JPS6185392A - Novel preparation of cephalosporin compound - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as an antibacterial agent, by a novel process, by condensing a novel substituted hydroxyiminoacetic acid compound with an amino cephem carboxylic acid compound. CONSTITUTION:The objective compound of formula IV can be prepared by condensing (Z)-2-aminothiazolyl-2-substituted-hydroxyiminoacetic acid compound of formula I (R<1> is H or lower alkyl; n is 2 or 3) or its reactive derivative with (6R, 7R)-7-amino-3-cephem-4-carboxylic acid compound (salt) of formula II [when R<2> is acetoxy, etc., R<4> is (protected) carboxy, and when R<2> is group of formula III (Y is H or hydroxymethyl), R<4> is -COO<->], and when R<4> is protected carboxyl, removing the protecting group. The starting compound of formula I is novel, and can be produced e.g. by reacting the butyric acid derivative of formula V (R<6> is H, etc.; X is halogen) with thiourea.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound represented by the general formula (wherein R1 is a hydrogen atom or a lower alkyl group, and pa represents a carboxy group or a group represented by the formula -C(1)).

R1 is an acetoxy group or (1-methyl-I H-tetrazol-5-yl) when R″ is a carboxy group
When the thio group or R'' is a group represented by the formula -COO-, it represents a group represented by the formula +-O, and Y represents hydrogen [child,
hydroxymethyl group or nonolbamoyl group; +1 represents an integer of 2 or 3; ) (6R,7R)-r
(Z)-2-(2-aminothiazol-4-yl)-2
-Oxiimino-acetamide]-3-cephemu-4-carboxylic acid compound or a pharmacologically acceptable salt thereof.

The above compound (1) has excellent antibacterial activity against a wide variety of microorganisms including Gram-negative bacteria and Gram-negative bacteria, and is a useful pharmaceutical compound as an antibacterial agent.

For example, compound (1) or a pharmacologically acceptable blue salt thereof may be used for Streptococcus spp.
It exhibits excellent antibacterial activity against various bacteria such as the genus ) and Pseudomonas, and is particularly characterized by exhibiting excellent antibacterial activity against both gram-negative bacteria and gram-negative bacteria. For example, Streptococcus fuecari
The minimum inhibitory concentration (M, 1.C) for CN478 (Agar plate dilution method, cultured at 37°C for 20 hours) was determined. 9 (6R, 7R) 1 of the present invention
(Z)-2-Cetamide 1-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate was prepared from the above-mentioned bacterium plus seven crude samples of 112.5 M, 1. C, is shown. In addition, the chemical compound (1) or its salt is Bacillus (13a
dllus) genus Escherichia
) genus, Talebsiella genus, Enterobacter genus.

Genus Serra/Ishi7 (5erratia), Citrobacter (cjtr.

bacter ) genus, Proteus x
) genus, Shigella genus, HaemOpH1luS genus.

It also exhibits excellent antibacterial activity against bacteria belonging to the genus Salmonella.

According to the present invention, the above compound (tl or a salt thereof has the general formula %) (where R+ is a hydrogen atom or a lower alkyl group, and 11 represents an integer 2 or 3) (Zl-2-aminothiazolyl- 2-i'l
Represents an i-substituted oxydioxynoacetic acid compound or its reactive derivative and a group represented by the general formula, where 1<'l;JR'' is an acetoxy group or (1-methyl-IH-tetrazol-5-yl)
When it is a thio group, it represents a carboxy group or, if protected, a group represented by the formula -COσ, and Y represents a hydrogen atom, a hydroxymethyl group or a carbamoyl group. )
(6R,7R)-7-amino-3-cephem-4-carboxylic acid compound or a salt thereof is subjected to a condensation reaction, and when R4 is a protected carboxy group, the protecting reagent is removed, and - 7 = General formula (where Ha is R2 is an acetoxy group or (1-methyl-
IH-tetrazol-5-yl)thio group, IC represents a group represented by the formula -COO, R'
, R'', Y and 11 have the same meanings as above], and if necessary, convert the product into a pharmacologically acceptable salt thereof.

Compounds represented by the general formula (01) which serve as starting materials in the present invention include compounds in which 1, for example, R1 is a hydrogen atom or a lower alkyl group such as a methyl group, an ethyl group, or a propyl group, and +n is an integer of 2 or 3. In addition, when R4 is a protected carboxy group, the protecting group for the carboxy group is hydrolysis.

