JPH01308285A - Beta-lactam derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> and R<2> are H or amino-protecting group; R<3> is H, salt-forming cation or protecting group of carboxylic acid; R<4> is H, halogen or lower alkyl) or salts thereof. EXAMPLE:p-Methoxybenzyl 7-amino-3-[(Z)-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4- car-boxylate. USE:An intermediate for beta-lactam-based cephem derivatives. PREPARATION:A phosphorus-ylide expressed by formula II is reacted with an aldehyde expressed by formula III normally in a solvent, such as THF, dioxane, methylene chloride, DMF or water, preferably at ambient temperature.

Description

Detailed Description of the Invention [Industrial Application Field] [In the general formula, R1 and R1 are a hydrogen atom or a protecting group for an amino group, and R3 is a hydrogen atom, a salt-forming cation or a protecting group for a carboxylic acid, R4 is a hydrogen atom, )\rogen atom or a lower alkyl group. ] or its salts. General formula (1)
The compound is a new substance and is a useful intermediate that can be converted into a β-lactam cephem derivative having antibacterial activity by condensing the amino group at the 7-position with an appropriate carboxylic acid.

[Conventional technology]

Conventionally, useful synthetic intermediates for cephem-based β-lactam agents include acetoxymethyl at the 3-position in the cephem nucleus, and various
Heterocyclic thiomethyl derivative at position, hydrogen type derivative with unsubstituted position at 3 [above, S, M it's u h'a s'hl'
.

β-Lactam Antibiotics.

R59 (1981)), 3-position unsubstituted vinyl body (J, An
tibiotics, 39, 101 (1986)).

[Problem that the invention seeks to solve]

The present inventors, with the aim of searching for new cephalosporin antibiotics, investigated new 3-position modified forms of cephalosporanic acid, which is a raw material for them, and found that the general formula [I]
The present invention has been completed based on the discovery that the novel β-lactam derivative of the present invention, represented by the following formula, in which a thiadiazole group is substituted at the β-position of the vinyl group, is a useful synthetic intermediate for cephem-based β-lactam agents.

[Means to solve the problem]

The compound represented by the general formula (1) has a cephem nucleus 3
It has a thiadiazole-substituted vinyl group at the position. This substituent has (E) and (Z') isomers based on geometric isomerism, and the present invention includes these (E) isomers, (Z) isomers, or mixtures thereof.

The salts of the compound of the present invention (1) include base and acid addition salts, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and salts with organic bases. , organic amine salts such as ethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, hydrochlorides, hydrobromide salts, sulfates, nitric acid.

salts, inorganic acid addition salts such as phosphates, formates, acetates, tartrates, methanesulfonates, Hensensulfonates, p
-Includes organic carboxylic acid or sulfonic acid addition salts such as toluenesulfonate.

R1 and R2 in the general formula [I] are a hydrogen atom or a protecting group for an amino group, and examples of the protecting group for an amino group include tertiary butoxycarbonyl, benzyloxycarbonyl, formyl, chloroacetyl, trityl, alkylsilyl, (Substituted or unsubstituted) phenylacetyl, (substituted or unsubstituted) phenoxyacetyl, substituted or unsubstituted 5-amino-5-carboxypentanoyl, and the like. moreover,
A dimethylamino methylene group, a (substituted or unsubstituted) benzylidene group, etc. formed by R1 and R2 are also included as a protecting group for the amino group in general formula (1).

However, in the meaning of the protecting group of R1 and R1, α-oximi,
It does not include groups that do not normally serve as protecting groups for amino groups in the field of penicillins and cephalosporins, such as the noaminothiazole acetyl group.

R3 is a hydrogen atom, a salt-forming cation, or a carboxylic acid protecting group 1. Protecting groups for carboxylic acids include alkyl groups, lower alkoxymethyl groups, lower alkylthiomethyl groups, lower alkanoyloxymethyl groups, lower alkoxycarbonyloxyalkyl groups, (2-oxo-1,3-dioxolen-4-yl)methyl Examples include groups commonly used in conventional penicillin and cephalosporin compounds, such as alkyl groups, aralkyl groups, aryl groups, and silyl groups. R4 is a hydrogen atom, a halogen atom, or a carbon number (1 to 30
) is a lower alkyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the lower alkyl group include a methyl group, an ethyl group, a butyl group, and the like.

Here, the term "lower" used in the present invention means □1 to 6 carbon atoms, unless otherwise specified.

The compound of the present invention is a phosphorus-ylide represented by the general formula (II) produced by the following method.
Let the aldehyde shown by act. Phosphorus-ylides of general formula (II) are available from J. Antibiotics.

