JPH02223544A - Lactic acid compound - Google Patents

Abstract

NEW MATERIAL:A lactic compound expressed by formula I [R<1> is lower alkoxycarbonyl-(lower)-alkyl or nitro-substituted phenyl (lower)- alkoxycarbonyl-(lower)-alkyl; X is halogen], reactive derivative in carboxyl group of the lactic compound usable in acylation reaction and salts thereof. EXAMPLE:4-Chloro-2-methoxycarbonylmethoxyimino-3-oxolactic acid. USE:Useful as a syn isomer of 7-acylamino-3-vinylcepharosporanic acid derivative having antimicrobial activity and synthetic intermediate for salts permissible as medicine thereof. PREPARATION:The aimed compound expressed by formula I is obtained from a compound expressed by formula II. Specifically, the aimed compound is obtained from 2-methoxycarbonylmethoxytmino-3-oxolactic acid tert. butylester obtained by starting from 2-hydroxyimino-3-oxolactic acid tert. butylester and sulfuryl chloride.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel butyric acid compounds, reactive derivatives thereof at the carboxy group and salts thereof which can be used in acylation reactions.

More specifically, the present invention discloses a novel butyric acid compound useful as an intermediate for the synthesis of a syn isomer of a 7-acylamino-3-vinylcephalosporanic acid derivative having antibacterial activity and its pharmaceutically acceptable salts, and an acylation reaction. It relates to reactive derivatives at the carboxy group thereof and salts thereof which can be used for.

The butyric acid compound of this invention can be represented by the following general formula.

[In the formula, R1 is a lower alkoxycarbonyl (lower) alkyl group or a nitro-substituted phenyl (lower) alkoxycarbonyl (lower) alkyl group, and X means a halogen] Used in the acylation reaction of the butyric acid compound (1) of the present invention Reactive derivatives at the carboxyl group of Uruso include acid halides, acid anhydrides, active amides, active esters, etc. Among these, preferred ones include acid chlorides, acid bromides, substituted phosphoric acids (such as dialkyl phosphoric acids, phenyl phosphoric acids, Shifuenyl phosphoric acid, Shihenzil phosphoric acid, halogenated phosphoric acid) mixed anhydride, dialkyl phosphorous acid mixed anhydride, sulfite mixed anhydride,
Thiosulfate mixed anhydride, sulfuric acid mixed anhydride, alkyl carbonate (
mixed anhydrides, aliphatic carboxylic acids (e.g. bivaric acid, pentanoic acid, impentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid, etc.), aromatic carboxylic acids (e.g. Benzoic acid, etc.) mixed acid anhydrides such as mixed anhydrides, symmetrical acid anhydrides,
imida sheet 4-substituted imidazole, dimethyl pyrazole, tria sheet active amide with imino group-containing heterocyclic compound such as tetrazole, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,
Mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-talesyl thioester, carboxymethyl thioester, pyridyl ester, bipenodyl ester, 8-quinolyl thioester, N-hydroxy compound (
For example, N,N-dimethylhydroxylamine, 1-hydroxy-2(IH)-pyridone, N-hydroxysuccinimide, N-hydroxyfuculimide, 1-hydroxyhencytriazole, 1-hydroxy-6-chlorobenzotriazole, etc.) active esters such as esters of

Salts of butyric acid compound (I) and its reactive derivatives at the carboxy group that can be used in the acylation reaction include pharmaceutically acceptable salts, especially conventional non-toxic salts; Salts with bases, i.e. salts with inorganic bases, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, salts with organic bases such as triethylamine salts, Pyridine salt, bifrin salt, ethanolamine salt, triethanolamine salt,
Organic amine salts such as dicyclohexylamine salt, N,N' dibenzylethylenediamine salt, salts with basic amino acids such as arginine, etc. are included.

Suitable examples included in the definitions used above are detailed below.

The term lower is used to include groups having from 5 to 7 subatomic atoms, unless otherwise specified.

Suitable examples of the lower alkyl moiety of "lower alkoxycarbonyl (lower) alkyl group" and "nitro-substituted phenyl (lower) alkoxycarbonyl (lower) alkyl group" include straight-chain or branched groups, such as methyl , ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, inpentyl, neopentyl, hexyl, etc., among which alkyl having a prime number of 1 to 4 is preferred.

In addition, suitable examples of the lower alkoxycarbonyl moiety in the "lower alkoxycarbonyl (lower) alkyl group" include methoxycarbonyl, ethoxycarbonylpropyloxycarbonyl, butyloxycarbonyl,
Included are inbutyloxycarbonyl, tertiary butyloxycarbonyl, pentyloxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, and the like.