It is preferable to use a protecting group that can be easily removed by conventional treatments such as acid treatment and reduction. Examples of such protecting groups include methyl and ethyl groups.

te@t, lower alkyl groups such as -butyl; substituted or unsubstituted phenyl lower alkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl; tri-lower alkylsilyl groups such as benzhydryl and trimethylsilyl; Examples include. Moreover, when R4 is a carboxy group.

Compound (II) is preferably converted into its salt prior to the condensation reaction. Preferred examples of the salt of compound (III) include inorganic salts such as sodium salt and potassium salt, and organic amine salts such as trimethylamine salt and triethylamine salt. In addition, compounds ([1 has a group represented by the general formula (where * means that the carbon atom is an asymmetric carbon atom, and R1 and 11 have the same meanings as above) have an asymmetric carbon atom] However, both the optical isomer and the racemate of the compound +If) can be used for the purpose of the present invention.

The condensation reaction between the compound ([11 or its reactive derivative and the compound side or its salt] can be easily carried out by a conventional method. For example, the condensation reaction between the free compound + II) and the compound (II) can be carried out using an appropriate method. Lu N' of dehydrating agent in solvent
Preferred examples include -(3-dimethylaminopropyl)carbodiimide, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalic acid chloride, and triphenylphosphine. Further, the Vilsmey Y reagent prepared from dimethylformamide and phosphorus oxychloride, dimethylformamide and oxalic acid chloride, dimethylformamide and phosgene, or dimethylformamide and thionyl chloride can also be used as the dehydrating agent. Examples of solvents include dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, di-10-methylformamide, and NN-dimethylacetamide.

Ethyl acetate, pyridine, water, etc. can be suitably used. This reaction is carried out at -50°C to 50°C, preferably at -30°C.
It is suitable to carry out the reaction at a temperature of 20°C to 20°C.

Furthermore, the condensation reaction between a reactive derivative of compound (Ill) and compound (@) or a salt thereof can be carried out in an appropriate solvent in the presence or absence of an acid-reducing agent.Compound (Ill)
Examples of reactive derivatives of 9 include acid halides (eg, acid chlorides, acid bromides) of compound fTI).

Mixed acid anhydrides (e.g., compound (mixed acid anhydride of Ill and carbonic acid γ-alkyl ester), active esters (e.g.).

p-nitrophenyl ester, 2. 4-dinitrophenyl ester, succinimide ester. phthalimide ester, benzotriazole ester, 2-pyrrolidon-1-yl ester), acid azide, acid amide (e.g. imidazole amide).

4-substituted-imidazoleamide, triazoleamide)
etc. are preferably mentioned. As a solvent.

For example, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dimethylformamide, N,N-dimethylacetamide, ethyl acetate, pyridine, acetone, water and the like can be suitably used. In addition, as a deoxidizing agent, alkali metal hydroxide (for example,
Sodium hydroxide.

potassium hydroxide), alkali metal carbonates (e.g.

sodium carbonate, potassium carbonate), alkali metal hydrogen carbonates (e.g. carbon θ hydrogen, potassium hydrogen carbonate), trialkylamines (e.g. 8 trimethylamine, triethylamine), NN-dialkylanilines (
For example, preferred examples include N,N-dimethylanimorpholine). This reaction is suitably carried out at -50°C to 50°C, preferably -30°C to 20°C.

When R4 is a protected carboxy group in the compound fl obtained in this manner, removal of the protecting group is easily carried out by conventional methods such as hydrolysis, solvolysis, acid treatment and reduction. be able to.

For example, the protecting group for a carboxy group can be tert-butyl. Examples of the acid include formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid octahydrochloride, and hydrogen bromide, and trifluoroacetic acid is particularly preferably used. This reaction can be carried out in a suitable solvent or in the absence of a solvent, and examples of the solvent that can be used include water, methanol, ethanol-9-acetic acid, and dioxane. This reaction was carried out at 0°C.
It is appropriate to conduct the actual SL at a temperature of ~70'C, preferably 0°C to 30°C.