■, 1738 (1985)
-m-Qi “4了I川-5-==(-=1-9-7=O
The two-bowl reaction is usually carried out in tetrahydrofuran, dioxane, methylene chloride dimethylformamide, water, or a mixed solvent thereof. Although the reaction temperature is not particularly limited, it is preferably around room temperature.

A compound in which R1 and RZ are both hydrogen atoms in the general formula [■] is formed by deprotecting the protecting groups R1 and RZ. This deprotection reaction is achieved by hydrolysis, reduction, or reaction using a Lewis acid. Acid hydrolysis is one of the common methods and is applied, for example, to eliminate alkoxycarbonyl groups, formyl groups, trityl groups, etc.

Acids used include formic acid, trifluoroacetic acid,
I)-) Organic and inorganic acids such as luenesulfonic acid, hydrochloric acid, and sulfuric acid. The reaction can be carried out without a solvent or in the presence of water, a hydrophilic organic solvent, or a mixed solvent. When using trifluoroacetic acid, the reaction may be carried out in the presence of anisole.

In addition, for the removal of the protecting group of general 2 [), R1, Rm,
The protecting group can be removed by reacting the compound CI) with an iminohalogenating agent and then with an iminoetherifying agent, and if necessary, hydrolyzing and attaching the resulting compound. Furthermore, a compound in which R3 is a hydrogen atom in general formula (1) is formed by eliminating the protecting group R3 of a carboxylic acid. For the elimination reaction of the protecting group of carboxylic acid, any commonly used method such as hydrolysis or reduction can be applied. Hydrolysis using an acid is one of the common methods and is applied, for example, to eliminate silyl groups, t-butoxy groups, p-methoxyhensyl groups, diphenylmethyl groups, etc.

On the other hand, the method for obtaining the desired ester from a compound in which R3 is a hydrogen atom in general formula (1) is a known and commonly used method, for example, using a metal salt of a carboxylic acid and a corresponding alkyl halide such as pivaloyloxymethyl halide in a solvent. This can be achieved by reacting inside.

The temperature for the above-mentioned removal of the protecting group and reaction of the ester is not particularly limited, and the reaction is usually carried out under cooling or at room temperature.

The β-lactam derivative represented by the general formula (1) of the present invention obtained by the above method can be protected, if desired, by condensation with a carboxylic acid that becomes a modified chain at the amino group at position 7 of the cephem nucleus. It can be converted into a cefprosporin derivative having antibacterial activity via removal of a group or the like. (See reference side below).

Reference Example 1 Formic acid (4", 3g.0.093mol) and acetic anhydride (9.4g, 0.093mol) were mixed and stirred at 50°C for 1 hour. 7-Amino-3-chloromethyl- 3-
Cephem-4-carboxylic acid p-methoxyhensyl ester p-)luenesulfonate (10 g, 0.01!
1 mo I) was suspended in dry THF (30 ml),
Triethylamine (1,87g.

0.01-9　m　o　+,　) was added dropwise and dissolved.

After cooling on ice, the formic acid-acetic anhydride mixture was cooled to room temperature,
Ethyl acetate (250 ml) and a small amount of saturated sodium hydrogen carbonate were added to the residue to dissolve it. The organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried, filtered, and concentrated, and the residue was washed with hexane to form crystals.
-chloromethyl-7-formylamino-3-cephem-
Obtained p-methoxybenzyl 4-carboxylate (7 g).

'H-, NMR (0MSO4-d6) δ 3.67
(qA,, J=18Hz, 2H), 3.78(s, 3H
), 4.55 (bs,, 2H).

5.22 (d, J=2Hz, IH),
5.27 (s, 2H), 5.87 (dd,
J=4Hz.

J=8Hz, IH), 6.417 (d,
J=9Hz, 2H), 8.16 (s,
LH), 9.10(d, J=8Hz, I
H).

The above 3-position chloromethyl compound (78g, 0.0], 8mo
I) was dissolved in DMF (20ml). Sodium iodide (2.7g, 0.018mol) and truffles!
: 7L/phosphine (7.1g, 0.027mo +
) was added, dissolved, and stirred at room temperature for 2 days. Isopropyl ether (400ml) and isopropyl alcohol (
400 ml) of the mixed solution. The precipitate was filtered to obtain 7-formylamino-4-(4-methoxyhensyloxycarbonyl)-3-cephem-3-ylmethyl triphenylphosphonium iodide (6.6 g).

' HN M R (D M S Od b ) δ 3.
64 (qAB, J = 18H2, 2H), 3.80 (s,
3H), 4.76 (qAIl, J=1
6H2゜2H), 5.14 (s,,2H),,
5.33 (d, d, J=4Hz, J=8Hz,
LH).