Preferred examples of the "lower alkoxycarbonyl (lower) alkyl group" defined in this way include methoxycarbonylmethylnylmethyl, etc., and "nitro-substituted phenyl (
Preferred examples of the "lower) alkyl group" include p-nitrobenzyloxycarbonylmethyl and the like.

Suitable "halogens" include chloro, bromo, iodo, and the like.

The butyric acid compound (1) of the present invention, its reactive derivatives at the carboxy group that can be used in the acylation reaction, and its salts can be produced by conventional methods, and the details are explained in Examples.

The compounds of the present invention are useful as synthetic intermediates for producing the syn isomer of 7-acylamino-3-vinylcephalosporanic acid derivatives having antibacterial activity and their pharmaceutically acceptable salts, as shown in the reaction formula below, for example. be.

(III) or a salt thereof (II) or a reactive derivative thereof at the amine group or a salt thereof IJ) or a salt thereof (V) or a pharmaceutically acceptable salt thereof; R is a carboxy (lower) alkyl group, R2 is a carboxy group or a retained carboxy group. Syn-isomer of 7-acylamino-3-vinylcephalosporanic acid useful as an antibacterial agent is obtained from the butyric acid compound of the present invention (
Details of the reaction to produce V) and its pharmaceutically acceptable salts are illustrated by the reference examples herein.

The syn isomer (V
) or its pharmaceutically acceptable salts exhibit high antibacterial activity inhibiting the growth of a wide range of pathogenic microorganisms, including Durham-positive and -negative bacteria, and are useful as antibiotics, especially for oral administration.

When administering Compound (V) or its pharmaceutically acceptable salts for therapeutic purposes, the compound (V) or its pharmaceutically acceptable salts may be administered as an active ingredient, together with a pharmaceutically acceptable carrier, such as a carrier suitable for oral, parenteral, or external use. They can be administered in the form of conventional preparations with organic or inorganic, solid or liquid excipients. Such formulations include solids such as tablets, granules, powders, and capsules, and liquids such as solutions, suspensions, syrups, emulsions, and lemonades.

Furthermore, if necessary, the above formulation may contain adjuvants, stabilizers, wetting agents, and other ingredients such as lactose, magnesium stearate, clay, sucrose, cornstarch, talc, stearic acid, gelatin, agar, pectin, peanut oil, and olive oil. , cocoa butter, ethylene glycol, and other commonly used additives.

The dosage of Compound (V) varies depending on the patient's age, condition, type of disease, and type of Compound (V) to be administered, but generally an amount of 1 mg to about 4000 mg or more can be administered to the patient per day. The average dose for one time is about 50 mg, 100 mg, 250 mg,
500mg, 1000mg, 2000mg can be used to treat diseases caused by pathogenic microorganisms.

Next, this invention will be explained in detail with reference to examples. Example 1 (1) 2-Hydroxyimino-3-oxobutyric acid tertiary butyl ester (syn isomer) (187 g) was mixed with ethyl acetate (280 mQ) and N. N-dimethylformamide (1
Potassium carbonate (166 g) was added to a solution of 87 mQ ) at room temperature. Methyl 2-chloroacetate (109 g) was added dropwise to the resulting suspension, and the mixture was stirred at room temperature for 7.5 hours. After adding ethyl acetate (280 mQ) to the reaction solution, inorganic substances were removed by filtration. The filtrate is washed four times with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 2 methoxy-bonylmethoxyimino-3-oxobutyric acid tertiary butyl ester (syn isomer) (246 g).

IR (liquid film) ' 1760.1740.1690.1
610 cm-'NMR (DMSO-d6.δ):
1.40 (9H, s), 1.23 (3H.

s), 3.62 (3H, s), 4.86 (2H
,5)(2)2-methoxycarbonylmethoxyimino-
Oxobutyric acid tertiary butyl enether (syn isomer) (
51.9 g) c> Add sulfuryl chloride (72.2
mQ ) was gradually added and stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting oil was diluted with ethyl acetate (
300mQ). This solution is washed once with 10% hydrochloric acid and four times with saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was
- Dilute with hexane (100 mQ) and concentrate to dryness.

The resulting white solid was washed with diisopropyl ether and dried to give 4-chloro-
Crystals (13.4 g) of 2-methoxycarbonylmethoxyimino-3-oxobutyric acid (syn isomer) are obtained.

