'1
-(4-carbamoyl-1-pyridinio)methyl-1-
Oxide-3-cephem-4-carboxylade bromide (syn isomer) Compound 1.509 obtained in step ① of Example 1 was dissolved in methylene chloride, and phosphorus pentachloride 0.429 was dissolved under cooling at -40°C.
and stir at -20 to -80°C for 20 minutes. W,7β-amino- with 0.5 ml of triethylamine
3-bromomethyl-1-oxide-8-cephem-4-
Add a dichloromethane solution of hydrochloric acid 4o, so9 of carboxylic acid tertiary butyl ester and triethylamine 0.28-.

Stir at around -50°C for 30 minutes. The reaction solution was mixed with 5% sodium bicarbonate water,
After washing with saturated saline, diluted hydrochloric acid, and saturated saline in this order, and diluting with anhydrous sulfuric acid, the solvent was distilled off. and stirred at room temperature for 20 hours. After distilling off the solvent, chloroform was added and the insoluble matter was removed.
, i1g solution with water.

Next, the mixture was washed with dilute hydrochloric acid, then saturated saline, dried over anhydrous sulfuric acid, and then the solvent was distilled off, followed by column chromatography using silica gel as a carrier (15% methanol-
(eluted with chloroform), the purification deviation was 0.4% for the title compound.
Obtain 2g.

[Step II) 7β-(2-(2-aminothiazol-4-yl)-2-((pyrazol-3-yl)methoxyimino)acetamide)-3-(4-carbamoyl-1
-Pyridinio)methyl-3-cephem-4-carboxilade (syn isomer) The compound 0°429 obtained in Step I was dissolved in 5 ml of dimethylformamide, and cooled to -60°C (near J) with 0.0% phosphorous trichloride. Add 1 ml and stir for 30 minutes.

Raise the temperature to around -80°C. Add chloroporum to the reaction solution, wash with ice, and dilute with anhydrous sulfuric acid). After drying with IJum, the solvent is distilled off and dried under reduced pressure with a vacuum pump to obtain an oily product.
Obtain Qtn9. Dissolve this in 98% formic acid 4γ+l,
Under water cooling, add 0.3 - of concentrated Ji acid and 1.5 -
Stir for an hour. Acetone was added under water cooling, and when the reaction mixture became transparent, a large amount of ether was added, and the precipitated crystals were collected by filtration to obtain 230 m9 of pale yellow powder. This is purified by column chromatography (5% tetrahydrofuran) using Diaion 11P-20 as the 1H form, followed by high performance liquid chromatography (carrier: Partsil (Whatman) + medium: 12% methanol) to obtain the title compound. 124 Tn9 is obtained. Melting point 160-175°C
(minute M) Elemental analysis Calculated value for 02alizINsOgSz・3H20 C48,82,H4,27,N 19.7
? Actual value 043.19. H3, 8B, N 1
9.70I 11V c+++: 3400
, 1? 70, 1660.

n1aX 610 FT-N MR (D20+IX; l, ppm, 2
00! H-z).

3.22 (I H, d, J-18Hz, 02H)
3.70 (Ill, cl, J-1811z, c
l-If) 5.28 (LH, d, J-511z,
06 H)5.35 (2H,S, N0CH2)5
．． 46 (III, 6. J-1411z, 011
26-CiOl; H2) 5.71 (Ill, d,
J-1411z, C1(2-NDCONH2)5.8
7 (II(,6,J-51(z,c7++)fl
, 54 (1,1+, d, J-2 summer + Z, pyrazole 7, 1.7 (Hi, s, thiazole 5th position 1
1) 7, 7 3 (Ill, 6, J-2Hz,
Pyrazole 5th position 11) 8, 4 4 (21!,
d, J-7+lz, H at pyridine 8.5 position) 1:1.
1 8 (21(, (], ]J-7112, Pyridine 2,6 H) Procedural amendment March 1982 SθEl Director General of the Patent Office 1, Month) Indication of 1982 4y, 7 Patent Application No. 182501 -2, Name of the invention 77 Allosborin derivative 3, Relationship between the parties making the amendment Patent publication ij;
3) No. 1 - A certain company? 1.