6.94 (d, J=9Hz, 2H), 7
．． 24 (d, J=10Hz, 2 Summer ()
, 1. □81 (s, 5H), 8.1
8 (s, LH)+' 9.17 (d, J
=8Hz, LH).

The above phosphonium salt (0.5 g, 0.67 mol) was dissolved in methylene chloride (5 ml). A 1N sodium hydroxide solution (0.75ml) was added, and the mixture was stirred at room temperature for 15 minutes. The organic layer was washed with an aqueous sodium chloride solution until the aqueous layer became neutral, then dried and concentrated, and the remaining precipitate was washed with hexane to give 7-formylamino-3-triphenylphosphoranylidenemethyl-3. -Cephem-4-carboxylic acid p-methoxyhensyl (0.32 g) was obtained.

LH-NMR (DMSO-d6) 63.2-3.6 (m
, 2H), 3.17 (s, 3H), 5.07 (s,
2H), 5.13 (d, J-4Hz.

LH), 5.23 (dd, J=4Hz,
J = 8H2, IH), 5.48 (d, J
=2.2.5Hz.

LH), 6.92 (d, J = 101 (z
, 2H).

7.53 (d,, J=10Hz, 2H),
7.77 (s, 15H), 8.13 (s,
IH).

8.81 (d, J=8Hz, LH).

IR(KBr) 3250. 3050. 295
0゜1?60. 1680. 1620. 1510°1480,, 1440. 1390. 1300°1
240, 1220. 1170. 1100°103
6, 1010. 1000. 890°820, 7
50. 720. 690. 520° Example 1 7-formylamino-4-(4-methoxybenzyloxycarbonyl)-3-cephem-3-ylmethyl iodide Triphenylphosphonium (4.5 g.

Using crude p-methoxybenzyl 7-formylamino-3-triphenylphosphoranylidenemethyl-3-cephem-4-carboxylate (3 g) prepared by the method of Reference Example 1, using methylene chloride (5.9 mol) as a raw material, 20ml) and 4-formyl-1゜2.3-thiadiazole (
1 g, 8.8 mrno +) was added. After stirring at room temperature overnight, the solvent was distilled off under reduced pressure and purified by silica gel column chromatography to obtain 7-formylamino-3-((Z)-
2-(1'.

2.3-thiadiazol-4-yl) vinylcou 3-cephem-4-carboxylic acid p-methoxyhensyl (0,6
g) was obtained as a yellow powder solid.

' HNMR (I) MS O' d a) 63.6
8 (qAB.

J-18Hz, 2H), 3.78 (s, 2H).

5.03 (s, 2H), 5,27 (d, J=5Hz
'.

IH), 5.86 (dd, J-9Hz, J=5H2,
LH), 6.72 (d, J=12Hz.

IH), 6.92 (d, J=9Hz; 2H).

6.97 (d, J-12Hz, LH), 7.28 (d
, J=9Hz, 2H), 8.18 (s.

IH), 9.04 (s, LH), 9.13 (d.

J=9Hz,,LH).

The above ester (0.6 g, 1.3 mmol) was dissolved in methanol (10 ml). Concentrated hydrochloric acid (0.1ml
) and stirred at room temperature for 2 hours. After distilling off the solvent, a small amount of water was added to the residue, and a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8 to 9. Ethyl acetate was added to dissolve, and the organic layer was separated. The organic layer was dried and the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain a yellow powder solid, which was 7-amino-3-((Z)2-(
1,2,3-thiadiazol-4-yl)vinylcou 3
-cephem-4-carboxylic acid p-methoxybenzyl (0
, 21g) was obtained.

'H-NMR (DMS○-da) δ 3.68
(QAIIJ=18Hz, 2H), 3.77 (s,
2H).

5.03 (s, 2H), 5.16 (d, J=5
Hz.

LH), 6.68 (d, J=12H2, LH>.

6.93 (d, J=9Hz, 2H), 6.96 (d
, J=12Hz, IH), 7.28 (d.

J=9Hz, 2H), 9.03 (s, IH).

Example 2 7-phenylacetamido-3-chloromethyl-3-L
! p-methoxybenzyl fuemu-4-carboxylate (,1
(Ig, 20 m, m o 1) and sodium iodide (3,,3 g, 22 mmo +) in DMF (,45
9 ml) Dissolved W, triphenylphosphine (5,
8! .

22 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. , the reaction mixture was added to inpropyl alcohol-diisopropyl ether (1:1.2000ml).