IR: 1745. 172
0, 1701. 1604 cm-INMR (
DMSO-d6,S): 366(3H,s), 4.79
(2Hs), 4.92 (2H.s) Example 2 (1) 2-Hydroxyimino-3-oxobutyric acid tertiary butyl ester (226g) was dissolved in ethyl acetate (565mQ
) and N,N-dimethylformamide (340ml
), and to this was added chloroacetic acid p-nitropencyl ester (231 g) and potassium carbonate (166.8 g).
After adding, the mixture was heated to 50°C and stirred for 5 hours. The reaction solution was mixed with ethyl acetate (1000mA) and water (1000mA).
mQ). The organic layer is separated, washed with water and saturated brine, and dried over magnesium sulfate. Concentrate the solution to obtain an oil. This is crystallized, washed with diisopropyl ether, and collected by filtration to obtain 2-(+)nitrobenzyloxycarbonylmethoxyimino (259.8 g). mp63-65°C0IR (Sujoor)
: 1760, 1740. 1700.
1620 cm-INMR (CDCl2) & +
1.53 (9) 1,s>, 2.33 (3H.s
)4, 90 (2H,s), 5.35 (2H.s)
, 7.55 (2H, d.

J=9.0Hz), 8.23 (2H.d.J=9.
0Hz>(2>2-(p-nitropenyloxycarponyl=14 methoxyimino)-3-oxobutyric acid tertiary butyl varnish 5
Acetic acid (40 mQ) was added to the solution (40 g) and heated to 45°C. This was added to sulfuryl chloride (42.6 mA) while stirring.
) was added dropwise over a period of 30 minutes, and then stirred at 50°C for 5 hours. The reaction solution was poured into dichloroethane (300mQ),
After washing with water, dry with magnesium sulfate. Concentrate the solution to obtain an oil. This was crystallized from n-hexane and dichloromethane and washed with a small amount of diisopropyl ether to obtain 4-chloro-2-(p-nitrohensyloxycarlevonylmethoxyimino)-3-oxobutyric acid (8.1 g).
). 1p81-83℃.

IR (Nujol)' 1760. 1730.
1710. 1610 cm-”NMR (DMSO
-de,S) =4.79 (28,s), 5.1
2 (2H1s), 5.38 (28,s), 7.
67 (2H, d, J=9.0Hz).

8.23 (28,d, J=9.0Hz>Example 3 (1) 2-(p-nitrobenzyloxycarbonylmethoxyimino)-3-oxobutyric acid tertiary butyl ester (
A:-")
1 liter) gradually. 2 at 18-20℃ after the completion of dropping.
Stir for an hour. The reaction solution is concentrated, and the precipitated crystals are collected by filtration. After washing with diisopropyl ether and air drying, 2-(
p-nitrobenzyloxycarbonylmethoxyimino)
-3-oxobutyric acid (63.3 g) is obtained. mp104
~108℃ IR (Nujol): 3120. 1780.
1730. 1690. 1610°15200mI NMR (DMSO-da, 8)' 2.33 (3
H9s), 5.09 (2)1-s), 5.38 (
2H, s), 7.65 (2H, d, J=9Hz
), 8.22(2H,d,J-9)1z) (2) Acetic acid (s
sn+Q). The reaction solution was heated to 40°C, and sulfuryl chloride (30 mQ) was added dropwise over 15 minutes.

After the dropwise addition is completed, the reaction temperature is raised to 50-53°C. After 5 hours, the reaction solution was poured into ice water (200 ml+) and extracted with ethyl acetate (zoomQ). The remaining aqueous layer is extracted again with ethyl acetate (100 ml+). The combined extracts were washed with water (100 mQ) and dried over anhydrous magnesium sulfate. Ethyl acetate is distilled off, and the remaining oil is crystallized from dichloroethane and diisopropyl ether and filtered. The crystals were washed with diisopropyl ether and 4-
Chloro-2-(p-nitropenylmethoxyimino)-3-oxobutyric acid (12.5 g) is obtained.

Reference Example I A Vilsmeier reagent prepared in 11N1 from N,N-dimethylformamide (376 mQ) and phosphorus oxychloride (4,46 mQ) was mixed with dry tetrahydrofuran (50 mQ).
). 4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyric acid (syn isomer) (10.5 g) is added to this suspension and stirred under water cooling to produce the above active acid solution. This solution was heated to -7-amino-3-vinyl-3-cephem-4-carbon #(L) at 30°C.
og) and trimethylsilylacetamide (35 g) were added to ethyl acetate (110 mQ) at once, and the mixture was stirred at 15°C for 1 hour. The reaction mixture was poured into water (100 mQ) and extracted with ethyl acetate (200 mQ).

The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. When the solvent is distilled off under reduced pressure and the residue is triturated with diisopropyl ether, ? -(4-chloro-2-methoxycarbonylmethquinimino-3-oxobutyramide)-3=vinyl-3-cephem-4-carboxylic acid (syn isomer) (16,75 g) is obtained.

