WO1992007840A1

WO1992007840A1 - Thiazole thioester derivative

Info

Publication number: WO1992007840A1
Application number: PCT/JP1991/001482
Authority: WO
Inventors: Takeo Kobori; Rumi Yamamoto; Mikako Fujita; Tamejiro Hiyama; Takatoshi Nagate
Original assignee: Taisho Pharmaceutical Co., Ltd.; Sagami Chemical Research Center
Priority date: 1990-11-02
Filing date: 1991-10-30
Publication date: 1992-05-14

Abstract

A compound represented by general formula (I), which is useful as an intermediate for the production of (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide-substituted cephalosporin derivatives having an excellent antibacterial activity, wherein R1 represents hydrogen or a hydroxyl protecting group.

Description

Specification

Thiazole thioester derivatives

Technical field

The present invention relates to a novel thiazole thioester derivative, and more particularly, to a (Z) 1-2- (2-aminothiazole-14-yl) 1 having excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria. The following formula useful as an intermediate for producing a cephalosporin derivative having a 2-hydroxyiminoacetoamide group:

In the formula, represents a hydrogen atom or a hydroxy protecting group,

With respect to the compound represented by

Background art

Conventionally, (Z) —2- (2-tritylaminothiazole-4-yl) -12-trityloxyiminoacetic acid of the following formula (1), (Z) —2— (2) of the following formula (2) —Trityloxyimino) -2- (2-aminothiazole-41-yl) acetic acid or (Z) of the following formula (3) —2 -— (2- (2-tritylaminothiazole-4-1) 7) C- (Z) -2- (2-aminothiazole) by reacting 12-tetrahydrobiranyloxyiminoacetic acid and the like with a 7-aminocephem compound and removing the protecting group. A method for producing a cephalosporin derivative having a [1-2-hydroxyiminoacetamide] group is known [R. Bucourt et. Al., Tetrahedron, 1978, 34, 2233; JP-A-56-21600; JP-A-2'-73090]. ,

(1) (2)

(3) In each of the above formulas, Ph represents a phenyl group,

However, the above-mentioned method is not suitable for the production of a cefm compound using a compound of the formula (1), (2) or (3), which is expensive as a condensing agent for 1-hydroxybenzotriazole and dicyclohexylcarbodiyl. This method is not preferable as a production method on an industrial scale in that a medium or the like must be used.

In contrast, the thiazole thioester compound represented by the formula (I) provided by the present invention can be produced at a very low cost, and has excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria. (Z) — 2- (2-Aminothiazol-4-yl) cephalosporin derivative having a 2-hydroxyiminoacetamide group at the 7-position (for example, JP-A-58-184036, (See JP-A-62-492 and JP-A-2-22283) are found to be extremely useful as production intermediates. Thus, the present invention has been completed.

Disclosure of the invention,

In the compound of the formula (I), the = = Ο ί ^ group can have any of the Z-type (sy η-type) or Ε-type (anti-type) configuration. Generally, the Z-isomer is preferred.

The `` hydroxy protecting group '' which can be represented by is any hydroxy protecting group which can be easily removed by a deprotecting group reaction such as hydrolysis or hydrogenolysis using an acid or a base as a catalyst. it can, for example, trityl, (p-Anishiru) Jifuenirumechiru such as Ariru substituted methylol ₀ Le group;. main Tokishimechiru, t one butoxymethyl, 2 main Tokishietokishime chill, 2, 2, 2-trichloromethyl E butoxy methyl Substituted methyl groups such as, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydroviranyl; 1-ethoxyhexyl, (1-methyl-1-methoxy) ethyl, 2,2,2-trichloro such substituents Echiru group _Echiru; trimethylsilyl, Toryechirushiriru, isopropyl dimethylsilyl, t Buchirujime Rushiriru, (triphenylmethyl) dimethylsilyl, t - butyldiphenylsilyl, methyl diisopropyl silyl, alkyl substituted silyl group such as triiso Purobirushiriru.

