JPS5838289A - Improvement of chemical process - Google Patents

Abstract

PURPOSE:To obtain a 3-substituted-thio-cephem derivative useful as an antibacterial agent, etc., in high yield, without using complicated procedure, by reacting a 3-hydroxy-cephem derivative with a substituted phosphorus halide in the presence of an organic base at low temperature, adding an organic base to the reaction product, and reacting with a substituted thiol. CONSTITUTION:The 3-hydroxy-cephem derivative of formulaI(R<1> is carboxylic acid residue inert to the reaction; R<2> is ester residue) is made to react with a substituted phosphorus halide derivative of formula II (R<a> and R<b> are 1-4C alkyl, alkoxy, substituted phenyl, etc.) in an inert solvent (e.g. acetonitrile) in the presence of an organic base (e.g. 4-N,N-dimethylamino-pyridine) at a low temperature. An organic base is added to the reaction product, and the product is reacted with the substituted thiol of formula R<3>-SH (R<3> is lower alkyl) at a low temperature to obtain the objective compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention involves reacting a substituted phosphorus halogenated derivative of an 8-hydroxy-cephem derivative in the presence of an organic base, then adding an organic base to the reaction product, and reacting a sequestered thiol. The present invention relates to an improved chemical method for producing 8-substituted thio-cephem derivatives.

Recently, 8-hydroxy-cephem derivatives have been developed with the corresponding 8-
It has been found that these 8-alkoxy or 8-chloro derivatives can be converted into alkoxy or 8-chloro derivatives and that these 8-alkoxy or 8-chloro derivatives are highly effective antimicrobial agents (GB 1454899, GB 1456!21). Publications, U.S. Pat. No. 4,064,848 and J. Med. Ch.
Em, Vol. 18, p. 408, 1975). Therefore, several economically advantageous methods for producing 8-hydroxy-cepham derivatives have been developed. Examples include a method by ozonolysis of a 3-exomethylene-cepham derivative; a method by ring substitution with 8-oxide of a penicillin ester, ozonolysis of an individual chain, and then ring closure.

The inventors of the present invention found that 8-1
! We have discovered that some hydroxy-thio-cephem derivatives have unique antibacterial properties, and have researched an economically advantageous method for producing these derivatives from 8-hydroxy-cephem.

Conventionally, a method via a sulfonic acid ester such as a tosyl ester or a methanesulfonyl ester at the 8-position is already known in order to produce an 8-substituted thio-cephem derivative from an -8-hydroxy-cephem derivative (Hel.
vechica Ohimica Acta.

58, p. 2487, 1975). However, the reaction rate in the step of obtaining 8-substituted thio-cephem derivatives from these sulfonic acid esters is slow, and since the reaction is carried out in the presence of a base, several tens of percent of Δ2 derivatives are produced as by-products. Therefore, in order to obtain only the ΔBm conductor having antibacterial activity, it is necessary to perform isomerization from Δ2 to Δ3 or a complicated purification process, which is by no means satisfactory.

From this point of view, the inventors of the present invention converted the hydroxyl group at the 8-position into a more reactive ester group, and then reacted it with a substituted thiol in the presence of an organic base at 0°C or lower. 8-i! does not require such complicated steps and has an excellent yield of over 80%. The present invention was achieved by discovering a manufacturing method for obtaining a Δ derivative of it-substituted thiol.

That is, this invention provides an 8-hydroxy-cephem derivative represented by the formula (I): (wherein R is a carboxylic acid residue that does not participate in the reaction; V is an ester residue) in an inert solvent. Formula (I): (wherein,
R1 and R are the same or different, each ol-c4
Alkyl L ol-a, phenyl or phenoxy group optionally substituted with 1 to 3 groups selected from alkoxy group, halogen atom, and nitro group; or 01 to C4
Alkoxy group, 08-8 cycloalkyl, Cto8 cycloalfoxy or halogen atom; X is halogen atom,
Nitrile group or azide group, provided that 1) R' and Rb
When either one of them is a halogen atom, the other is a group other than a halogen atom, and (2) when X is a nitrile group or an azide group, R1 and or the same or different phenoxy group, 08-8 cycloalkoxy group or Of~4 alkoxy group) is reacted with a substituted phosphorus halide derivative represented by the formula:
Reaction with a substituted thiol represented by the formula (W): R''-811 (Otori) (wherein R is a lower alkyl group): [wherein, R' t R'' and ujl are defined as above. The present invention provides an improved chemical method characterized by obtaining an 8-substituted-thio-cephem derivative represented by the formula (1) and the formula (seal).

