JPH0215073A - Thiazoleacetic acid derivative - Google Patents

Abstract

NEW MATERIAL:The thiazoleacetic acid derivative of formula I (R<1> is lower alkanoylamino) (syn isomer) and its reactive derivative and salt at the carboxyl group. EXAMPLE:2-Cyclopentyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer). USE:Useful as a synthetic intermediate for an antibiotic cephalo compound or its salt. PREPARATION:The compound of formula I can be produced according to the reaction formula by reacting a compound of formula II or its reactive derivative at the amino group or their salt with a lower alkanoic acid (e.g., formic acid, acetic acid and propionic acid) or its reactive derivative at the carboxyl group or their salts. The reaction is carried out usually in the presence of an inorganic or organic base under cooling or at room temperature.

Description

Detailed Description of the Invention The present invention relates to the acylation reaction of amine groups of thiazole acetic acid derivatives (syn isomers) represented by the general formula (wherein R means a lower alkanoylamino group) and cephalosporin compounds. It concerns the reactive derivatives thereof at the carboxy group as well as their salts which can be used.

The object compound (I) of this invention is novel and can be produced by the method shown in the following scheme.

1 or a reactive derivative thereof at the amine group or a salt thereof (in the formula, R1 means a lower alkanoylamino group). This can lead to reactive derivatives at the carboxy group that can be used in acylation reactions of the group.

Examples of the salts of the target compound (1) include metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts; ammonium salts; organic amine salts such as triethylamine salts and dicyclohexylamine salts;

Details of examples of definitions used in each of the preceding and subsequent descriptions in this specification are as follows.

The phrase "lower" means 1 to 6 carbon atoms unless otherwise specified.

Examples of the lower alkanoyl in the "lower alkanoylamino group" include formyl, acetyl, propionyl, butyryl, inbutyryl, valeryl, invaleryl,
Examples include pivaloyl and hexanoyl.

Examples of reactive derivatives at the carboxy group of compound (I>) that can be used in the acylation reaction of the amine group of the cephalosporin compound include acid halides, acid anhydrides, activated amides, and activated esters. In detail, acid chloride, acid azide, dialkyl phosphoric acid mixed acid anhydride, phenyl phosphoric acid mixed acid anhydride, diphenyl phosphoric acid mixed acid anhydride, dibenzyl phosphoric acid mixed acid anhydride, halogenated phosphoric acid mixed acid anhydride, etc. substituted phosphoric acid mixed acid anhydrides, noalkyl phosphorous acid mixed acid anhydrides, sulfite mixed acid anhydrides, thiosulfuric acid mixed acid anhydrides, sulfuric acid mixed acid anhydrides, alkyl carbonic acid mixed acid anhydrides, aliphatic carboxylic acids (e.g. Pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid,
Acids with acid anhydrides such as trichloroacetic acid) mixed acid anhydrides, aromatic carboxylic acids (e.g. benzoic acid) mixed acid anhydrides, symmetrical acid anhydrides, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole, etc. Amide, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N+=CH-
Conister, vinyl ester, propargyl ester,
p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-
ditrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or N.

N-dimethylhydroxylamine, 1-hydroxy-2
-(IH)-pyridone, N-hydroxyphthalimide,
Examples include esters such as esters with N-hydroxyphthalimide, 1-hydroxy-6-chloro-IH-benzotriazole, and the like.

Next, a method for producing the object compound of the present invention will be explained in detail.

Compound (I) or a salt thereof, which is the object of the present invention, is obtained by adding a lower alkanoic acid or a reactive derivative at its carboxy group or a salt thereof to compound (I) or its reactive derivative at its amine group or its salt. Manufactured by reaction.

Examples of reactive derivatives at the amine group of compound (I[) include Schiff's base (imino type or its enamine type isomer) produced by the reaction of compound (l[) with a carbonyl compound (for example, acetoacetic acid, etc.) ), a silyl derivative or compound (II) produced by the reaction of compound (IF) with a silyl compound such as bis(trimethylsilyl)acetamide or trimethylsilylacetamide, and 3
Derivatives produced by reaction with phosphorus chloride, phosgene, etc. are included.

Salts of compound (I()) include salts with organic acids such as acetate, maleate, tartrate, benzenesulfonate, and toluenesulfonate, hydrochloride, hydrobromide, sulfate, and phosphorus. Acid addition salts such as salts with inorganic acids such as acid salts, metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts, salts with inorganic bases such as ammonium salts, triethylamine salts, dicyclohexylamine salts, etc. Examples include organic amine salts.

