JPH0128748B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (In the formula, R is a hydrogen atom or a protecting group for an amino group, and R ¹ is an alkyl group.)
The present invention relates to a formyl-2-(2-aminothiazol-4-yl)acetic acid derivative and a method for producing the same. The compounds of the present invention are novel compounds and are useful as raw materials for penicillin or cephalosporin modifiers. Conventionally, penicillin and cephalosporin compounds have shown broad antibacterial activity against Gram-positive and Gram-negative bacteria, and several semi-synthetic penicillins or cephalosporins have been commercially available and are used clinically as therapeutic agents for various infectious diseases. There is.
However, there are only a few therapeutic agents that exhibit antibacterial activity against bacteria such as Aeruginosa and Mycobacteria that cause clinically serious infections. Additionally, these commercially available drugs are unstable against β-lactamases produced by resistant bacteria;
It has drawbacks such as low antibacterial activity against drug-resistant bacteria, which is currently a clinical problem. (WE Wick
"Cephalosporins and Penicillins, Chemistry
and Biology”, edited by EHFlynn, Academic
Press, New York., NY, 1972; Chapter 11). Therefore, the search for β-lactam compounds that have antibacterial properties that are effective against such pathogenic bacteria is still ongoing. The present inventors have discovered a novel 2-formyl-2-(2-aminothiazole-
When the 2-halomethylene-2-(2-aminothiazol-4-yl)acetic acid derivative produced from the present compound is successfully synthesized and used as a modifier for penicillin or cephalosporin compounds, The new penicillin or cephalosporin derivatives produced have a broad antibacterial spectrum and are resistant not only to gram-positive bacteria but also to gram-negative bacteria, especially Bacillus aeruginosa, M. aeruginosa, and Escherichia coli, which are the clinical problems mentioned above. Shows antibacterial power,
Furthermore, it was discovered that it exhibits extremely strong antibacterial activity against resistant Gram-negative bacteria, leading to the completion of the present invention (see Reference Examples below). As a compound represented by the general formula [], 2
-formyl-2-(2-aminothiazole-4-
yl) acetic acid, 2-formyl-2-(2-formylaminothiazol-4-yl)acetic acid, 2-formyl-2-(2-acetylaminothiazol-4-yl)
yl) acetic acid, 2-formyl-2-(2-chloroacetylaminothiazol-4-yl)acetic acid, 2-
Formyl-2-(2-trifluoroacetylaminothiazol-4-yl)acetic acid, 2-formyl-
2-(2-t-butoxycarbonylaminothiazol-4-yl)acetic acid, 2-formyl-2-(2
-tritylaminothiazol-4-yl)acetic acid,
2-formyl-2-(2-unsubstituted and substituted aminothiazol-4-yl)acetic acid such as 2-formyl-2-(2-trialkylsilylaminothiazol-4-yl)acetic acid, methyl, ethyl, t- Mention may be made of 2-formyl-2-(2-unsubstituted and substituted aminothiazol-4-yl)acetic acid esters such as butyl, benzyl, trichloroethyl, diphenylmethyl ester. The structure of the compound of the present invention is represented by the general formula [] Although the general formula [] is the keto type structure of the compound of the present invention, it can also be represented by the enol structure general formula ['] as a chemical equilibrium. 2-formyl- represented by the above general formula []
The reaction formula for producing the 2-(2-aminothiazol-4-yl)acetic acid derivative is as follows. (In the formula, R is a hydrogen atom or a protecting group for an amino group, R ¹ is an alkyl group, and X is a halogen atom.) Below, embodiments of each production method will be described. [Method A] This book The method involves producing a compound of the general formula [] by reacting a 2-(2-aminothiazol-4-yl)acetic acid derivative represented by the general formula [] with a formic acid ester in the presence of a base. Regarding the synthesis of the 2-(2-aminothiazol-4-yl)acetic acid derivative represented by the general formula [],
For example, Heterocyclic Compounds: Thiazole
and lts Derivatives Vol.34, part2; Edit.by J.
