JPS60214783A - 2-amino-4-hydroxythiazoline derivative and its salt - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R1 is carboxyl or lower alkyl which may be substituted with protected carboxyl; Z is -SR<4> (R<4> is alkyl, aralkyl, aryl), halogen] and its salt. EXAMPLE:2-( 2-Amino-4-hydroxy-2-thiazolin-4-yl )-2-( syn )-methoxyiminothioacetic-S-methyl ester. USE:A synthetic intermediate of cephalosporin having high antibiotic action. PREPARATION:A compound of formula V (X is halogen; wavy line is a syn or anti isomers or a mixture thereof) is allowed to react with thiourea to give the compound of formula I b (the syn isomer) in the form of crystals and the unreacting anti isomer of formula V is combined with a dried acid such as hydrogen chloride to effect isomerization into the syn isomer. Then, the above cyclization is effected to obtain only the syn isomer easily.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 2-amino-4-hydroquidithiazoline derivatives, specifically 2-amino-4-hydroquidithiazoline derivatives represented by the following general formula.
This invention relates to amino-4-hydroquidithiazoline derivatives (synisomers) and salts thereof.

More specifically, since cephalosporins having excellent antibacterial activity can be easily obtained using a 2-amino-4-hydroxythiazoline derivative represented by the general formula CI) or a salt thereof, the present inventors discovered that the compound represented by the general formula [I] and its salts are useful as intermediates for the production of cephalosporins, and completed the present invention.

Therefore, the object of the present invention is to provide a novel 2-amino-4-hydroxythiazoline represented by the general formula [I] useful as an intermediate in producing the cephalosporins.
An object of the present invention is to provide derivatives and salts thereof.

For example, a cephalosporin (syn isomer) represented by the following formula and a salt thereof can be derived from the derivative represented by the general formula [I] of the present invention or a salt thereof.

The cephalosporin (syn isomer) represented by the above general formula [■] and its salts are disclosed in Japanese Patent Application Laid-open No. 57-99592, Japanese Patent Application No. 57-200382, Japanese Patent Application No. 58-67871, and Japanese Patent Application No. 58-115565. and 58-114313
As described in the issue, it has a broad antibacterial spectrum and not only shows excellent antibacterial activity against Durum-positive bacteria and Gram-negative bacteria, but also exhibits stable properties against β-lactamases produced by bacteria. It exhibits excellent therapeutic effects on diseases of humans and animals when administered orally or parenterally.

The present invention will be further explained in detail below.

In this specification, unless otherwise specified, alkyl refers to linear or branched C1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert
-7'Tyl, pentyl, hexyl, heptyl, octyl, dodecyl, etc.; alkenyl is C! ~1o alkenyl, e.g. vinyl, allyl, isopropenyl, 2-
Pentenyl, butenyl, etc.; Aryl is, for example,
Phenyl, tolyl, naphthyl, indanyl, etc.; aralkyl is, for example, benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl, etc.; acyl is Cl
-11 acyl, such as acetyl, propionyl, butyryl, piparoyl, pentanecarbonyl, cyclohexanecarbonyl, benzoyl, naphthoyl, furoyl,
Thenoyl, etc.; halogen atoms are, for example, fluorine,
It means chlorine, bromine, iodine atoms, etc., respectively, and lower means 1 to 5 carbon atoms.

Furthermore, among the various terms used in this invention, for example, alkyl, alkenyl, aryl, aralkyl,
Terms such as acyl have the above meaning unless otherwise specified.