Examples of lower alkanoic acids include formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid; bivaric acid, hexanoic acid, and the like.

Further, as the reactive derivative at the carboxy group of the lower alkanoic acid, the same ones as those exemplified as the reactive derivative at the carboxy group of compound (1) can be mentioned.

This reaction typically involves water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride,
The reaction is carried out in a solvent such as tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or other common organic solvents that do not adversely affect the reaction, and these solvents can also be used in combination with water.

When using a lower alkanoic acid in the form of a free acid or a salt thereof in this reaction, examples include N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'
-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexylde, N.N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N'-(3-dimethylaminopropyl)carbodiimide, N, N'-carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclol-soxylimine,
Alkoxyacetylene, 1-alkoxy-1-chloroethylene, 1-(4-chlorobenzenesulfonyloxy)
-6-chloro-IH-benzotriazole, phosphorous acid trialkyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid isopropyl ester, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, saiko salyl chloride, triphenylphosphine, N-ethylbenz isoxazolium salt,
Advantageously, it is carried out in the presence of a condensing agent such as N-ethyl-5-phenylinxazolium-3'-sulfonate, Vilsmeier's reagent prepared by reaction of dimethylformamide with thionyl chloride, phosgene or phosphorus oxychloride. be.

In addition, this reaction also involves alkali metal bicarbonate, tri(lower)
Alkylamine, pyridine, N. The reaction may be carried out in the presence of an inorganic or organic base such as N-di(lower)alkylbenzylamine or N-(lower)alkylmorpholine.

Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature.

The object compound (1) of this invention is useful as an antibacterial substance and has the general formula (wherein R has the same meaning as above, R2 is a carboxy group or a protected carboxy group, and R3 is a lower alkanoyloxy group or a lower alkyl group). It is useful as an intermediate for synthesizing a cephalometric compound or its salts, each of which may have a thiadiazolylthio group or a tetrazolylthio group.

This cephalometric compound (A) is produced by the following method.

Method 1 (II[) or a reactive derivative thereof at the amino group or a salt thereof (I) or a reactive derivative thereof at the carboxy group or a salt thereof (A) or a salt thereof (wherein R1, R2 and R3 are each (same meaning as above) Compound (A) or its salts may be added to Compound (I) or its reactive derivatives at the amine group or salts thereof; It is produced by reacting with salts of

Examples of the reactive derivatives at the amine group of compound <1) and their salts include those exemplified as the reactive derivatives at the amine group of compound (I[) and their salts.

Suitable examples of reactive derivatives at the carboxy group of compound (1) include the above-mentioned "reactive derivative at the carboxy group of compound (I) that can be used in the acylation reaction of the amine group of a cephalosporin compound". Examples can be given.

Suitable salts of the compound or product (A) include inorganic salts, organic salts, organic acid salts, inorganic acid salts, and salts with amino acids. Examples of inorganic salts include metal salts, such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), and ammonium salts. Examples of organic salts include organic amines. Salts (e.g. trimethylamine salt, triethylamine salt, ethanolamine salt, jetanolamine salt, pyridine salt, piconone salt, dicyclohexylamine salt, N,N' dibenzylethylenediamine salt, etc.), salts with amino acids include arginine salt, asparagine salt, etc. Examples include acid salts, glutamic acid salts, and the like.

This reaction is carried out under the same reaction conditions as described in g. above.

The present invention will be explained below with reference to Examples.

Example 1 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) (50 g) in the presence of potassium carbonate (65.8 g) and dimethylformamide (150 mff)
was reacted with cyclopentyl bromide (47.4 g) to obtain ethyl 2-cyclopentyl oxydiimino-3-oxobutyrate (syn isomer) (68.7 g).

Oily substance.

1, R, (liquid film) ' 1740.1670.1495
．． 1430 cm-'N-M, R8 (CC14=f;
) :1,32 (3H2t, J=7Hz> , 1.
4-2.2 (88,m>, 2.33 (3H,s)
, 4.27 (2H, q.

J=7H2), 4.87 (IH, II+) (2)2
-Ethyl cyclopentyloxydiimino-3-oxoacetate (syn isomer) (89 g) and sulfuryl chloride (26,5
mQ ) in acetic acid (1l19rnQ) to form 2
-Cyclopentyloxyimino-3-year-old xo-ethyl 4-chlorobutyrate (syn isomer) (69 g) was obtained. Oily substance.