In this reaction, when trifluoroacetic acid is used as the acid, it is preferably carried out in the presence of 3-anisole. In addition, when one of the carboxyl groups is a radical kahenzyl M, p-methoxybenzyl lu or 1; tp-nitrobenzyl group, the removal of these protecting groups is carried out by contacting in the presence of a catalyst in a hydrogen gas stream. : It can be carried out by using one element.The catalyst can be one, for example, palladium-barium carbonate.

Palladium/carbon, palladium black, etc. are preferred = 13
- can be lost. This catalytic reduction reaction is preferably carried out in a suitable solvent at normal pressure to pressurized temperature of 0°C to 100°C, particularly IO'c to 40'C. As the solvent, for example, methanol, ethanol, tetrahydrofuran, water, etc. can be suitably used.

In addition, 1 compound obtained by the method of the present invention (in 11, pharmacologically acceptable salts include 1, for example, non-toxic metal salts such as catrium salts, potassium salts, calcium salts, and aluminum salts; trialkylamines (for example, triethylamine)) Examples include salts with non-toxic amines such as, salts with inorganic acids such as hydrochloric acid and hydrobromic acid; salts with organic acids such as oxalic acid and tartaric acid. It can be easily obtained by treating with an equal amount of an alkaline reagent or a liquid at around room temperature.

Note that 1 the raw material compound of the present invention (Ill is a new compound,
(However, -COOR' is a carboxy group or a protected carboxy group, X is a halogen atom + R' and n have the same meanings as above.) A butyric acid derivative represented by thiourea and a solvent (water or water) A deoxidizing agent (N,
N-dimethylaniline, triethylamine, organic tertiary amines such as pyridine, etc.) in the presence of about 10°C to 8°C.
It can be produced by reacting at 0°C and, when -COOR' is a protected carboxy group, removing the protecting group.

Example 1 +11 (6R,7R)-7-amino-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate monohydriodide monohydrate 13121 was suspended in chloroform L50nrt<t , trimethylchlorosilane 28.5 m/at -10-0°C, pyridine 17,
-5 by adding 8 ml and triethylamine 3.1F
Stir at -0°C for 2 hours.

(21(Zl-2-(2-aminothiazol-4-yl)-2-(((3S)-2-pyrrolidon-3-yl)t
-1-diimino)acetic acid 6752 was dissolved in N,N-dimethylacetamide 200m/triethylamine 2
．． 61' is added, heated and dissolved at 65 to 70°C, and then cooled. Next, add 50m/f of chloroform to this.
Cool to ~25°C and stir at the same temperature to add A-oxyphosphorus chloride 38
Drop 4v. The reaction solution obtained in this way is prepared as described in (1) above.
in? q into the solution at -15 to -20°C. After dropping and stirring for 15 minutes at the same temperature, add 15% saline 2 + 10
ml and stirred for 20 minutes at 0-5°C.

The aqueous layer is separated and washed with chloroform, and then the chloroform is removed from the aqueous layer under reduced pressure. The aqueous layer is passed through a column packed with 700+ u/d of non-ion exchange resin Di-ion Hp-2, washed with about 6/d of water, and eluted with 20% methanol. (6R17R)-7-1 (Zl
-2-(2-aminothiazol-4-yl)-2-[(
(3S)-2-pyrrolidon-3-yl)oximino”
acetamido)-3-(1-pyridiniomethyl)-3-
Cephem-4-carboxylate 9.7F is obtained as a pale yellow powder. Yield 709b NMR (D, 0) δ: 2.2-2.7 (2H, m), 3.13.8 (
4H, rll).

5.05(IH,t, J=77(Zl5.2R(11
1, d, J=51]z).

5.36 (lTT, d, J = 14Hz),
5.63 (Hl, d, J = 14T-Iz).

5.87 (LHld 1.T=5Hz), 6.9
8 (IHLs).

8.10 (2T-T, t, J=7.5th),
8.57 (Lt, , J=7.5Hz).

8.98 (2I(, d, J=7.5TTz) Example 2~Chapter The following collated material was obtained by carrying out the same procedure as in the above example.

(2) (6R,7R)-((Zl-2-amitunaazol-1-yl)-2-CC(3R)-2-pyrrolidon-3-yl)oximino]acetamide)-3-(1
-pyridiniomethyl)-3-cephem-4-carboxylate NMR (D2n) δ: 2.1-2.7 (2B, m), 3.1 3.
7 (4H, m), 4. 'J -5,5(4H,m
).

5.79 (IHld, J=5)Tz), 6.9
2 (1) Ls), 7.8-9.1 (5Tl, m
) [α), + 45.7° (C = 1. water) (31 (6
R,7R)-((Zl-2-(2-aminothiazole-
4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetamide l-3-(4-carbamoyl-1
-pyridiniomethyl)-3-cephem-4-carboxylate M, p, 163-166 °C (decomposition) NMR (CF,
Co, D) δ: 2.5-3.0 (2H, m), 3.5-4.0 (
4'H1m), 5.2-5.5 (3H,m)5.
5-5.8 (lH9m), 5.9-6.2 (H
(, m), 7.35 (LH9s) 8.4-8.7
(2H, m), 9.1-9.4 (2)], m)+4
1 (6R,7R)-((Z)-2-(2-aminothiazol-4-yl)-2-(2-pyrrolidon-3-yl)oximino) Acetamide l-3-(4-hydroxymethyl-1 -pyridiniomethyl)-3-cephem-
4-carboxylate M-p, 162-184°C (decomposed) NMR (D, O
) δ: 2.3-2.7 (2H, m), 3.1-3.7 (
4H, m'), 4.8-5.0 (2'H, m).

5.03 (2)-I, s), 5.24 (IT(
, d, J=5Hz).

5.3-5.6 (ITl, m), 5.83 (I
II, d, J=5Hz), 681 (IIl,
s).

78-B, 2 (211, rn'), 8.6-9.
0 (2H・m)Open (61n,7R)-((Zl2-
(2-aminothiazol-4-yl')-2-[(2
-pyrrolidon-3-yl)oxyimino]acetamide l
-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate M-T)-1
28-135°C (decomposition) NMR (D!0) δ.

2.1-2. F! (2H, m), 3.1-3.8
(4)1. m), 4.86 (2H1s) ・
4.9-5.1 (2H, m), 5.27 (IH,
d, J-5Hz).

5.3-5.6 (IH, m 1.583 (LH, d
, J=5Hz), 6.96 (IH,s).

7.7-8.2 (lH9m), 8.3-8.6 (I
T(,m), 8.6-9°I(2Tl,m)+61
(6R,7R)l(Z)-2-(2-ami)
-2-((2-piperidone-
3-yl)oximino]acetamide)-3-[(1-
Methyl-I H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid.

NMR (D20) δ: =19-1.5-2.3 (4H-m), 3.0-3.4 (
2H, m), 3.4-3.6 (2H, m).

3.90 (3T-T, m), 4.0-4.2 (
2T-T, m), 5.03 (IHld, J=
57(z).

-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]γcetamide 1-3- ((1-methyl-
I H-tetrazol-5-yl)thiomethyl]-3-
Cephemu 4-carboxylic acid sodium salt NMR (DMSO-a,/) δ.

2.1-2.5 (2)Lm), 3.1-3.5 (
2ILm), 3.94 (3H,s)4.2-4.5
(2H1m), 4.6-4.8 (lH,m),
5.03 (IH9d, J=5Hz), 5.5-5
．． 8 (lH, m), 6.76 (lH, s)
, 7.3 (2H, broads).

8.00 (lH,s), 9.55 (if(,
broad)+8+ (6R,7R)i(car 2-(
2-minothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oximino]acetamide)-3-((1-methyl-I H-tetrazole-
5-yl)thiomethyl)-3-cephem-4-carboxylic acid, sodium salt NMR (■) 20) δ: 2.1-2.7 (:ll'lT, mL 2.89
(3TLs), 3.2-3.8 (4'lLrn
).

4, Q5 r311. s), 4. c15-4.3
(2T(,m), 4.9-5.3 (2T(,m)
.

5.73 (lT1.d - J= 5Tiz),
'7.00 (ITT, s) Example 9 +11 7-γ minocephalosporanic acid 309 N,N
- Suspend in 30ml of dimethylacetamide, add 99ml of trimethylchlorosilane and 6.6ml of pyridine, stir and dissolve at 5-15'C, and -25--
2. Cool to ]℃.

+21 (Zl-2-(2-amitunaazole-4-
) = 2- + ((3S)-2-pyrrolidone-3
-yl)-oximinol acetic acid 279 to N,N~dimenalacetamide 80rn! 1.12 of triethylamine was added thereto, dissolved by heating at 65 to 70°C, and then cooled to room temperature. Add 20 ml of chloroform to this solution and add 1 ml of phosphorus oxychloride at -30 to -20°C.
．． 659 was added dropwise and stirred at 1X for 10 minutes. This was added dropwise to the solution obtained in the above ill at -25 to -15°C and stirred for 30 minutes at the same temperature. Add 200 rnl of ethyl acetate and stir at 0 to 10°C for 30 minutes.

The organic solvent layer was then separated, washed with water, and extracted with an aqueous solution of hydrogen carbonate. The extract was added to Hp-20
was passed through a column packed at 400 m/pack and eluted with water.

The obtained eluate was dried under reduced pressure, acetone was added to the residue, and the residue was collected by filtration to obtain (6R,7R)-7-((712-(2
-aminothiazol-4-yl)-2-[((3S)-
2.99% of 2-pyrrolidon-3-yl)oximinoacetamido)cephalosporanic acid sodium salt is obtained.

NMR (D, O) δ: 2.12 (3H0s), 2.3-2.6 (2T(
, m), 3.2-3.9 (4H, m).

4.75 (l) (, d, J-13Hz), 4.
95 (IHod, J = [3Hz).

5, LO (lH9t, J=7Hz), 5.26 (
lH,d, J=5Hz).

5.85 (LH9d, J=5Hz), 7.08
(lH,s) Example 10 TZI-2-(2-aminothiazol-4-yl)-(
[(3S)-2-pyrrolidon-3-yl]oxyimino)acetic acid 1.351' to N,N-dimethylacetamide 4
0rnl and tributylamine at 1.85 F, heated to dissolve at 60 to 70°C, and cooled to room temperature. This solution H was dissolved in 20 ml of methylene chloride containing 165 g of (6R,7R)-7-aminocephalosboranic acid tertiary butyl ester.
To the solution, 0.889% of 1-hydroxybenztriazole and 1359% of N,N'-dicyclohexylcarbodiimide are added at 0 to 5°C, and the mixture is stirred at the same temperature for 5 hours. 504 ml of water and 100 □l of ethyl acetate were added to the reaction solution, stirred, and insoluble materials were filtered off. The organic solvent layer is separated, dried, and then dried under reduced pressure. 30rn of trifluoroacetic acid left! Add 1 rnl of anisole and stir at room temperature for 20 minutes. The reaction mixture was dried under reduced pressure, 15 Fnl of water was added to the residue, and then sodium hydrogen carbonate was added to make it slightly alkaline and insoluble matter was filtered off. Dye the filtrate
The column is passed through a column packed with 150 ions of Hp-20 ions. Then, by eluating with water and drying the eluate under reduced pressure (
6R,7R)-7-NZ)-2-(2-amitunaazol-4-yl)-2-[((3S)-2-pyrrolidone-
1.29 of 3-yl)oximino]acetamido)cephalosporanic acid sodium salt is obtained.

The physicochemical properties of the -23 product were consistent with those obtained in Example 9.

Example 11 +11 (6R,7R)-7-amino-3-(l-methyl-I H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid benzhydryl ester 2.59% was dissolved in tetrahydrofuran 30%. , / dissolved in -2
Cool to 0 to -15°C.

+21 (Zl-2-(2-aminothiazole-4-
yl)-2-(((3S)-2-pyrrolidon-3-yl)oximino)acetic acid was added to a mixture of 60 g of N,N-dimethylacetamide and 08 g of triethylamine and dissolved by heating at 65 to 75°C. , cool to -20-15°C. Next, 1.12% of isobutyl chlorocarbonate was added to this.
It was added dropwise at 20 to -15°C and stirred at the same temperature for 30 minutes. This reaction solution was added to the solution prepared in (1) above at -20 to -1
After adding at 5°C and stirring at the same temperature for 2 hours.

Stir at -5 to θ°C for 1 hour. Add 50ml of cold water and 100ml of ethyl acetate to the reaction solution and stir. The organic solvent layer is separated, washed with water, and then dried under reduced pressure. Anisole 1v for the balance
and σ trifluoro vinegar m 3o Jd at room temperature.
Stir for 0 minutes. The reaction solution was dried under reduced pressure and 20% of water was added to the remaining balance.
ml, then 1 thorium hydrogen carbonate is added to make it alkaline and extracted with neal. 6) The aqueous layer is taken, passed through a column packed with 300 μl/n of Dyleion TIp20, washed with water, and eluted with 10% methanol.

The eluate was dried under reduced pressure, γ-cetone was added to the residue, and the residue was collected by filtration to obtain (6R,7R)-7-NZI-2-(2-minothiazol-4-yl)-2-[((3Uimo Soru 5 -yl)childophthyl-3-cephem-4-
1.19 of monothorium carboxylic acid salt is obtained.

NMR(DMSOda)δ.

2.0-2.5 (2H1m), 3.13.5 (2
H, m), 3.03 (3H, m).

4.1-4.5 (2H, m), 4.6-4.8 (
LH,m), 5.04 (IH,d.

J=5TTz), 5.5-5.7 (IH, m)
, 6.76 (H(,s) , 7.3 (2)T.

broad, s), 7.98 (IHJ)
, 9.57 (lH, broad) Example 12 +II (6R,7R)-7-γ minnow 3-(l-methyl-IH-tetrazol-5-yl)-child ofthyl-
3-cephem-4-carboxylic acid 1.65 $1 N.

15 rnl of N-dimethylacetamide and 5 rnl of chloroform
After suspending the mixture in a mixed solution of 300 ml of N,0-bis(trimethylsilyl)acetamide 302 and dissolving it at 10 to 20°C, the mixture is cooled to -30 to -20°C.

+2) Add 820 ml of oxalic acid chloride dropwise to 440 ml of dimethylformamide and 10 J@M of chloroform at 0 to 5°C, stir at the same temperature for 30 minutes, and cool to -30 to -25°C.

+3+(Zl 2- (2-γminothiazol-4-yl)-2-1((33)-2-pyrrolidon-3-yl)
Suspend 1.35y of acetic acid (oxyimino) in 40ml of N,N-dimethylacetamide and add 0.55y of triethylamine.
9 was added and dissolved by heating at 65 to 70°C, and then cooled to dryness in the room. Next, add chloroform IW to this and -30 ~
Cool to -20℃ and add the solution prepared in (2) to -30℃.
It was added dropwise at ~-20°C and stirred at the same temperature for 15 minutes.

This reaction mixture was added to the solution prepared in (1) above.
It was added dropwise at ~-15°C and stirred at the same temperature for 30 minutes. anti-26
For the time being, 50 ntl of water and 150 r++j of chloroform are added to the liquid.
Add.

Furthermore, after adding sodium hydrogen carbonate to make it slightly alkaline, the aqueous layer is separated. Chloroform the water layer? 'Hair, cleanse, water I; After distilling off the chloroform in 1 under reduced pressure, 300 m of Gui V Fuion) (T)-20! Fill it and conduct to the tank. The column is washed with water and eluted with 1096 methanol. The eluate was dried under reduced pressure, and the remaining residue was heated to 7 L with γ-cetone (6R, 7R)-7-(
(Zl-2-r2-aminothiazol-4-yl)
2 [((3S') 2-pyrrolidone-13-
IH-J, j,,,
LH Ri was 1υ.

The physicochemical properties of this product were consistent with those obtained in Example 11.

Reference Example 1 (1) 3189 2-hydroxyimino-3-oxobutyric acid ethyl ester was added to 150 ml of acetone in iW%IL, and 83 ml of anhydrous potassium carbonate was added to the solution. in the mixture = 2
Add one drop of 7-3-promol 2-pyrrolidone 332 at 20-25° C. and stir the mixture at the same temperature for several hours. Add 1/2 portion of ice water to the reaction mixture, and extract the mixture with ethyl acetate. After drying, the extract is concentrated under reduced pressure to remove the solvent. The residue is crystallized from diisopropyl ether, and the crystals are collected by filtration. By recrystallizing the crystals from ethyl acetate, IZl-2-[2- pyrrolidon-3-yl)oxyimino]-3-oxobutyric acid ethyl ester 322 is obtained as colorless needles.

M, I), 92-93°C NMR (CDC/,) δ: 1.33 (3H1j, J = 8Hz), 2.00
(3H9s).

2.05-2.85 (2H, m), 3.3-3.
7 (2H, m).

4.37 (2T(,Q, J=8H2), 4.9
8 (IHlt, J=7Hz) 7.53 (IH,
broads) +21 (Zl-2-[(2-pyrrolidon-3-yl)oximino]-3-oxoyl acid ethyl ester I4
．． 5. methylene chloride 60. , / and add sulfuryl chloride 9.6F to the solution. Heat the mixture to 15-25℃
Stir for 40 hours. The reaction mixture is concentrated to dryness under reduced pressure. Dissolve the residue in chloroform and wash the solution with water. After drying the chloroform solution, it is concentrated to dryness under reduced pressure.

Crystallize Misusada with ether and collect 5 crystals. It was decided to recrystallize the crystals from ethyl acetate, resulting in fZ)-2-((
6.52 of 2-pyrrolidon-3-yl)oximino]-3-oxo-4-chloro 1sll ethyl ester are obtained.

M, p, 102-103°C NMR (CDCe, )a: 1.34 (3H1t, J=7TIz1, 2.0
-2.9 (2H1m).

3.3-3.6 (2H1m), 4.39 (211
, q, J=711z).

4.62 (2)1. s), 5.20 (Hl, t
, J=7T'(z).

7.54 (IH,5) (3) IZ-2-[(2-pyrrolidon-3-yl)
oximino]-3-oxo-4-chlorobutyric acid ethyl ester 27.79 and thiourea 7.69
200 m/ of N,N-dimethylaniline 20' is added to the mixture. The mixture is stirred at 20-25° C. for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure.

The residue is dissolved in chloroform and the solution is washed with water and aqueous sodium bicarbonate. After drying the chloroform solution, it is concentrated under reduced pressure to remove the solvent. By crystallizing the residual substance with an inproper tool and filtering the crystals, 1Z)-2-
(2-Aminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oximino]acetic acid ethyl ester 17.55' is obtained.

M, p, +56-158°C NMR (DMSO-d,) δ: 1.28 (3H9t, J=7Hz), 1.8
-2.6 (2H, m).

3.1-3.5 (2H, m), 4.32 (2H, q
, J=7Hz).

4.77 (IH, t, J-7,5Hz), 6
．． 93 (LH,s) 7.30 (2H1s), 7
．． 98 (IHLs) + 41 (Zl 2- (2-amitunaazol-4-yl)-2-[(2-pyrrolidone-
3-yl)oximino]acetic acid ethyl ester 3.09
Suspend in 60 Hdl of methanol, and add 2N to the suspension.
Add hydroxide + l-IJum lOd. mix 30
Heat to reflux for minutes.

After cooling, the mixture is neutralized with 20 mZ of IN hydrochloric acid and the mixture is concentrated to dryness under reduced pressure. Crystallize the residual with 10 J of cold water = 30
- and dried under reduced pressure at 70°C to obtain (Zl-2-(
2-γminothiazol-4-yl)-2-r(2-pyrrolidon-3-yl)oxyimino]acetic acid 222 is obtained as colorless prismatic crystals.

M, I), 158-159°C (decomposition) NMR (DM
SO-ds) δ: 19-2.7 (2T(,m), 3.1-3.4 (
2H, rn).

4.79 (LH,t, J=7Hz), 6.
90 (IT(,s).

7.30 (2)1. broads), 8.0
0 (TH, 8) Reference Example 2 (11(R1-3-hydroxy-2-pyrrolid:z['
l'etrabydron l, etters, 2
617 (1971) ] 21' in 30 ml of acetone
Suspend the mixture in water, add 15ml of 2N sodium hydroxide at room temperature to dissolve, and cool to -3 to 5°C. To this was added 57 g of p-toluenesulfonyl chloride, and the mixture was stirred at the same temperature for 1 hour, and then stirred overnight at 10-15°C. Approximately 10 rnl of 2N hydrochloric acid was added to the reaction solution to adjust the pH to 2, and acetone was distilled off under reduced pressure. After the resulting aqueous solution is extracted with chloroform, the extract is washed with saturated brine and then dried. Next, chloroform was distilled off under reduced pressure, and the resulting residue was crystallized by adding ether and recrystallized from ethyl acetate (R1-
3-(p-tosyloxy)-2-pyrrolidone 3.5F is obtained.