There is a bibliography in V. Metzer, Wiley & Sons, p.173. This method requires the presence of a base. Examples of the base include alkali metals such as sodium and potassium, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal alkoxides such as sodium methoxide and t-butoxypotassium, n-butyllithium and phenyllithium. A wide variety of organic alkali metals can be used. The amount of base to be used is sufficient to be an equimolar amount or several times the molar amount. In carrying out the reaction, it is preferable to use a solvent, and examples of the solvent include hydrocarbon solvents such as hexane, benzene, and toluene, ether solvents such as diethyl ether, dimethoxyethane, and tetrahydrofuran, methanol, ethanol, and t- Examples include alcoholic solvents such as butanol and aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and hexamethylphosphotriamide. The reaction can be carried out at a temperature ranging from 0° C. to the boiling point of the solvent, but it proceeds smoothly at room temperature without using any special cooling or heating means. [Method B] This method uses γ-halo-α expressed by the general formula []
A compound represented by the general formula [] is produced by reacting -formylacetoacetate with a thiourea represented by the general formula []. The compound of general formula [] can be prepared by a known method [E.Benary and F.Ebert, Ber., 56B , 1897
(1923)], methyl γ-chloro-α-formylacetoacetate, ethyl γ-chloro-α-formylacetoacetate, t-butyl γ-chloro-α-formylacetoacetate, γ-chloro-α -benzyl formylacetoacetate, γ-chloro-α-trichloroethyl formylacetoacetate, γ-chloro-
Examples include γ-chloro-α-formylacetoacetate such as diphenylmethyl α-formylacetoacetate and the corresponding γ-bromo-α-formylacetoacetate. On the other hand, thioureas represented by the general formula [] are thiourea or thiourea derivatives, but as thiourea derivatives, N-substituted thioureas such as N-(2,2,2-trichloroethoxidecarbonyl)thiourea Thiourea may be mentioned. In carrying out the reaction, it is preferable to use a solvent, and examples of the solvent include water, alcoholic solvents such as ethanol and methanol, tetrahydrofuran,
Mention may be made of ethereal solvents such as dioxane. This reaction is carried out at room temperature or under heating. Hereinafter, the present invention will be explained in more detail with reference to Reference Examples and Examples. The antibacterial activity in the reference examples is expressed in minimum inhibitory concentration (MIC) (unit: μg/ml).
The measurement was carried out by the Japanese Society of Chemotherapy, Minimum Inhibitory Concentration Measurement Revision Committee [Chemotherapy, Vol. 29, No. 1, 76
~79 pages (1981)]. Example 1 50% sodium hydride (0.33g, 6.99mmol)
After washing with n-hexane, freshly dry THF (10
ml) and cooled on ice. Add 2-(2-
t-Butoxycarbonylaminothiazole-4-
A solution of ethyl acetate (1.0 g, 3.4 mmol) and ethyl formate (0.30 g, 4.1 mmol) in dry THF (15 ml) was added dropwise with stirring. 8.5 at room temperature after dropping
Stir for hours. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After washing with saline, it was dried with sodium sulfate. Evaporation with the solvent gave ethyl 2-formyl-2-(2-t-butoxycarbonylaminothiazol-4-yl)acetate (1.0 g, 93%). NMRδ (CDCl ₃ ): 1.23 (t, 3H), 2.07 (s, 9H),
4.20 (q, 2H), 7.40, 7.50 (s, 1H), 7.96,
8.13 (s, 1H). Example 2 50% oily sodium hydride (69.6g, 1.45mol)
After washing with n-hexane (200 ml x 2), it was suspended in dry THF (435 ml). This suspension contains 2-
(2-aminothiazol-4-yl)ethyl acetate (135g, 0.725mol) and ethyl formate (107.3g,
1.45 mol) was dissolved in dry THF (1450 ml) and added dropwise with stirring at room temperature. After stirring for 14 hours after the dropwise addition, a 50% acetic acid aqueous solution was added to adjust the reaction solution to pH 7. After extraction with ethyl acetate, the aqueous layer was further extracted with