IR (Sujoor): 3200. 1760.
1727. 1702°1650 cm-1 NMR (DMSO-d6.δ): 3.66 (3)
1. s), 3.50.3.88 (2H, ABqj=1
8Hz), 4.73 (2H,s), 4.88 (
2H.

s), 5.15 (1)1. d, J=5)1z),
5.26 (1)1. d.

J=11Hz), 5.55 (LH, d,, T=
18Hz>, 5.90 (IH.

dd, J=5Hz, 8Hz>, 6.90 (L
H, dd, J = 11Hz.

18) 1z>, 9.42 (IH, d, J=8Hz
>Reference Example 2 N, N-'; Vilsmeier reagent prepared from methylformamide (3.4 g) and phosphorus oxychloride (7.1 g) is suspended in dry tetrahydrofuran (aomQ).

4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyric acid (syn isomer) (10 g) was added to this suspension.
was added under water cooling and stirred at the same temperature for 1 hour to produce the above active acid solution. This solution was mixed with ethyl acetate (163ml) of 7-amino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester hydrochloride (16.3g) and trimethylsilylacetamide (40g) under cooling at -30°C.
Add to Q) twice and stir at -15°C for 1 hour. The reaction mixture was poured into water (100 mQ), and then ethyl acetate (2
00mQ). The extract is washed with a saturated aqueous solution of sodium hydrogen envyate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. When the solvent is distilled off under reduced pressure, 7-
(4-Chloro-2-methoxycarbonylmethoxyimino-3-oxbutyramide)-3-vinyl-3-cephem-4-carboxylic acid benzhuman norester (syn isomer) (21.8 g) is obtained.

IR (Sujoor): 3260. 1770.
1750. 17081660 am' NMR (DMSO-d6.δ): 3.55.3.9
4 (2H, ABqJ=18Hz), 3.65 (3
H, s), 4.75 (2H, s), 4.87 (2
H, s), 5.22 (IH, d, J=5Hz),
5.23 (LH, d.

J=11Hz), 5.57 (LH, d, J=17)
1z), 5.85 (IHdd, J=5Hz, 8H
z), 6.71 (IH, dd, J=11Hz17H
2), 6.90 (LH,s), 7.28 (10
H, m>, 9.46 (LH, d, J = 8 Hz) Reference example 3 7-(4-chloro-2-71-oxycarbonylmethane2〇-toximinol-3-oxobutyramide)-3-vinyl-3 -cephem-4-carboxylic acid (syn isomer) (2,
Thiourea (0g) was suspended in water (20mQ).
0,683g) and sodium acetate (1,84g) at 40%
The mixture was added at °C and stirred at the same temperature for 1.5 hours. 1 of the reaction solution
After adjusting the pH to 2.8 with 0% salt, the mixture was stirred for 20 minutes under water cooling. The precipitate was collected by filtration, washed with water, and dried over phosphorous oxide to give 7-[2-(2-aminothiazol-4-yl)-
2-methoxylponylmethoxyiminoacetamidoco-3-vinyl-3-cephem-4-carboxylic acid (synisomer) (1.9 g) is obtained.

IR (Nujol): 3240. 1760
(Broad), 1724. 1650 (broad) cm-' NMR (DMSO-d6. δ): 3.50
．． 3.88 (2H, ABq.

J=18)1z), 3.65 (3H,s), 4.
67 <2H, s), 5.17 (IH, d, J=5)
1z), 5.28 (IH, d, J=11Hz>,
5.51 (IH, d, J=18Hz), 5.75 (
1)1. ddJ=5Hz, 8Hz).

6.73 (IH, s), 6.88 (1B, dd,
J=11Hz, 18Hz).

9.50 (IH, d, J=8Hz) Reference Example 4 (1) 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxbutyramide)-3vinyl-3
-cephem-4-carboxylic acid benzhydryl ester (
Add thiourea (0.0%) to a mixed solution of (2.0g)
,5g) and sodium acetate (1.34g),
Stir at °C for 4 hours. The reaction solution was diluted with ethyl acetate (100m
Q) and wash the extract twice with a saturated aqueous solution of sodium chloride. After drying this solution over magnesium sulfate, the solvent was distilled off under reduced pressure.
4-Carboxylic acid benzhydryl ester (syn isomer)
(2.0 g) is obtained.

IR (Nujol): 3440. 3260.
1778. 1740. 1720°1662, 16
20 cm' NMR (DMSO-9,8): 3.3-3.9 (
2H, m), 3.63 (3H, s), 4.67
(2)1. s), 5.23 (1)1. d, J
=5Hz).

5.26 (18, d, J=11Hz), 5.60
(IH, d, J=18Hz).