The 8-human O4 Ccephem conductor of general formula (I) used in this invention will be explained.

The carboxylic acid residue that does not participate in the reaction of group R1 is represented by formula 9 (
1) and a group that does not participate in the reaction with the compound of formula (1), and is a group that does not participate in the reaction with the compound of formula (1), and is a group that does not participate in the reaction with the compound of formula (1).
It means a group known as a fecal chain. Based on this R'O
O- is an acyl group derived from an aliphatic carboxylic acid, such as an acetyl group, a chloroacetyl group, a bromoacetyl group, a propionyl group, a formyl group, an acyl group derived from an aromatic Ii1 sulfonic acid, such as a benzoyl group, Phenylacetyl group, phenoxyacetyl group, α-aminophenylacetyl group with protected amino group, α-amino-1,4 cyclohexadien-1-ylacetyl group with protected amino group, etc.; acetyl derived from heterocyclic carboxylic acid Groups such as thenyl acetyl group, α-amino thenyl acetyl group with protected amino group, formula (W
): (In the formula, 2 is a protecting group, R4 is a lower alkyl group, an aliphatic carboxylic acid ester group, or a protecting group). Examples of the above-mentioned protected amino groups include tertiary butoxycarbonyl group, benzyloxycarbonyl group, 4-
methoxy-benzyloxycarbonyl group, 4'-nitrobenzyloxycarbonyl group, 2,2.2-trichloroethoxycarbonyl group, and methylacetoacetate group)
.

The ester group -ooOTL of Otsu's invention is one that can protect the carboxyl group for the substituted phosphorus halide derivative used in the reaction of Jin's invention, and after the reaction, it can be decomposed by hydrolysis, solvolysis or reductive decomposition. Includes a removable group or a group that can be hydrolyzed and removed in vivo.

Among the above ester groups, groups that can protect the carboxyl group for the former substituted phosphorus halide derivative and can be removed after the reaction include esters formed by alcohols and carboxyl groups.

Preferred examples of alcohols that form esters include t-butanol, 2-chloroethanol, 2-bromoethanol, 2.2.2-) dichloroethanol,
2-Methylsulfonylethanol, 2-ethylsulfinylethanol, benzoylmethanol, benzyl alcohol, p-nitrobenzyl alcohol, p-methoxybenzyl alcohol, diphenylmethanol, triphenylmethanol, trimethylacetyloxymethanol, 8-hydroxy-8-methyl- Examples include 1,8-hydroisobenzolan-1-one, 5-hydroxy-5-methyltetrahydrofuran-2-one, 1-1-butyroxybutanol, and 5-hydroxyindan.

Other examples include methanol, ethanol, propatool, butanol, p-bromobenzoylmethanol, 2,6-di-t-butylbenzene-1,4-diol, acetoxymethanol, and phenol.

Among the esters formed with the above alcohols, esters that can be reductively decomposed include p-nitrobenzyl ester, benzyl ester, benzhydryl ester, p-
There are methoxybenzyl ester, trichloroethyl ester, and halogen ethyl ester, and among these, p-nitrobenzyl ester and trichloroethyl ester are preferred.

Furthermore, examples of groups that can be removed by strong acids include diphenylmethyl group, p-methoxybenzyl group, and trityl group.

Further, examples of groups that can be hydrolyzed and removed in vivo include acetokylemethyl group, pivaloyloxymethyl group, α-ethoxycarbonylethyl group, and phthalidyl ester group.

Such a compound of formula (1) is reacted with the substituted phosphorus halide derivative of formula (1) in an inert solvent in the presence of an organic base at low temperature. This reaction is thought to produce a compound represented by formula (ma): (wherein ni, n*, R@ and R are the same as defined above).