A mixed solvent of THF-ethyl acetate (1:1, 250 ml x 2) was extracted. The extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and 2-formyl-2
-(2-formylaminothiazol-4-yl)
Ethyl acetate (117.5 g, 67%) was obtained as white crystals. Melting point: 179-180℃. IR (KBr): 3290, 1710, 1690, 1620 cm ^-1 . NMR δ (CDCl ₃ - d _{6 -} DMSO): 1.33 (t, J = 7
Hz, 3H), 4.16 (q, J=7Hz, 2H), 7.50 (s,
1H), 8.00 (s, 1H), 8.53 (s, 1H). Mass m/e (%): 242 (M ⁺ , 32), 196 (95), 168
(100), 140(71). Elemental analysis value C ₉ H ₁₀ N ₂ Calculated value as OS ₄ :
C, 44.62; H, 4.16; N, 11.56; S, 13.24. Analysis value:
C, 44.65; H, 4.13; N, 11.62; S, 13.34. Example 3 Ethyl γ-chloro-α-formylacetoacetate (0.613 g, 3.18 mmol) and thiourea (0.48 g, 6.36
mmol) in 50% aqueous ethanol (20 ml),
Stirred at room temperature for 16 hours. It was concentrated under reduced pressure and the residue was brought to pH 7 with sodium bicarbonate solution. After filtering the precipitated crystals, they were dried over phosphorus pentoxide under reduced pressure to obtain ethyl 2-formyl-2-(2-aminothiazol-4-yl)acetate (0.45 g, 66%). NMRδ ( _d6 -DMSO): 1.26 (t, J=7Hz, 3H),
4.17 (q, J=7Hz, 2H), 6.83 (s, 1H),
7.50 (bs, 1H), 8.00 (s, 1H). Reference example 1 Dimethylformamide (1.58g, 21.6mmol)
After cooling on ice, add phosphorus oxychloride (2.64 g, 17.3 m
mol) and stirred at room temperature for 2 hours. Add 2-formyl-2-(2-t-butoxycarbonylaminothiazol-4-yl)ethyl acetate (4.52 g, 14.4 mmol) to this reaction solution and add dehydrated ethyl acetate (20 ml).
The solution was added dropwise. After stirring at room temperature for 24 hours, sodium hydrogen carbonate was added to adjust the pH to 8.0. The reaction solution was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oil. When the solvent was distilled off, 2-chloromethylene-2-(2-t-butoxycarbonylaminothiazol-4-yl)acetic acid (E)-isomer (1.36 g, 57
%) was obtained. NMRδ ( _CDCl3 ): 1.16 (t, J=7Hz, 3H), 1.53
(s, 3H), 4.17 (q, J=7Hz, 2H), 7.20
(s, 1H), 7.56 (s, 1H). Reference example 2 A solution of 2-chloromethylene-2-(2-t-butoxycarbonylaminothiazol-4-yl)ethyl acetate [(E)-isomer] (2.61 g, 7.84 mmol) in ethanol (40 ml) was added with 1N sodium hydroxide ( 13
ml) and stirred at room temperature for 2 days. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After separating the aqueous layer, the pH was adjusted to 1.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and then dried over sodium sulfate. When the solvent was distilled off, 2-chloromethylene-2-(2-t-butoxycarbonylaminothiazol-4-yl)acetic acid [(E)-isomer] (1.36 g, 57%) was obtained. NMRδ ( _d6 -DMSO): 1.50 (s, 9H), 5.76 (bs,
2H), 7.23 (s, 1H), 7.56 (s, 1H). Reference example 3 2-Chloromethylene-2-(2-t-butoxycarbonylamiothiazol-4-yl)acetic acid [(E)-isomer] (0.70 g, 2.29 mmol) was suspended in methylene chloride (10 ml) and added to ice. While cooling, phosphorus pentachloride (0.48 g, 2.29 mmol) was added. After stirring for 30 minutes, the mixture was further stirred at room temperature for 30 minutes. When the reaction solution was concentrated under reduced pressure, 2-chloromethylene-2-(2-
t-Butoxycarbonylamino-1,3-thiazol-4-yl)acetic acid chloride was obtained. On the other hand 7-
Amino-3-(1-methyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.75 g, 2.29 mmol) Ethyl acetate (10 ml)
Bis(trimethylsilyl)acetamide (0.88 g, 4.35 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After cooling the reaction solution on ice, the 2-
A solution of chloromethylene-2-(2-t-butoxycarbonylaminothiazol-4-yl)acetic acid chloride [(E)-isomer] in methylene chloride (10 ml) was added dropwise. After stirring for 2 hours under ice cooling, add ice water (10 ml).