The precipitate was collected by filtration and then dried under reduced pressure to obtain a white crystalline compound. After dissolving this compound in methylene chloride (30 ml), 4-formyl-1,2,3-thiazole (2,
7 g, 24 mmol I) was added, and a saturated aqueous sodium hydrogen carbonate solution (30 ml) was added, followed by stirring at room temperature for 18 hours. After the reaction solution was separated, the methylene chloride layer was washed with water. It was dried over magnesium sulfate and the solvent was distilled off to obtain a residue.

Purified by column chromatography, 7-phenylacetamide-3-((Z)-2-(
1,2,3-thiadiazol-4-yl)vinyl]-3
-cephemu-4-carboxylic acid p-methoxybenzyl (7
, 6 g, yield 70%).

'H-NMR (δ, CDC1,) i3.48 (d, J=
18Hz, LH>, 3.73 (d.

J=18Hz, IH), 3.77 (s, 3H).

5.05 (d, J-5Hz, 2H), 5.25 (d,
J-5Hz, ]H), 5.79 (dd.

J=5Hz, J=8Hz, IH), 6.70(d,
J=12Hz, IH), 6.92 (d.

J-9Hz, 2H), 6.98 (d,
J=12Hz, LH), 7.40 (d,
J=9Hz.

2H), 7.42 (s, 5H), 9.
03 (s.

IH), 9.17 (d, J=8Hz,
IH).

IR (KBr); 3300. 3050°2970
, 1770. 1665. 1620°1540,
1520. 1380. 1360°1300, 12
50. 1180. 1100°1030, 980.
825. 700°5 40cm-'.

Example 3 -20 = Phosphorus pentachloride (8.12 g,
39 mmol) was added and cooled to 5°C. Pyridine (1
0.39g+130mmo I) was added and stirred for 1 hour. Add 7-phenylacetamide-3- to this reaction solution.
Add p-methoxybenzyl ((Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephemu-4-carboxylate (7,27 g, 13 mmo 1),
Stirred at 5°C for 4 hours. The reaction solution was cooled to -30°C,
Dehydrated methanol (53 ml) was added and stirred for 1 hour.

The reaction solution was returned to -10°C, water (1'0ml) was added,
Stir for a minute. After adding saturated sodium hydrogen carbonate to the reaction solution to adjust the pH to 4, the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography to give 7-amino-3-[(Z) as a pale yellow powder.
-2-(1°2.3-thiadiazol-4-yl)vinyl]-3-cephemu-4-carboxylic acid p-methoxybenzyl (3; 9 g, yield 70%) was obtained.

Example 4 Benzhydryl 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate (12.8 g,
Triphenylphosphine (6.9 g, 26.4 mmol) and sodium iodide (3.96 g) in a DMF (32 ml) solution of 24 mmol +).

26.4 mmo+) was added thereto, and the mixture was stirred at room temperature for 3 hours.

The reaction solution was added to ethyl acetate (500ml).

After filtering the precipitate, it was dried to obtain a white crystalline compound (21
, 56g) was obtained. After dissolving this compound (17.72 g) in methylene chloride (30 ml), 5-formyl-4
-Methyl-1,2,3-thiadiazole (2,49 g,
19.4 mmol 1) was added thereto, and further a saturated aqueous sodium hydrogen carbonate solution (30 ml) was added, followed by stirring at room temperature for 3 hours. The reaction solution was separated, and the methylene chloride layer was washed with water. After drying with magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography to obtain 7-phenylacetamido-3-(2-(4-methyl-1,2,3-thiadiazol-5-yl)vinyl copolymer). 3-position double bond isomer of benzhydryl 3-cephem-4-carboxylate (E/Z=
1/3.5.5.69 g, yield 47%) was obtained.

' HN M R (CD C13, E and 1 of the 2 isomers
:3.5 mixture) δ2,50 and 2.56 (s, 3H)
, 3.20 (ABq, J=18Hz, 2H), 3.6
0 (s, 2H).

4.96 and 5.03 (d, J = 4.5Hz.

IH), 5.89 (d, d, J=4.5Hz.

J=9Hz, IH), 6.33 (d, J=12Hz,
LH), 6.53 (d, J=12Hz, IH)
, 6.76 (s, IH).

7.13-7.26 (m, 15H), I
R (KB r) 3300. 3050°1790,
1730. 1680. 1530°1380, 1
220. 11.80. 1090°1005, 74
0. 70(lend-'.