Representative Takebi 11: Takeshi Miya - Husband 4, Agent Tokyo H1 Kawayo Hiku [] 1 Overseas 3-cho 1'l 14-103
・ Postal Code 10:3 No. 3 Seisaku Co., Ltd. Telephone: (272) 0 61 16, Contents of the Amendment (1) ``Aminothiazole'' in the second line of page 28 of the specification shall be corrected to ``tritylaminothiazole.'' .

(2) Specifications) () On page 82, line 8, "aminothiazole" is corrected to "tritylaminothiazole."

(3) On the last line of page 85 of the specification, which says ``Pyridine 2nd and 6th position rules'', change the next line and add the European text.

[Example 5 7β-(2-(2-aminothiazol-4-yl)-2
-((1-methylpyrazol-5-yl)methoxyimino)acetamide)-8-(1-hyridinio)methyl-3-cephem-4-carboxilade (Syn!・
+I'LQ-) [Step 1] 1-Methyl-5-hydroxymethylpyrazoletrahydro7ran 20 (suspended in 117 and added to this).

Add 50 ml of a tetrahydro 7 run solution containing 7.89% of ethyl 1-methyl-5-virazolecarpoxylate dissolved therein dropwise at 0°C. After adding 0 drops, stir at room temperature for 1 hour, then add aqueous ether little by little. After decomposing excess reagent,
Insoluble matter is filtered off.

After concentrating the mother liquor, add 800 mZ of chloroborum and dilute with sulfuric acid). After drying with IJum, the solvent was distilled off to obtain the title compound 5.2.
7 is obtained as an oil.

GW-NMR (GDG13, ppm) 3, 8 1 (3H, s, IJ-0113) 4
, 6 2 (2) 1, s, CH20n 0, 1 4
(IH, 6, J-1.5Hz, H at the 4th position of pyrazole) 7-2 9 (IH, d+ J-1.51
1z, H at the 3rd position of pyrazole) [Step ■] 5 ml of 1-methyl-5-chloromethylpyrazole hydrochloride thionyl chloride was added dropwise to Compound 5.29 obtained in [Step ■] under water cooling, and then heated to 90°C. Heat for 15 minutes. Add ether to the residual solid to obtain 5.79fi. Melting point 89-92°C0 [Step I] 1-Methyl-5-phthalimide secondary oxymethylpyrazole 8.39 ml of N-hydroxyphthalimide was dissolved in 70 vrl of dimethylformamide, 9.4 ml of potassium carbonate and 18-crown-6- Add ether 500tM9.

To this solution was added a solution of compound 'h 5.79 obtained in [Step 1] dissolved in dimethylbormamide 70111j, and 6
Stir at 0°C for 15 hours. Insoluble matters are removed and the mother liquor is concentrated. The residue was partitioned between chloroform and saturated hydrogen carbonate solution, and the chloroform layer was washed with water and dried over sodium sulfate. The solvent is evaporated and the residue is triturated with ether to give the title compound 6.49. Melting point 177-17
8℃.

GW-NMR (CDCl2.pl)m)4.12 (
8H,s, N-CH3)5.21 (2H,s, G
l! zO) 6.29 (LH, d, J-1,511z
, pyrazole 4th position Q) 11) 7.87 (1!+, 6
．． J-1,5Hz, pyrazole 3rd position o) 7.77
(4H,s, phenyl) [Step ■] 1-Methyl-5-aminooxymethylpyrazolniji
5.7 ml of the compound obtained in the K salt [Step 1] was added to 82 ml of ON-hydrochloric acid.
and heated under reflux for 1 hour. After the reaction is completed, the mixture is cooled with ice, the precipitated crystals are filtered off, and the mother liquor is concentrated to dryness. The residue was treated with ether to powder.