In each formula in this specification, R1 represents a carboxyl group or a lower alkyl group which may be substituted with a protected carboxyl group, and R3 represents a hydrogen atom or a carboxyl protecting group. As protecting groups for carboxyl groups, those commonly used in the field of penicillin and cephalosporin compounds can be mentioned.
No. 7-99592, No. 58-77886, Patent Application No. 1983
-200382, 5F+-67871, 5g-
The carboxyl group-protecting groups described in No. 113565 and No. 58-114313 can be used. In addition, each adult R3 has an exomethylene group at the 3-position and a carbon-
Indicates a nitrogen-bonded optionally substituted heterocyclic group, such as tetrazolyl,
Indicates a divalent group forming a 5-membered or 6-membered group. ), for example, 1.2.6-thiadiazine-1
, 1-dioxide, and isothiazolidine-1,1-dioxide groups. More specifically, 1-(1,2,3,4-tetrazolyl), 2-(1,2,3,4-tetrazolyl), 1-(1,2,3-triazolyl), 2-(1 ，
2,3-)riazolyl), 1-(1,2,4-triazolyl), 4-(1,2,4-1riazolyl), 2.3-
dioxo-1,2,3,4-tetrahydropyrazinyl,
3.6-thioxo1.2.3.6-titrahydropyridazinyl, 6-oxo-1,6-cyhydropyridazinyl, 2-oxo-1,2-dihydropyrazinyl, 6- Oxo-1,6-dihydropyrimidinyl, 2-oxo-1,
2-dihydropyrimidinyl, 1,2,6-thiadiazin-1,1-dioxido-2-yl, isothiazolidine-
Examples include 1,1-dioxide-2-yl group.

Examples of substituents on the heterocyclic group include a halogen atom, a nitro group, an alkyl group, an aralkyl group,
Aryl group, alkenyl group, hydroxyl group, alkoxy group, cyano group, amino group, alkylamino group, dialkylamino group, acylamino group, acyl group, acyloxy group, acylalkyl group, carboxyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group , carbamoyl group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, hydroxyalkyl group, hydroxyiminoalkyl group, alkoxyalkyl group, carboxyalkyl group, sulfoalkyl group, sulfo group, sulfa Examples include a moylalkyl group, a sulfamoyl group, a carbamoylalkyl group, a carbamoylalkenyl group, an N-hydroxycarbamoylalkyl group, and the above-mentioned heterocyclic group may be substituted with one or more of these substituents. Among these substituents, the hydroxyl group and the amino group may be protected with the Yato group of the hydroxyl group and amino group described in JP-A No. It may be protected with a carboxyl group-protecting group. R4 is optionally substituted alkyl,
It represents an aralkyl or aryl group, and examples of the substituent thereof include those exemplified as the substituent for the heterocyclic group of R3. Further, among these substituents, the hydroxyl group and the amino group may be protected by the hydroxyl and amine protecting groups exemplified by %R'', and the carboxyl group may be protected by the carboxyl group protecting group exemplified by R1. .

Salts of the compounds of general formula CI) or [II) include salts with basic groups or acidic groups conventionally known in the field of penicillin and cephalosporin compounds.

Examples of salts with basic groups include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, etc.@salts with mineral acids; oxalic acid, cono-phosphoric acid, formic acid, trichloroacetic acid, trifluoroacetic acid, etc. Which organic carboxylic acid salt; methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2,4,6-) IJ methylbenzenesulfonic acid) Examples of salts with acidic groups include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; triethylamine, trimethylamine, aniline, N
, N-dimethylaniline, pyridine, dicyclohexylamine and other nitrogen-containing organic bases. The present invention also covers all optical isomers of the salt conductor (syn isomer) of the general formula [I] and its salts (for example, the optical isomers that arise because the 4-position carbon atom of the thiazoline ring is an asymmetric carbon isomers, etc.), crystalline forms, and hydrates.

The compound of the present invention and the compound of general formula [11] can be produced, for example, according to the method shown below.

(The following is a blank space) Manufacturing method [■] [■] [■] [1'l] [X) [IX] or a salt thereof [IIr) [II] General formula used in the manufacturing method of the present invention [11] and [I
As the salt of the compound of general formula [1] and [■]
Examples of the salts of the compounds include those listed above.

Next, each method for producing the compounds of general formulas [■] to (XI) will be explained as follows.

The compound of the general formula [V) can be produced by the method described in Japanese Patent Application No. 172254/1984 (reaction with thiol, nitrosation, alkylation, halogenation, etc.) or by a method known per se.

0) Method for producing a thiazoline derivative of the general formula [Ib) or a salt thereof (ring-closing reaction) The thiazoline derivative of the general formula [Ibl] or a salt thereof can be obtained by reacting a compound of the general formula [v] with thiourea. Specifically, by reacting thiourea with the compound of the general formula [■] in the following solvent under the following reaction conditions, the general formula [I] is produced as crystals from within the reaction system.
A thiazoline derivative (syn isomer) of El] or a salt thereof can be selectively obtained. Solvents used in this reaction include ethyl acetate, acetone, dioxane, tetrahydrofuran, acetonitrile, and acetic acid.