Of these hydroxy protecting groups, preferred are (p-anisyl), diphenylmethyl, t-butoxymethyl, tetrahydroviranyl, (1-methyl-1-methoxy) ethyl, and the like. Is preferred o

The thiazole thioester compound of the formula (I) of the present invention can be produced, for example, by the method shown in the following reaction formula A. Reaction formula A

(W) (V)

In the above reaction formula, represents a hydroxy protecting group, R ₂ represents a carboxy protecting group, three Xs each independently represent an aryl group or an alkoxy group, and three Ys each independently represent an alkyl group. Or two of them, Y, together with the N atom to which they are attached, may further contain a heteroatom such as N, S, O, etc. Preferably a 5- or 6-membered nitrogen-containing heterocyclic group).

A “carboxy protecting group” represented by R ₂ is any carboxy protecting group that can be easily removed by a deprotecting reaction such as hydrolysis using an acid or base as a catalyst, for example, methyl, ethyl, propyl And tert-butyl and the like; and substituted or unsubstituted aralkyl groups such as p-ditrophenylmethyl and diphenylmethyl. Further, the phosphorus compound represented by X ₃ P includes a phosphine compound and a phosphorous acid compound, and specifically includes triarylphosphines such as triphenylphosphine; trimethyl phosphate, triethyl phosphite, and the like. And the like.

Further, tertiary amine compounds represented by Y ₃ N include, for example, N-alkyl-substituted nitrogen-containing heterocyclic compounds such as N-methylmorpholine, N-methylpyridine and N-methylpyrrolidine; triethylamine, Ν, Ν — Trialkylamines such as disopropylethylamine, and the like.

Hereinafter, the reaction represented by the reaction formula (1) will be described in more detail step by step. Process (A):

In this step, the protecting group is added to the hydroxyimino group of the compound of the formula (式) as a raw material.

This is the step of introducing (R i).

Examples of reagents for introducing a protecting group include aryl-substituted methyl chlorides such as trityl chloride and (P-anisyl) diphenylmethyl chloride; methoxymethyl chloride, and t-butoxymethyl chloride. Ride, 2-methoxyethoxymethyl chloride, 2,2,2-trichloroethoxymethyl chloride, bis (2-chloroethoxyquin) methyl chloride, 2- (trimethylsilyl) ethoxymethyl chloride Substituted methyl chlorides such as Ride; substituted methyl chlorides such as 1-ethoxyl-chloride, 1-methyl-1-methoxyl-chloride, 2,2,2-trichloromethyl chloride; trimethylsilyl chloride Ride, triethylsilyl chloride, isopropyldimethylsilyl chloride, t-butyldi Phenylsilyl chloride, methyldiisopropylsilyl chloride And alkyl-substituted silyl chlorides such as triisopropylsilyl chloride; ethers such as dihydrobilanisoproenylmethyl ether; and the like. The amount of the protecting group-introducing reagent to be used is not particularly limited, but is usually in the range of 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of the compound of the formula (III).

The reaction can be carried out in the presence of a base such as pyridine or triethylamine, or an acid such as benzenesulfonic acid or ρ-toluenesulfonic acid, if necessary. In general, it is preferable to use a solvent for the reaction. For example, a solvent that does not participate in the reaction, such as tetrahydrofuran, ethyl acetate, dichloromethylene, and N, N-dimethylformamide can be used. The reaction temperature is not particularly limited, but usually room temperature is used.

Process (B):

In this step, the compound of the formula (W) is produced by reacting the compound of the formula (m) obtained in the step (A) with thiourea.

The reaction of the compound of formula (m) with thiourea is usually preferably carried out in a mixed solvent of water such as tetrahydrofuran, ethanol, N, N-dimethylformamide and the like. It can range from about 0 to about 70 ° C, preferably from about 10 to about 40 ° C.

The amount of thiourea used is not strictly limited, but is generally in the range of 1 to 10 mol, especially 1 to 2 mol, per mol of the compound of the formula (ffl).

Process (C):

This step (C) is a step of hydrolyzing the compound of the formula (IV) obtained in the above step (B) to obtain a free carboxylic acid of the formula (V). The hydrolysis reaction of the compound of the formula (IV) can be performed in the presence of a base according to a conventional method. Suitable bases that can be used include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. The reaction is preferably performed using a solvent. For example, a mixed solvent of tetrahydrofuran, dioxane, ethanol, methanol, or the like and water can be used. The reaction temperature can usually be in the range of about 0 to about 200 ° C, preferably about 80 to about 120 ° C.