5.86 (LH, dd, J-5Hz, 8Hz>,
6.50-7.03 (LH.

m), 6.76 (LH,s), 6.88 (
IH, s), 7.28 (10H, m>, 9.5
6 (IH, d, J=8Hz) (2) 7-[2-(2-
Aminothi(r-4-yl)-2-methoxycarbonylmethoxyiminoacetamide]-3-vinyl-3
-cephem-4-carboxylic acid benzhydryl ester (
syn isomer) (2.0 g) of dichloromethane (amQ)
2. Anisole (2 ml) was added to the solution at room temperature under stirring.
2.2 Add trifluoroacetic acid (amQ) and stir for 1 hour. The reaction solution was submerged in diisopropyl ether (5omQ), and the precipitate was collected by filtration. This precipitate was dissolved in a 5% aqueous sodium hydrogen suboxide solution (2omQ) and then adjusted to pH 3.0 with 10% hydrochloric acid. When the precipitate is collected by filtration, washed with water and dried, 7-[2-(2-aminothiazole-
4-yl)-2-methoxycarbonylmethoxyiminoacetamidoco-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1,35 g) is obtained.

IR (Nujol): 3240. 1760
(Broad>, 1724. 1650 (Broad) .nl-1 Reference Example 5 7-[2-(2-aminothiazol-4-yl)-2-
Methoxycarbonylmethoxyiminoacetamidocarboxylic acid (syn isomer) (2.0g) and! ! #A reaction mixture of sodium hydrogen (L8g) added to water (40mQ) is stirred at 40-45°C for 7 hours. The reaction solution was adjusted to pH 5.0 with acetic acid. After adjusting to 0, nonionic adsorption resin "Diaion HP-20, (trademark, manufactured by Mitsubishi Chemical Corporation) (20
+IIQ) column chromatography and elute with water. The eluate was adjusted to pH 2.0 with 10% hydrochloric acid under water cooling. 2 to i1! II! The precipitated solid was collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2
-Carboxymethoxyiminoacetamidoco-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0
．． 9g) is obtained.

IR (Nujol) i 3350. 17
70, 1680. 1640 cm-”NMR
(DMSO-d6, δ): 3.70
(2H, q, J=18Hz), 4.62 (2H.
s), 5.21 (IH, d, J=5Hz),
5.82 (IH, dd.

J=5Hz. 8Hz), 5-6 (2H.m>
, 6.82 (LH.s).

7, 22 (2H, broad s), 6.5-7
．． 5 (LH, m), 9.50 (LH, d, J=
8Hz) Reference Example 6 7-[2-(2-aminothiazol-4-yl)-2-
Ethoxyluponylmethoxyiminoacetamide co-3
-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.45 g) and sodium bicarbonate (0.6
3 g) in water (15 mA) is stirred at room temperature for 7 days. After adjusting the reaction solution to pH 6.0 with acetic acid, a nonionic adsorption resin "Diaion HP-20 J (3
0ml! > column chromatography and elute with water. The eluate was diluted with 10% hydrochloric acid under water cooling p)12. 2
When the precipitated solid is filtered and dried, 7-
[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamide Fl-3-vinyl-3
-Cephem-4-carboxylic acid (syn isomer) (0.7g
).

Reference example? N,N-dimethylformamide (1.78mQ)
A Vilsmeier reagent was prepared from phosphorus oxychloride (2.11ml) and 4-chloro-2
-(p-nitrobenzyloxycarbonylmethoxyimino)-3-oxobutyric acid (6.98 g) was added and stirred for 30 minutes under water cooling to prepare the above active acid. 7-Amino-
3-vinyl-3-cephem-4-carboxylic acid (4 g) was suspended in water (zsml) and potassium carbonate (2.44
Add g) and allow it to dissolve. Add acetone (28I) to this solution.
After adding IIQ) and stirring at -3 to 3°C, the above active acid is added. Adjust the pH to 7-8 with a 20% aqueous potassium carbonate solution. After stirring at -3 to 3°C for 40 minutes, thio-sodification (2.
69g) and adjust the pH to 6~ with 20% potassium carbonate aqueous solution.
Adjust to 6.5. After stirring at room temperature for 2.5 hours, the pH was adjusted to 3 with concentrated hydrochloric acid, and the solvent was distilled off under reduced pressure. Then, under water cooling, the pH was adjusted to 2.0 with 10% hydrochloric acid. 8, stirred for 30 minutes, filtered, and dried to give 7-[2-(2-aminothiazol-4-yl)-2-6-(p-nitrobenzyloxycarbonylmethoxyimino)acetamide]-3- Vinyl-3-cephem-4-carboxylic acid (syn isomer) (9.31 g) is obtained.

IR (Nujol)' 1765. 1680.
1630 cm-'NMR (DMSO-d6.S)
:370 (2H9m), 486 (2Hs), 5.2
(IH, d, J=5)1z), 5.33 (
LH, d.