Examples include methylene chloride, chloroform, benzene, and dimethyl cellosolve, and a mixture of these solvents may be used if desired.

Further, this reaction usually proceeds at -40 to 30°C, preferably -30 to 20°C, and the reaction time is usually 30 minutes to 5 hours, preferably 30 minutes to 3 hours.

When the compound of general formula [V] is a syn isomer, the amount of thiourea to be used may be 1 mol or more per 1 mol of the syn isomer. When the compound of general formula [V) is a mixture of syn isomer and anti isomer, the amount of thiourea to be used is:
It may be adjusted as appropriate depending on the composition ratio of the syn isomer and the anti isomer of the compound of general formula [v]. In that case, the generated compound (syn isomer) of the general formula (:Ibl) selectively precipitates as crystals from the reaction system, and the anti-isomer of the compound of the general formula [V], which is an unreacted product, is released into the system. Then, if an acid such as dry hydrogen chloride or dry hydrogen bromide is added to this remaining anti-isomer to isomerize it to the syn isomer, and the main closed-monkey reaction is performed again, the syn Only the isomer can be isolated. In this way, only the syn isomer can be easily produced. The end point of this reaction can be easily confirmed by commonly used methods such as TLC.

The obtained compound was determined by UV%NMR, “C-NM
It was confirmed that the compound was a thiazoline compound by
No. 54 describes a method for obtaining a thiazole compound represented by the general formula by reacting a raw material similar to that of the present invention, that is, a compound of the general formula [V] with thiourea, but under the conditions of the present invention. According to the method, the desired thiazoline derivative (syn isomer) can be selectively obtained without producing the above thiazole compound.

(b) Process for producing acid halide of general formula [Ia] or its salt General formula CI! ] or a salt thereof has the general formula [Ib
It can be easily obtained by reacting the compound or a salt thereof with a halogenating agent that usually converts a thioloester into an acid halide, preferably, for example, chlorine or bromine. This reaction is carried out in a continuous solvent, and any solvent may be used as long as it does not adversely affect this reaction. For example, solvents such as methylene chloride, chloroform, ethylene chloride, ethyl acetate, etc. A mixture of two or more solvents is used. In addition, the amount of the halogenating agent used is based on the general formula [Ib]
The amount is 1 to several equivalents relative to the compound or its salt. The reaction is usually carried out at a temperature ranging from -30°C to room temperature, and the reaction time is from several minutes to several hours, preferably from 15 minutes to 2 hours.

(-) Process for producing a compound of the general formula [1111] or a salt thereof (acylation reaction) A compound of the general formula [■] or a salt thereof is prepared by preparing the compound of the general formula [■] or a salt thereof, usually in the presence or absence of a base in an appropriate solvent. It can be obtained by reacting the compound of general formula [Ia] or a salt thereof with the compound of general formula [■] or a salt thereof. Any solvent may be used as long as it does not adversely affect the reaction, such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, methyl acetate, ethyl acetate, N
, N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, dimethyl celisol, dimethyl sulfoxide, sulfolanato, and mixtures of two or more of these solvents are used. Bases used in this reaction include inorganic bases such as alkali hydroxide, alkali hydrogen carbonate, alkali carbonate, alkali acetate, trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine, etc. tertiary amine or dicyclohexylamine,
Secondary amines such as diethylamine are mentioned.

In addition, the compound of general formula [IV] or a salt thereof can be prepared by a conventional three-position conversion reaction of 7-aminocephalosporanic acid in the presence of an acid (JP-A No. 57-99592, Japanese Patent Application No. 57-118). -200382, 57-20.6873, 58-67871, 58-113565, 58
-114313 etc.) and then introducing a protecting group into the carboxyl group at the 4-position.

In addition, the compound of general formula [IV] or a salt thereof can also be used as a reactive derivative at its amino group, and examples of such a reactive derivative include the compound of general formula [IV] or a salt thereof. Silyl compounds such as bis(trimethylsilyl)acetamide, trimethylsilylacetamide, trimethylsilyl chloride, trichloride (CHs CH2O)! PCI,CCCOCl! P
Phosphorus compounds such as C1 or (C4H@)3SnC1
Examples include those frequently used in acylation reactions, such as silyl derivatives, phosphorus derivatives, or tin derivatives produced by reaction with tin compounds such as silyl derivatives.