Example 5 Phosphorus pentachloride (5.83 g, 28 mm o 1)
was suspended in methylene chloride <50 ml), and pyridine (
7,39'g, 93 mmol) was added at 5-10°C, and stirring was continued for 40 minutes. To this, benzhydryl 7-phenylacetamido-1-(2-(4-methyl-1,2゜3-thiadiazol-5-yl)vinylcou-3-cephem-4-carboxylate (E/Z=1/3.5, 5.69
g, 9.36 mmo I) was added in one portion at 5° C. and the mixture was stirred at the same temperature for 3 hours. Methanol (
38 ml) was gradually added at -50°C, and the mixture was heated at -50 to -30°C.
The mixture was stirred for 1 hour. Add water (7 ml) at -10°C,
After the reaction temperature was set to 0° C., the mixture was stirred for 10 minutes. The reaction solution was adjusted to pH 6 with saturated sodium bicarbonate solution, and then extracted with methylene chloride. After washing with water, the methylene chloride layer was dried with magnesium sulfate. After evaporating the solvent, ethyl acetate was added to the residue. After filtering the precipitate, it was washed with ethyl acetate to give 7-amino□-3-((Z)-2-(4-methyl-
1,2,3-thiadiazol-5-yl)vinylcou 3
-cephem-4-carboxylic acid benzhydryl (2,06
g.

A yield of 45% was obtained.

'H-NMR (CDCI, -d6DMSO) 62.5
0 (s, 3H), 2.80 (bs.

2H), 3.46 (ABq, J-18Hz
.

2H)', 4', 89 (d, J=3Hz,
IH).

5.10 (d, 1=3Hz, IH), 6.
36 (d, J-12Hz, 1'H), 6.
59 (d, J=12Hz, IH), 6.7
6 (s, “I H), 7.17~7.26 (m
.

10H).

TR(KBr) 3425. 2960°1765,
1720. 1600. 1390°137'0.1
290.1220,1100° Reference Example 2-(1,1 (Z)-2-(2-)ditylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (1,58'g,
2.35mmol 1) was dissolved in THF-methylene chloride (20mmol
1-10 ml) of a mixed solvent and cooled to 5°C.

To this reaction solution was added HOB T (0.32 g, 2.4 mmo
+), then DCC (0.50g, '2.4mm
o +) was added thereto, and the mixture was stirred at the same temperature for 2 hours. After the reaction solution was filtered, 7-amino-3-((Z)-1-(4
-Methyl-1゜2.3-thiadiazol-5-yl)vinyl]-3-cephemu-4-carboxylic acid henzhydryl (0.98 g, 2.0 mmo I) was added and the mixture was heated at 5°C for 22 hours.
Stir for an hour. After the reaction solution was concentrated, the concentrate was purified by column chromatography to obtain 7-C(Z)-2-('2-')ditylaminothiazol-4-yl)-2'-trityl as a yellow powder compound. oxyiminoacetamide) -3'-((Z) -'2-(4-methyl-
1,'2.3-thiadiazol-5-yl)vinyl]-
3-cephemu-4-carboxylic acid benzhydryl (1,
38 g, yield 60.5%').

'H-NMR (CDC11) δ, 2.50 (S
, "3'H), 3.10 (ABQ', 'J=18H
z.

2H),'5.13 (d,'J-4,5Hz.

I H), 6', 16" (d, 'd +" J
-4,5Hz'.

J=9Hz, LH), 6', 39 (s", 'I H
”).

6.43 (d, J=12H2, 1'M).

6.80 (s, IH), 7.10-7.4
0 (m, 40H).

IR (KB r) 3400. 3075°30'2
5. 1790. 1730. 1530°1500,
'1'440. 1220. 960°750, 70
'Ocm-'.

Reference Example 2-(21 7-((Z)'-2-' (2-tritylaminothiazol-4-yl)-2-)lythyloxyimino-acetamide)-3-((Z) -1-(4 -methyl-1,2
, 3-thiadiazol-5-yl) vinylcy 3-cephem-4-carboxylic acid benzhydryl (1,38g+
Formic acid (14 ml) was added to the mixture and stirred at room temperature for 1 hour. Add concentrated hydrochloric acid (Q, 1.1ml) to the reaction solution.
was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was washed with ether to obtain a yellow powder. This product is hydrogen carbonate) and dissolved in an aqueous solution of HP-
Purified by 20 column chromatography, 7-((Z)
-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide)-3-C(Z)-2-(4
-Methyl-1,2,3-thiadiazol-5-yl)vinyl c-3-cephem-4-carboxylate sodium (7
9■) was obtained.

'H-NMR (D20) δ2.55 (s, 3H
).

3.39 (ABq, J=18Hz, 2H).

5.36 (d, J=5Hz, 1.H), 5.843
l- (d, J=5H2,LH), 6:, 57 (
d.

J=11Hz, LH), 6.61 (d.

J-11Hz, LH), 6.91 (s.

IH).

IR(KBr) 3425. 1765°16is,
16. '00,1540.1390゜1 360cm-
'.