J=11.5)1z), 5.36 (2H,s),
5.56 (IH, d.

J=16)1z), 5.85 (IH, dd, J=8
Hz, 5H2>, 6.83(LH,s), 6.9
6 (IH, dd, J=16Hz, 11.5)1z>
.

7.62 (LH, d, J=8Hz>, 8.17 (
IH, d, J = 8Hz).

9.63 (IH, d, J=8Hz) Reference Example 8 (1) N,N-dimethylformamide (t, 7gmQ)
A Vilsmeier reagent was prepared from phosphorus oxychloride (2,11 mm) and 4-chloro-2(p-nitrohensyloxycarbonylmethoxyimino)-3- in dry tetrahydrofuran (35 mm) and dry ethyl acetate (7 mc).
Oxobutyric 9 (6.98 g) was added and stirred for 30 minutes under water cooling to obtain an active acid solution. 7-amino-3-vinyl-3-
Cephem-4-carboxylic acid (4g) in water (2gmm)
Next, potassium (2.44 g) was added and dissolved. Add acetone (2 gmu) to this solution and
Add the above active acid solution while stirring at 3°C. 20%
Adjust the pH to 7-8 with an aqueous potassium carbonate solution. -3～3
Stir for 40 minutes at °C. Ethyl acetate was added to the reaction solution, and then the pH was adjusted to 3 with 10% hydrochloric acid. The organic layer is washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 7-[4-chloro-2-(p-nitrobenzyloxycarbonylmethoxyimino)-3-oxobutylamidoyo-3-vinyl-3-cephem-4-carboxylic acid (8.45 g). ) Get it.

IR (Nujol)' 1765. 1715.
1670 cm”-1HMR (DMSO-d6.f
)' 370 (2H1m) -4,77 (2Hs
), 5.08 (2)1. s), 5.23 (LH
, d, J=5Hz).

5.32 (LH, d, J=11Hz>, 5.38
(2H, s), 5.60 (1u, d, J=uuz),
5.83 (1)1. dd, J=8Hz, 5Hz>.

6.96 (IH, dd, J-17Hz, 11Hz)
, 7.67 (IH, d.

J=8Hz>, 8.23 (1)1. d, J-8Hz
), 9.53 (LH, d.

J=8Hz) (2) The above target compound (8.45g) was mixed with water (4umQ
), adjust the pH to 6 with a 20% aqueous potassium carbonate solution, and dissolve. Tetrahydrofuran (40 mm ) is added, and thiourea (2.42 g) is added at room temperature. 20
% potassium carbonate aqueous solution to 6 to 6.5, and stirred at room temperature for 2 hours and 30 minutes. The reaction solution was adjusted to pH 3 with concentrated hydrochloric acid, and the solvent was distilled off under reduced pressure. While cooling with water, adjust the pH to 2.8 with 10% hydrochloric acid and stir for 30 minutes. When the crystals are collected by filtration and dried, 7-[2-(2-aminothiazole-4
-yl)-2-(p-nitropenzyloxycarponylmethoxyimino)acetamitoco-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (9,02g
).

IR + 1765. 1680.
1630 cm-'(3)7-[2-(2-aminothiazol-4-yl)-2-(p-nitrobenzyloxycarbonylmethoxyimino)acetamitoco-3-
Vinyl 3-cephem-4-carboxylic acid (syn isomer) (
Add water (2QmQ ) to 2g) and cool to 5°C. Next, sodium hydrogen (0.3 g) was added to this suspension and dissolved. Next, a 30% aqueous sodium hydroxide solution is added at 0 to 3°C to adjust the pH to 113 to 115.

After stirring for 80 minutes, the pH was adjusted to 2.1 with 6N-hydrochloric acid, and the mixture was heated at 5°C.
Stir for 1 hour. The resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)ace).
Amitoko-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (115 g) is obtained.

Reference Example 9 <1) p-Nitrobenzyl alcohol (45g) and N
, a solution of N-dimethylaniline (372 mQ) dissolved in diisopropyl ether and diethyl ether (300 mQ)
Add 2-bromoacetate (25 mm) to 3
It is added dropwise at 0-35°C and stirred at the same temperature for 1 hour.

The reaction mixture is submerged in ice water and the organic layer is separated. After washing this organic layer with a 5% aqueous sodium hydrogen carbonate solution, the solvent was distilled off to produce 2-bromoacetic acid p-nitrobenzyl ester. N,N dimethylformamide (1
N-hydroxyphthalimide (39,
3g) and triethylamine (5gmQ) and stirred at room temperature for 1 hour. The reaction solution was submerged in ice water, and the precipitate was collected by filtration and washed with water, resulting in 2-phthalimidooxyacetic acid p-nitrobenzyl ester (69,268).