was added to the reaction solution. The reaction solution was ethyl acetate (40ml x
2), washed with brine, and dried over sodium sulfate. When the solvent was distilled off, 7-[2-chloromethylene-2-(2-t-butoxycarbonylaminothiazol-4-yl)acetamide]-3
-(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid [(E)
-isomer] (1.25 g, 89%). NMR (δ d ₆ -DMSO) 1.50 (s, 9H), 3.70
(q _AB , J=15Hz, 2H), 3.92 (s, 3H), 4.31
(q _AB , J=15Hz, 2H), 5.10(d, J=3Hz,
1H), 5.73 (dd, J=3Hz, J=9Hz, 1H),
7.23 (s, 1H), 7.40 (s, 1H), 9.26 (d, J=
9Hz, 1H). Reference example 4 7-[2-chloromethylene-2-(2-t-butoxycarbonylaminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid [(E)-isomer] (1.45g, 2.35m
mol) in anisole (7 ml) and heated to 0-5°C.
After cooling to , trifluoroacetic acid (20 ml) was added and stirred for 24 hours. The reaction solution was concentrated under reduced pressure, water (20 ml) was added to the residue, and the pH was adjusted to 7.5 with an aqueous sodium hydrogen carbonate solution. After extraction with ether (30 ml), the mixture was extracted with a mixed solvent of ethyl acetate and ether (40 ml, 1:1). After separating the aqueous layer, it was cooled on ice and diluted with 10% hydrochloric acid.
The pH was set to 2.2. After filtering the precipitated crystals and washing with water,
Dry under reduced pressure over phosphorus pentoxide to give 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl- 3-cephem-4-carboxylic acid [(E)-isomer] (0.624 g) was obtained. NMRδ( _d6 −DMSO)3.66(q _AB , J=15Hz, 2H),
3.89 (s, 3H), 4.26 (q _AB , J=15Hz, 2H),
4.73 (bs, 3H), 5.03 (d, J=4.5Hz, 1H),
5.73 (dd, J=4.5Hz, J=9Hz), 6.89 (s,
1H), 7.30 (s, 1H), 9.79 (d, J=9Hz,
1H). Reference example 5 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-
Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid [(E)-isomer] (0.624 g) was dissolved in ethyl acetate:methanol and dissolved in 2N sodium 2-ethylhexanoate. n
- Butanol solution was added. Crystals were precipitated from the reaction solution and filtered. Washed with a small amount of ethyl acetate and ether, dried in vacuo over phosphorus pentoxide, and washed with 7-
[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-
Sodium 3-cephem-4-carboxylate [(E)-
isomer] (0.361 g) was obtained. The results of antibacterial activity are shown in Table 1. Melting point: 171-175℃ (decomposition). NMRδ( _d6 −DMSO)3.59( _qAB , J=15Hz, 2H),
3.92 (s, 3H), 4.43 (q _AB , J=15Hz, 2H),
5.00 (d, J=3Hz, 1H), 5.69 (dd, J=3
Hz, 9Hz, 1H), 6.89 (s, 1H), 7.30 (s,
1H), 9.73 (d, J=9Hz, 1H). Elemental analysis value C ₁₆ H ₁₄ ClN ₈ O ₄ S ₃ Na・H ₂ O Calculated value: C, 34.63; H, 2.91; N, 20.19. Analysis value: C, 35.23; H, 3.00; N, 19.24. Reference Example 6 Ethyl 2-formyl-2-(2-formylaminothiazol-4-yl)acetate (1.0g, 4.1m
mol) in DMF (5 ml), added phosphorous oxychloride (0.78 g, 5.14 mmol), and then dissolved at 100°C for 1 hour.