Process (D):

In this step, in the presence of a compound of phosphorus compounds of formula (V) (X ₂ P) and tertiary _D Amin compound (Y ₃ N), crimped react with di Chio benzothiazole, expression of interest (I The compound of 1) is produced.

The amount of dithiobenzothiazole used is not particularly limited.

The compound (V) can be used in an amount of 1 to 10 mol, preferably 1 to 1.5 mol, per 1 mol of the compound. The phosphorus compound and the tertiary amine compound are each in an amount of about 1 to about 1.5 mol per 1 mol of the compound of the formula (V).

It is convenient to use it within the enclosure.

The reaction is generally carried out in a solvent inert to the reaction, such as acetonitrile, acetone, tetrahydrofuran, and dichloromethane, at a temperature in the range of about -20 to about 100 ° C, preferably about 0 to about 60 ° C. Can be.

The compound of formula (1-1) thus formed is separated and purified from the reaction mixture after completion of the reaction by a method known in the art, for example, crystallization, filtration, washing, drying, etc. can do.

The compound of the formula (I-11) may be further converted to a compound of the formula (I) in which R, is a hydrogen atom by removing the hydroxy protecting group (Rn), if necessary. can do. The removal of the hydroxy protecting group can be performed by selecting deprotection reaction conditions known per se according to the type of the protecting group. For example, when the hydroxy protecting group is trityl, tetrahydroviranyl, (p-disyl) diphenylmethyl, 2,4-dimethoxybenzyl, etc., for example, hydrochloric acid, sulfuric acid, phosphoric acid, etc. It can be removed by hydrolysis using an inorganic acid or an organic acid such as trifluoroacetic acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, ττ toluenesulfonic acid, and methanesulfonic acid. The acid can be used usually in a catalytic amount or a large excess, and the reaction temperature is in the range of about 120 ° C to about 80 ° C, especially about 0 ° C to about 60 ° C. can do.

The thiazole thioester compound of the formula (1-1) provided by the present invention is useful as an intermediate for producing a cephalosporin derivative having antibacterial activity. For example, the compound of the formula (I-11) of the present invention is

In the formula, R ₃ represents a hydrogen atom or a carboxy protecting group, R ₄ represents a hydrogen atom or a 3-position substituent commonly found in cephalosporin compounds, and reacted with a 7-aminocephem compound represented by the following formula:

(VH)

Wherein R _u , R ₃ and R ₄ are as defined above,

The compound shown by the following formula is formed, and then the hydroxy protecting group of Ru is removed to obtain the following formula

Wherein R ₃ and R ₄ are as defined above,

Can be led to the cephalosporin derivative represented by

The reaction between the compound of the formula (I-11) and the compound of the formula (VI) according to the present invention is inactive in the reaction of, for example, acetone, tetrahydrofuran, ethyl acetate, dichloromethylene, N, N-dimethylformamide and the like. In a suitable solvent, it can be carried out usually at a temperature in the range of about 150 to about 100 ° C, especially about 15 to about 60 ° C.

The removal of the hydroxy protecting group (R u) from the resulting compound of the formula (νπ) can be carried out by selecting the deprotecting group reaction conditions known per se according to the type of the protecting group. For example, when the hydroxy protecting group is trityl, tetrahydroviranyl, (p-anisyl) diphenylmethyl, 2,4-dimethylbenzyl, etc., these protecting groups can be removed by hydrolysis using an acid. it can. Suitable acids that can be used for this hydrolysis include, for example, inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; trifluoroacetic acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, P-toluenesulfonic acid, methanesulfonic acid Organic acids such as acids can be mentioned. Usually, the acid It can be used in a medium amount or a large excess amount. The reaction temperature is usually preferably in the range of about 120 ° C. to about 8 ° C., especially about 0 ° C. to about 60 ° C. The reaction time can be generally about 0.5 to 24 hours. In the reaction, alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; ketones such as acetone; nitriles such as acetonitrile; or a mixed solvent of these solvents and water can be used. Also, a large excess of acid may be used as a solvent.

The resulting cephalosporin derivative is obtained by removing unreacted raw materials, by-products, solvents, etc. from the reaction mixture by a conventional method (extraction, evaporation, washing, concentration, precipitation, filtration, drying, etc.) It can be isolated by treating it by a processing method (adsorption, elution, distillation, precipitation, precipitation, chromatography, etc.).