1, R, (liquid film): 1750.1735.1465
．． 1435 cm''''1N, M, R, (CC14,t!
i): 1.33 <3H, t, J=7)1z),
1.3-2.4 (8H, m), 4.28 (2H
, q, J=7)1z), 4.46(2H,s), 4
．． 86 (IH,s) (3) Ethyl 2-cyclopentyloxyimino-3-year-old xo-4-chlorobutyrate (syn isomer) (69.0 g) and thiourea (20.Lg) were dissolved in sodium acetate trihydrate. (35.9g), water (172mg
) and ethanol (172 mg) to give ethyl 2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (
37.5 g) was obtained.

m, p, 134-136°C 1, R, (streak 3-l): 3490. 345
0. 3250. 3120. 1735°1540,
1460 am-1 N, M, R, (DMSO-ds-8>' 1
, 25 (3H1t, J=7Hz >.

1.62 (8H, broad s), 4.27
(28,q, J=7Hz).

4.70 (1)! , m), 6.85 (LH,s)
, 7.20(2)1. s) <4) Ethyl 2-cyclopentyloxydiimino-2-(2-aminothiazol-4-yl)acetate (syn isomer)
(37.4 g) was mixed with a 2N aqueous sodium hydroxide solution (13
2ffljl), methanol (132mt) and tetrahydrofuran (1001111) to give 2-cyclopentyloxyimino-2-(2
-aminothiazol-4-yl)acetic acid (syn isomer) (
29,01<) was obtained. m, p, 186℃ (decomposition)
: 1, R, (Stripe 3-R): 3330. 31
20. 1635. 1450 am”N, M,
R, (DMSO-d6.δ)' 1.1-2.2 (
8H, m), 4.68 (LH, m), 6.81
(LH,s), 7.18 (2H, broad
5) (5>2-cyclopentyloxyimino-2-(2
-aminothiazol-4-yl)acetic acid (syn isomer) (
8,5 g) and 2,2,2-trifluoroacetic anhydride (2
2.0 g) was reacted in the presence of bis(trimethylsilyl)acetamide (14.5 g) and dry ethyl acetate (85 mN) to give 2-cyclopentyloxyimino-
2-[2-(2,2,2-trifluoroacetamide)
Thiazol-4-yl]acetic acid (syn isomer) (10,
47[) was obtained. m, p, 186-188°C.

1, R, (Sugital): 3200. 313
0. 1720. 1590°1580 cm” N, M, R, (DMSO-ds, 6): 1-3
4-2.22 (8H1m>, 4.81 (IH, m)
, 7.71 (LH,s) Example 2 Formic acid (14.4 g) was added to acetic anhydride (32 g) under water cooling, and the mixture was stirred at 40 to 45°C for 1 hour. 2-Cyclopentyloxydiimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (20 g) and tetrahydrofuran (100 ml) were added to the above solution under water cooling, and the mixture was heated at 35°
The mixture was stirred at C for 3 hours. The solution was concentrated under reduced pressure and the residue was triturated with diisopropyl ether and dried over phosphorus pentoxide to give 2-cyclopentyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (
9.04 g) was obtained. m, p, 158°C (decomposition).

1, R, (Sugital): 3100. 173
0. 1695. 1685. 1550°1495
am-1 N, M, R, (DMSO-9, 1; ): 1.
2-2.3 (8H, +n), 4.77(l)l, Finchit, J=4Hz), 7.93 (IH,
s), 9.37 (IH, s) Reference Example 1 Phosphorous oxychloride (974 mg) in a solution of dimethylformamide (464 mg) and tetrahydrofuran (3 mQ)
was added dropwise over 3 minutes at -5 to -10°C, and then tetrahydrofuran (L2111EI) was added. 10 minutes later,
To this solution was added 2-cyclopentyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.5 g) at -5 to -10°C and stirred for 10 minutes to form a clear solution. (Solution A) was obtained.

On the other hand, 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2,27 g) was mixed with triethylamine (1,3 g) and 5
It was dissolved in a 0% acetone aqueous solution (23+1111) with stirring. Add 0 to 5 of the solution A obtained above to this solution.
°C,, p) 16.5-7.5-11' under stirring + mi 1. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into a solution of water and ethyl acetate and adjusted to pH 3.0 with 10% hydrochloric acid.
The insoluble matter was removed by filtration, the filtrate was extracted twice with ethyl acetate, the extract was washed three times with saturated aqueous sodium chloride solution, and then dried over magnesium sulfate.