M, p, 148-149°C [α]. +17,7° (c=l, methanol) NMR (
Cr)C/,)δ: 2.0-2.7 (2H, m), 2.43 (3T
], s), 3.1-3.5 (2TT, m).

4.91 (T(,t, J=7Hz), 7.2(I
T-T, broadL 7.32 (2TI.

d, J=9Hz), 7.84 (2H, d, J=9
Hz) (2) fRl-3-( obtained in (1) above)
p-)Syloxy)-2-pyrrolidone 1.53 F and potassium carbonate 1, Stir overnight at the same temperature, add water to the reaction solution, and extract with chloroform. Wash the extract with water, dry, and concentrate to dryness under reduced pressure. Add isopropyl ether to the residue to crystallize, and recrystallize from aqueous methanol. From 1 thing to do IZ-2-
<2-aminothiazol-4-yl)-2-(((3S
)-2-pyrrolidon-3-yl)oxyiminomonoacetic acid ethyl ester 086 was obtained.

M, p, 160-163°C [α1. ) River 59° (C=1.methanol) NMR (]
')N,4SO-d,)δ:1.27 (311,t
, J=7H, ), 1.93-2.60 (2H,
m).

34-3.5 (2H, m), 4.32 (2Ti
, q, J=7)1z).

4.74 (HT, t, J=7Hz), 6.
93 (ITl, s), 7.30 (2TI, S
).

7.96 (I H9s ) (3) Hydroxylation of the ester 107 obtained in (2) above
Add thorium 027F to 41 J of methanol-water mixed solution (methanol:water-3:1) and heat at 20°C for 1 hour (
Worship and dissolve. Add % hydrochloric acid to this reaction solution and add pT(
5 and distill off methanol under reduced pressure. 10 for the balance
Add 96 hydrochloric acid and adjust to TI3. Cool on ice. By filtering the precipitated product, washing it with methanol, and turning it over (Z
l-2-(2-aminothiazol-4-yl)-2-(
((3S)-2-pyrrolidon-3-yl)oximino)acetic acid 730~ was obtained.

M, p, 199-2 (') OoC (decomposition) -33 = [α) ” -50,8° (C = 1. water) NMR (D2
0+NaHCOB) δ: 2.0-2.7 (2H, m), 3.3-3.6
(2H1m).

4.95 (IH9L, J=8Hz), 6.9
0 (IH,S) Reference Example 3 By carrying out the same procedure as in Reference Example 2 using (S)-3-hydroxy-2-pyrrolidone, (Z)-2-(2-aminothiazol-4-yl)-2 -r(3R)-(2-pyrrolidon-3-yl)oximino]acetic acid is obtained.

Claims (1)

[Claims] 1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (However, R^1 is a hydrogen atom or a lower alkyl group, and n represents an integer 2 or 3.) (Z)-2-aminothiazolyl-2-substituted oxyiminoacetic acid compound or its reactive derivative and its general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III) (However, R^2 is an acetoxy group, (1-methyl- 1H-
Tetrazol-5-yl)thio group or a group represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R^4 is R
When ^2 is an acetoxy group or (1-methyl-1H-tetrazol-5-yl)thio group, a carboxy group or a protected carboxy group, R^2 is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the case of a group represented by the formula -C
It represents a group represented by OO^-, and Y represents a hydrogen atom, a hydroxymethyl group or a carbamoyl group. ) with (6R,7R)-7-amino-3-cephem-4-carboxylic acid compound or its salt, and R^
When 4 is a protected carboxyl group, the protecting group is removed, and if necessary, the product is converted into a pharmacologically acceptable salt thereof. General formula ▲ Numerical formula, chemical formula, table, etc. ▼(I) (However, R^3 is a carboxy group when R^2 is an acetoxy group or (1-methyl-1H-tetrazol-5-yl)thio group, and R^2 is the formula ▲Math. , chemical formulas, tables, etc. If the group is represented by ▼, the formula -COO^-
represents a group represented by R^1, R^2, Y and n have the same meanings as above. ) (6R,7R)-
[(Z)-2-(2-aminothiazol-4-yl)-
2-oximino-acetamide]-3-cephem-4-
A method for producing a carboxylic acid compound or a pharmacologically acceptable salt thereof.