By using the thiazole thioester compound of the present invention, the reaction proceeds under neutral conditions, and as a result, the desired cephalosporin derivative can be obtained with high purity and high yield.

Example

Hereinafter, the present invention will be described more specifically with reference to examples.

Example 1

2-ethylhydroxymino 3-oxo-41-chlorobutyrate (50.0 g, 0.26 mol) and trityl chloride (79.0 g, 0.28 mol) Was dissolved in dichloromethylene (340 ml) and cooled to 5 ° C. A solution of triethylamine (39., 4 ml) in dichloromethylene (50 ml) was added dropwise to the reaction solution. After returning the reaction solution to 25 ° C, the mixture was stirred for 3 hours. After adding water (200 ml) and extracting with dichloromethylene, the solvent _c washed with water was distilled off, the residue was dissolved in tetrahydrofuran (THF) (330 ml), and thiourea (39.3 g, 0.52 mol), sodium acetate ( (0.3 g, 0.52 mol) was added as an aqueous solution (330 ml). The mixture was stirred at 40 ° C for 7 hours. The reaction mixture was extracted with ethyl acetate and washed with water. The solvent c was distilled off, and ethyl acetate was added to the residue, followed by cooling. The precipitate was filtered to obtain ethyl (Z) -2- (2-aminothiazole-4-yl) -12-trityloxyiminoacetate as a crystalline compound (50.5 g, yield: 34%). .

IR (KB r, dis c., Cm " ¹ ) 3450, 3250, 3100, 2980, 1730, 1610, 1530, 1440, 1370, 1260, 1230, 1170, 1030, 960, 765,

750, 695

NMR (CDC 13, 5) 1.28 (t, J = 7Hz, 3H) .4.37 (q, J = 7Hz, 2H) .6.43 (s, 1H), 7.10-7. 53 (m, 15H z)

Example 2

Ethyl (Z) — 2— (2-Aminothiazoyl 4-41-yl) Dissolve 2-1-2-tri'-tiloxyiminoacetate (41., lg, 0.09 mol) in dioxane (296 ml) and give 2 N hydroxylation Sodium (90 ml) was added, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated, water was added to the residue to form a solution, and the solution was washed with ethyl acetate. The aqueous layer was adjusted to pH 4.0 with 2N hydrochloric acid, and the precipitate was filtered. After washing with getyl ether and drying, (Z) —2- (2-aminothiazole-4-yl) -12-trityloxysiminoacetic acid was obtained as a crystalline compound (31.0 g, yield: 80%) ).

IR (KB r, dis c., Cm- ¹ ) 3440, 3250, 3060,

1710, 1610, 1530, 1490, 1440, 1370, 1270, 1180, 965, 840, 745, 695

NMR (DMSO-de, <5) 6.70 (s, 1H), 7.00-7.51

(m, 15H)

Example 3

N-methylpyrrolidone (1.0 ml, 10.4 mmol) in acetonitrile solution of ethyl (Z) -2- (2-aminothiazole-4-yl) 12-trityloxyiminoacetic acid (5.15 g, 12.0 mmol) ), N-methylmorpholine (1.15 ml, 10.4 mimol) and 2,2-dibenzodiazolyl disulfide (3.98 g, 12.0 mimol) were added at room temperature. The mixture was cooled to 0 ° C and triethyl phosphite (2. 13.2 mmol) and stirred for 16 hours. The insoluble matter was filtered off, washed with acetonitrile and dried. (Z) -2- (2-aminothiazole-4-yl) _2-trityloxyiminoacetic acid 2-benzothiazolylthioester (4.34 g , Yield: 63%).

Melting point: 159-161 ° C

I R (KB r, d i s c., Cm-ri 3450, 3060, 1710, 1610, 1540, 1440, 1370, 1310, 1205, 1050, 980, 915, 900, 860, 760, 700

NMR (DMS O— d ₆ , δ) 6.86 (s, 1 H) 7.67 (s, 15 H), 7.60 to 7.75 (m, 2H). 8.10 to 8.38 ( m, 2H)

Elementary analysis: as _{_{_{_{C 31 H 22 N 4 0 2}}}} S 3

Calculated values C: 64.36, H: 3.81, N: 9.69, S: 16.61 Observed values C: 64.11, H: 3.77, N: 9.57, S: 16.41 Example 4