Example 6 Benzhydryl two-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate (40g+7
Triphenylphosphine (21,7 g) in a solution of 5 mmol 1) in DMF (100 ml).

83 mmol) and sodium collate (12.4 g.

83 mmo, l) was added thereto, and the mixture was stirred at room temperature for 2.5 hours.

The reaction solution was added to ethyl acetate, and the precipitate was collected by filtration.

The precipitate was washed with ethyl acetate and dried to obtain a white crystalline compound (74.62 g). This compound (29.3g, 3
3rhm61) was dissolved in methylene chloride (70ml),
4-formyl-5-methyl-1,'2. ．． ．． 3-thiazizole (4,231,'33rnmot) was added, and then a saturated aqueous sodium bicarbonate solution (49.5 ml) was added, and the mixture was stirred at room temperature for 1 hour and 10 minutes. The reaction solution was separated, and the methylene chloride layer was washed with water. After drying with magnesium sulfate,
The solvent was distilled off to obtain a residue. Purified by column chromatography to obtain 7-phenylacetamide-3-(2-(5
-methyl-1,2,3-thiadiazole-4-yl)
3-position double bond isomer of benzhydryl]-3-cephemu-4-carboxylate (E/Z=1/2.3, 6.2
1 g, yield 45%).

'HNMR (CDCa, E and 2 isomers 1:2.3
mixture) δ2.50 and 2.55 (s, 3H),
3.57 (ABq, J-18Hz, IH),
3.73 (s, 2H).

5.18 (d, J-4, 5Hz, IH).

5.90 (, d, d, J=4.5Hz,
J=9H2,LH), 6.45 (d, J
= 12Hz, L H), 6.92 (s
', L H)'.

7, (15(d, J = 12 Hz, I H
).

7.28-7.60 (m, 15H).

jR(K,B,r)'330(1,,1780,172
5°1670', 1530. 1500. 137
0°1310, 1295. 1240. 1215°11?5. 1085. 1005. 755°7'4
0,700cm-weight.

Example 7 Me A suspension of phosphorus pentachloride (4.23 g, 20.3 mmol I) in methylene chloride (38 ml) was added to pyridine (5.35 g).
, 67.7 mmo I) was added at 5 to 10°C and stirred for 1 hour. This was added to 7-phenylacetamide-3-(2
-(5-Methyl-1,2,3-thiadiazol-4-yl)vinyl]-3-cephemu-4-carpodic acid benzhydryl (E/Z=1/2.3.4.12 g, 6
．． 8 mmo 1 ) was added in one portion at 5° C. and the mixture was stirred at the same temperature for 2 hours. After cooling the reaction solution to -78°C, methanol (28 ml) was added, and the reaction temperature was increased to -30°C.
and stirred for 1 hour. After the reaction temperature was further returned to -10°C, water (5 ml) was added and stirred for 20 minutes. The reaction solution was adjusted to pH 7 with a saturated aqueous sodium hydrogen carbonate solution, and then
Extracted with methylene chloride. After washing with water, the methylene chloride layer was dried with magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography to obtain 7-amino-3
'-((Z)-2-(5-methyl-1,2,3-thiadiazol-4-yl)vinyl]-3-cephemu4-
Benzhydryl carboxylate (1.5 g, yield 45%) was obtained.

'HNMR (CDCIH) 61.75 (s.

2H), 2.31 (s, 3H), 3.52 (d, J
=16Hz, 2H), 4.80(d, J=4.5H2,
IH), 5.10 (d, J=4.5Hz, IH), 6.
38 (d, J=12Hz, IH), 6.85 (d, J=
12Hz, IH), 6.93=36= (s, IH), 7.10~7.60 (m
.

10H).

IR(KBr) 3415. 1765°1720,
1365. 1240. 1215°1170, 1
080. 740. 695ca+-'.

Reference Example 3-(1) (Z)-2-(1-)lytylaminothiazol-4-yl)-2-)lythyloxyiminoacetic acid (1,17g, 1
．． Dissolve 7 mmol in THF (15 ml) and heat at 5°C.
It was cooled to To this reaction solution was added HOBT (0.27 g, 1.
9 mmo +) was added, then DCC (0,36 g, 1
．． 7 mrnol) was added thereto, and the mixture was stirred at the same temperature for 2 hours. After filtering the reaction solution, 7-amino-3-[(Z)-
2-(5-methyl-1゜2.3-thiadiazole-4-
yl)vinyl]-3-cephemu-4-carboxylic acid henzhydryl (0.85 g, 1.7 mmol) was added,
The mixture was stirred at ℃ for 2 days. After the reaction solution was concentrated, the concentrate was purified by column chromatography to obtain 7-,((Z)-2-(2-1-rithylaminothiazol-4-yl)-2-)rityl as a yellow powder compound. oxyiminoacetamide)-3-[CZ)-2-'<5-methyl-1,2
,3-thiadiazol-4-yl)vinyl]-3-cephemu-4-carboxylic acid benzhydryl (1,17 g,
Yield: 59%).

