JPS63277684A - Production of 7beta-aminothiazolylalkenoylamino-3-cephem-4-carboxylic acid - Google Patents

Abstract

PURPOSE:To obtain (with industrial advantage) the title compound which is used as an antibacterial against gram-positive and -negative bacteria, by reaction of haloacetoamide-cephemcarboxylic acid with an alkanal and thiourea. CONSTITUTION:The subject compound is obtained by reaction of 7beta- haloacetoamide-3-cephem-4-carboxylic acid of formula I (R<1> is H, substituent in cephalosporin chemistry; R<2> is H, carboxyl-protecting group; Hal is halogen) with an alkanal of the formula: R<6>CHO (R<6> is alkyl) such as propanal and thiourea.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the formula (I): (wherein Ro is an alkyl group, R1 is a hydrogen atom or a substituent at the 3-position in cephalosporin chemistry, and R'' is a hydrogen atom or a carboxy protecting group. ) 7β-aminothiazolylalkenoylamino-3-cephem-4
- It relates to a method for producing a carboxylic acid compound.

Aminothiazolylalkenoyl cephalosporins represented by formula (I) are useful compounds that exhibit antibacterial activity against Durham-positive bacteria and Durham-negative bacteria when administered orally (Japanese Patent Application Laid-Open No. 57-93982, Japanese Patent Publication No. 59-9308
No. 6).

When the method described in this literature was repeated, it was confirmed that in the above formula ([), E and Z isomers related to the configuration of Ro were produced in almost equal amounts, making it unsuitable for industrial implementation. The main product of this invention is the Z isomer.

In view of the usefulness of the compound of formula (I), the present inventors conducted repeated research with the aim of developing a new method for producing the compound. or a 3-position substituent in cephalosporin chemistry, R8 is a hydrogen atom or a carboxy protecting group, Hal is a halogen atom)
Reacting a β-haloacetamido-3-cephem-4-carboxylic acid compound with an alkanol and thiourea of the formula (I[f)R'CHO(I) (wherein Ro represents an alkyl group). The present inventors have discovered that the present invention can be manufactured more efficiently.

The term alkyl group R0 refers to a straight or branched alkyl group having 1 to 8 carbon atoms.

Specific examples of the alkyl group R0 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, cyclopropyl, cyclobutyl, pentyl, isopentyl, neopentyl, tertiary pentyl, cyclopentyl, methylcyclopentyl, hexyl, methylpentyl. , dimethylbutyl, cyclohexyl, heptyl, methylhexyl, cycloheptyl, methylcyclohexyl, dimethylpentyl, dimethylcyclopentyl, octyl, and the like.

Examples of the 3-position substituent R1 of cephalosporins include 1
-5C alkanoyloxy, halogen, 1-5C alkoxy, 1-5C alkylthio, 1-5C alkenylthio, 1-5C alkyl, 1-5C alkenyl, heterocyclic ring containing 1-4 nitrogen, oxygen or sulfur as a heteroatom thio (especially triazolylthio, tetrazolylthio, thiadiazolylthio, thiadiazolylthio, etc., which may have 1-5c alkyl, alkoxy, substituted methyl, etc.),
Mention may be made of groups known as substituents at the 3-position of Cephasporin, such as substituted methyl. Here, as substituents for substituted methyl, in addition to pyridinium, substituted pyridinium, etc., the above-mentioned halogen, hydroxy, 1-
Preferred are 5c alkoxy, 1-5C acyloxy, 1-5C alkylthio, 1-5C haloalkylthio, 1-5C cyanoalkylthio, heterocyclic thio, and the like. Hydroxy, halogen, dimethylamino, carboxy, carbamoyl, and the like are useful as the substituent that binds to the substituted alkyl.