The amount of the compound of general formula [Ia] or its salt to be used is not particularly limited, but is usually about 0.8 to 2.0 times the amount of the compound of general formula [Ia] or its salt, preferably about 1.
It is 0 to 1.5 times the mole. This reaction is usually -50 to 5
The reaction is carried out at 0°C, preferably -35 to 25°C, and the reaction time is usually several minutes to several hours.

B) Process for producing a compound of general formula [II] or a salt thereof (dehydration reaction) A compound of general formula [■] or a salt thereof can be obtained by subjecting a compound of general formula [■] or a salt thereof to a dehydration reaction.

This reaction is preferably carried out in a solvent, and the intoxicant may be any solvent that does not adversely affect the reaction (for example, water, methanol, ethanol, acetone, acetonitrile, nitromethane, methyl acetate, Solvents such as ethyl acetate, chloroform, methylene chloride, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or a mixture of two or more of these solvents are used.Also, this reaction is carried out in the presence of an acid. The acid is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, vinegar, lifluoroacetic acid,
p-) Protic acids such as luenesulfonic acid and mesitylenesulfonic acid - Lewis acids such as boron trifluoride, aluminum chloride, and zinc chloride; complex compounds of boron trifluoride and Lewis acids such as diethyl ether, etc. can be used. Further, the amount of acid used is not particularly limited, but it is preferably o, ooi to 1.5 times the molar amount of the compound of general formula [m] or its salt.

Furthermore, when the solvent used is a non-aqueous solvent, a suitable dehydrating agent such as anhydrous magnesium sulfate or molecular sheep may be added to the reaction system.

This reaction is usually carried out under cooling to room temperature, and the reaction time is usually several minutes to several tens of hours.

The compound of the general formula [■]-(X) or a salt thereof obtained in this way can be isolated and separated by a conventional method, and the compound of the general formula [■] or a salt thereof can be isolated and separated by a conventional method. It can also be used in the next reaction without isolation or separation.

Next, the present invention will be explained with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 +1) (i) 4-promo 2-(syn)-methoxyimino-3-oxothiobutyric acid-8-methyl ester 2B,
4t is dissolved in 200ml of ethyl acetate, and 7.6t of thiourea is added over 10 minutes at 15-20°C. Then, after reacting at the same temperature for 1 hour, the precipitated crystals are filtered to obtain 2-
(2-amino-4-hydroxy-2-thiazoline-4-
yl)-2-(syn)-methoxyiminothioacetic acid-8-
Hydrobromide of methyl ester 30.2t (yield 91.
5).

IR (KBr) cm″″1; νc=o 1670.16
40(li) Instead of ethyl acetate in (i) above, acetone, dioxane, tetrahydrofuran,
Acetonitrile, acetic acid, methylene chloride, chloroform,
Similar results are obtained if the above reactions are carried out using benzene or dimethyl cellosolve, respectively.

(The following compound was obtained in the same manner as (i) above.

0 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-diphenylmethoxycarbonylmethoxyiminothioacetic acid-8-methyl ester hydrobromide IR (KBr) c *-1; νc=o 1760.17
40.1650 (hydrobromide salt of 212-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminothioacetic acid-8-methyl ester 8.Of water-cooled Below 200 - ethyl acetate and 10 - water
Suspended in a mixed solvent of 4.0- and sodium bicarbonate. O
Add f and stir for 5 minutes. Then, the organic layer was separated and washed with 100 d of water.

Dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 30 m of benzene was added to the resulting residue, and the crystals were collected by filtration to give 2-(2-amino-4-hydroxy-2-thiazoline) with a melting point of 127-130°C. -4-yl)-2
-(Syn)-methoxyiminothioacetic acid-8-methyl ester 5,2f (yield 86.7%) is obtained.

IR(KBr) clrL-1; νc=o 164O
NMR (d6-DMSO) δ value; 2.36 (3H,m, -8CHg).

6.16 (IH, bs, -0H).