Solvents used in this reaction include halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride,
dichlorobenzene, etc.), esters (ethyl acetate, butyl acetate, methyl benzoate, etc.), ketones (acetone, cyclohexanone, benzophenone, etc.), ethers (diethyl ether, ethylene glycol dimethyl ether,
(tetrahydrofuran, tetrahydropyran, dioxane, anisole, etc.), carboxylic acids (acetic acid, propionic acid, etc.), organic bases (butylamine, triethylamine, pyridine, picoline, etc.), amides (dimethylformamide, dimethylacetamide, hexamethyl) phosphorotriamide, etc.), organic nitriles (acetonitrile, propionitrile, butyronitrile, benzonitrile, etc.)
and alkyl sulfoxides (such as dinotylsulfoxide). Among these, ethylene chloride, acetonitrile, tetrahydrofuran and methylene chloride are preferably used alone or in combination.

Further, examples of substituted phosphorus halide derivatives that can be used include the following. Diphenylchlorophosphate, phenylchloro-phenylphosphonate, phenyldichlorophosphate, ethylchloro-phenylphosphonate, dichloro-phenylphosphonate, diethylchlorophosphate, diphenylphos-7-olyl chloride, diphenylphosphoryl bromide, bis-(2-chlorophenyl) ) phosphoryl chloride, bis-(8-chlorophenyl) phosphoryl bromide, bis-(β-fluorophenyl A/) phosphoryl chloride, bis-(4-iodophenyl) phosphoryl bromide, bis-1,8-
dichlorophenyl) suphoryl chloride, bis-(8
, 4-dichlorophenyl) phosphoryl bromide, bis-(4-methylphenyl) phosphoryl chloride, bis-(4-butylphenyl) phosphoryl bromide, bis-(8,4-dimethylphenyl) phosphoryl chloride , bis-(8-chloro-4-methylphenyl) phosphoryl chloride, bis-(3-methoxyphenyl) phosphoryl chloride, bis-(4-methoxyphenyl) phosphoryl chloride, bis-(8-butoxy) phenyl)phosphoryl chloride, bis-(4-nitrophenyl)phosphoryl chloride, bis-(8,4,5-)rimethoxyphenyl)phosphoryl chloride, bis-(8,4,
5-) Rimethoxyphenyl) phosphoryl bromide, bis-(2-methoxy-8-methyl-4-fluorophenyl) phosphoryl chloride, dicycloprobyl phosphoryl chloride, dicyclobrobyl phosphoryl bromide , dicyclohexylphosphoryl chloride, dicyclohexylphosphoryl bromide, dicyclooctylphosphoryl chloride, dicyclooctylphosphoryl bromide, dimethylphosphoryl azide, dimethylphosphoryl cyanide, diethylphosphoryl azide, diethylphosphoryl cyanide, diphenylphosphoryl azide,
Diphenyl phosphoryl cyanide, dicyclohexyl phosphoryl azide, dicyclohexyl phosphoryl cyanide, methyl phosphoro dichloridate, methyl phosphoro dibromidate, ethyl phosphoro dichloridate, ethyl phosphoro dibromidate, provil phosphorodichloridate, isoprobyl phosphorodichloridate, butylphosphorodichloridate, phenylphosphorodichloridate, phenylphosphorodibromidate, 2-chlorophenylphosphorodichloridate,
2-chlorophenylphosphorodibromidate, 8-chlorophenylphosphorodichloridate, 8-fluorophenylphosphorodichloride a9+”-), 2,4-dichlorophenylphosphorodichloridate, 2,4-dichlorophenylphosphorodibromidate ), 8.4-dichlorophenylphosphorodichloridate, 4-methylphenylphosphorodichloridate, 8-chloro-4-methylphenyl phosphorodichloridate, 8-methoxyphenylphosphorodichloridate, 4-methoxyphenylphosphorodichloridate Chloridate, 8-butoxyphenylphosphorodichloridate, 4-nitrophenylphosphorodichloridate, 8゜4,5-)rimethoxyphenylphosphorodichloridate, cyclobrovir phosphorodichloridate, cyclopentylphosphorodichloridate , cyclohexylphosphorodichloridate, cyclohexylphosphorodibromidate, cyclooctylphosphorodichloridate, methylmethylphosphonochloridate, methylmethylphosphonochloridate, methylphenylphosphonochloridate, ethylmethylphosphonochloridate, ethyl Ethylphosphonochloridate, ethyl ethylphosphonochloridate, ethyl phenylphosphonochloridate, ethyl-8-chlorophenylphosphonochloridate, ethyl-2,4-dichlorophenylphosphonochloridate, ethyl-4-
Methylphenylphosphonochloridate, ethyl-4-
Methoxyphenylphosphonochlorotate, ethyl-4
- ditrophenylphosphonochloridate, ethylcyclopentylphosphonochloridate, phenylmethylphosphonochloridate, - phenylphenylphosphonochloridate, phenylphenylphosphonobromidate, phenyl-4-'imethylphenylphosphonochloridate date, phenylschiff a hexylphosphonochloridate, 2,4-dichlorophenylethylphosphonochloridate, tome 4-dichlorophenylphenylphosphonochloridate, 2,4-dichlorophenylcyclohexylphosphonochloridate,
4-nitrophenylethylphosphonochloridate, 4
-nitrophenylphenylphosphonochloridate, 4
-Nitrophenylcyclohexylphosphonochloridate, 8,4.5-)rimethoxyphenylethylphosphonochloridate, 8,4.5-trimethoxyphenylphenylphosphonochloridate, cyclopentylethylphosphonochloridate, cyclopentyl Phenylphosphonochloridate, cyclohexylphenylphosphonochloridate, dimethylphosphinyl chloride, dimethylphosphinyl bromide, diethylphosphinyl chloride, diethylphosphinyl bromide, dipropylphosphinyl chloride, diisopropylphosphinyl Chloride, dibutylphosphinyl chloride, diphenylphosphinyl chloride, diphenylphosphinyl bromide, bis-(2-chlorophenyl)phosphinyl chloride, bis-(2-chlorophenyl)phosphinyl bromide, bis-(8 -chlorophenyl)phosphinyl chloride, bis-(8-fluorophenyl)phosphinyl chloride,
Bis=(2,4-dichlorophenyl)phosphinyl
LiF, Hy (8-methoxyphenyl)phosphinyl chloride, bis-(4-methoxyphenyl)phosphinyl chloride, bis-(8-butoxyphenyl)bosphinyl chloride, bis-(4-nitrophenyl)phosphinyl chloride, bis -(8,4,
5-trimethoxyphenyl)phosphinyl chloride, dicyclopropylphosphinyl chloride, dicyclopentylphosphinyl chloride, dicyclohexylphosphinyl chloride, dicyclohexylphosphinyl bromide and dicyclooctylphosphinyl chloride .

Among these, diphenylchlorophosphate, phenylchloro-phenylphosphonate, phenyldichlorophosphate, ethylchloro-phenylphosphonate, methyl-chloro-phenylphosphonate, dichloro-phenylphosphonate and diethylchlorophosphate are suitable. Preferred are phosphate, phenylchloro-phenyl sulfate, phenyldichlorophosphate and ethylchloro-phenylphosphonate.

The organic base used in the reaction of the compound of formula (1) with the compound of formula (1) in the method of this invention is an organic base of an 8th nitrogen atom substituted with at least 14Ii1 lower alkyl groups. This 8th class nitrogen atom may form a part of a ring. Specific examples include tri-lower alkyl amines, aralkyl di-lower alkyl amines, and N-lower alkyl nitrogen-containing heterocyclic compounds. Specific examples of tri-lower alkylamine include trimethylamine, triethylamine, diisopropylmethylamine, diisopropylethylamine, diethylmethylamine, and the like. As the aralkyl di-lower alkylamine, N,N-dimethylbenzylamine, N,N
-dimethylbenzylamine and the like. Examples of N-lower alkyl nitrogen-containing heterocyclic compounds include 4-N, N-
Dimethylaminopyridine, 4-N, N-diethylaminopyridine, N-methylmorpholine, N-ethylmorpholine, N-methylpiperidine, N-ethylpiperidine, N
-Methylpyrrolidine, N-ethylpyrrolidine, N,N
-dimethylpiperazine and their homologues. The above-mentioned organic base has the function of accepting the acid produced by the reaction, and is added in at least an equimolar amount or in a slightly excessive amount for the purpose of acting as an acid acceptor. Furthermore, some types of organic bases have the effect of promoting reactions, and such organic bases can be used for the purpose of catalysts.

Organic bases that act as catalysts include methyl group-substituted organic bases. For example, trimethylamine, diethyl-
Methylamine, diisopropylmethylamine, N, N
-dimethylbenzylamine and its homologs, 4-N,
N-dimethylaminopyridine and its homologues, N-methylmorpholine, N-methylpiperidine and its analogs, N-methylpyrrolidine and its analogs, N,N-dimethylpiperazine and its analogs, and the like.

Therefore, when such a methyl group-substituted organic base is intended as a catalyst, it is sufficient to add a small amount of the so-called catalytic amount. When it also serves as an acid acceptor, it is used in an amount slightly in excess of the theoretical amount sufficient to accept at least the acid produced in the reaction. On the other hand, it may be preferable to use a combination of an organic base that exhibits an acid-accepting effect and an organic base that exhibits a catalytic effect. For example, diisopropylethylamine, 4-N,N-dimethylaminopyridine, N-methylmorpholine, , N-
dimethyl-benzylamine, N-methyl-piperidine,
Combinations with N-methylpyrrolidine or N,N-dimethylpiperazine may be mentioned.

In the above reaction, low temperature means 0°C or lower, general temperature -40°C to 0°C.
°C, preferably j, t-80'C to -10'C.

The reaction of the above reaction product with the substituted thiol is then carried out at the same low temperature as the above reaction.

An organic base is added at this time. This organic base may be the same as or different from that used in the reaction, but the organic base here is mainly used for the purpose of accepting the acid produced by the reaction.

In other words, there would be no need to add an organic base for catalytic purposes in the reaction of the reaction product with the substituted thiol. In addition, when using the same organic base as in the previous reaction, the required amount may be added in advance from the beginning, but
Generally, it is preferable to add it again during a subsequent reaction.

The reaction product thus obtained gradually precipitates in the reaction solution, depending on the combination k of the merchandising at the 7-position and the ester group at the 4-position. Next, add ice water as needed to adjust the pH to 2.5~
7 and remove the solvent under reduced pressure to collect the product. C
When this is washed with the above-mentioned inert solvent and dried in vacuum, the corresponding compound of formula (1) of Δ3 is obtained, and moreover, it is obtained in a high yield of 80% or more.

Next, the present invention will be explained by examples, but the present invention is not limited thereto.

Liquor example 1 Dry acetonitrile 40sJK,? -β-phenylacetamide-8-hydroxy-3-ceph-4-carboxylic acid-p-nitrobenzyl ester 5.6F (12mM)
1 IN 4 Sase, stir the power and bulk atmosphere -20
Cool to 0 and add 2 o 4-N,N-dimethylamino-pyridine, diisopropyl-ethylamine L4sH1rU
Add dienyl-chlorophosphate 18sZ.9. The reaction mixture was stirred at the same temperature for about 80 minutes to obtain a clear solution. After confirming the completion of the reaction with TLc, the reaction solution was cooled to -80'', 14 TId of diisopropyl-ethylamine was added, and about 81 ml of methyl-mercaptan was blown into the reaction mixture with stirring.

The reaction was continued with stirring at -26 to -80°C for about 2 hours (
(crystal precipitation), and after confirming the completion of the reaction by TLO, acetic acid 0.
Add 5 Wt and make 9.

The product was collected, washed with 71 It of cold acetonitrile, 10 W of isopropyl ether, and then dried under vacuum.

Yield s4.91Sf (yield 88%) Ol1lpi! 8
1℃ (public record). IIL (winged shawl) vine 81180°1
'176 (β-5 Rifim>, 1706, 18503
-1°UVλmax 1819m. Nl [凰＄ (0M8
0-ds-ODOJs), δ value (66ita
z), 8.118 (8H, B/B-01[,), 8J
1 (2H.

B/fl-2>, 11.68 (!II, 8/ph-OH
,), 6.08(1■, dl(J-4,611[Z)/
1f-6), 6.78 (!lf, 8/-OH, -pH-
NO, ), 5.64 (IH,, ad, (J-4,6,
J-7,8Hz)/ll-7), 7.29 (IsI1
%8/ph-OIi, ), 7.68.8.20 (4
Il, 2Xd, (J-84) /ph-No,)
, 8.88 (II!, d, (J-7,8)/NH), in the above reaction for 4-N,N-dimethylamino-pyridine! 7KN-methylmorpholine, N,N-dimethyl-
Very similar results were obtained using benzylamine or N-methylpiperidine.

In addition, in the above reaction, diphenyl-chlorophos 7z-+o
Similar results were obtained using p<yenylphosphonic acid phenyl ester monochloride.

Example 2 7-β-puenoxyacetamide 8-in place of γ-β-phenylacetamide 8-hydroxy-8-cephem-4-carbon II-p-nitrobenzyl ester in Example 1 Hydroxy-8-772mu-4-carboxylic acid-p-nitrobenzyl ester at 5.8 f (12r
mhL), using N-methyl-morpholine 2NI in place of 4-N,N-dimethylamino-pyridine,
Other post-reaction treatments were carried out in the same manner as in Example 1 to obtain the title compound. Yield: 82%, 196'C (scale) to 11p195,
IR (x Scholl) 1-1 82803 (NH), 178551 (β-lac 1-1 Tam), 17003. 1870cm, UVλ1a
ax (96% ethanol), 818mm, 260-1H
MR (CDOjs), δ value, 2.87 (811[,87
B-CjFi,), 8.61 (!■, 8/ll-2),
4.69 (tH,8/phOOIt,), a, osc
tll.

a, (z-t4Hz)/11[-6), 6.87(2
11,8/-cg, phNO,), 6.81 (I H
,, ad.

(J = 8.11 Hz, 4.4 Hz), 6.8
9 to 7.66 (6■, m/mrO 臘, 6H% NH),
7.60.848 (4H, ad%J-8, gfl[z)
, Run f18 7-β-phenylacetamide in Example 1.

-8-hydro-3-cephemu-4-carboxylic acid-p
-The reaction was carried out in the same manner as in Example 1, except that 7-β-phenoxyl tando 3-hydroxy-3-cephem-4-carbon II-/phenylmethyl ester was used in place of the nitrobenzyl ester. Add ice water to the liquid,
The r.sub.8.6 was adjusted with dilute hydrochloric acid, most of the solvent was distilled off under reduced pressure, and the solid matter was collected and recrystallized from benzene+ethyl acetate to obtain the title compound. Yield 81%, tmp'17~
79°C 1UV
DOIs), δ value, 105 (8II, 87a(1
! ■S), 2.99.8.44 (2H15B (L, J-
16,4/■-2), t, 5s (2H18/phOc), 6.00 (1", d, J-4,8/He), 6.6
9 (111, ad, J-4,8, J-9,0/■-7
), 6.96-7.16 (16E[Ii/16mro
w■tOHphs), 106 (1st ward, d, J-9
, 0/l'Tμ) Example 4 7-β-phenooxyaceta? )'−
7-β-phenylacetamide-8-hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester instead of 8-hydroxy-8-cephem-4-carboxylic acid-diphenylmethyl ester, and 4-N , N-dimethylamino-pyridine was replaced with N,N-dimethyl-benzylamine, and the post-reaction treatment was carried out in the same manner as in Example 8, to obtain the title compound. Vehicle collection 81%, mptsi~1
96℃ (decomposition), UVI wax @t @rrm
(96% ethanol), IIL, ty
aoaT” (β-lactam), 1700m” (ester), 11K (ODOj,) a value, 1°9G (III,
8/8-O”s)s 191.11.88 (2fI,
Mu B (1 (J-16,8fIm)/fI-2), 8.6
4 (2J8/ph-Ca,), 4.96
(1fI% d, (J-4, BfIx
)/f[-6), ls, 62 (III, da
(J-4,8,8,11K)/f1-7), 6.86
(IH, 131011 [1>hm), 7.
88 (III, m/ph % Nu) Example 5 7-β-phenylacetamide-8-hydroxy-8-cephem- 4-carbo/acid-p-nitrobenzyl ester O group? To? -β-acetamide 8-hydroxy-8-cephem-4-1 rubonic acid p-nitrobenzyl ester, and N,N-dimethylbenzyl amine in place of 4-N,N-dimethylamino-pyridine. The title compound was obtained by performing the same post-reaction treatment as in Example 1. Yield 80%, IEIp248°C (decomposition), t
ryλ1m&X12Qnm, 260 yen, IR (wing 1-
), 1780s" (β-lactam), 1 17103.1650ci"1, NMR (DM80-d
), 1.94 (8flI%8/CH, (30), 2
．． 40 (81%8/5-CH,), 8.86 (2■, 8
/H-2), 6.14 (lfi, d, J-4,8
/1I-6), 5.41 (21K, 8/CFIj-ph
-NO, ), 6.64 (IH, ad, J-48, J
-8,2■2/El-7>, 7.71.8.26 (
4H, dX2, J-9, GHz/Mroa+ fI),
8.86 (III%d%J” 8J Hz/NH) Real-6 7-β-phenylacetide 8-hydroxy-8-cephem-4-1 rubon a-,'-nitrope/dyl ester 5sssyt- suspended in dry acetonitrile 10-
Cool to -20'O. To this was added 0.895 g of diisopropyl-ethylamine and 9
Add 10 MIt. 0.46- of diphenyl-clodiphosphate is added under stirring while displacing t-is in the reactor. A clear solution is soon obtained. To this, 0.895 g of diisopropyl ethyl azate and 2'l of n-butyl mercapta were added.