The 3-position substituent R, I in the above cephalosporin chemistry
Specific examples include hydrogen, halogen (fluorine, chlorine, bromine, etc.), hydroxy, alkoxy (methoxy, ethoxy,
propionyloxy, etc.), alkylthio (fluoroethylthio, trifluoroethylthio, etc.), alkenylthio (vinylthio, etc.), acyloxy (acetyloxy, propionyloxy, benzoyloxy, methanesulfonyloxy, etc.), alkyl (methyl, ethyl, etc.), Alkenyl (vinyl, cyanovinyl, carboxyvinyl, protected carboxyvinyl, trifluorovinyl, etc.), alkynyl (ethynyl, propargyl, etc.), heterocyclic thio (triazolylthio, methyltriazolylthio,
thiadiazolylthio, methylthiadiazolylthio, tetrazolylthio, medyltetrazolyldio, etc.), halomethyl (fluoromethyl, rialomethyl, etc.), and acyloxymethyl (acetoxymethyl, propionyloxymethyl, carbamoyl) oxymethyl,
methylcarbamoyloxymethyl, ethylcarbamoyloxymethyl, etc.), alkoxymethyl (methoxymethyl, isopropoxymethyl, propenylthiomethyl, fluoroethoxymethyl, etc.), alkylthiomethyl (methylthioethyl, cyanomethylthiomethyl, difluoromethylthiomethyl, etc.), Alkenylthiomethyl (vinylthiomethyl, propenylthiomethyl, etc.), heterocyclic thiomethyl (triazolylthiomethyl, thiadiazolylthiomethyl, methyltetrazolylthiomethyl, aminothiadiazolylthiomethyl, protected aminothiadiazolylthiomethyl) , aminomethylthiadiazolylthiomethyl, triazolylthiomethyl, methyltriazolylthiomethyl,
Tetrazolylthiomethyl, methyltetrazolylthiomethyl, propenyltetrazolylthiomethyl, cyanoethyltetrazolylthiomethyl, aminoethyltetrazolylthiomethyl, sulfaminoethyltetrazolylthiomethyl, dimethylaminoethylmethyltetrazolylthiomethyl, amidinoaminoethyl Tetrazolylthiomethyl, ureidomethyltetrazolylthiomethyl, carboxymethyltetrazolylthiomethyl, carbamoylmethyltetrazolylthiomethyl, carbamoylethyltetrazolylthiomethyl, methylcarbamoylmethyltetrazolylthiomethyl, hydroxycarbamoylmethyltetrazolylthiomethyl, carbamoyl Methylcarbamoylmethyltetrazolylthiomethyl, methoxycarbamoylmethyltetrazolylthiomethyl, ureidomethyltetrazolylthiomethyl, hydroxyethylureidomethyltetrazolylthiomethyl, sulfomethyltetrazolylthiomethyl1. Hydroxyethyltetrazolylthiomethyl, chloroacetoxyethyltetrazolylthiomethyl, tetrahydropyranyloxyethyltetrazolylthiomethyl,
Dihydroxypropyltetrazolylthiomethyl, methoxyethyltetrazolylthiomethyl, hydroxypyridylcarbamoylmethyltetrazolylthiomethyl, aminohydroxythiazolyltetrazolylthiomethyl, protected carboxymethyltetrazolylthiomethyl, protected sulfomethyltetrazolylthiomethyl, protected hydroxyethyltetrazolylthiomethyl, indolylthiomethyl, triazinylthiomethyl, hydroxyoxodihydrotriazinylthiomethyl, etc.), heterocyclic methyl (tetrazolylmethyl, methyltetrazolylmethyl, etc.), pyridiniomethyl (pyridiniomethyl, carbamoylpyri diiniomethyl, cyclopentanopyridiniomethyl, cyclohexanopyridiniomethyl, methylpyridiniomethyl, diethylpyridiniomethyl, etc.), haloalkylthiomethyl (fluoroethylthiomethyl, trifluoroethylthiomethyl, etc.), Examples include cyanoalkylthiomethyl (cyanomethylthiomethyl, cyanoethylthiomethyl, etc.).

Carboxy-protecting group R2 is a carboxy-protecting group with 1 to 19 carbon atoms (reactive (eg, pharmaceutical salt-forming groups and pharmacologically active ester-forming groups).

Typical examples include alkyl esters having 1 to 8 carbon atoms (methyl, methoxymethyl, ethyl, ethoxymethyl,
esters of iodoethyl, propyl, isopropyl, ethoxyethyl, methylthioethyl, methanesulfonyl ethyl, butyl, isobutyl, trichloroethyl, t-butyl, etc.), alkenyl esters having 2 to 8 carbon atoms (vinyl, propenyl, allyl, prenyl esters, etc.) , aralkyl esters having 7 to 19 carbon atoms (benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylmethyl, phenethyl, trityl, di-t-butylhydroxybenzyl, phthalidyl, phenacyl ester) ), aryl esters having 6 to 12 carbon atoms (phenyl, tolyl, diisopropylphenyl, xylyl, trichlorophenyl, pentachlorophenyl, indanyl esters, etc.), esters with N-hydroxyamino compounds having 1 to 12 carbon atoms (acetone oxime , acetophenone oxime, acetaldoxime, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.), silyl esters having 3 to 12 carbon atoms (trimethylsilyl, t-butyldimethylsilyl, dimethylmethoxysilyl ester, etc.), carbon There are protecting groups constituting stannyl esters (such as trimethylstannyl esters) having numbers 3 to 12. This protecting group moiety may further have various substituents.

Since this carboxy protecting group is removed before the final target product, its structure is not necessarily important as long as the purpose of protection is achieved, and a wide range of equivalent groups (amide, acid anhydride with carbonic acid or carboxylic acid, etc.) can also be used.

The pharmaceutical carboxy protecting group R2 mainly includes salt-forming groups and pharmacologically active ester-forming groups.

Among the salt-forming groups R, light metal atoms (lithium, sodium, ,.

Potassium, magnesium, calcium, aluminum, etc.) are suitable for medicinal use.

Alkylamine having 1 to 12 carbon atoms (trimethylamine,
triethylamine, methylmorpholine, etc.) and aromatic bases having 4 to 9 carbon atoms (pyridine, collidine, picoline,
A salt-forming group R″ commonly used in penicillin and cephalosporin chemistry that constitutes salts (quinoline, dimethylaniline, etc.)
is suitable for synthesis, preservation, etc.

The pharmacologically active ester-forming group Rt is an ester that exhibits antibacterial activity upon oral or parenteral administration. Representative examples include 1= having 2 to 15 carbon atoms, each of which may have a substituent;
Oxygenated substituted alkyl esters (linear, branched, cyclic or partially cyclic alkanoyloxyalkyl esters (acetoxymethyl, acetoxyethyl, propionyloxymethyl, pivaloyloxymethyl, pivaloyloxyethyl, cyclohexaneacetoxyethyl, cyclohexanecarbonyl) oxycyclohexylmethyl ester, etc.), alkoxycarbonyloxyalkyl esters having 3 to 15 carbon atoms (ethoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl, isopropoxycarbonyloxypropyl, t-butoxycarbonyloxyethyl, isopentyloxycarbonyloxypropyl) , cyclohexyloxycarbonyloxyethyl, cyclohexylmethoxycarbonyloxyethyl, bornyloxycarbonyloxyisopropyl ester, etc.)
, alkoxyalkyl esters having 2 to 8 carbon atoms (methoxymethyl ester, etc.), 2-oxacycloalkyl esters having 4 to 8 carbon atoms (tetrahydropyranyl, tetrahydrofuranyl ester, etc.), 8 to 12 carbon atoms
substituted aralkyl esters (phenacyl, phthalidyl esters, etc.), aryl esters having 6 to 12 carbon atoms (phenyl, xylyl, indanyl esters, etc.), alkenyl esters having 2 to 12 carbon atoms (allyl, 4-methyl-
2-oxo-1,3-dioxolylmethyl ester, etc.).

The number of carbon atoms includes substituents.

As the halogen Hal, in addition to chlorine, bromine, and iodine, so-called pseudohalogens such as alkanesulfonyloxy and arylsulfonyloxy can also be mentioned as groups that exhibit equivalent effects.

The compound represented by formula (1) can be produced according to the following reaction formula.

The compound of formula (II), which is the starting material for the process of the invention, is a reactive derivative of an amine (■) and 4-haloacetoacetic acid. For example, a haloacetoacetyl halide prepared from amine (I), diketene and a halogen (HalCH=COCHtCO11al)
, tertiary amine, aromatic amine (triethylamine,
When reacted in the presence of dimethylaniline, pyridine, etc.) in an inert solvent (halohydrocarbon, etc.) at a temperature of -506C to 30C, haloacetoacetamidocephem compound (II) is obtained. The product can typically be isolated by solvent extraction, washing, drying, crystallization, etc.

[Condensation Reaction] To produce compound (1) from compound (II), a Knoevenagel condensation reaction is used.

That is, compound (II) and an alkanal represented by the formula R'CHO or a reactive derivative thereof are usually condensed in an inert solvent (alcohol, pyridine, acetic acid, benzene, toluene, xylene, cyclohexane, dioxane, etc.) in the presence of a condensation catalyst. , tetrahydrofuran, halohydrocarbon, etc.), -5
at a temperature of 0°C to 110°C until the end of the reaction (for example, 0.5
24 hours), the haloacetylalkenoylaminocephem compound (II°) can be produced.

Here, as a condensation catalyst, ammonia, primary amines (methylamine, ethylamine, butylamine, aniline,
benzylamine, etc.), secondary amines (dimethylamine, diethylamine, piperidine, piperazine, morpholine, etc.), tertiary amines (triethylamine, tri(2)
-hydroxyethyl)amine, Triton B, etc.), aromatic amines (pyridine, picoline, lutidine, nicotine, etc.), weakly basic anion exchange resins (Amberlite IR
-45, IR-4B, Duolite A-4, etc.), alkali metal hydroxides and other bases, and their aliphatic or aromatic carboxylates (formic acid, acetic acid, phenylacetic acid, benzoic acid, etc.), as well as acids (sulfuric acid, acetic acid, toluenesulfonic acid, etc.), amino acids (alanine, glycine, etc.)
, Lewis acids (zinc chloride, copper acetate, etc.) may also be used as long as the raw materials and products are not decomposed.

This reaction is preferably carried out under dehydrating conditions such as using a dehydrating agent (such as a molecular sieve), dehydrating distillation, or azeotropic distillation.

The resulting compound (II') can be isolated or subjected to the next reaction without isolation.

[Thiazole ring-closing reaction] The generated compound (II゛) is dissolved in an inert solvent (ethanol,
acetone, etc.), add thiourea or a reactive derivative thereof while stirring under water cooling, and react at -1θ to 50°C for several hours. The reaction mixture is subjected to solvent extraction, and the extract is washed, dried, purified by chromatography using silica gel, etc., and recrystallized from an appropriate solvent to obtain the desired compound (I).

Each of the above synthesis methods is usually carried out at -30 to 100°C, particularly -20 to 100°C.
The reaction is often carried out at a temperature of 50° C. for 10 minutes to 10 hours. These are carried out in a solvent, if necessary under anhydrous conditions. Any other conventional law may be applied.

Reaction solvents include hydrocarbons (pentane, hexane, octane, benzene, toluene, quinlenate), halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene, etc.), ethers (diethyl ether, methyl isobutyl ether, etc.). , dioxane, tetrahydrofuran, etc.), ketones (acetone, methyl ethyl ketone, cyclohexanone, etc.), esters (ethyl acetate, isobutyl acetate, methyl benzoate, etc.), nitrohydrocarbons (tromethane, nitrobenzene, etc.), nitriles (acetonitrile, benzonitrile, etc.), Amides (formamide, acetamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, etc.), sulfoxides (dimethylsulfoxide, etc.), carboxylic acids (formic acid, acetic acid, propionic acid, etc.), organic bases (diethylamine, triethylamine, pyridine, picoline, Examples include industrial solvents belonging to other series such as collidine, quinoline, etc.), alcohols (methanol, ethanol, propatool, hexanol, octatool, benzyl alcohol, etc.), water, and mixtures thereof.

The desired product is obtained by removing impurities (unreacted raw materials, by-products, solvents, etc.) from the reaction solution using conventional methods (extraction, evaporation, washing, concentration, precipitation, filtration, drying, etc.). It can be isolated by post-treatment (adsorption, elution, distillation, precipitation, precipitation, chromatography, etc.).

The production method of the present invention is a novel method different from conventional methods, which consists of reacting the amine (IV) or its reactive derivative with the corresponding carboxylic acid or its reactive derivative. Compound (I) obtained by the method of the present invention can be used as it is in the preparation of various pharmaceutical preparations in the same way as compounds obtained by conventional methods.

Compound (I) exhibits strong antibacterial activity against aerobic and anaerobic bacteria, particularly against Durham-positive and -negative bacteria, and is characterized by its absorption, excretion, and distribution upon oral administration. For the prevention and treatment of human infectious diseases, the daily dose is usually 0.1 to 6 g (injection), 0.5 g, formulated by conventional methods.
Administer ~5g (orally), 0.01~100iy (externally, suppositories, etc.). Various additives, other types of antibacterial agents, etc. can be used for formulation.

It can also be used as a raw material for the synthesis of other antibacterial agents and as a material for bacterial susceptibility testing.

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

In the reaction formulas in Examples, some cephem rings that undergo no structural changes due to the reaction are omitted.

Abbreviations used in the examples have the following meanings.

br = wide E t4N = triethylamine ph = phenyl Ac0H = acetic acid EtCHO = propionaldehyde EtOAc = ethyl acetate EtOH - ethanol POM - pivaloyloxymethyl group Example 1 1. Diketene (2,46 u (2,31 mmol) of methylene chloride (121ff) solution with Brt(1,53RI2
, 29.8 mmol) in methylene chloride (6ffR) was added dropwise at -30°C for 10 minutes, and then further heated at -30°C for 10 minutes.
Compound (3) is prepared by stirring for half an hour. NH1 body (l
methylene chloride (60
EbN (1,68 m(, 12
mmol), then add the previously prepared methylene chloride solution of (3) all at once. After stirring at -40°C for 20 minutes, it was quenched with water, extracted with EtOAc, and washed with water.
% NaHCO3, water and drying with NatSO4.

After concentration, the residue was chromatographed on silica gel and the eluate was recrystallized from methylene chloride to give (2) (2,59
9.40%) are obtained as fine white crystals. mp
= 105~IO9℃.

NMR (CDC13-DMSO) δ, 90MHz (CD
Clff-keto/enol #2/1 in DMSO solution
mixture): 1.20 (s, 9H), 3.49, 3.61
(AI3q, 2 H, J = 18 Hz), 3.6
6 (s, 4/3H), 3.90 (s, 2/3H), 4.
24 (s, 4/3H), 4.7 3, 4.9 3 (AB
Q, 2H,'J= 1 3Hz), 5.

06 (d, IH, J=5Hz), 5.46 (s, 1/3
H), 5.69 (dd, IH, J=5.8Hz), 5.
80, 5.90 (ABq, 2H, J=5Hz), 6.2
5 (brs, 2H), 9.04 (d, 1/3H, J=8
H2), 9.10 (d, 2/3 H, J = 8 Hz
).

IR (nujol) cm-': 3440, 3290, 1
765.1730,1695,1645°2, compound (
2 x 220 x 9, 0.4 mmol) of CH.

EtCHO (115 μQ) was added to the Cl2 (6a+f2) suspension.
, 1.6 mmol), AcOH (19 uQ, , 0.33
mmol), piperidine (16 μL 0.16 mmol)
Then, add 4A molecular sieve (appropriate amount) and stir at room temperature for 1 hour and 15 minutes. The reaction suspension becomes a homogeneous solution within a few minutes.

The reaction is quenched by adding water, decanted to remove the molecular sieve, extracted with EtOAC, washed with water and dried over Na, So4. After evaporation of the solvent, the residue (2
35jIg) was dissolved in EtOH4xQ, and while cooling with water, thiourea (24λ9.0, 32 mmol) was added and stirred for 3 hours. Water, EtOAc and 5% NaH were added to the reaction solution.
Add CC)+. The EtOAc extract was washed with water (3 times), dried over Na, So, and then chromatographed on silica gel to obtain (5) as a pale yellow powder (87j!2,
(2) total yield of 38%).

Example 2 1, diketene (1,l 7rp, Q, 15mmol)
A solution of C1t in carbon tetrachloride (2,1611+mol/mO, 6,7m(
1, 14, 5 mmol) was added dropwise over 4 minutes at -30°C. Stir for an additional hour and a half at the same temperature. N H, body (
EhN (1,8
4xf2.13.2 mmol), stirred for several minutes,
When the suspension becomes a solution, add the previously prepared methylene chloride solution (7) all at once. After stirring at −30°C for 1 h, quenching with water and extraction with EtOAc followed by N
aCl HtO15%NaHCO3, NaCl-Ht
Wash with O and dry with NatSO. Chromatography of the residue and recrystallization of the eluate from Et'0ACCHzCIt gives (6Xl, 789.59%) as fine white crystals.

mp=98-105°C.

NMR (CDC1, -DMSO) δ, 90 MHz (DM
SO-CDC1, keto/enol #2/l mixture in solution): 1.22 (s, 9H), 3.47, 3.59 (
ABq, 2H, J=I 9Hz), 3.63Gs, 4/
3H), 4.0Q (s, 2/3H), 4.34 (s, 4
/3H), 4.80, 5.00 (ABq, 2H, J=1
4Hz), 5°01 (d, IH, J=5Hz), 5,4
7 (s, 1/3H.

H, +lactam), 5,83,5.91 (ABQ, 2H
.

J=5Hz), 8.76(d, 1/3H, J=81-1
z), 8.99 (d, 2/3H, J=8I-Iz).

IR (Nujol) cR-heavy: 3450, 3300, 1
770.1740,1700,1655°2, compound (
60202 mg, 0,4 mmol) of CH.

EtCHO (114 μ(1,
1.6 mmol), AcOH (7 μL 0.12 mmol
), piperidine (8 μC, 0.08 mmol) and then 4A molecular sieves (appropriate amount) were added and
Stir for half an hour.

The reaction suspension becomes a homogeneous solution within a few minutes. The reaction solution was quenched by adding water, the molecular sieve was removed by decantation, and then extracted with EtOAc, washed with water, and N
Dry with av S 04. Residue 237R after solvent distillation
Dissolve 212mg of the
(53m9, 0.35mmol) was added and stirred at room temperature for 1 hour and 25 minutes. The reaction solution was cooled to 0°C, thiourea (24 mg, 0, 32 mmol) was added, and the mixture was stirred for 1 hour and 25 minutes. Water, EtOAc, and then 5%
Add NaHCOs. Dry the EtOAc extract with Na, So. Chromatography on silica gel gives (5) as a pale yellow powder (63R9, (6
) with a total yield of 32%).

Example 3! , a solution of C1t in carbon tetrachloride (2
,1611111101'/112.6 ,7 ridge,
14.5 mmol) was added dropwise over 3 minutes at -30°C. Stir for an additional 50 minutes at the same temperature. NH, body (8
02,209,6 mmol) of methylene chloride (30xe
) EhN (1,0x12.7.2 mmof) in suspension,
Next, add the methylene chloride solution of (7) prepared earlier to 30%
Add all at once at ℃. After stirring for 1 h, quenching with water and extracting with EtOAc, NaCl HxO15
Wash with %NaHCO3 and NaCl HzO. After drying over NatSO and concentration, the residue is chromatographed on silica gel. Recrystallization of the eluate from CH,C12-hexane gives (9X1°459.50%) as fine white crystals. mp=144~146℃
.

NMR (CD CI3) δ, 90MH2 (CDC1, mixture of keto/enol = 5/2 in solution): 3.1
3 to 3.63 (ABX AB, 2H, JAB = 19Hz
), 3.58 (s, 10/7H, CHzCONH (keto)), 3.94 (s, 4/7H, CICH, (enol)), 4.17 (s, I O/7H, CICH * (keto) )), 4.88 (d, 1f-1, J=5Hz), 5.
29(s, 2/7H.

/7H, J=5,9H2), 5.91(dd, 2/71
-1. J=5.9Hz), 6.53~6.63(ABX
X, IH), 6.95 (s, IH), 7.2-7.5
011. IOH).

IR(CHCl,)Cx-':3410,3320.
1785.1725,1685,1640°2, CH of compound (9) (194m9, 0.4mmol).

EtCHO (114 μQ, 1
．． 6mm.

l), AcOH (7 μC, 0.12 mmol), piperidine (8 μg, 0.08 Illflol), then 4
Add A molecular sieve (appropriate amount) under water cooling. After stirring at room temperature for 55 minutes, the reaction was quenched by adding water,
After removing the molecular sieve by decantation, it is extracted with EtOAc, washed with water, washed with 5% NaHCO, and NaCl HzO, and dried with Na, So.

250 x g of the residue after solvent distillation was dissolved in 2 m of acetone, NaI (60319,0,411111101) was added and stirred at room temperature for 1 hour and 10 minutes.The reaction solution was cooled to 0 °C, and thiourea (27D, 0, 36 mmol)
and stirred for 1 hour and 30 minutes. Water, EtOA in the reaction solution
c Then add 5% Na HCOs. The EtOAc extract was extracted 3 times) and dried over N at SO 4 . Chromatography on silica gel gives (10) as a pale yellow powder (54x9, total yield from (2) 2
5%).

NMR (CDCIs) δ, 90MHz: 1.05 (t,
3H, J=8Hz) 2.39 (quintet, 2H, J=8H
z), 3, J~3.72 (ABX AB, 2H, JAB
= 19H2), 4.99 (d, IH, J = 5Hz), 5
．． 38 (brs, 2H), 6.00 (dd, I) (, J
=5.81(z), 6°30(s, IH), 6.4
2(t, IH, J=8H2), 6°58~6.68(
ABX's X, IH), 6.96 (s, IH), 7.2~
7.6 (m, 10H), 8.16 (d, IH.

J = 8 Hz).

Claims (1)

[Claims] 1. Formula (II): ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 is a hydrogen atom or a 3-position substituent in cephalosporin chemistry, R^2 7β-haloacetamido-3-cephem-4-carboxylic acid represented by the formula (III): R^0CHO(III) (wherein R^ 0 represents an alkyl group) Formula (1) characterized by reaction with alkanal and thiourea: ▲There are numerical formulas, chemical formulas, tables, etc.▼(I) A method for producing a 7β-aminothiazolylalkenoylamino-3-cephem-4-carboxylic acid compound shown in