The mixture was heated and stirred for hours. After the reaction solution was cooled to room temperature, a 1N aqueous sodium hydroxide solution was added to adjust the pH to 7. It was extracted with ethyl acetate and dried over sodium sulfate. The solvent was distilled off and ethyl 2-chloromethylene-2-(2-dimethylaminomethyleneaminothiazol-4-yl)acetate [(Z)
-:(E)-isomer=1:2.7] was obtained as an oil (1.4 g). NMRδ( _CDCl3 )(Z)-isomer: 1.40 (t, J=7Hz, 3H), 3.06
(d, J=2Hz, 6H), 4.40 (q, J=7Hz,
2H), 6.76 (s, 1H), 7.33 (s, 1H), 8.16 (s,
1H). (E)-isomer: 1.30 (t, J=7Hz, 3H), 3.10 (s,
6H), 4.26 (q, J=7Hz, 2H), 7.00 (s,
1H), 7.50 (s, 1H), 8.30 (s, 1H). Reference example 7 Formic acid-acetic anhydride was added to a mixture of 2-chloromethylene-2-(2-dimethylaminomethyleneaminothiazol-4-yl)ethyl acetate [1.4 g, (Z)-:(E)-isomers = 1:2.7]. (2.8 ml) was added and stirred at room temperature for 2 days. Water was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate and washed with an aqueous sodium hydrogen carbonate solution and then with water. After drying with sodium sulfate and distilling off the solvent, ethyl 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetate [1.2 g,
(Z)- and (E)-isomers] were obtained. Purification by column chromatography gave the (E) isomer (0.65 g) and the (Z)-isomer (0.19 g). (E)-isomer melting point: 103-4℃. IR (KBr): 1710, 1695, 1565, 1290, 1260 cm ^-1 . NMR δ (CDCl ₃ ) 1.26 (t, J = 7Hz, 3H), 4.20
(q, J=7Hz, 2H), 7.14 (s, 1H), 7.60
(s, 1H), 8.48 (s, 1H), 12.22 (bs, 1H). Mass m/e (%): 260 (M ⁺ , 16), 234 (21), 232
(58), 186 (24), 151 (100). Elemental analysis value _{: C9H9ClN2O3S} Calculated value: C, 41.46; H, 3.48; _N , 10.75. Analysis value _: C, 41.55; H, 3.42; N, 10.80. (Z)-isomer Melting point: 140-142℃. IR (KBr): 1740, 1660, 1460, 1370, 1345,
1285, 1200, 1035cm ^-1 . NMRδ (CDCl ₃ ): 1.36 (t, J = 7Hz, 3H), 4.34
(q, J=7Hz, 2H), 6.96 (s, 1H), 7.20
(s, 1H), 8.50 (s, 1H), 9.96 (bs, 1H). Mass m/e (%): 262 (9), 260 (M ⁺ , 25), 234
(21), 232 (56), 186 (22), 151 (100). Elemental analysis value as C ₉ H ₉ ClN ₂ O ₃ S Calculated value: C, 41.46; H, 3.48; N, 10.75. Analysis value: C, 42.13; H, 3.63; N, 10.35. Reference example 8 Ethyl 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetate [5.16 g,
0.0198 mol) [(Z)-isomer] was suspended in 11 ml of tetrahydrofuran, and potassium hydroxide (3.32 mol) was suspended in 11 ml of tetrahydrofuran.