and stirred at -20°C for 17 hours. Acetic acid 0.15
-, the precipitated product was collected and washed with a small amount of a7tonitrile and isopropyl nityl cooled to 10°C.
A crude product of 0JIF was obtained. Purified by analytical PLO.

(Benzene; ethyl acetate V = 2:1) Collection vehicle 66% oil
Pt87-188℃ (decomposition), UVλIl&X 81
8 nm (96% ethanol), IR (Sujoor), 1
7803' (β-lactaf), 1-203 (ester) NMR (00 (Jg) δ value, 0.91-2.65 (7
kK.

m/(3, (tI, OH,), 2.81 (2E[
%'bt/8-on, -), 8.54 (2F[, S/on-2), 164 (21%8/pho also), 4.97 (1
fI.

d, (J-4,7IIZ)/H-6), 5.34 (21
1,810 also ph-No, ), 5.72 (IH%dd(
J-4,7,8JfiZ/H-7), 6.81(lli
d(J-8,2H2)/NH), 7.31 (5L 8
/phO[,), 7.67.8.20 (dX2, (J.

Claims (1)

[Claims] 1. A 3-hydroxy-cephem derivative represented by formula (I): (wherein, R is a carboxylic acid residue that does not participate in the reaction; V is an ester residue) ! in the presence of an organic base at low temperature under the formula (■):
Phenyl or phenoxy group optionally substituted with 1 to 8 groups selected from 1 to C4 alkyl group, 01 to 04 alkoxy group, halogen atom, and nitro group; or 0
1 to 04 alkoxy group, 08-4 cycloalkyl, 0 to 8 cycloalkoxy or halogen group; x is a halogen atom, nitrile group or azide group, provided that 1) R''
When either one of and Bb is a halogen atom, the other is a group other than a halogen atom, and (2) when X is a nitrile group or an azide group, R1' and Hb are the same or different phenoxy groups, Oto8 Cycloalkoxy group or 0
1-4 alkoxy group), then an organic base is added to the reaction product, and at a low temperature, the reaction product is reacted with a substituted phosphorus halide conductor represented by the formula (R"-8H) ( (In the formula, R is a lower alkyl group) It is reacted with a substituted thiol represented by the formula (W): An improved method of a chemical method characterized by obtaining an 8-substituted-thio-cephem derivative represented by: 8. The method according to claim 1, wherein the organic base is trimethylamine, triethylamine,
Diisopropylmethylamine, diisopropylethylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, 4-N,N-dimethylamino-pyridine, 4-N,N-diethylamino-pyridine, N-
3. The method according to claim 2, which is methylmorpholine, N-ethylmorpholine, N-methylpiperidine or N-ethylpiperidine. 4. The organic base used in the reaction between the compound of formula (1) and the compound of formula (1) is substituted with at least one lower alkyl group in an equimolar or slightly excessive amount of the compound of formula <1). a tertiary nitrogen atom-containing organic base and a catalytic amount of at least 1
1. The method according to claim 1, wherein the method uses an organic base containing an 8th-class nitrogen atom substituted with methyl groups. 5. Diisopropylethylamine in an equimolar or slightly excessive amount as the compound of formula (1) as an organic base, and a catalytic amount of 4-N
, N-dimethylaminopyridine, N-methyl-morpholine, N,N-dimethyl-benzylamine or N-methyl-piperidine. 6. The organic base used in the reaction between the compound of formula (1) and the compound of formula (1) and the compound of formula Claim I! which is the same organic base used during the reaction with the compound of 1)! The method according to any one of items 1 to 8. 7. The method according to claim 1, wherein the reaction temperature is 0° C. or lower. & Claim 7, wherein the reaction temperature is 140 to 0°C.
The method described in section. 9. The method according to claim 8, wherein the reaction temperature is -80 to -10°C.