(Z) -2- (2-Aminothiazole-4-yl) A solution of 1-2-trityloxixiaminoacetic acid (1.07 g, 2.5 mmol) in acetonitrile (10 ml) was added to N-methylpyrrolidone (0.2 ml). m 1, 2.1 mimol), N, N-diisopropylethylamine (0.38 ml, 2.1 mimol) and 2,2-dibenzothiazolyl disulfide (0.83 g, 2.5 mi) Was added in room ί¾. The reaction solution was cooled to o ° C, and triethyl phosphite (0.47 ml, 2.7 mmol) was added, followed by stirring for 16 hours. The insolubles were filtered off, washed with acetonitrile and dried, and (Z) -2- (2-aminothiazol-4-yl) -12-trityloxyiminoacetic acid 2-benzthiazolylthioester (0.87 g) , Yield: 60%).

Reference Example 11

7-Amino-3-([Z) -2- (1,2,3-thiadiazol-4-yl) ethynyl] 13-cefm-14-diphenylmethyl carboxylate (0.48 g, 1 mmol) was converted into THF ( (Z) — 2- (2-aminothiazole-14-yl) -12-trityloxyiminoacetic acid 2-benzothiazolylthioester (0.57 g, 1 mmol) And stirred at 25 ° C for 8 hours. After concentrating the reaction mixture, the residue was purified by column chromatography to obtain diphenylmethyl 7-[(Z) -2- (2-aminothiazol-4-yl) -12-triethyl as a powdery compound. Chilloxyminoacetamide] 1 3— [(Z) -2- (1, 2, 3—H (Asian 4-ethyl) ethynyl] -3- (4-phen-carboxylate) (0.179 g, yield: 89%).

IR CKB r, dis c., Cm " ¹ ) 3430, 3050, 1780, 1715, 1675, 1610, 1520, 1490, 143.5, 1365, 1295, 1215, 1170, 1080, 1030, 995, 955, 900, 885, 750, 690, 630

NMR (CDC 13, δ) 3.45 (m, 2H), 5.41 (d, J = 5 Hz, lH), 6.10 (dd, J = 5 Hz, J = 9 Hz, 1 H) .6.66 (s, 1 H) 6.74 (d, J = 12Hz, 1H) .6.84 (s, lH), 6.94 (d, J = l 2Hz, 1H), 7.10 to 8.00 (m, 25H), 9.01 (s, 1H)

Reference Example 11-2

The product of Reference Example 1-1 (1.77 g, 2 mmol) was added to 88% formic acid (5 ml), and the mixture was stirred at 25 ° C for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to isopropyl ether. The precipitate was filtered and washed with isopropyl ether. Add anisol (3 ml) to the reaction. After cooling to 5 ° C., trifluoroacetic acid (10 ml) was added, and the mixture was stirred for 1 hour. This reaction solution was added to isopropyl ether. The precipitate is filtered, washed with isopropyl ether and dried, and as a powdery compound, 7-[(Z) -2- (2-aminothiazol-4-yl) -12-hydroxyiminoacetamide] -3 — [(Z)-2- (1,2,3-thiadiazol-1 4-yl) -ethynyl] _3-seffemu-4-carboxylate trifluoroacetate (0.95 g, 80% yield) was obtained. .

IR (KB r, dis c., Cm " ¹ ) 3300, 3100, 1780,

1680, 1600, 1600, 1540, 1410, 1360, 1240, 1200, 1140, 1010, 800, 720

NMR (DMSO-de, δ 3.50 (m, 2H), 5.20 (d, J = 4.5 Hz, lH), 5.76 (dd, J = 4.5 Hz, J = 9 Hz, lH ), 6.66 (d, J = 12Hz, 1H), 6.83 (s, lH), 6.92 (d, J = 12Hz, 1H), 7.33 (bs, 2H) ), 9.00 (s, lH), 9.50 (d, J = 9Hz _; 1H)

Reference Example 2-1

Bivaloyloxymethyl 7-amino-3-[(Z) -2-(1,2,3'thiadiazol-41-yl) ethynyl] -13-cefm-14-carboxylate oxalate (0. 103 g, 0.2 mmol) in THF (8 ml) was dissolved in (Z) -2- (2-aminothiazol-4-yl)-2-trityloxyminoacetate 2-benzothiazolyl The thioester (0.113 g> 0.2 millimol) was added and stirred at 25 ° C for 1.6 hours. After concentrating the reaction mixture, the residue was purified by column chromatography to give pivaloyloxymethyl 7-[(Z) -2- (2-aminothiazole) as a powdery compound (0.129 g, yield: 71%). 1-41) 1 2—Trityloxyximinoacetamide] 1 3 — [(Z) —2— (1,2,3-thiadiazol-4-1-yl) -ethynyl] —3—sefumu 4 One carboxylate was obtained.