6.82 (2H, bs, -NHt)13CNMR (
d6-DMSO) δ value; 11.10 (-8CHs).

43.51 (C-5).

62.19 (-00Hs) 1 102.43 (C-4).

161.85 (C-2”).

190.26 (-C-8-) 1 MS (m/e) i 250 (M++1) UV (CxHsOH) i λmax 232 (S) (g=8167) In the same manner, the following compound was obtained.

0 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-diphenylmethoxycarbonylmethoxyiminothioacetic acid-8-methyl ester Melting point: 140-142°C IR (KBr) cfn −1; ν(=0 1728,1
652 NMR (d, -DMSO) δ value; 2.36 (3H, s, -8CH3) + 6.17 (IH, bg, -0H).

6.84 (3H, bs, -NH2, -CH).

7.32 (10H, s, -□×2) Example 2 (Li 4-bromo 2-methoxyimino-3-oxothiobutyric acid-8-methyl ester (mixture of syn and anti forms) 50.FllF in ethyl acetate 400 2-( 2-amino-4
Hydrobromide 31.4f (yield 47.5%) of -hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminothioacetic acid-8-methyl ester is obtained. The IR of this compound was consistent with that obtained in Example 1 (1)(i).

Oi) Add 300 stl of water to the filtrate obtained in (#) above.
! Wash twice with water and dry with anhydrous magnesium sulfate. Then, 5. dry hydrogen chloride was added under water cooling. After introducing Of and leaving it for 5 hours at room temperature, the reaction solution was again washed twice with 300 m of water. After drying the organic layer with anhydrous magnesium sulfate,
Add 3.9 f of thiourea over 30 minutes at 15-20°C. After reacting at the same temperature for 1 hour, the precipitation ability is collected by filtration and washed with ethyl acetate 2-(2-amino-4-
Hydrobromide 10.1F (15,3T) of hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminothioacetic acid-8-methyl ester is obtained.

The IR of this compound was consistent with that obtained in Example 1 (1) (1).

Example 3 (i) 4-Bromo-2-methoxyimino-3-oxothiobutyric acid-8-methyl ester (syn and anti mixture) 50. Dissolve Of in 250 m of acetone, -2
Add 7.5 f of thiourea over 1 hour at 5 to -20°C. After reacting at the same temperature for 2 hours, filtering the precipitated crystals and washing with acetone 50-, 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)
-Methoxyiminothioacetic acid-8-methyl ester hydrobromide 30.9f (yield 47.5f) is obtained.

IR (KBr) z-1; νc=o 1650ω)
The filtrate obtained in (i) above is concentrated under reduced pressure, and the resulting residue is dissolved in 200 d of ethyl acetate.

Then, after washing with 200 g of water, it is dried with anhydrous magnesium sulfate. After introducing dry hydrogen chloride 2, Of at 0-5 °C and reacting for 5 hours at room temperature.

Wash twice with 100% water and dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was dissolved in acetone 120- and thiourea 3-3 was dissolved at -25 to -20°C.
,02 was added over a period of 1 hour. After reacting at the same temperature for 2 hours, filtering the precipitated crystals and washing with 20 m of acetone, 2
-(2-amino-4-hydroxy-2-thiazoline-4
-yl)-2-(syn)-methoxyiminothioacetic acid-8
- Hydrobromide of methyl ester 10.1f (yield 15
, 5chi) is obtained.

IR(KBr)am-1sνc=o 1650(ii)
2-(2-amino-4 obtained in (i) and 0) above
The hydrobromide salt of -hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminothioacetic acid-8-methyl ester was treated in the same manner as in Example 1(2), with a melting point of 127 to 2-(2-7minor-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminothioacetic acid-8-methyl ester exhibiting a temperature of 130°C was obtained.

Physical properties of cono compounds (IR, NMR, lsC-NMR, M
S.

UV) was consistent with that obtained in Example 1(2).

Example 4 2-(2-amino-4-hydroxy-2-thiazoline-
4-yl)-2-(syn)-methoxyiminothioacetic acid-
Hydrobromide of 8-methyl ester20. Of was suspended in 100 g of anhydrous methylene chloride, and chlorine 8,6 was added at 0 to 5°C.
100 d of an anhydrous methylene chloride solution containing f was added dropwise over 10 minutes.