The title compound 4.49 is obtained. Melting point 14+1~145°C
00W-NC00W-N, ppm) 4.06 (an, S, N-0H3) 5.84 (
2! +, S, CH20) 6.80 (IH, d,
J-1,5) 1z, H at position 4 of pyrazole) 7.92 (
IH, 6, J-1,5Hz, H at the 3-position of pyrazole)
- ((1-Methylpyrazol-5-yl)methoxyimino]acetic acid [Step ■] ?J compound 2.49 was dissolved in water 5-,
Add 2 parts of sodium hydrogen carbonate to this. This solution is added to a mixture of 4.5 glyoxylic acid (2-tritylaminothiazol-4-yl) and 130 ml of methanol. 111. at room temperature for 5 hours. After stirring, the solvent was distilled off and the residue was dissolved in chloroform and washed with water. It was dried over sodium sulfate, the solvent was distilled off, and ether was added to the residue to form a powder to obtain 5.3 g of the title compound. Melting point: 176~ 180
°C, (decomposition point).

CW-NMR (C, DC13, 'ppm) 3.69 (
311,s, N-1.3) 5.11 (211,s
, October 20) 6.16 (IH,s, pyrazole 4th position 106.52 (I H,s, thiazole 5th position I+
) [Step ■] 7β-(2-(2-aminothiazol-4-yl)-2
-((1-methylpyrazol-5-yl)methoxyimino)acetamide)-3-(1-pyridinio)methyl-8
-cephem-4-carboxilade (:/nY・1・1
Triethylamine 0.14y4 was added to a mixture of 528m9 of the compound obtained in the intervention [Step 1] and 20ml of methylene chloride.
Add phenyl N-phenylphosphoramide chloridate 2 (i 8 m9) and stir at room temperature for 3 hours. To this, add 7-amino-3-(1-pyridiniomethyl)-cephem-4-cal J? salt 45
0++19. N,0-bistrimethylsilylacetamide O, '15ml and methylene chloride 3 (After adding a mixture of 1+f dropwise, stir at room temperature for 15 hours. Wash with water and saturated brine, then sulfuric acid). Dry with IJum. , the solvent is distilled off and a yellow powder is obtained! ]00m9 is obtained. Formic acid l〇- and concentrated hydrochloric acid lrnl were added to this, and after stirring at room temperature for 1.5 hours, acetone was added under water cooling to dissolve insoluble matter, and then ether was added. The resulting precipitate was collected by filtration and thoroughly washed with ether.

500 m9 of yellow powder are obtained. This is Diaion op
-20 (solution W + 8% tetrahydrofuran-water) and further purification by high-performance liquid chromatography (carrier Partsil, solvent 15% methanol-water) to obtain the title compound, 301+ Da.

F T −N M R (D20 + p p m )3
．． 00 + 3.50, (2H, ABq, J-17
Hz, 02-Summer () 3.88 (8II, s, N
-0113) 5.11 (III, d, J-511
z, 06-11) 5.31 (2H, 8,0112
0) 5.36.5.58 (2!I, AB-q, J-1
(iHz, -〇H2-+N trowel 5.79 (2H, cl
, J-5 positive (z, C7-+()6.43 (IH, S
, H at position 4 of pyrazole) 7.04 (N+, s, H at position 5 of thiazole) 7.38 (Ill, s, H at position 8 of pyrazole) 8.15 (2+1. t, J-7Hz
, H at position 8,5 of pyridine) 8.64 (IH,t,
J-7Hz, H)s at position 4 of pyridine, 99 (2H,
a, J-71,12, H at the 2,6 position of pyridine) Example 6 7β-(2-(2-aminothiazol-4-yl)-2
-((1-methylpyrazol-3-yl)methoxyimino)acetamide)-a-(1-pyridinio)methyl-3
-Cephem-4-carboxilade (French surname of Shin γ) [Step 1] Suspend in 1-methyl-3-hydroxymethylpyrazoletrahydro7ran 200- and add to this.