IR (KB r, dis c., Cm- ¹ ) 3300, 3100, 1 770,

1670, 1600, 1540, 1410, 1360, 1240, 1220, 1 155, 1010, 1000, 800, 7 10

NMR (CDC 13, δ) 1.20 (s, 9H), 3.19, 3.61 (AB q, J = 18Hz, 2H), 5.21 (d, J = 5Hz, 1H), 5.82, 5.94 (AB q, J = 5Hz, 2H), 5.96 (dd, J = 5Hz, J = 9Hz, 1H), 6.79 (d, J = 12 Hz, 1 H), 6.82 (s, 1 H), 7.01 (d, J =

1 2 H z, l H), 7.20 to 7.50 (m, 15 H), 8.37 (s, 1 H)

Reference Example 2-2

The product of Reference Example 2-1 (0.20 g, 0.23 mimol) was dissolved in 88% formic acid at 25 ° C and stirred for 2 hours. Benzene was added to the reaction solution, and the mixture was concentrated under reduced pressure. Benzene was added to the residue, stirred for a while, and the benzene layer was removed by decantation. The residue was dried over phosphorus pentoxide under reduced pressure. This was dissolved in aqueous ethyl acetate, and sodium hydrogen carbonate was added to adjust the pH to 6.5. The ethyl acetate layer was separated, washed with water, and dried over magnesium sulfate. The solvent was distilled off, and pivaloyloxymethyl 7-[(Z) —2- (2-aminothiazol-4-yl) -1-2-hydroxyiminoacetamide] —3— was obtained as a yellow powdery compound. [(Z) —2- (1,2,3-thiadiazol-41-yl) ethynyl] —3-cephemu-4-carboxylate (0.10 g, yield: 73%) was obtained.

I R (KB r, d i s c., Cm-3330, 2980, 1870, 1750, 1710, 1660, 1520, 1360, 1220, 1120, 980, 800

NMR (CDC 13, 5) 1.18 (s, 9H), 3.42, 3.62 (A B q, J = 18Hz, 2H), 5.21 (d, J = 5Hz, 1H), 5.45 (bs, 2H), 5.8 (d, J = 5Hz, 1H), 5.91 (d, J = 5Hz, 1H), 5.98 (dd, J = 5Hz, J = 9Hz, lH), 6.00 (d, J = 12Hz, 1H), 6.84 (d, J = 12Hz, lH), 7.14 (s , LH), 8.40 (s, 1H), 11.06 (bs, 1H)

Reference Example 3-1

7-Amino-3-vinyl-3-cefume-4 Dissolve diphenylmethyl rubinate (0.392 g, 1 mmol) in THF (15 ml) and add (Z) -2- (2-aminothiazole-4-) B) To the mixture was added 12-trityloximinoacetic acid 2-benzothiazolylthioester (0.567 g, 1 mmol), and the mixture was stirred at 25 ° C for 15 hours. After concentrating the reaction mixture, the residue was purified by column chromatography to obtain diphenylmethyl 7-[(Z) -12- (2-aminothiazole-14-yl) -2-trityloxy as a powdery compound. [Siminoacetamide] -13-vinyl-13-cefume-4-carboxylate (0.706 g, yield: 88%) was obtained. TR (KB r, dis c., Cm " ¹ ) 3430, 3050, 1780, 1710, 1680, 1620, 1510, 1470, 1430, 1355, 1295, 1210, 1160, 1085, 1020,

995, 955, 9H 0, 885, 755, 690, 635 NMR (CD C 13, 6) 3.37.3.57 (AB q, J = 18Hz,

2H), 5.08 (d, J = 5Hz, 1H), 5.31 (d, J =

10 Hz, lH), 5.46 (d, J = 1 7 Hz, 1H), 5.97 (dd, J = 5 Hz, J = 9 Hz, lH), 6.71 (s, 1H) .7.15 (s, 1H) 7.17 (dd, J = 10Hz, 5 = 11 Hz, 1H), 7.20-7.60 (m, 25H)