Then, after reacting at the same temperature for 30 minutes, the precipitated crystals were collected by filtration and washed twice with 20 m of anhydrous methylene chloride to reduce the melting point to 1.
2-(2-amino-4-
Hydrobromide salt of hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminoacetic acid chloride 14.
6f (yield 75.5%) is obtained.

IR (KBr ) cm-1; vc=o 1780 Also, the following compound was obtained by using ethyl acetate as a solvent instead of anhydrous methylene chloride and reacting in the same manner as above.

0 Hydrobromide melting point of 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-diphenylmethoxycarbonylmethoxyiminoacetic acid chloride; 11B to 120'G (decomposition) I R (K B r ) cm-1; νc=o 176
4.1740.1642 Example 5 2-(2-amino-4-hydroxy-2-thiazoline-
4-yl)-2-(syn)-methoxyiminothioacetic acid-
Hydrobromide of 8-methyl ester20. Of was suspended in 200°C of anhydrous methylene chloride and 10°C of bromine was added at 0-5°C.
6f was added dropwise over a period of 20 minutes. Then, at the same temperature, 30
After reacting for a minute, the precipitated crystals are collected by filtration and washed twice with 20% of anhydrous methylene chloride.
-(2-amino-4-hydroxy-2-thiazoline-4
-yl)-2-r-syn)-methoxyiminoacetic acid bromide hydrobromide salt 17. O2 (yield 77.4 h) is obtained.

IR(KBr)cm-” +νc=o 1818 Reference Example 1 (l) 2-Hydroxyimino-3-oxothiobutyric acid-8
-Methyl ester20. Of was dissolved in N,N-dimethylformamide lO〇-, and potassium carbonate was added at 0 to 5°C.
7.1f and chloroacetic acid tert-butyl ester 2
After sequentially adding 2.4F, the mixture was allowed to react at room temperature for 3 hours. The reaction solution was introduced into a mixed solvent of 400 m of ethyl acetate and 200 at of water.

Then, the organic layer was separated and diluted with 200 d of water and 2 d of IN-hydrochloric acid.
After sequentially washing with 00- and 200 Int of saturated saline, drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 100% diisopropyl ether was added to the resulting residue.
2-tert-butoxycarbonylmethoxyimino-3-oxothiobutyric acid-8-methyl ester 14.4
f (yield 42.2%) is obtained.

IR(KBr) cm-' i νc=o 1732.1
700.1664 NMR (CDCIs) δ value; 1.50 (9H+s, -C(CH3)s).

2.39 (3H, s, CI(s)).

2.46 (3H, s, -CHl).

4.63 (2H, s, -0CH2CO-)(21
2-tert-butoxycarbonylmethoxyimino-3
-Oxothiobutyric acid-8-methyl ester 10, Or 0
Add over 10 minutes to 10-fluoroacetic acid cooled to ~5°C. After reacting at 0 to 5°C for 1 hour, the solvent was distilled off under reduced pressure.

When diisopropyl ether 50- is added to the resulting residue and the crystals are collected by filtration, 2-
Carboxymethoxyimino-3-oxothiobutyric acid-8-
Methyl ester 7,2t (yield 90.5t) is obtained.

IR (KBr) cm-11 c-o 1734.1
700.166ONMR(d, -DMSO) a value; 2.36 (3H-s, -CHn) -2,45(
3H,s, -CH5).

4.85 (2H, s, 0CHICo Reference Example 2 11) Water 330 l117! Sodium nitrite 38
．． CM' and 66.12 kg of 3-oxothiobutyric acid-8-methyl ester were added, and 4N-sulfuric acid 2
10 d was added dropwise over 30 minutes. After the dropwise addition was completed, the reaction was continued at the same temperature for 30 minutes, and then the reaction solution was diluted with 500% ethyl acetate.
1 nt. The organic layer is separated, washed with 500 m of water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was dissolved in sodium carbonate 1
After dissolving in an aqueous solution 650- containing 06f, methanol 150- is added. Add 75% of dimethyl sulfate to this solution.
7f was added dropwise at 15 to 20°C, and then reacted at the same temperature for 2 hours. Then, the reaction solution was introduced into ethyl acetate 1i, and the organic layer was separated, washed with 300ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
If the obtained residue is distilled under reduced pressure, the boiling point will be 80-86°C.
/2mHf to obtain 60.4f (yield: 68.9t) of thio-2-methoxyimino-3-oxothiobutyric acid-8-methyl ester (mixture of syn and anti forms).

If this mixture is separated and purified by column chromatography (U-optical silica gel C-200, elution solvent: n-hexane-benzene), the oily substances 2-(syn) to methoxyimino-3-oxothiobutyric acid-8-methyl The ester and 2-(anti)-methoxyimino-3-oxothiobutyric acid-8-methyl ester are obtained.

02-(Syn)-methoxyimino-3-oxothiobutyric acid-8-methyl ester v m / -% \ 1 ・To U-- 1g 9n
1gon tg FONMR (CDC1m) δ value; 2.42 (311, s).

2.48 (3H, i).

4.18 (3H, s) 02-(anti)-methoxyimino-3-oxo-1-thiobutyric acid-8-methyl ester IR) cm'-"; νc=o 1750.
16RONMR (CDCI,) δ value; 2.41 (3H, a).

2.42 (3H, s).

4.16(3H,5) (2) 2-methoxyimino-3-oxothiobutyric acid-8-
Methyl ester (mixture of syn and anti isomers) 10.
Of is dissolved in 1,4-dioxane 150-, and pyridinium-1-hydropromite 0-no-bromide 20-
．． Add 1F and react at room temperature for 4 hours. Then, the solvent was distilled off under reduced pressure, and 10% of ethyl acetate was added to the resulting residue.
Add 0 m and 100 m of water. Separate the organic layer and
After sequentially washing with 100 ml of a % sodium bisulfite aqueous solution, 100 ml of water and 100 ml of saturated saline, it is dried over anhydrous magnesium sulfate. If the solvent is distilled off under reduced pressure,
4-Bromo-2-methoxyimino-3-oxothiobutyric acid-8-methyl ester (mixture of syn and anti forms)
11.6F (yield: 8060 buns) was obtained.

If this mixture is separated and purified by column chromatography (Wako silica gel C-200, elution solvent: n-hexane-benzene), each oily substance 4-bromo 2-(
Syn)-methoxyimino-3-oxothiobutyric acid-8-methyl ester and 4-bromo-2-(anti)-methoxyimino-3-oxothiobutyric acid-8-methyl ester are obtained.

04-Bromo 2-(syn)-methoxyimino-3-oxothiobutyric acid-8-methyl ester IR (nee F)
CWL-” j pc=o 1705. 1665HM
R(CDCl2) δ value; 2.52 (3H,m, -8CHI).

4.21 (3H, a, -0CHB).

4.42 (2H,a,BrCH寞-) 1’tNMR (CDCh) a value; 11.30 (-8CH3).

29.76 (BrCHl-).

64.97 (-〇〇Hs　).

1 04-7'o-2-(anti)-methoxyimino-3
-Oxothiobutyric acid-8-methyl ester IR(2)) ff1-1: Wc=o 1720
．． 1655HMR (CDCIs) δ value; 2.41 (3H, a, -8CHl).

4.21 (3H,a, -0CHI) -4,23
(2H, s, Br CHl ) The following compound was obtained in the same manner.

04-bromo 2-carboxymethoxyimino-3-oxothiobutyric acid-8-methyl ester (mixture of syn and anti forms) Melting point: 110-114°C IR (KBr) cm-1iνc-o 1724.165
2HMR(d6-DMSO) a fit C2,50
(3H,s, -8CH3).

4.61 (2H+a, BrCH2C0-).

4.93 (2H, 1I, 0CHICO-).

9.27 (IH, bs, -COOH) Furthermore, the above 4-bromo 2-carboxymethoxyimino-3-oxothiobutyric acid-8-methyl ester is reacted with diphenyldiazomethane by a conventional method, and then,
The following compound was obtained by column separation.

04-bromo-3-oxo-2-(syn)-diphenylmethoxycarbonylmethoxyiminothiobutyric m-5-methyl ester IR (KBr) cm-1; νc=o 1750.17
14.1680.166 ONMR (CDCIs) δ value collection 2.46 (3H,s, -80Hs).