Ethyl 1-Methylpyrazole-3-carboxilade 16% dissolved in tetrahydrofuran solution 100%
Add dropwise at °C. After the dropwise addition, stir at room temperature for 1 hour.
Next, water-containing ether is added little by little to decompose the excess water-purified aluminum lithium. After removing the liquid by filtration and concentrating the mother liquor, chloroform 5QQnJ was added and dried over sodium sulfate. The solvent was distilled off to obtain the title compound 12 as an oil.

CW-NMR (CDG13.ppm) 8.81 (81(,s,N-Cl43)4.61
(2H, s, 0Ii20 ) it, 20 (IH,
d, J-2Hz, pyrazole 4th position) 1) 7.25
(IH, d, J-2Hz, pyrazole 5th position σ month) [
Step (1) 1-Methyl-3-chloromethylpyrazole hydrochloride Thianyl chloride 9 ml was added dropwise to Compound 12 obtained in Step I under water cooling, and then heated at 90° C. for 15 minutes.

Ether is added to the residual solid, which is thoroughly crushed, collected by filtration, washed thoroughly with ether, and dried to obtain the title compound 14. Melting point≦14=97°C0GW-NMR (D20.ppm) 8,'J8 (all, s, N-Cl43)4
．． 70 (2H, s, Cu2O) 6.57 (LH, d, J-2H7, H at the 4th position of pyrazole) 7.82 (LH, d, , J'-2Hz, H at the 5th position of pyrazole) [Step ■] 1-Methyl-3-7thalimidoxymethylpyrazole 8.52 N-hydroxymethylimide was dissolved in 3Qml of dimethylformamide, 4.5q of potassium carbonate and 1
Add 8-crown-6-ether 200+719.

A solution of compound 89 obtained in [Step 1] dissolved in 3 Qml of dimethylformamide is added to this solution, and the mixture is stirred at 60°C for 15 hours. Insoluble matters are removed by filtration and the mother liquor is concentrated. The residue was partitioned between chloroform and saturated sodium bicarbonate solution. The chloroporm layer was washed with water and then dried over sodium sulfate. The solvent was evaporated and the residue 111 was treated with diethyl ether to powder to obtain 3.5 ml of the title compound. melting point 12
2-124'C.

GW-NMll (CDCja, ppm) 3.82
(811, s, H-13) 5.21 (2)], s
, Cl120 )6.45 (N(,6,J-21(
z, H at position 4 of pyrazole) 7.32 (Ill, 6.
J-2Hz, H at position 5 of pyrazole) 7.76 (4H
, 8, phenyl) [Step ■] Compound 8.39 obtained in 1-methyl-3-aminooxymethylvirazole dihydrochloride [Step ■] was converted into (31J-hydrochloric acid QQ
mt and heated under reflux for 1 hour. After the reaction is completed, the mixture is cooled on ice, the precipitated crystals are filtered off, and the 4 liquid is concentrated to dryness. The residue is treated with ether and pulverized to give 2.5 g of the title compound. Melting point 112-115"C0 aw-NMR (Dzo, ppm) 4.02 (3! (, s, N-C City) 5.20 (2
H, s, CH20) 6.64 (IH, 6, J-2Hz, H at the 4th position of pyrazole) 7.80 (IH, d, J-2Hz, (7,)H at the 5th position of pyrazole) [Step ■] 2 -(2-tritylaminothiazol-4-yl) 22-((1-methylpyrazol-l)methoxyimino)
Dissolve 2.4 ml of the compound obtained in acetic acid [Step 1] in 7-7 of water, and add 29 ml of sodium bicarbonate little by little to this. This solution is added to 15 Qml of methanol containing 4.59 glyoxylic acid (2-)rithylaminothiazol-4-yl). After stirring at room temperature for 5 hours, the solvent was distilled off, and the remaining solution was dissolved in chloroform, washed with water, dried over sodium sulfate, and the solvent was distilled off. Ether was added to the residual liquid to form a powder to obtain the title compound 59. Melting point 125-182°C (decomposition point).