'HNMR (CDCIs) δ2.43 (s.

, 3H), 3.41 (ABq, J=18Hz.

2H), 5.22 (d, J=4.5Hz.

IH), 6.12 (d, d, J=4.
5Hz.

J=9Hz, IH), 6.42 (d,
J=12H2, IH), 6.82 (d, J
=12H2, IH), 6.89 (s, IH
).

7.15-7.50 (m, 40H).

7-((Z)-2-(2-)ditylaminothiazol-4-yl)-2-trityloxyiminoacetamide)-37((Z)-2-(5-methyl-1.2.3)
-thiadiazol-4-yl)vinyl]-3-cephemu-4-carboxylic acid benzhydryl (0.5 g, 0.4 m
Formic acid (5 ml) was added to the mixture (mol) and stirred at room temperature for 2 hours. Concentrated hydrochloric acid (40 μl) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was washed with ether to obtain a powder. This product was dissolved in an aqueous sodium bicarbonate solution and purified by HP-20 column chromatography to give 7= ((Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide)-3- ((Z)-,2-(5-methyl-1,2,3-
Sodium thiadiazol-4-yl)vinyl]-3-cephemu 4-carboxylate (0.13 g) was obtained.

'HNMR ((DZO) δ2.46 (s, 3H).

3.27 (ABq, J=t 7Hz, 2H).

5.1T (d, J = 4.5Hz, I
H).

5.71 (d, J=4.5Hz, IH).

=40- 6.52 (d, 'J=12Hz', IH).

6.65 (d, J=12Hz, LH).

6.80 (s, LH).

IR (KBr) 3400, 1760° 1665.1610, 1535. ．． 1390°1355
0-1° Reference Example 3-+31 7- ((Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-((
Z)-2-(1,2,3-thiadiazol-4-yl)
Sodium vinylcou 3-cephem-4-carboxylate (
0.20g + 0.39mmo 1) in DMF (2
ml) and dissolved in code methyl pivalate (0.19 g
, 0.8 mmol 1) was added under water cooling. After stirring the reaction solution for 15 minutes under water cooling, water (30 ml) was added and extracted with ethyl acetate (30 ml). The organic layer was washed with water and then dried over magnesium sulfate.

After evaporation of the solvent, the residue was triturated in diethyl ether to give 7-((Z)-2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-((Z)
-2=(1,2,3-thiadiazol-4-yl)vinyl]-3-cephemu-4-carboxylic acid pivaloyloxymethyl (0.08 g) was obtained.

'HNMR (CDCIm) δL,, 1B (s.

9H), 3.42 and 3.62 (ABq, J=1'8Hz
, 2H), 5.21 (d', J=5Hz, IH
), 5.45 (bs, 2H).

5.80 (d, J=5Hz, IH),
5.91 (d, J=5Hz, LH), 5.
98 (d.

d, J=5Hz,'-J=! JHz, IH).

6, ', 0'0'' (d, J=12Hz, IH)
.

6.84 (d, -J=12Hz, 'IH)'.

7.14 (s, IH), 8.40 (s
, IH).

1 1; 06 (b s, i H).

IR(KBr) 3330. 2980°17B0.
1750. 1710. 1660°1520, 1
360. 1220. 1120°9 B 0. 80
0cn-'.

43-Example 8 A solution of p-methoxybenzyl 7-formylamino-3-triphenylphosphoranylidenemethyl-3-cephem-4-carboxylate (2.8 g, 4.5 mmo +) in methylene chloride (42 ml) - Add formyl-1,2,3-thiadiazole (0.47 g, 4.1 mmol),
The mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 7-formylamino-3-((Z)-2-(1,2,3-thiadiazol-4-yl)vinylc-3-cephem-4). -p-methoxybenzyl carboxylate (0,37 g, l[120
%) was obtained.

'H-NMR (CDC11) 63.25 (ABq.

J = 18 Hz, 2'H), 3', 70
(s.

3H), 5.07 (s, 2H), 5.13 (d, j
=5Hz,'L H')+'5.97 (d.

d, J = 5 Hz', J' = 10 H'
z), 6.50(d, J='12Hz, 1')t')
-,','6.76 (d, J=12Hz, LH),6.
7'9 (d, J=10#z, 2H), 7t21 (d, J
=10Hz, 2H), 8.29(s, IH), 8.50
(s, IH).