4.OF! (2H,s,BrCHlCO-).

4.87 (2H, ■, -OCH Mayuzumi CO~).

6.95 (IH, s, -CM") t 7.29 (IOH, s, 2 x 2) Reference Example 3 (11piparoyloxymethylef-amino-3-(5
-methyl-1,2,3,4-tetrazol-2-yl)
Methyl-Δ8-cephemu 4-carboxylate 4.1
F is dissolved in a mixed solvent of 321 Itl of ethyl acetate and 8-N,N-dimethylacetamide and cooled to -30°C. Then, 3.5 of the hydrobromide of 2-(2-amino-4-human 2-thiazolin-4-yl)-2-(syn)-methoxyiminoacetic acid chloride was added,
React at -30 to -20°C for 2 hours. The reaction solution was mixed with 50 sd of ethyl acetate and saturated hydrogen carbonate)
0m into a mixed solvent. Then, the organic layer is separated, washed with 50 ml of water, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, 50 d of diethyl ether is added to the resulting residue, and the crystals are collected by filtration, resulting in a melting point of 8.
Piparoyloxymethyl exhibiting 5-87°C (decomposition) = 7
-[2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminoacetamide)-3-(5-methyl-1,2,3,4-tetrazole- 4.8f (yield: 78.4) is obtained.

IR(KBr) cfn-1; νc=o 1790.
1750.167 ONMR (CDCIg) δ value; 1.19 (9H,s, -C(CHl)3).

3.29 (2H18, C2-H)? 3.93 (3H,s, -0CHI).

5.00 (TH, d, J=5Hz, Cg-H
).

5.73-6.03 (3H, m, C7-H, -0CH2
CO-) UV (C, gOH) + λmix 260 (ε=9375) (2) Pivaloyloxymethyl = 7-[2-(2-amino-4-hydroxy-2-thiazolin-4-yl)- 2-(shin)-
methoxyiminoacetamide]-3-(5-methyl-1
,2,3,4-tetrasol-2-yl)methyl-Δ3
- Cephemu 4-carboxylate 6.12f is dissolved in an acetonitrile solution 60- containing concentrated hydrochloric acid o, i- and reacted at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was mixed with 100 W of ethyl acetate and 100 W of water.
After sequentially adding t, hydrogen carbonate (p) using +3 um
Adjust to H6.0. Then, separate the organic layer and add 10% of water.
After washing with 0- and drying with anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure.

When diethyl ether 30- is added to the resulting residue and the crystals are collected by filtration, the crystals show a melting point of 127-128°C (decomposition). )-2-(syn)-methoxyiminoacetamide]-3-(5-methyl-1,2,3,4-tetrazol-2-yl)methyl-Δ1-cephemu 4-carboxylate 5.63F (yield 94 .89b) is obtained.

IR(KBr)cm-1rpc=o 1780.174
3.1675 NMR (d, -DMSO) δ value; 1.15 (9H+s, C(CHI)s) C2,
43 (3H, s, N>worm).

3.47 (2H1, b s , Cg H) C3, F
lO(3H, lI, -0CHs).

5.15 (I H+ d, 5Hz, C6-H)
.

5.55 (2H-b s l'Qcu, ) C5,
63~5.98 (3HT nl t C? Hr -
OCH2O) C7,14 (2H, bs, NH -)
.

9.58 (IH, d, J=8Hz, -CONH-)U
V(C,H,0H)i λmax 235 (ε=19394) λmax 26
0 (ε=16061) Patent applicant Toyama Chemical Industry Co., Ltd.

Claims (1)

[Scope of Claims] +13 A 2-amino-4-hydroxydithiazoline derivative (synisomer) represented by the general formula and a salt thereof. (2) Claim No. (1) in which z is a halogen atom
2-amino-4-hydroxythiazoline derivative (syn isomer) and its salt as described in 2. (3) z is -SR4 group C In the formula, R4 has the same meaning as above. ) as set forth in claim 11).
Amino-4-hydroxythiazoline derivatives (syn isomer) and salts thereof. (Claim No. (3) in which 41R4 is an alkyl group)
The 2-amino-4-hydroquidithiazoline derivative (synisomer) and its salt as described in 2.