g, 0.0594 mol) in water (55 ml) and cooled on ice.
dripped. After the addition, the mixture was stirred at room temperature for 3 hours. The reaction solution was ethyl acetate-ether (40ml x 2, 1:1)
After extraction with a mixed solvent, the aqueous layer was separated and cooled to 0°C. The pH was adjusted to 2.0 with 2N hydrochloric acid. The precipitated crystals were filtered, washed with water, air-dried, and then dried over phosphorus pentoxide under reduced pressure. A pale yellow powder (4.87 g) was obtained. As a result of spectral analysis, it was found that this product contained a deformylated product of the above-mentioned carboxylic acid. After adding acetic acid-formic anhydride (10 ml) to the above powder compound, the mixture was stirred at room temperature for 4.5 hours. Concentrate under reduced pressure and convert the residue to n-
After washing with hexane and drying under reduced pressure over potassium hydroxide, 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid [(Z)
-isomer] was obtained as a white powder (4.46 g, 97%). Melting point: 145-147℃ (decomposition). NMRδ ( _d6 -DMSO): 7.13 (s, 1H), 7.23 (s,
1H), 8.50 (s, 1H). IR (KBr): 3575, 3200, 3050, 2950, 2450,
1680, 1565cm ^-1 . Reference example 9 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid [(Z)-isomer]
(2.0 g, 0.0086 mol) and 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-cephem-4-carboxylic acid benzhydryl ester (4.25 g, 0.0086 mol) in tetrahydrofuran-methylene chloride ( 300ml, 1:2) of mixed solvent. N,N'-dicyclohexylcarbodiimide (1.77 g, 0.0086 mol) was added to this solution, and the mixture was stirred at room temperature for 4 hours. This reaction solution contains N,
N'-dicyclohexylcarbodiimide (0.177g,
0.00086 mol) was added thereto, and the mixture was further stirred at room temperature for 1 hour. Concentrate under reduced pressure and add methylene chloride (80ml) to the residue.
was added and filtered. The filtrate was concentrated under reduced pressure to obtain an oil. This product was purified by column chromatography to give a light yellow powder of 7-[2-chloromethylene-2-(2-formylaminothiazole-
4-yl)acetamido]-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-3
-Cefem-4-carboxylic acid benzhydryl ester [(Z)-isomer] (4.92 g, 81%) was obtained. NMRδ (CDCl ₃ ): 3.66 (m, 2H), 3.72 (s, 3H),
4.26 (m, 2H), 5.07 (d, J=6Hz, 1H),
5.92 (dd, J=4.5Hz, 6Hz, 1H), 6.76 (s,
1H), 6.89 (s, 1H), 6.96 (s, 1H), 7.33 (m,
10H), 8.13 (d, 1H), 8.36 (s, 1H). Reference example 10 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-
3-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester [(Z)-isomer] (4.92
g, 0.0069 mol) was dissolved in methylene chloride (60 ml) and cooled to 0-5°C. Add anisole (5 ml) followed by trifluoroacetic acid (25 ml),
Stirred for 1.5 hours. The mixture was concentrated under reduced pressure, ethyl acetate (60 ml) and water (25 ml) were added to the residue, and the mixture was cooled on ice. A saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8.30. After extraction, separate the aqueous layer and add ethyl acetate (40ml x
3) was extracted again. After separating the aqueous layer, cool it on ice for 2N
- Adjust the pH to 2.0 with hydrochloric acid. The precipitated crystals were filtered, air-dried, and then dried over potassium hydroxide under reduced pressure to give 7-[2-
Chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid [(Z)-isomer ] (3.40 g, 94%) was obtained as a white powder. NMRδ ( _d6 -DMSO): 3.63 (m, 2H), 3.89 (s,
3H), 4.26 (m, 2H), 5.13 (d, J=4.5Hz,
1H), 5.76 (d, d, J = 4.5Hz, 9Hz, 1H),
7.00 (s, 1H), 7.03 (s, 1H), 8.46 (s, 1H),
9.60 (d, J=9Hz, 1H). Reference example 11 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-
3-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid [(Z)-isomer] (3.40 g, 0.00645 mol) was dissolved in methanol-tetrahydrofuran (100 ml, 1:1 ) and cooled on ice. Phosphorus oxychloride (1.98 g, 0.0129 mol) was added and stirred for 2 hours.
Water (30 ml) was added to the reaction solution, and then saturated sodium hydrogen carbonate was added to adjust the pH to 5. The mixture was concentrated under reduced pressure at room temperature. The residue was cooled with ice, and saturated sodium hydrogen carbonate was added to adjust the pH to 7.5. This mixture was extracted with ethyl acetate (40 ml x 2), the aqueous layer was separated, and after cooling on ice, 2N hydrochloric acid was added to adjust the pH to 2.0. The precipitated crystals were filtered, air-dried, and then dried under reduced pressure over phosphorus pentoxide to give 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H- Tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid [(Z)-isomer] (2.3 g, 69%) was obtained as a white powder. NMRδ ( _d6 -DMSO): 3.69 (m, 2H), 3.96 (s,
3H), 4.30 (m, 2H), 5.16 (d, J=4.5Hz,
1H), 5.76 (dd, J=4.5Hz, 7.5Hz, 1H), 6.40
(s, 1H), 6.86 (s, 1H), 7.13 (bs, 2H),
9.56 (d, J=7.5Hz, 1H). Reference example 12 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-
Add water (15 ml) to methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid [(Z)-isomer] (2.3 g), and add saturated sodium hydrogen carbonate while stirring to adjust the pH to 7. .1.
This solution was purified by passing it through an XAD-2 column and
-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium [( Z)-isomer] was obtained as a white powder in an amount of 0.5 g. The results of antibacterial activity are shown in Table 1. NMRδ( _d6 −DMSO): 3.48(q _AB , J=18Hz,
2H), 3.94 (s, 3H), 4.34 (q _AB , J=12Hz,
2H), 5.02 (d, J = 5Hz, 1H), 5.62 (dd, J
=5Hz, 8Hz, 1H), 6.42 (s, 1H), 6.84 (s,
1H), 7.14 (bs, 2H), 9.48 (d, J=8Hz,
1H). Elemental analysis value C ₁₆ H ₁₄ ClN ₈ O ₄ S ₃ Na・2H ₂ O Calculated value: C, 33.54; H, 3.17; N, 19.56. Analysis value: C, 33.02; H, 3.12; N, 18.94.

[Table] *Control is cefothiam

Claims (1)

[Claims] 1. General formula 2-formyl-2-(2-aminothiazol-4-yl)acetic acid derivative represented by (wherein, R is a hydrogen atom or a protecting group for an amino group, and R ¹ is an alkyl group). 2 In the presence of a base, the general formula A general formula characterized by reacting a 2-(2-aminothiazol-4-yl)acetic acid derivative represented by and a formic acid ester (HCOOR ² ) A method for producing a 2-formyl-2-(2-aminothiazol-4-yl)acetic acid derivative represented by: (In the formula, R is a hydrogen atom or a protecting group for an amino group, R ¹ is an alkyl group, and R ² is an alkyl group or an aryl group). 3 General formula General formula characterized by reacting γ-halo-α-formylacetoacetic acid ester represented by the general formula RNHCSNH ₂ with a thiourea represented by the general formula RNHCSNH 2 A method for producing a 2-formyl-2-(2-aminothiazol-4-yl)acetic acid derivative represented by: (In the formula, R is a hydrogen atom or a protecting group for an amino group, R ¹ is an alkyl group, and X is a halogen atom.)