The solvent was distilled off, and the residue was triturated with diethyl ether, filtered, and dried to give 7-[2-cyclopentyloxyimino-2-(2-formamidothiazol-4-yl)acetamitoco-3-(1°3. 4-thiadiazole-2
-yl)thiomethyl-3-cephem-4-carboxylic acid isomer) (2.8 g) was obtained.

L, R, (Xdi94)' 3240. 3180
．． 1780. 1670°1540 cm-1 N, M, R, (DMSO-da, δ): 1.2
-2.3 (8)1. m>, 3.72 (2H, s),
4.45 (2H, ABq, J=14Hz), 4.
74 (IH9i road s), 5.17 (LH
, d, 5Hz), 5.82 (LH, dd, J=
5 and 8 Hz>, 7.36 <IH,s).

8.56 (LH, s), 9.52 (IH, s),
9.55 (IH, d.

J=8Hz), 12.56 (LH, broad
S) Reference Example 2 The following compound was obtained in the same manner as in Reference Example 1.

7-[2-cyclopentyloxyimino-2-(2-formamidothiazol-4-yl)acetamide]-3
-(IH-tetrazol-5-yl)thiomethyl-3-
Cephem-4-carboxylic acid (syn isomer).

1, R, (sujiv-ru)' 3150. 177
0. 1660 cm-1N, M, R (DMS
O-da, S)' 1.37-2-33 (8N1
m), 3.75 (2H, m), 4.38 (2H
, ABq, J: 14.0Hz), 4.78 (IH,
m), 5.21 <IH, d, J=5.0Hz)
, 5.88 (IH, dd, J=5.0 and 8.
0Hz), 7.42 (LH.

s), 8.56 (1)1. s), 9.62
(IH, d, J=8.0)lz) Reference Example 3 7-[2-cyclopentyloxyimino-2-(2-formamidothiazol-4-yl)acetamitoco-3
-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2
, 7g) in methanol (27mQ) was added concentrated hydrochloric acid (1, 7g) to a methanol (27mQ) solution of
8 g) was added thereto, and the mixture was stirred at room temperature for 2 hours. Insoluble matters were removed by filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was triturated with diethyl ether and dried to give a powder of 7-[2-cyclopentyloxydiimino-2-(2-aminothiazole-4). -yl)acetamitoco-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (2.9 g) was obtained. Dissolve this powder (2.9 g) in an aqueous sodium hydroxide solution,
The pH was adjusted to 7.5. This solution was adjusted to pH 3.0, and the formed precipitate was collected by filtration and washed with water.
4-yl)acetamitoco-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer) (1.95 g) was obtained.

1, R, (Z-e-L): 3260. 176
0. 1645. 1520 am-'N, M,
R, (DMSO-da, δ): 1.2-2.3 (
8B, m), 3.69 (2H, s), 4.43
(2H, ABq, 14Hz), 4.66 (IH
, broad s), 5.12 (IH, d, J=
5Hz), 5.73<IH, dd, J=5 and 8
Hz), 6.67 (LH,s).

7.17 (2H, broad s), 9.43
(LH, d, J=8)1z).

9.51 (LH,s) Reference example 4 The following compound was obtained in the same manner as in Reference Example 3.

7-[2-cyclopentyloxyimino-2(2-aminothiazol-4-yl)acetamide]-3-(IH
-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m, p, 1
85-190°C (decomposition).

IR9 (Sugitar): 3260. 176
0. 1640 cm-1N, M, R, (DMS
O-da, δ): 1.17-2.30 (8H, m
), 3.71 (2H, ABq, J=18Hz>, 4
．． 32 (2H, ABq.

J=13.0Hz>, 4.68 (IH, m>, 5
．． 14 (LH, d.

J=4.0Hz>, 5.76 (IH, dd, J=4
．． 0 and 8.0Hz>, 6.71 (IH,s),
9.50 (IH, d.

J4. (OHz)

Claims (2)

[Claims] (1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 means a lower alkanoylamino group) Reactive derivatives at their carboxy groups and their salts that can be used in chemical reactions. (2) 2-cyclopentyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer)
The compound according to claim 1, which is