(2) Add 100% hydrane monohydrate (
A solution of 537 g) in methanol (7 mQ) was added, and the mixture was stirred at room temperature for 30 minutes. Add 20% hydrochloric acid (70%) to the reaction mixture under ice-cooling.
mQ ) and stirred at the same temperature for 10 minutes. Insoluble materials were removed by filtration, and pyridine (15 mQ) and (2-formamidothiazol-4-yl)glyoxylic acid (15 g) were added to the filtrate.
After addition, the mixture was stirred at room temperature for 25 hours. The reaction solution was adjusted to pH 7.5 with a 10% aqueous sodium hydroxide solution and washed with ethyl acetate. The resulting aqueous solution was adjusted to pH 2.0 with 10% hydrochloric acid.
and then extracted with ethyl acetate. This extract was treated in a conventional manner to obtain 2-(p-nitrohensyloxycarbonylmethoxyimino)-2-(2-formamidothiazol-4yl)acetic acid (syn isomer) (217 g).

IR (striped seal): 1770. 1680.
t630. 1600. 1510°12000m
I NMR (DMSO-d6.δ): 4.95 <28
．． s), 5°40 (2H.

s), 7.52 (IH, s), 7.65.8.2
0 (4H, dd.

J=9Hz>, 8.55 (IH,s>, 12
．． 60 (LH, Broad 5) (3) N,N-dimethylformamide (1,67mQ) and phosphorus oxychloride (1
,9gmu) of tetrahydrofuran (50.4mQ )
Prepare the Vilsmeier reagent from the solution using a conventional method. To this reagent was added 2-(p-2l-lobenzyloxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (synisomer) (7.35 g) under water-cooling and stirring. Stir at temperature for 30 minutes. The obtained above active acid solution was mixed with 7amino-3-vinyl-3-cephem-4-carboxylic acid (3.4 g) and trimethylsilylacetamide (11.8 g) (7) ethyl acetate (3
5mQ) solution at -20"C, -20 to -10°C
Stir for 1 hour. Water and ethyl acetate were added to the reaction solution, and the separated organic layer was washed with water and then dried. This solution was treated in a conventional manner to obtain a yellow powder of 7-[2-(p-nitrobenzyloxycarbonylmethquinimino)-2-(2-
Formamide thiazol-4-yl)acetamide]-
3-vinyl-3-cephem-4-carboxylic acid (/n isomer) (6.8 g) is obtained.

IR: 3250. 1765.
1680. 1520 am-INMR (DMSO-
d6+D20. S): 3.70 (2H, m)
, 4.87(2)1. s), 5.12 (LH, d
, J=5)1z), 5.28 (IH, d.

J=LH(z), 5.35 (28,s),
5.58 (1)1. d.

J=18)1z), 5.83 (LH, dd, J=8
Hz, 5Hz), 6.95(1)1. dd, J-1
8) 1z, 11Hz), 7.45 (LH,s),
7.63 (2H, dJ-9Hz), 8.17 (2
H, d, J=9Hz>, 8.50 (IH, s), 9
．． 68 <IH, d, J=8Hz) (4) 7-42-(
p-nitrohensyloxycarbonylmethoxyimino)
-1-(2-formamidothiazol-4-yl)acetamitoco-3vinyl-3-cephem-4-carboxylic acid (syn isomer) (6,7 g) in methanol (57 mQ
) Add concentrated hydrochloric acid (J, 4mQ) to the solution and stir at 30°C for 1 hour.

After concentrating the reaction solution and washing with isopropyl ether, 7-[2-(p-nitrohensyloxycarbonylmethoxyimino)-2-(2-aminothiazole-4-
) acetamidoyo 3 vinyl-3-cephem-4-
Carboxylic acid hydrochloride (syn isomer) (4,47g)
get.

IR (striped seal): 3300. 1780.
1750. 1660°16100m I NMR (DMSO-da, l; )' 3-75 (
2) 17s) -4-86' (2) 1°s), 5.30
(LH, d, J=5Hz), 5.35 (IH, d
J=11Hz>, 5.43 (2H,s), 5.6
2 (LH, d.