GW-NMR (CDC13+ppm)
8-'IO (3LS, N'CHs)5,
2 7 (211, s, Ciiz0)6, 1 1
(1) 1, d, J-1.5Hz, pyrazole 4
position II) 6, 6 5 (IH, s, thiazole 5th position σ month 1) 'I-2 7 (1 (iH, 81) lythyl and pyrazole 5th position H) [] 2 degrees ■] 7β-(2 -(2-aminothiazole-4・-・r)
-2-((1-methylpyrazol-3-yl)methoxyimino)acetamide]-8-acetoxymethyl-3-cephem-4-carboxylic acid dihydrochloride [Step 1] Compound 1.052 was added to methylene chloride. 3o
-, 270 mg of 1-hydroxybenzotriazole, dicyclohexyllupodiimide u 4
Add 1 2 m9. After stirring at room temperature for 3 hours, 30 m2 of methylene chloride containing 3-acetoxymethyl-7-amino-3-cephem-4-carvone (3; gHy414rr9 and triethylamine 0.sm7) was added and stirred overnight at room temperature. Filter off the substance and reduce the mother liquor to 10%
citric acid.

Wash with water and saturated brine in that order, dry with sulfuric acid (IJ), and then evaporate the solvent. Treatment of the residue with ether gives a yellow powder of 1.59%. This was then added with formic acid IQ++ under water cooling.
+ and 0.6- of concentrated hydrochloric acid were added, stirred at room temperature for 2 hours and then dried, ether was added to the residue and the precipitate was collected by filtration. This was thoroughly washed with ether and dried to produce the title compound 810
Get R+9.

GW-NMR (DzO, ppnn) 2, 2 5 (8+1, s, OCOCH3) 8
, (1 5 ( 3H, s, N (E) + 3)
5, 1 5 (01, d, J-41 (z, C6
-105, 30 (2H, s, CH20)5,
7 6 (H(, d, J-4Hz, Or-11
)6, 5 2 (IH, 6, J-1.5)iz
, H at position 4 of pyrazole) 7, 1 2 ( Ill, s
, thiazole 5th position l( )7,70(LH,
6, J=1.5Hz, H at the 5th position of pyrazole) [Step ■
] 7β-(2-(2-aminothiazol-4-yl)-
2-((1-methylpyrazol-8-yl)methoxyimino)acetamide)-3-(1-hyridinio)methyl-8-cephem-4-carboxylade (ren γ
, 1・tI 5 rnl (1) Heat the mixture at 75°C for 2 hours under nitrogen flow.

After the reaction is complete, add dropwise to 400 d of acetone. The precipitate was collected by filtration, washed with acetone, and then diluted with Diaion Hp-2o (i
B5% tetrahydrofuran-water) and further purified by high performance liquid chromatography (carrier, Vertsil, solvent 1).
Purification with 5% methanol-water) yields 25m9 of the title compound.

FT-NMR (DzO, ppm)

Claims (1)

[Scope of Claims] (1) Cephalosporin derivatives and salts thereof (2) 7β-( 2-(2-aminothiazol-4-yl)-2-((pyrazol-3-yl)methoxyimino)
Compound (3) 7β according to claim 1, which is the syn isomer of (acetamido)-3-(1-pyridinio)methyl-3-cephem-4-carboxylad or a salt thereof
-(2-(2-aminothia, zol-4-yl)-2-
((pyrazol-4-yl)methoxyimino)acetamide)-8-(1-pyridinio)methyl-3-cephem-
Compound (4) according to claim 1, which is the syn isomer of 4,-carboxilad or a salt thereof
-(2-aminothiazol-4-yl)-2((pyrazol-3-yl)methoxyimino)acetamide)-3-
(41-carbamoyl-1-pyridinio)methyl-3-
Compound (5) according to claim 1, which is a syn isomer of cephem-4-carboxilade or a salt thereof; base, 115
: Compounds represented by hydrogen, lower alkyl, or protective groups that can be removed by hydration or reduction, and their salts.