8.81 (d, J=10Hz, If-1).

The above ester (1.35 g, 2.9 mmol 1) was dissolved in methanol (25 ml) and concentrated hydrochloric acid (0', 25 mmol) was dissolved in methanol (25 ml).
1) was added thereto, and the mixture was stirred for 6 hours under water cooling and for 1 hour at room temperature. After the reaction solution was concentrated under reduced pressure, saturated sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with methylene chloride. After washing with water, it was dried with magnesium sulfate.

The solvent was distilled off, and the residue was purified by column chromatography to obtain 7-amino-3-((Z)-1-(1°2.3-thiadiazol-4-yl)vinylcy-3-cephem-4.
p-methoxybenzyl -carboxylate (0.58 g, yield 45%) was obtained.

' HN M R (D M S Od b ) δ3.7
4 (s.

3H), 4.97 (s, 2H), 5.00 (d, J=
5Hz, IH), 5.26 (d.

J=5Hz, IH), 6.50'(d, J=12Hz,
LH), 6.76 (d, J=12Hz, IH), 6.
82 (d, J-10Hz.

2H), 7.13 (4, J=10Hz.

2H), 8.84 (s, IH).

Reference Example 4 7-C(Z)-=2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamide)-3-[(1-liphenylphosphoranylidene)methyl2-3-cephem- Diphenylmethyl 4-carboxylate [JP-A-62-491] (3.1g, 2.9mmo
I) was dissolved in ethyl acetate, 5-formyl-1,2,3
-Thiadiazole (0.35 g, 3.1 mmol I) was added and stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography.
-((Z)-2-(2-tritylaminothiazole-4
-yl)-2-)lythyloxyiminoacetamide)
-3-C(Z)-2-(1,2,3-thiadiazole-
Benzhydryl (5-yl) vinylcy 3-cephem-4-carboxylate (0.67 g, yield 26%) was obtained.

1H-NMR (CDC13) 63.44 (m.

2H), 5.04 (d, J=5H2, IH).

6.05 ('d, d, J=5Hz, J'=9H
z.

IH), 6.48 (s, IH), 6.91 (s, I
H), 6.94 (d, J=12Hz, LH), 7.1
~7.7 (m, 41H).

8.33 (s, IH).

Formic acid (8.5 ml) was added to the above ester (0.67 g, 0.74 mmol) and stirred at room temperature for 1 hour. Concentrated hydrochloric acid (0.75 ml) was added to the reaction mixture and stirred at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, ' -48
- After adding sodium bicarbonate to the residue and adjusting the pH to 7.4, the solution was purified by HP-20 column chromatography to obtain 'l-((Z)-2-(2-aminothiazole-
4-yl)-2-hydroxyiminoacetamide)-3
-((Z)-2-(1,2゜3-thiadiazole-5-
Sodium (14) vinylcou-3-cephem-4-carboxylate was obtained.

'H-NMR (D, O) 63.27 (d, J=
18Hz, IH), 3.55 (d, J=18H2,
IH), 5.38 (d, J=5Hz, LH), 5.
85 (d, J=5Hz, LH), 6.58 (d
, J=11Hz, IH), 6.77 (d, J=11
Hz, IH), 6.90 (s, IH).

8.67 (s, IH).

Procedural amendment (voluntary) June 16, 1989 Director General of the Japan Patent Office Yoshi 1) Takeshi Moon 1, Indication of the case 1988 Patent Application No. 209433 2, Name of the invention β-lactam derivative 3, Person making the amendment Relationship to the case Patent applicant: Tokyo Choda Fumaru Uchi Choumehan J Address: 1-4-5-4 Marunouchi, Chiyoda-ku, Tokyo, Specification to be amended, Column 5 of “Detailed Description of the Invention”, Amendment Contents (]) 118 gJ on page 12, line 6 of the specification of the present application '7
．． Corrected to ``8g''.

(2) Structural formula on page 15, line 3 Correct.

(3) On page 19, line 3, "1thiazole" is corrected to "thiadiazole."

(4) Structural formula on page 25, line 9 %formula% Correct.

(5) On page 33, line 9, "1thiadiazole" is corrected to "rthiadiazole."

(6) "14-il" in the second line from the bottom line of page 44 and the third line of page 46 is corrected to "5-il."

that's all

Claims (1)

[Claims] (1) General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the general formula, R^1 and R^2 are hydrogen atoms or protecting groups for amino groups, and R^3 is hydrogen atoms and salt-forming cations. or a carboxylic acid protecting group, R^4 is a hydrogen atom, a halogen atom or a lower alkyl group. ] A β-lactam derivative or a salt thereof.