J=18Hz>, 5.85 (LH, dd, J=8H
z, 5Hz), 6.93 (IH, s), 7.02
(LH, dd, J48Hz, 11Hz>, 7.7
0 (2H, d, J=9Hz>, 8.25 (2H, d
, J-9Hz), 9.73 (IH, d, J=8Hz) Reference Example 10 7-[2-(2-aminothiazol-4-yl)-2-
(p-Nitrohensyloxycarbonylmethoxyimino)acetamitoco-3-vinyl 3-cephem-4-carboxylic acid (syn isomer) (4.4g) in water (5QmQ)
After the mixture is suspended in water, an equimolar amount of sodium hydrogen is added and dissolved. Insoluble materials were removed by filtration, and the filtrate was lyophilized to obtain the sodium salt (4.8 g) of the above compound. This compound is N,
Pivalic acid iodomethyl ester (1,9
Add a solution of g) in N,N-dimethylformamide (5 mQ) and stir at the same temperature for 15 minutes. The reaction solution was sank into a mixture of ethyl acetate (200 mQ) and water (200 m11) (7), and the ethyl acetate layer was separated. Add this solution to 5%
Wash with aqueous sodium hydrogen hypooxide solution and dry with magnesium sulfate. The solvent was distilled off in a conventional manner and powdered with diethyl ether to give 7-[2-(2-aminothiazole-
4-yl)-2-(p-nitrobenzyloxycarbonylmethoxyimino)acetami)']-3-vinyl-3
-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer) (3.18 g) is obtained.

IR (Sujimeal): 3300. 1770.
1740. 1680 cm-'NMR (DMSO
-d6+D20. δ): 1.17 (9H, s),
3.70 (2H, m), 4.83 (2H, s),
5.27 (IH, d.

J=5Hz>, 5.37 (2H,s), 5.
4 <IH, d, I=11Hz) 5.87 (LH, d
d, J=8Hz, 5Hz>, 5.88 (2H
, m).

6.83 (LH, s), 6.90 (IH, dd
, J=18Hz, 11Hz).

7.27 (2)1. m), 7.68 (2H, d
, J=8Hz>.

8.22 (2M, d, J=8Hz), 9.67
<IH, d, J=8Hz) Reference Example 11 (1) N,N-dimethylformamide (8.8g), phosphorus oxychloride (18.4g) and ethyl acetate (35mQ
) to Vilsmeier reagent using a conventional method? A Adjust.

A solution of this reagent in tetrahydrofuran (1somQ) contains 4
-Chloro-3-oxo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)butyric acid (37.6g
) was added under water cooling and stirred at the same temperature for 30 minutes to prepare the above active acid solution. On the other hand, 7-amino-3-vinyl-3
-Cephem-4-carboxylic acid (22.6 g) is dissolved in a mixture of water (16 omQ) and acetone (160 ml) (7) containing potassium carbonate (t3.sg). To this solution was added the active acid solution obtained above at 13-3"C, and the mixture was stirred for 30 minutes at the same temperature while maintaining the temperature at 16.5-75% (20% 0% potassium carbonate aqueous solution). -3
-Sakiso-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)butylamitoco-3-vinyl-
A solution of 3-cephem-4-carboxylic acid is obtained.

2) After adding thiourea (1i, ag) to this solution,
Stir at room temperature for 2.5 hours while maintaining the pH at 6.0 to 6.5 with a 0% aqueous potassium carbonate solution. The reaction solution was adjusted to 9) 13.0 with 10% hydrochloric acid, and the solvent was distilled off under reduced pressure. The remaining solid was collected by filtration, washed with water, and dried to give 7-[2-
(2-aminothiazol-4-yl)-2-(2,2,
2-Trichloroethoxycarbonylmethoxyimino)acetamidogo 3-vinyl-3-cephem-4-carboxylic acid (32.3 g) is obtained.

IR (Sujimeal): 3270. 1760
(Broad), 1663 (Broad) Cm' NMR (DMSO-d δ)' 3.68 (2H
, m), 4.87 (2)1゜6゜s), 4.93 (2Ls>, 5.17 (IH,
d, J=5.0Hz>.

5.28 (IH, d, J=12.0Hz), 5.5
3 (LH, d.

J=18.0Hz), 5.73 (IH, dd, 5
．． OHz, 8.0Hz>.

6.83 (IH, s), 6.87 (LH, dd,
J=12.082゜18.0Hz), 9.53 (
LH, d, J=8.0Hz>(3)? -[2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetamitoco-3-vinyl-3-cephem-4-carboxylic acid (1
,0g) at 25°C and sodium bicarbonate (0.7g) at 25°C.
(14111u) and stirred at 25-27°C for 4 hours.

The reaction solution was adjusted to pH 2.2 with 10% hydrochloric acid under water cooling, and the precipitate was collected by filtration. When this precipitate is washed with water and dried, 7
-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamide]-3-vinyl-
3-cephem-4-carboxylic acid (syn isomer) (0,4
5g).

Claims (1)

[Claims] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a lower alkoxycarbonyl (lower) alkyl group or a nitro-substituted phenyl (lower) alkoxycarbonyl (lower) alkyl group, and X is a halogen A butyric acid compound represented by the following, a reactive derivative at its carboxy group that can be used in an acylation reaction, and salts thereof.