Reference Example 3-2

The product of Reference Example 3-1 (0.70 g, 0.87 mimol) was dissolved in 88% formic acid (5 ml) at 25 ° C and stirred for 2 hours. Benzene was added to the reaction solution, and the mixture was concentrated under reduced pressure. Isopropyl ether was added to the residue, stirred for a while, and then filtered. This compound was dissolved in anisol (2 ml) and cooled to 5 ° C. Add trifluoroacetic acid (85 ml) and add 1 hour It was stirring. The reaction solution was concentrated under reduced pressure, and the residue was added to isopropyl ether. The precipitate was filtered, washed with isopropyl ether and dried. This was suspended in water, adjusted to pH 6.5 with sodium hydrogen carbonate, and insolubles were filtered. The filtrate is ice-cooled, adjusted to pH 2.5 with 2N hydrochloric acid, and the precipitate is filtered, washed with water and dried, and dried with 7-C (Z) -2- (2-aminothiazole-141-yl). [1-2-Hydroxyiminoacetamide]] 1-3-vinyl 3-cefume-4-carboxylic acid (0.14 g, yield: 34%) was obtained.

IR KB r, dis c., Cm " ¹ ) 3325, 3100, 1775, o 1690, 1625, 1600, 1570, 1525, 1415,

1400, 1360, 1305, 1245, 1180, 1140, 1015, 900, 810, 780, 750, 600, 560 MR (DMS O- d 6. 5) 3.52, 3.84 (AB q, J = 18 Hz, 2H), 5.18 (d, J = 5 Hz, lH), 5.30 (d,. J = 11 Hz, lH), 5.58 (d, J = 18 Hz, 1H) _Λ

5.79 (dd, J = 5Hz, J = 9Hz, 1H), 6.68 (s, lH), 6.93 (dd, J = 1Hz, J = 18Hz, 1H), 7.10 (s, 1H), 9.48 ( d, J = 9Hz, 1H)

Industrial applicability ''

The compound provided by the present invention exhibits excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria. (Z) -2- (2-aminothiazol-4-yl) -12-hydroxyiminoacetamide Is useful as an intermediate for producing a cephalosporin derivative having a thiol group, and by using this compound, the reaction can be allowed to proceed under neutral conditions. The desired cephalosporin derivative can be obtained with high purity and high yield.

Claims

The scope of the claims

Expression

In the formula, represents a hydrogen atom or a hydroxy protecting group,

A compound represented by the formula:

2. The compound according to claim 1, which is benzothiazole-2-yl-2 ((Z) _2-aminothiazolu-4-yl) -1-2-trityloxyiminothioacetate.

3 expression

Wherein R _tl represents a hydroxy protecting group,

A compound represented by the formula

X ₃ P or Y ₃ N

In the formula, three Xs each independently represent an aryl group or an alkoxy group, and three Ys each independently represent an alkyl group, or two of the Ys represent the N atom to which they are bonded. Together represent a nitrogen-containing heterocyclic group which may further contain a hetero atom such as N, S, 0, etc. In the presence of a phosphorus compound or a tertiary amine compound represented by the formula

2. The method for producing a compound according to claim 1, wherein the compound is reacted with dithiobenzothiazole represented by the formula, and if necessary, the hydroxy protecting group (Ru) is removed from the obtained product.

4. Expression

Wherein R represents a hydroxy protecting group, R ₂ represents a carboxy protecting group,

Reacting thiourea with a compound of formula

Wherein: and R ₂ have the above meanings;

4. The method according to claim 3, wherein the compound of the formula (V) is produced by hydrolyzing the compound of the formula (V).

5 Expression

In the formula, Rn represents a hydroxy protecting group,

The compound represented by the formula '

Wherein R ₃ represents a hydrogen atom or a carboxy protecting group, R ₄ represents a hydrogen atom or a 3-position substituent commonly found in cephalosporin compounds, and is reacted with a 7-aminocephem compound represented by the formula: A formula characterized by removing a hydroxy protecting group (Ru) from the obtained compound.

Wherein R ₃ and R ₄ have the meaning described above,

A method for producing a cephalosporin derivative represented by the formula: