JPS59112989A - 2-thiacephem and (5r)penem derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel process for the preparation of (5R) venem compounds of the general formula (5R) and their pharmaceutically and/or veterinarily acceptable salts.

In the general formula ill, R1 represents a hydrogen atom or an organic group, R2 represents a hydrogen atom or a carboxy protecting group, and Y represents a hydrogen atom or a halogen atom or an organic group.

The organic group represented by R1 includes optionally substituted aliphatic or cycloaliphatic groups.

Aliphatic groups are preferably alkyl groups having 1 to 12 carbon atoms and optional substitutions may be one or more hydroxy, amine, cyano and/or mercapto groups.

Hydroxy, amine and mercapto groups may be free or protected. Particularly preferred alkyl groups are methyl and ethyl, especially the latter, and preferred substituents for such groups are hydroxy groups, which may be free or protected. 6B, 8R or/)R,F
A 1-hydroxyethyl group having a 3S configuration δ is particularly preferred. Cycloaliphatic groups are preferably monocyclic alkyl groups having 4 to 7 carbon atoms. Cyclo is particularly preferably methyl and cyclohexyl. The optional substituents are preferably selected from alkyl groups having 1 to 6 carbon atoms, such as methyl or ethyl groups, hydroxy, amine and mercapto groups, and hydroxy, amino and mercapto groups are free fc is protected.

The carboxy protecting group R2 may be any n group which together with a moiety of -COO forms an esterified lr carboxy group. Examples of carboxy protecting groups are in particular alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl or U
t-Butyl, a halo-substituted alkyl group having 1 to 6 carbon atoms, e.g. j dichlorotyl, 2
alkenyl groups having ~4 carbon atoms, such as allyl,
optionally substituted aryl groups such as phenyl and p-nitrophenyl, aryl-substituted alkyl groups (the alkyl part of which has 1 to 6 carbon atoms [L and the aryl part of which is optionally substituted )
For example benzyl, p-nitrobenzyl and p-methoxybenzyl, aryloxy-substituted alkyl groups (the alkyl part of which has 1 to 6 carbon atoms) such as phenylenemethyl or benzhydryl, 0-nitrobenzhydrinoL1 acetonyl, Funds such as trimethylsilyl, diphenyl-t-butyl-silyl and dimethyl-t-butyl-silyl are included. The ractical meaning of R2 as a carboxy-protective group is also. All residues such as acetoxymethyl, pivaloyloxymethyl or phthalidyl are included which are esters known to hydrolyze in vivo and have advantageous pharmacodynamic properties.

When Y is a halogen atom, it is preferably fluorine,
It is a chlorine or bromine atom.

When Y represents an organic group, it is preferably a free or circulating hydroxy group (b+ optionally by a halogen atom, containing 2 to 6 carbon atoms'<7
a formyloxy group or 2 to 6 carbon atoms substituted by an acyl group or by an amine, hydroxy or mercapto group (the amine, hydroxy or mercapto group is optionally in the reversed form) Acyloxy group bearing an atom (C1 unsubstituted or N-alkyl substituted
fC, carbamoyloxy group, (at optionally one or more), rogene atom, formyl group, acyl group having 2 to 6 carbon atoms and (also Fi) amino, hydroxy or mercapto group (amine an alkoxy group with 1 to 12 carbon atoms or an alkylthio group with 1 to 12 carbon atoms, where the hydroxy or mercapto group is optionally in the protected form fLfC, (e) unsubstituted or meta or rose
1-'pyridinium group 1 (f+ heterocyclylthio group -8-Het (Het
represents a saturated or unsaturated heterocyclic ring metal containing at least one oxygen, imitate and/or nitrogenous heteroatom, and preferably IA) unsubstituted or one or more (a') to 1 to 6 carbon atoms! alkoxy groups containing from 2 to 6 carbon atoms, aliphatic acyl groups containing 2 to 6 carbon atoms, hydroxy groups and/or norogen atoms, (b) unsubstituted or one or more hydroxy groups and (or) an alkyl group having 1 to 6 carbon atoms substituted by a hydrogen atom; (a') unsubstituted or one or more hydroxy groups; and/or an alkenyl group having 2 to 6 carbon atoms substituted by a hydrogen atom, (d') having the general formula -8-R3, where R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; ) or a group of the general formula -8-C!H2-000R4 (wherein R4 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a carboxy-protecting group); Formula -((1!H2)m-000R4 or IchishoH-OCX)R4 or -(OHM)m-ON ma or -(C!H2), -0ONH2tid-(OH2
) m-8OroH (wherein m is 0.1.2 or 6 and R4 is as described above), 9 and R5 and R6 respectively 21,
are the same or different and represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aliphatic acyl group, or if one of R5 and R6 is hydrogen, the other can also be an amino-carrying aM) a 5-atom or 5-atom heteromonocyclic ring containing at least one double bond and at least one oxygen, sulfur and/or nitrogen heteroatom or (Bl fused heteromonocyclic ring), substituted by At least two double bonds each of which is the same or different and is a 5- or 6-atom detection term containing at least one oxygen, nitrogen or nitrogen heteroatom; a heterobicyclic ring containing a heterobicyclic ring (the heterobicyclic ring is unsubstituted or as defined above (a'))
, (b'), (a'), (a') and (f'), substituted by one or more substituents f
(is) is].

In the above definitions tAl and (Bl), preferred halogens are chlorine, bromine and iodine, preferred -iM;'z alkyl groups are methyl and ethyl, preferred alkenyl groups are allyl, preferred aliphatic acyl groups. is acetyl, the carboxy protecting group may be any of the groups indicated above for the R2 customary moiety, and the free sulfo and carboxy groups optionally present are salted, for example as sodium or potassium salts. The heteromonocyclic ring of (Al) is, for example, an optionally substituted thiazolyl, triazolyl, thiacyaso-1-nor, tetrazolyl or triazinyl ring.

Suitable substituents on such rings include, for example, amine, hydroxy, oxo and C1-C6 alkyl groups, preferably methyl'' or ethyl (c1-C6 alkyl groups optionally include carboxy, sulfo, cyano, carbamoyl, amine). , methylamino or dimethylamino
one or more replacements selected from n replaced by the replacements selected from n. The bicyclic ring of (Bl) is, for example, a tetracylopyridazinyl group optionally substituted by amino or carboxy.

In formula +11 above, the optional amino, hydroxy or mercapto protecting groups are those commonly used in nidiline and cephalosporin chemistry for these functionalities. These include, for example, optionally substituted acyl groups, especially non-substituted acyl groups such as acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, benzyl or p-bromophenacyl, and triarylmethyl groups, especially triarylmethyl groups. Phenylmethyl, silyl group, especially trimethylsilyl, dimethyl-t-butylsilyl, diphenyl-t-butylsilyl i 7 (Ut-phthoxycarbonyl, p-nitrobenzyloxycarbonyl, 2.2.2-)lichloroethoxycarbonyl, benzyl, It can be groups such as pyranyl and nitro. In particular, when the R1 substituent in formula (11) is a hydroxyalkyl group, suitable protecting groups for the hydroxy function are p-nitropenzyloxycarbonyl, dimethyl-t-butyl-silyl, diphenyl-t-butylsilyl. , trimethylsilyl, 2,2
．． 2-) Lichloroethoxycarbonyl, benzyl, p
-bromo-phenacyl, triphenylmethyl and hyaranyl. All alkyl and alkenyl groups, including the aliphatic hydrocarbon portions of alkoxy, alkylthio and acyloxy groups, may be branched, straight chain or straight chain.

Pharmaceutically and (also l-f:) veterinary acceptable salts (1. acids of inorganic acids such as hydrochloric acid or sulfuric acid or organic acids such as tartaric acid, fumaric acid or methanesulfonic acid); Salts of hydroxides of hyalkali metals or alkaline earth metals, especially with bases, such as hydroxides such as sodium hydroxide and potassium hydroxide, or organic bases such as triethylamine, pyridine, benzylamine or collidine. .Kobunanahanawa is a base consisting of a compound of the formula (11) in which R2 represents a hydrogen atom and one of the bases mentioned above, especially sodium hydroxide or hydroxide.

Compounds of general formula (11) obtainable by the method of the present invention are described in our British Patent Specification No. 204565.
It is a known compound described in No. 9 and No. 8210410. Their compounds are potent broad-spectrum antibacterial agents and are therefore useful in the treatment of bacterial infections in warm-blooded animals, particularly humans, by enteral or parenteral administration.

Desulfurization term shrinkage of 2-thiacephem (wherein R1, R2 and Y are as previously described) is a known method for the production of 2-thiacephems, but the method suffers from poor or unfavorable stereoselectivity. There is. Although the carbon atom at position 6 has an R configuration, desulfurization is usually biologically inert (5S
) - is Nemu (“J.

Am, Ohem, Soc, J M Volume 101 No. 6306
(1979) and (5S)- and (5R)- are mixtures of nem ("J.

Ohem, Soc, Oommun, J 1982 No. 8
Page 09) Give a meeting. The present inventors have discovered that (5R)-<Nem can be obtained by such a non-reactive ring contraction if the substituents R1, R2 and Y and the bath agent for the method are appropriately selected. Tetrahear
onLetters' Volume 24, page m3283 (1983
Published in 2007). However, it is not desirable (5S)
- In order to avoid losses in the formation of the isomer and its separation from the desired (5R)-isomer, a general stereoselective clearly desirable.

The present invention seeks to provide a method for the total production of (5R)-benem with the general formula (It'(r*) as described above, and the method comprises Oxidation of 2-thiacephem with the general formula (1) to give a sulfone with the general formula (1)00R2, where R1, R2 and Y are as previously described, and expulsion of the 4iAE lj dioxide. and if necessary convert the obtained (5R)-?nem of the general formula (1) into another compound gJ of the general formula +11 and (also Vi) if necessary the general formula ( The process consists of converting the obtained compound of formula (1) into its salt and/or, if necessary, obtaining from the salt the free compound of general formula (1).

Oxidation can be carried out using oxidizing agents commonly used to convert all organic sulfides to the corresponding sulfones. Suitable oxidizing agents are peracids such as m-chloroperbenzoic acid or peracetic acid. The reaction is generally carried out in an inert solvent at a temperature of 0 to 60°C, preferably 4 to 30°C.

Shrinkage of the sulfone due to loss of sulfur dioxide can be easily accomplished by heating in an inert organic bath such as dichloroform or benzene. In some cases, ring lines may occur naturally at room temperature as well.

2-thiacephem (R of the carbon atom at the 6-position of Ill
The configuration is maintained throughout the process, so that (5R)-venem is fully obtained. Loss of sulfur dioxide from thiosulfonates is sometimes reported [e.g.
em, soc, J 1956, p. 1665 and [J
, org, ohem, J m vol. 35, p. 178 (19
[70]] However, it is noteworthy that this reaction set little precedent with respect to yield and mildness of operating conditions and was only then applied to the synthesis of β-lactamated products. It is the right thing to do. Non-invention is '! ! :Ta(
5R)-configuration of 2(l[I @!J'
(i- Provides all methods to obtain.

According to the invention, the compound of general formula (') can be produced by the method shown in the following reaction scheme.

In the formula, R1, R2 and Y are as described above.

2 is a group of 2-SR7 (wherein R7 represents an alkyl group having 1 to 8 carbon atoms, a phenyl or tolyl group or preferably a heterocyclic group), especially 2-(nzothiazolylthio); or a 1-methyl-tetrazol-5-yl-thio group, (11) a group of formula 5OOR8 (wherein R8 represents an optionally substituted lower alkyl group, preferably methyl), lower alkyl or aryl; or (iVl-8-R7, in which R7 is an optionally substituted a lower alkyl or aryl group, preferably a methyl, phenyl or p-)lyl group; and LH a halogen atom, an alkanesulfonyloxy group or an allenesulfonyloxy group, preferably a methanesulfonyloxy group shows.

Compounds of the general formula (IVI) used as starting materials are:
They are known compounds or can be obtained from known compounds by procedures known per se. The preparation of some representative compounds is shown in the Examples.

A compound of general formula (1) is first subjected to ozonolysis to obtain a compound of general formula (1). Next, the hydroxyl group is converted and the obtained compound of the general formula (■) is completely destroyed to obtain a compound of the general formula tUt in which all Y atoms are hydrogen atoms.

If necessary, the methyl group is then .logogenated to obtain a compound of the general formula tUt, where Y is .logen.

In another method, compounds of general formula (IV) can be prepared by methods known per se (allylic, ene-type or electrochemical halogenation, [TθtrahedronLetter
sJ 1980 No. 71 and 551 A% 1981
1982, p. 3195 and p. 2187, 1982). The obtained compound of general formula tVl is then subjected to ozonolysis. Next, the hydroxyl M of the obtained compound of the general formula is converted to 4￥L, and the purified compound of the general formula is cyclized to obtain the compound of the general formula (11).

The group Y in the compounds of the general formulas (Vl, (■D), (IXI and According to the preferred characteristics of the present invention, this conversion is preferably carried out on compounds of the general formula.

The enol (Vll
or conversion of the hydroxy group in (vlI) into a radical,
Mesylation is preferred. The present invention surprisingly shows that this reaction has no effect on the subsequent cyclization if it is carried out in tetrahydrofuran instead of the ubiquitously used halogenated hydrocarbon. A suitable compound is a mesylate with Z alkene configuration (lxl or (1
I have found that 1) is almost exclusively quenched with thorns.
"oan, J." giving a 1:1 mixture of Z isomers.

Ohem-J Vol. 55, p. 2873 (1977) s
“J-c!hem.

Soc, Chem, Comm, J 1981 No. 94
7 pages and [J.

Chem, EIoc, Ohem, OomM, J 197
9th year, No. 666].

(Mll) t or (force cyclization is N
a2s, NaH8%Bu4NH8, or by reaction with H2S in the presence of a base such as triethylamine or pyridine.

Cyclization of 2 represents a group other than SR7 (IXJ) is usually carried out by chromatographic separation or heavy metal salt (Ag
+, pb2+) as precipitation total required by-product R
Instead of 45H (eg mercaptobenzthiazole), ZHC91J offers the distinct advantage of total release of readily separable, normally water-bathable by-products (phenylsulfinic acid, succinimide).

Compound tn+ (Y=H
), we have found a way to carry out such a transformation in high yields, against the reasonable possibility of excluding the possibility of 6-methyl radical rogenation. It is thus possible to obtain the compound tnl (Y=halogen), which is a valuable intermediate for the synthesis of the highly active nem antibiotic (1).

The preferred no-rogenation reagent for such transformations is N-
Promosuccinimide and this one is 20-1
Acid scavengers such as epoxides (e.g. propylene oxide), alkaline earth metal oxides (e.g. calcium oxide) or molecular sieves in solvents such as ben7ane or carbon tetrachloride, ethyl formate at temperatures in the range of 30°C. Azobisisobutyronitrile in the presence of a scavenger or peroxide is used in the presence of a radical inducing agent such as inzoyl.

Compound (I[] (Y = halogen) can be converted into compound (fil (Y = M group)) by a reaction known per se. For example, as follows.

(1) Compound tI[l (Y-Br or ag is
unstable with inorganic acids, by gentle hydrolysis, or by reaction with oxidation oxide/dinotyl sulfoxide/water, or by reaction with strong inorganic acid salts, such as nitrates or I got Esther, and this Esther is out of money!'i!
Compound +III (Y-Y) by hydrolysis in the same reaction medium to obtain the desired parent alcohol
411I' or protected f'-OH). Preferred salts of this type are AgNO3, Ag]tO
4. NaNO3.

(2) The compound ([1(Y=Br or C4) is converted to the compound (If) (Y=OH) as described above, and then a suitable incyanate (e.g. trichloroacetyl isocyanate) is converted to the compound ([1(Y=Br or C4) Y=OOONH
The compound (Il
(Y = unsubstituted or reduced N-alkyl substituted carpamoyl oxine group).

(3) Compound (III: (Y=Br't or cg) can be prepared by reacting with a suitable salt of the corresponding carboxylic acid in a suitable solvent or under a phase transfer catalyst or compound till (Y=OH) Compound (■) (Y = niacyloxy) can be converted by converting to 1 and then carrying out conventional acylation.

(41 Compound (III (Y=Br or ag) is reacted with the corresponding MS-net in the presence of a base in a suitable solvent such as tetrahydrofuran, acetone, acetonitrile or dimethylformamide or preformed with base HEI- It can be converted into the compound (Ill (Y=S-Het) by reacting with a salt of Wet. A suitable base is triethylamine,
- Preformed salts are sodium salts, e.g. sodium 1
-Methyl-1,2,3,4-tetrazol-5-yl-
It is a mercaptide.

Due to the remarkable tendency of 6-hydroxymethyl-2-thiacephem-4-carboxylate to lactonize, it is susceptible to nucleophilic attack by the hydroxy group adjacent to the carboxy moiety to which R2 is attached in the aforementioned method (1). To relative inertness! It is preferred to represent somewhat bulky groups forming esters such as 6-butyl esters. In addition, since the 2-human, roxymethylznemcarpoxylate Nd does not easily lactonize, the corresponding benem (1
) It is advantageous to deprotect the hydroxy group from its protected form after the contraction step. For example, the compound tu
l (Y=Br)k can be converted to compound (II) (Y=ONO2). This compound can be easily isolated, purified if necessary, and desulfurized to the corresponding venem (1). Reductive hydrolysis of this compound (eg Zr7CH, , COH) gives the free hydroxy derivative without problems.

-0OORDue to the different stabilities of venem and 2-thiacefem bales to conditions that are compatible with 2-ester ester hydrolysis, a significant advantage of the present invention is that ester hydrolysis that is incompatible with venem versus 2-thiacefem precursor It can be carried out and the ring contraction can be played! il [to acids or to salts with organic or inorganic bases or, if necessary, to the various unstable esters which can be formed in the reaction system, such as trimethylsilyl, t-butyldimethylsilyl or t-butyldiphenylsilyl esters. This means that it can be carried out.

The following examples fully illustrate the invention. Abbreviation Me s But,
Ph, MS%pNB, THF, EtOA
c %DM80, MeON fison methyl%
t-)fl, phenyl, methanesulfonyl, p-nitrobenzyl, tetrahydrofuran, ethyl acetate, dimethylsulfoxide and acetonitrile. NMR
The spectra were analyzed on a Hitachi PerkinElmer 6Q MHz and Tahab Lutzker 90MH2. The separation of the internal lines of the AB quarter refers to the spectrum taken at t' for the latter.

Example 1 Diphenylmethyl 6,6-dibromopenicillanate 6,6-dibromo in acetonitrile (450rnI!,) was prepared by adding nidylanic acid (90r) to diphenyldiazomethane (49M) in the same solvent (i50-). It will be dealt with by dissolution. After 1 hour at 20° C., the solid formed is collected by filtration and washed with multiple portions of ethyl ether to yield the title product 1161i. The second samurai, 1i (95
') Get all. Yield 95% A sample for fractionation is obtained by crystallization from chloroform. Melting point 157-158'. νmaX (CHC43 film) 1800.175 group-1; δ (CDC1ro) 1
．． 24 and 1.58 (sonzof”L6H,s, OMe
2), 4.61 (IH, e, N・O)1・OO), 5
．． 80 (1H.

s, N-0R-8), 6.91 (IH, s, 0OH),
and 7.30 ppm (I QH.

s, Ar).

C! The elemental analysis results for 21H19Br2NO3s are as follows.

Calculation value: 48.02 3.64 2゜67 6.10 30.43 Experimental value: 47.
80 3.63 2,64 5.95 30.49 cases
2 6th-butyl 6,6-dibromopenicillanate method (A
l Triethylamine (
67go) and pct5 (56?). After stirring for 1 hour, the reaction mixture was evaporated in vacuo (dried benzene was added and removed) and the crude acyl chloride was dissolved in dichloromethane (200 m6) and 0aO0
5 (,50V) in the presence of car 6-butanol (
500rnl) for 24 hours. The suspended salts were removed from the solution and washed with an entirely aqueous NaHOO bath (some unreacted starting material was recovered by back extraction of the acidified aqueous washes), decolorized with charcoal and evaporated. The title product is obtained, which is then crystallized from 7'L all diinpropyl ether. 69160). Melting point 120-12
1℃. νmaX (CHCt3 film) 1800 and 1740 crn-1; δ (CDC43) 1.98 (1
5H, El, But and aH5), 2.05 (5H
, e, 0H4), 4.38 (IH, s, N-0H-C
o), and 5.70(IH,s,NN-Cll5)p
p0 Method (B) 6,6-dibromopenicillanic acid (1!M')'eo-fi3Mphthyl-N in dichloromethane (500d)
, N-diisopropyl-isourea (2sy). The reaction mixture was completely filtered and the bath liquid was completely aqueous N.
Wash with aHOO5. Crystallization of the product from diisopropyl ether gives the title compound 8r (47%).

Example 6 Diphenylmethyl 6α-bromo-6β-[1(R1-hydroxyethyl]-henicylanate - THF (900
Diphenylmethyl 6,6-dibromobenicillao) (12(In)k) in m1) is treated with a solution of ethylmagnesium bromide (1 molar equivalent) in ethyl ether.

After 20 minutes at -750, acetaldehyde (25,7 m
l) k is added and the mixture is stirred for a further 20 minutes at -75°C.

After cooling with saturated aqueous NH4at (400 g), partitioning between water and ethyl ether and then removing the solvent gave the crude product, which was separated by total silica gel chromatography (benzene/ethyl acetate). Separately, the title compound 67f (60%) is obtained as a foam. Crystallize (diisopropyl ether) to a solid. Melting point 65-7
0°. νmax (film) 34'50.1785 and 1740α-1; δ(CDC15) 1.22 and 1
．． 60 (Sonozog3H, S, OMe2), 129 (
511,d,, T=6Hz, OH3・OH), 2.
90 (IH, d, OH), 4.17 ('IH, m, OH
3.0H-OH), 4.58 (IH,s, N-CH-0
0), 5.49 (IH, s, N・OH・S), 6.9
0(1H,8,0OHPh2), and 7.3(1[]
H, s,, h) ppm.

Using a similar procedure] tertiary butyl 6.6-
Dibromo is prepared by starting from nisilate to form 5-butyl 6α-bromo-6β-(1(R1-
Hydroxyetheno is removed to give nisilate. δ(
CDC1x, ) 1.28 ('3H.

JJ=6H2,OH3・OH), 154(12H,s,
But and aH3), 1.65 (5H, s, OH
5), 2.65 (1H, B, aH-on), 4.25 (
IH, m.

OJ・0H(OH)・OH), 4.40(IH, θ, N
-0H-Co), and 5.51 ppm (IH,s,N
-0H-8).

Example 4 Diphenylmethyl 6α-(1(■-hydroxyethyl)
- Honeysilate-1-oxide 95% ethanol (4
diphenylmethyl 6α-bromo-6β-(
1(R1-Hydroxyethyl)-penicillanate to 10
%PcVCaOO3(25f) and OaC! 03
Hydrogenate at 50 psio in the presence of (i i r ). The reaction mixture is filtered and evaporated to give a residue, which is partitioned between brine and dichloromethane.

After removing all the solvent, crude diphenylmethyl 6α-(1(R
1-Hydroxyethyl]- to obtain nisilate, this A'
iChloroform 500m/! 85% MOPBA (1
7? ) for 1 hour at 0-5°C. The filtered solution is then washed with aqueous NaHCO3 and the solvent removed to yield the crude title product 40 f (88%) as a foam. This 11 can be used as is or purified by silica gel chromatography. νmax(0
HO15 film) 1790 and 1750m”; δ
(0DC1,,) 0.94 and 1.67 (fL3H,s, OMe2), 1.67 (3H,d, J
=6Hz), 3.55(1'H, (1(1,J-2 and 6.5Hz, OR・0H-OH), 4.25(IH,
m, OH4・C! H(OH)・C! H), 4.64 (I
H, 6°N-0H-Co ) 44.98 (I H, d
, J=2H2, Of (bit 0H-8), 6.98 (IH.

s, 0OHPh2), and 7.30CIDH,
s, Ar) p, pm 0 3M7'thyl 6-C1 ( R1-Hydroxyethyl]-o Nisilaneto 1-oxide (75%) is obtained. νll1tL'X (film) 5440.178
5 and 1740 nee 1° Example 5 Diphenylmethyl 6α-[1(R1-m tertiary butyldimethylsilyloxyethyl]-benicylane obtained in Example 4 n
Crude diphenylmethyl 6α-CI (R1-hydroxyethyl)-henicylanate-1-oxide (40?
f) Dissolved in DMF (350 g) and stirred for 6 hours at 50-55 DEG C. in the presence of imidazole (185 g) and 6-butyldimethylsilyl chloride (27 g). The reaction mixture is partitioned between ethyl ether and brine and the organic layer is soaked several times with water.

Evaporation of the solvent and chromatography on silica gel gives the title product 222. νmaX (beat at3 film) 1790 and 17s5pn-1; δ (ODCL3
)0.06(6H,S.

EtiMe2), 0.88 (13H,e, But and 0H3), 1.3 (3H,a.

, T=6Hz, OH3・OH), 1.7 (3H, s
, OH3), 3.4 (IH, dd, J = 2 and 4.5 Hz, 0H-OH-OH), 4.40 (IH, m
, OH3・CH・OH), 4.55(II(, 日, N−
C! H・C, 4.88 (IH, d,, T=2.C!
H・9dan・S), 6.9 (IH, s, 0OHPh2),
and 7.25 ppm (10H, s, Ar).

A similar procedure was used and the sixth tabutyl 6α-(
'NRI-Hydroxyethyl]-henisilanato-1-
5-butyl 6-[1(R1
-5th-butyldimethylsilyloxyethyl]-henicillaneto-1-oxide is obtained. νmaX(CHC
63 film) 1785 and 1750 cm-1; J
(ODO/4) 0.06 (6H,s, SiMe2), 0
．． 88 (9H, e, 5iBut), 1.25 and 1.66 (so f'l-5H+ 8 eOMe2)
, 1.28 (3H, d, J=6Hz, OH3・OH),
1.45 (9H, s.

OBu';), 3.5 (IH, da, , T-2 and 5Hz, 0H-(EH-OH), 4.4 (IH, S, N
-0H-Co), 4.5 <1a, m, an3-an-
aH), and 4.9 ppu+(IH, d, J=2H
z, O total OH・8).

Example 6 Diphenylmethyl 6α-C(R1-p-nitropenzyloxytriponyloxyethyl)-sunisilaneto 1
- oxide diphenylmethyl 6α-[1
(■-hydroxyethyl:]-:=silane-) -1-
Acylation with the oxide kp-nitrobenzylchlorocarbonate gives the title product as a foam. δ(
cDOt3) 0.96 and 1.7[J(So几zonn3H
,s, OMe2), 1.52(,3H,d, J=6H
2, OH5・OH), 3.8K IH, dd, J=
2 and 6H2, OH・OH*OH), 4.66 (IH
, s, N-0H-Co), 4.99 (IJ(, d, J=
2Hz, 0H-OH-8), 5.28 (2H, e, 0
OH2Ph), 5.35 (1H, m, OH3・OH・O
H), 7.01 (IH, s, 0 (1! HPh2), 7.
40(10H,n], Ar), 7.55 and 8.26
pII) m(sonzon2H, d, J=8Hz, Ar
).

By the same experimental procedure, 6-butyl 6α-[1
(RI-p-nitrobenzyloxycarbonyloxyethyl)-penicylanate-1-oxide is obtained.

By a similar experimental procedure and by using trichloroethyldichlorocarbonate instead of p-nitrobenzylchlorocarbonate, 6-butyl 6α-[1('BJ-trichloroethoxycarbonyloxyethyl]-penicylanate- 1-oxide and diphenylmethyl 6α-[1(Ri)lichloroethoxylponyloxyethyl]-haesilanate-1-oxide are obtained.

Example 7 3(81-[1(R1-hydroxyethyl)-4(R
1-benzthiazolyldithio-1-(1-methoxycarbonyl-2-methyl-1-bro)-2-enyl)-azetidin-2-onemethyl 6α-(-1(R1-hydroxyethyltubenicillanate- A mixture of 1-oxide (52) and 2-mercaptobenzthiazole (3,D4?) is refluxed in dry toluene for 2 hours. The bath is removed in vacuo and the crude product is used in the next step. .

The following compounds are obtained using similar procedures.

3(S)-(1(R1-6th t-butyldimethylsilyloxyethyl E-4<R)-benzthiazolyl-1-
(1-Methoxycarbonyl-2-methyl-1-flobu-2-enyl)-azetidin-2-one. Methyl 6α-[
Starting from 1(R1-i3ff&butyldimethylsilyloxyethyl]-sunisilaneto 1-oxide. Reaction time extended to 6 hours. νrnaX (CHCt3 film) 1770 and 1744 cm−1; δ(ODO13
) 0.02 and 0.04 (fL3H,s, Si
Me2) 0.84 (9H, s, 5iBut), 1.
23 (3H, d, J=6Hz, 'OH3・OH),
1.91(3H,s,=C=C-0H,3,58(,
IT (, ad, , T-2 and 3.5Hz, CH
an-aH), 3.69 (3H, e, 0OH3), 4.
23(IH, m, (!H3・OH・OH), 4.82(
11(,s,N-C!H-C,O), 5.07 (2H
, m, OH2=C), 5.42 (IH, d, J=2
H2,0H-(3H・S), and 7.2-7.9
ppm (4H.

m, Ar); 3(81-C1(R1-hydroxyethyl)-4(R1
-Benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one. diphenylmethyl 6α-(
1(R1-Hydroxyethyl coupe nicillanate-1-
From oxide! f3 shot.

νmaX(CHC Otsu 3 film>5400.1765 and 1740cTn-1; δ(ODO15) 1.22
(6H, d, J=6Hz, OH5・OH), 1.6[]
(3H, e.

= c-an5), 2.78 (IH, br s, OH),
3.42 (IH, dd, J-2 and 6H2,0H-O
H・OH), 4.18(IJ(, m, OJ・0HOH
・OH), 4.93 (IH, s, N-0H-00), 4
．． 90-5.10 (2H, m, cH2=O), 5.38
(IH, ci,, T=2H2,OH'OH・S), 6
．． 89 (IH, s, 0OHPh2), and 7.15~
7.90 ppm (14H, m, Ar); 3 (81-C
I+1'tl-833-butyldimethylsilyloxyethyl)-4(RJ-benzthiazolylbenthio1-(
1-tert-butoxycarbonyl-2-methyl-1-prop-2-enyl)-y-zin-2-one. Starting from 5th-butyl 6α-(1(R1-6th-butyldimethylsilyloxyethyl)-penicylanate-1-oxide. Reaction time 6 hours. δ(CD(3L'3)α[16
(6H, θ, SiMθ2), 0,9 (9H, s, 5iB
), 1.26 (3H, d, J=6Hz, OH3
・OH), 1.48 (9H, e, 0Bui;), 1.
95 (5H, El, =C-CH3), 5.4CI (I
H, all.

J=2 and 04Hz, 0H-OH-0)T), 4.2
0(IH, m, CH3・(EIIOH), 4.71(1
1,s, N-CI(-Co), 5.1(2H,'br
s, OH2=O), 5.42 (IH, d,, T=2Hz
, 0H-OH・S), and Z2~Z9pI)m(4H
, II].

3(81-CI (R1-tailed 31tnibutyldimethylsilyloxyethyl)-4(BJ-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-zetidin-2-one.νmaX(film ) 1772 and 1743 cm; δ(ODOt5) 0.05(6
H,s, EliMe2), 0.80 (9H.

s, SiBu'l:), 1.29 (6H, d, J=6H
z, OH5・OH), 1.95 (3H, s.

= c-cH3), 3.45 (IH, aa, J = 2 and 4Hz, OH-OH-OH), 4, 26 (IH, m
,CH3・C! H'OH), 4.95 (IH, e, N
-C! H-00), 5, o8 () H, ABq, internal line separation 5Hz, OH2=O), 5.55 (IH,
d,, T=2Hz, OH-OH・S), 6.95CI
H,8,OOHPh2), and 7.1 ~aDppm
(14H,m,Ar): 3(81-[1<R1-trichloroethoxycarbonyloxyethyl]-4(R1-benzthiazolyldithio-1-(1-methoxycarbonyl-2-methyl-1-prop- 2-enyl)-azetidine''2-one. Starting from methyl 6α-(1(R1-hlichloroethoxylponyloxyethyl)-benicylanate-1-oxide. νmax(CHOt3) 1775 and 1 745crn-1; a (cDcz3)1.48
(3H,d, J=6Hz.

q and 3・OH), i. 91 (5H, day, -0-OH5
), 5.69 (5H,s, OCH3), 3,70(
IH, dd, OH-OH・CH) 4.68 (e, 2H
, OCH3), 4.76 (im.

8, N-OH-CO), 5.03-5.30 (2H,
m, OH2=O) - 5.23 (IH, m.

OH3-OH-OH), 5.32 (IH, d, J-2
Hz, OH-OH・S), and 7, 10 = 7.96
ppm (4H, I4], Ar);
1(R)-)lichloroethoxylponyloxyethyl)-4(R)-benzthiazolyldithio-1-(1
-m3M butoxycarbonyl-2-methyl-1-prot-2-enyl)-acetidin-2-one and 6(El
+ - (1<R1-trichloroethoxysulfonyloxyethyl) -4 (R1-benzthiazolyldithio-1-(1-diphenylmethoxysulfonyl-2-methyl-1-prop-2-enyl)-acetedine-
2-one was obtained 7'L% and methyl 6β-[1(R1
Starting from -i tertiary butyldimethylsilyloxyethyl]-benicylanate-1-oxide, 3(R1 - (
1 (R1-6th-butyldimethylsilyloxyethyl)-4(R)-benzthiazolyldithio-1-(1-
Methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one was obtained.

Example 8 3'(81-C1 (RJ-hydroxyethyl)
-4(R1-benzthiazolyldithio-1-(1-methoxycarbon'yl-2-hydroxy-1-promy1-
enyl)-acetidin-2-one The purified crude 3(Sl-C I (R1-
hydroxyethyl)-4(, RJ-benzothiazolyldithio-1-(1-methoxycarbonyl-2-methydithio-
1-Prop-2-enyl)-azetidin-2-one is dissolved in dry dichloromethane (300d) and treated with a stream of ozone at -70°C until TLO shows that all starting material has reacted. Sweep with Luoyan Jinhua and then add acidic sodium sulfate (10'r) to -60°C.
Add with . The mixture is brought to room temperature under vigorous stirring and then filtered. The bath solution was washed with aqueous 4% NaHOO3 and Na2
Dry over SO4 and evaporate. The residue is taken up in ethyl ether, all undissolved material is removed and the bath is evaporated to give the crude title product. A portion is purified by flash chromatography on silica gel (vinegar conveniently uses an ethyl/cyclohexane mixture as eluent). δ(0DO63)1.35(3H,d,J=7Hz,
0)15・OH), 2.1iC3H,e,I:! H3)
, 2.75 (IH, br 8.OH)% 3.44 (
IH, dd, J=2.0 and 5. OH2, OH・0H
-OH), 3.79 (3H,s, 00H3), 4.2
6 (IH, 'm, OJ"OH"OH), 5.29 (IH
, d, J-2,0Hz, 0H-DH-8), and 7.
25-7.95 ppm (4H, m, Ar).

The following compounds are obtained using similar procedures.

3(St-C1(R1-5th-butyldimethylsilyloxyethyl)-4tRI-benzthiazolyldithio-
1-(1-methoxycarbonyl-2-hydroxy-1-
prop-1-enyl)-acetedin-2-one. Crude 3(81-41(bo-6th-butyldimethylsilyloxyether)-4(RI-benzothiazolyldithio-1-
(1-methoxycarbonyl-2-methyl-1-prop-
Starting from 2-enyl)-acetidin-2-one. νm
ax (film) 3350, 1770 and 166
0cm-1;/j (CDC43) 0.05 and 0.0
7 (6H, Sonzo fLo, SiMe2), 0.87 (9
H,s.

5iBui;), 1.27 (3H, d, J=6.5
Hz, OJ・OH), 2.07 (3H, s.

-a-cu5), 3.53 (IH, da, J=2.2 and 4.2H2,OH-0H-OH), 3.74 (3H
,El,QC! 1-3), 4.26 (IH, m, O
H3・OH-0H), 5.66(IH,d,,,T
-2,2H2,0H-C! H'S), 7.2-7.9(
4H, m, Ar), and 12.37 ppln (I
H,br s,OH);3tRJ-(1(RJ-6th-butyldimethylsilyloxyethyl)-4(R1-
Benzthiazolyl ditheo-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one. 3(R1-[1(R1-tert-butyldimethylsilyloxyethyl)-4(R1-
Methyl-1-procy-2-enyl)-azenadine-2-
Starting from on. νmaX (film) 3200.177
3,1710.1665 and 162On-1; δ(0
DCz3) 0.20 (6H,s, E1iMe2), 0
．． 94 (9H, s, 5iBu1:), 1.52 (3H.

d', J=s6H2,C! H3・CH), 2.17
(3H, br s, -0-OH3), 6.6-3
．． 7(4H, slcl(1,0OH3 and aH-cu
-aH), 4.4 (1H, ln, OH5・tsui-CH),
5.25 (1B', d, 0H-OH-8), and 7.
5-7.9ppm (4[(.

m, Ar); Ro(81-[1(R1-hydroxyethyl]-4(R1
-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-prop-1-enyl)-acetidin-2-one crude 6(Sl-[1
Starting from tRI-hydroxyethyl)-4fRI-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one. 'maxccHO15fui/lz
3400.1770.1730 and 1650 3(Sl-C1(R1-6th-butyldimethylsilyloxyethyl)-4(R1-benzthiazolyldithio-
1-(1-diphenylmethoxycarbonyl-2-hy)-
Roxy1-prop-1-enyl)-acetidine-2-
on. Crude No.3(sl-(11RI-ffi3Mbutyldimethylsilyloxyethyl)-4(R1-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidine Starting from -2-one. νmax (cHats film) 3400.1775° 1735.1700 sh
, 1655 and 1610 cm-1; δ(ODO't3
) 0.06 (6H,s, SiMe2), 0.82 (
9H, s, But), 1.26 (i, cl,, r=
6H2,C! H3・C! H), 2.08(!il(,s
, -0@0H3), 3.33(IH, ad, , T=2
and 5.5H2,0H-CH・OH), 4.18(I
H, m, OJ・OH・OR), 5.22 (1H, d, J
=2Hz, 0H-CH-8), 6.86(IH,e,
0 (EHPh2), and 7.2-7.9 ppm (1
4H,m,Ar);3(8+-[1(RJ-)lichloroethoxylponyloxyethyl)-4(R1-benzthiazolyldithio-1-(1-methoxycarbonyl-2-hydroxy-1 -Zolobo-1-enyl)-acetidin-2-one.δ(CDCl2)1.50(3H,d
, J=6H2゜O! ! 3・OH), 2.14(+H,s
, -0-OH5), 3.67 (IH, dd, J=2.2
and 5.5Hz, 0R-OH-OH), 5.82(5
H, e, 0OH3), 4.62 (2H, A, Bq,
J-12H2, internal line separation, 2H2,0OH2
), 5.10-5.40 (2H, m, 0H3-OH
-OI ('i? and aH-an-s), 7.2 [1
~8. [l 0 (4H, m, Ar), and 12.40
ppm (IH, br s, OH); and in a similar manner starting from the corresponding 6-butyl ester or diphenylmethyl ester 3(81-(: 1 (R1-
Trichloroethoxycarbonyloxyether ml -4
(R1-benzthiazolyldithio-1-(1-tert-butoxycarbonyl-2-hydroxy-1-prop-1-
enyl)-acetidin-2-one, 3(Sl -C1(
R1-trichloroethoxycarbonyloxyethyl]-
4(R1-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-prop-1-enyl)-acety')n-2-one and 3(S
l-C1(R1-tert-butyldimethylsilyloxyethyl)-4(■-benzthiazolyldithio1-(1-
Tertiary butoxysulfonyl-2-hydroxy-1-pro-1-1-enyl)-acetidin-2-one is obtained.

Example 9 3(131-C1(R1-hydroxyethyl) -4(
Rr-benzthiazolyldithio-1-(1-methoxycarbonyl-2-methylsulfonyloxy-1-prop-
1-enyl)-acetidin-2-one 6(Ell-C1(R1-hydroxyethyl)-4(■-benzthiazolyldithio 1) in anhydrous dichloromethane (8 ml.)
-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one C150M
'; 1% O, 8 mmol) bath solution was heated to -40°C sequentially.
triethylamine (0,043d, 0.5 mmol) and methanesulfonyl chloride (0,024m
/, 0.31 mmol). Reaction mixture total 5
After 5 minutes, cool with cold aqueous 2% NaHOO5. Removal of the solvent from the organic layer gives the crude title product (quantitative yield)
.

This is used as it is in the next step.

By the same experimental procedure, 5(81-[1(R1-3rd
butyldimethylsilyloxyethyl]-4(R1-benzthiazolyldithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one, 3( 8) -(1tR)-
6-butyldimethylsilyloxyethyl) -4(R
1-benzthiazolyldithio-1-(1-methoxycarbonyl-2-methylsulfonyloxy-1-pro1
-1-Enginyl)-acetidin-2-one is obtained. A portion of this product was purified by total flash chromatography (silica gel, using an ethyl acetate/cyclohexane mixture as eluent) to produce E and 1=1 of the two isomers.
The pure title compound is obtained as a mixture. νmaX (film) 1885.1730°1363, Oyohi 116
5cm-1; δ(0DC13) 0.05 and 0.1
0 (So3H,s, SiMe2), 0.88 (9
H, s, 5iBut), 1.29 (3H, a.

J-6,5Hz, OJ・OH), 2. ? 0 and 2.5
3(3I(, that's 2% e.

-〇・CH5), 6.18 and 3.29 (,5H, so f'Ls, 5O20H3), 3.42 (IH, m
, 01101110H), 6.71 and 3.78 (3
H, sonzo fL 8, 0CH5), 4.30 (IH,
m, (3H3・OH・OH), 5.59 and 5.64
(IH, Sokuzo fLd, J-2H2,0H-OH-
8), and Z12 to 7.96 ppm (4H, m, Ar
).

Using tetrahydrofuran as a solvent in place of dichloromethane suppresses the formation of the undesired E and E isomers and, as a result, preserves the collection of the pure 2 isomers. δ
((lDCt5) 0.05(6H, s.

SiMe2), 0.88 (9H, o, 5iBut), 1
．． 29 (+H, d, J = 6.5Hz.

0H3-OH), 2. ri3(3H,e,=C・0H3
), 3.29(3H,s,5o2cH3), 3.42(
IH, dd, J=2 and 5H2,0H-OH-cH)
, 3.71 (3H, s.

00H5), 4.30(IH, m, OH3・0H-O
H), 5.59 (IH, d, J-2 &.

OH-OH・S), and 7.12 to 7.95 ppm (
4H, m, Ar).

His method of operation (using tetrahydrofuran as a bath agent in the mesylation step) gave the following compounds:
Ru.

3(R1-[1(R1-6th-butyldimethylsilyloxyethyl)-4(■-benzthiazolyldithio 1[
1-methoxycarbonyl-2-methylsulfonyloxy-1-prop-1-(Zl-enyl]-acetidine-2
-On. 3(R1-[1(iso-6th-butyldimethylsilyloxyethyl)-4(R1-benzthiazolyldithio-1-(1-methoxycarbonyl-2-hydroxy-
Starting from 1-prop-1-enyl)-acetidin-2-one. νmaX (CHC63 film) 1775,1
755.1365 and 1165 儒−1; δ(ODC4
3) 0.18 (6H,s, SiMe2), [1,88(
9H.

s, 8iBu), 1.42 (3H, d, J=6.
5Hz, OH5・OH), 2.33 (5H.

9,=O-cH3), 3.05(3H,O,5020
H3), 3.45 (3H, e, 00H5), 3.62
(IH, da, C!H-OH-01(), 4.3(I
H, m, OJ・CH-CH), 5.40 (IH, d,
J=5Hz, 0H-OH-9), and 7.15-7.
85 ppm (4H, m, Ar); 3181-(1(R1-hydroxyethyl, 1-4(
R1-penzthiazolyl dithi m-1-[1-diphenylmethoxycarbonyl-2-methylsulfonyloxy-1
-prop-11z1-enyl]-azetidin-2-one. 3(Sl-C1(R1-hydroxyethyl)-4(
R)-penztifzolyldithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-prono-1
-enyl)-acetidin-2-one. νmaX
(Film) 3400.1775, 1750.1365
and m−1 at 1170; Lj(ODO63) 1.22
(5) 1, d, J=6,5Hz, OH5・OH),
2.43 (3H, s, = C-0H5), 3.13 (3H
, El, iEo, 2cH5), 6.35 (IH, da,
J=2.5 and 4H2.

0H-OH-CH), 4. i (IH, m, OHx
, ・CH-CT(), 5.40(IH,, d, J=
2.5Hz, (3H-OH・El), 6.85(IH
, e, 0OHPJ) and Z1~7.9 ppm (1
4H, m, Ar); 5(Si[:1(R1-tert-butyldimethylsilyloxyethyl]-4(RJ-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-(Zl- Methylsulfonyloxy-1-prop-1-enyl)-acetidin-2-one.6tsl-
(1(R11!5-butyldimethylsilyloxyethyl)-4(R1-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-prop-1-enyl)-7zetidine-2- Starting from on.

νInaX (CHC43 film) 1775.172
5,1570. and 1175 cm−1; δ(cDcz
3) 0.1 (6H,s, SiMe2), 0.9 (9
H,s, 5iEu'e), 1.28(3H,a.

J=6Hz, OH3・OH)%2.5(6H,s,-C
-OH5), 3.25(3H,e.

5o2QH3), 3.35(ILdd, J-2,5 and 5Hz, 0H-(EH・OR), 4.20(IH,'
m, OH3・[EH・OH), 5.50(IH, ci
, J=2.5Hz, 0H-OH・Eri, 6.9(IH,
s, 0(3HP)i2), and 7.1-7.9pp
m (14H.

m, Ar); 3 (St -C1(R1-W-5h'ibutyldimenanosilyloxyethyl) -4(R1-benzthiazolyldithio-1-(1-6th-butoxycard-di-2-2- (Zl-methylsulfoninoxy-1-laroso-1-enyl)-azetidin-2-one.3 (81=
(11R1-is#butyldimethylsilyl7xethyl:) -4(R1-benzthiazolyldithio-1-(1
-ysu butoxycarbonyl, -2-hydroxy-1-
Starting from prop-1-enyl)-acetidin-2-one. ν1IlaX (film) 1776.1710°1
570 and 1165 cm-1; δ(ODOt3)0.
06 (6H, s, SiMe2), 0.87 (9H, o
, 5iBut), 1.25("+14.a, J=6Hz
, OJ・CH), 1.49 (9Jsi, 0Bui;),
2.45 (5H, e, =O-OH3), 3.25 (3H
.

s, 5O2C'H5), 3.35(11(, dd, J
= 2.5 to 5Hz), 4.3 ('IH.

m, OH3・CH・CH), 5.60 (IJd, J
=2.5Hz, OR'OII・S), and 7.1~
7.9ppm (4H, m, Ar); 3(Sr [1(R
1-trichloroethoxycarbonyloxyethyl)-4
(R1-Benzthiazolyldithio-1-[1-methoxycarbonyl-2-methylsulfonyloxy-1-prof-1-tZl-enyl]-7tidin-2-one.3
(81-[1tR1R1-trichloroethoxycarbonyloxyethyl4(R1-benzthiazolyldithio-1
-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-aceticine-2-, +721)-
Departure. νmax (CHCl5 film) 1780,
1755 sh.

1750, 1380.1250 and 1167 cm
;δ(ODOz5) 1.48(3H.

d, J=6Hz, CH3・(!H), 2.52(
3H,8,=C"C!H3'), 3.25(3H.

s, 5O20H3), 6.72 (4H, s + dd, O
OJ and an-OH-C! H), “4.6
8 (2H, s, OCH2), 5.2 (111, m, OH
3・OH・OH), 5.47 (IH.

d, J=2.5H2,0H-OH・S), and 7.1
−7.9 ppm (4H, m, Ar); 3tSl −[: 1
tRl-trichloroethoxycarbonyloxyethyl)
-4(R)-benzthiazolyldithio-1-[:1-
m3-butoxycarbonyl-2-methylsulfonyloxy-1-proso 1 (Zl-enyl)-azetidin-2-one and 6(81-C1(R)-IJ chloroethoxycarbonyloxyethyl)-1Ftl-benzthiazolyl dithio-1-[:1-diphenylmethoxysulfonyl-2-methylsulfonyloxy-1-prop-1(z)-enyl]-acetidin-2-one or samurai n
Ru.

Example 10 5tSl -(1(R1-methylsulfonyloxyethyl)-4(R1-benzthiazolyldithio-1-(1-
Methoxycarbonyl-2-methylsulfonyloxy-1
-Prop-1-enyl)-acetidin-2-one In the reaction described in Example 8, when the starting material is exposed to a total excess (2 molar equivalents) of methanesulfonyl chloride/triethylamine, the title product is EC20%) and Z
The mixture of isomers (80%) was obtained as a foam with a constant yield. νn1aX (film) 1780
, 1760.1660 and 1170m-1; δ(OD
Ot3) 1.58 (6H, d, J=6Hz, OH3・C
! H), 2.22 and 256C6H, ;Crezof”
L s , E and Z isomers =c-OH5), ro,
00(3H,s, 0H3SO on human'a*sylxfld
2), , 5.20 (IH, aa.

J=2.2 and 4.5Hz, CH1 engineering/OH), 5
．． 28 (3H,s, 0H5SO2 on croton adduct)
, 3.76 (3H,s, OCH3 people 5.11 (1H
, m.

OH6.0H-OH), 5.52 (IH, d, J=2.
2Hz, 0H-OH・S), and 7.30 to 7.9
5ppm (4H, m, Ar).

%3tel-[1tPjl-methylsulfonyloxyethyl]-4(R1-benzthiazolyldithio-1
-CI-cyphenylmethoxy7carponyl-2-methylsulfonyloxy-1-procy-1-(2)-enyl]-
Azetidin-2-one was prepared and the following tincture data are presented. νmax (film) 1777.17
28.1360 and 117QCm-1; δ(ODO1
3) 1.50 (3H, d, J=6Hz, OH3・OH)
, 2.52 (3H, s, = C-OH5), 2.9 (3
H, e, hydroxyethyl territory cube-so 2
), 5.23 (6H.

day, cH3so2 on croton adduct), 3.62 (I
H, dd, J=2.5 and 5.5H2,0H-OH・
OH), 5.05 (1H, ro, OH3・OFI・C
H), 5.45(1H, (1,',:J=25H2,O
H-Tsu-s), 6.95 (I H, S, Q concave Ph,
and 7.10-7.95ppm (14H, m, Ar)
'.

Example 11 3(sl -(1(R1-5th class butyl dinotylsilyl-1-(1-methoxycarbonyl-2-) IJ fluoromethylsulfonyloxy-1-zoroso-1-enyl)-acetidin-2-one- Crude 5 (81-
[:11R1-i tertiary butyldimethylsilyloxyethyl)-4tRJ-benzthiazolyldithio-1-(1-
Methoxycarbonyl-2-hydroxy-1-procy 1
-enyl)-acetidin-2-one (30019) k
Jtlli is then treated with triethylamine (170 μt) and trifluoromethanesulfonic anhydride (180 μt). After work-up and chromatography, the two separated isomers of Rukki were isolated to /l.
It is obtained as a Q-shaped product. E isomer max (C'HO
t3) 1778.

1730.1420.1215. and 1135cwL
-1; δ(CD0L5) (1,08(6H,s,S
iMe2), O, R6 (9H,e, 5iBut), 1
．． 26 (3H, a.

J=6Hz, OJ・CH), 2.05(3H,s
, =O-OJ), 3.46 (IH.

dd, 2.2 and 4Hz, 0HaCH-OH
), 3.81 (5H, s, 0OH3), 4.28 (
IH, m, CH3・OH・OH), 5.76 (1H, d
, J=2.2Hz, OH-se・S), and 7.25~
7.90 (4H, m, Ar); Z isomer (among others) J (C
D073) 2.45 (3H, e, =O-OH3), 3.
40 (IH, dd, J=2o and 4Hz, 0H-OH-
OH), 5.64 (6H, e, QC!'H3), 4
．． 30 (IH.

m, 0k15・0H-OH), and 5.65ppm (
1H, cJ-, J=QH2, CH・ze・S).

Example 12 Methyl (7s, 5lt) -7-[: 1 (Parent-5th-butyldimethylsilyloxyethyl]-6-methyl-2
- Thiacephem-4-carpoxylate A bath of triethylamine (0,5d) in dichloromecne (10d) is saturated with hydrogen sulfide at -50°C. After purging with nitrogen, 0.34 cc of this bath &L Carbonyl-2-methylsulfonyloxy-1-prob-1-enyl)-acetidin-2-one (75ltg% 0.12
1 mmol) in a cold (-50°C) bath solution.

The mixture is warmed to the chamber and then washed with water,
a2so4) and evaporate. Separation of the new compound from the 2-mercaptobenzthiazole formed and a small amount of impurity 9VJ is achieved entirely by silica gel clot gelation (using ethyl acid/cyclohexane as bath release agent).

The title compound (19'g, 20%) is thus obtained as white crystals. One point 85-87℃. λmaX(ut
oH) 223 (ε-4,773), 277 (6,33
5), and 626 (2,922) nm, νmax(
CHC63 film) 1785 and 176° crn-
1; δ(CI)O43)0.08(6H,e, SiM
e2), 0.88 (9H, e, 5iBxt), 1
．． 25 (3H, (1, J=6Hz, OH3・OH),
2.22 (3H, e, C!H3), 3.07 (IH
, aa, J=2.2 and 3.5Hz, '0H-OH-
CiH), 3.8 (3H,S.

ou6), 4.36 (IH, m, OH3, Tan, C!H
), and 4.62 ppnn (I H.

d, J=2.2Hz, 0H-OH-EI).

The original analysis result for Oj 6a27No4sis2 is as follows.

Calculated value: 49.52 6.99 Ro, 60 16
．． 46 laughter experience [k:49.08 6.96
3.52 Instead of 15.16H2B/NBt3, a bath solution of Na5H (0.9 molar equivalents) in DMF was used and cooling (partitioning between H20 and 'EkOAc) was carried out at 0 °C for 1 hour. If done within minutes, the isolated yield of pure title product increases to 40-45%.

The yield is further enhanced (up to 60-65%) when the above process is carried out on the geometric z-isomer of all starting materials. Contrary to this, the E isomer has a very low content of the title product,
Give only.

By the same experimental procedure, 3(R1-CI (R+
-5th-class bunaldimethylsilyloxyethyl]-4(R
)-Benzthiazolyl ditheo-1-(1-nodoxycarbonyl-2-methylsulfonyloxy-1-prop-1
-enyl)-a(methyl (7R,6R) starting from thidin-2-one -7-(1(■-6th-subbutyldimethylsilyloxyethyl)6-methyl-2-thiacephem-4-carboxylate νmaX (film) 1785 and 1725 cm-1; δ(OD5
000D3) 0.03 and 0.05 (son-f:'
n3H,s, SiM'e2), 0.84(9H,s,
5iBut), 1.19 (3H, d, 6.5H
z, OH3・OH), 2.08 (3H, s, O
H3),! +, 72 (3H, S, 0OH3), 4.11
(IH, ad, J=5.5 and 8. (IH2, C!H
-4.OH), 4.20 (IH.

m, CH3・OH・OH), and 5.01 ppm (I
H, a, J = 5.5Hz, OH・OH@S).

Example 16 Methyl (7S, 6R) -7-[1(R)-Hydroxyethyl]-6-methyl-2-theacephem-4-carboxylate OH 020H5 The crude 5<8) obtained in Example 9 -C , 1 (phrase-hydroxyethyl:] -4 (Ft, l-benzthiazolyldithio-1-(1-methoxycarbonyl-2-/f memethylsulfonyloxy-1-prob-1-enyl)-azetidine-2 -one (145 μ, 0.287 mol) was dissolved in completely anhydrous dimethylformamide (2Td) and Na,H8 in the same solvent (1.6nr1) at +20°C.
(16 mf/% 0.287 mmol) in a freshly prepared bath solution. The mixture was stirred for a total of 2 minutes and then partitioned between ethyl acetate and water.

After repeated washing with water, the solvent was removed to obtain a residue.
Pressure chromatography treatment on 'Lk silica gel (using ffF=ethyl acid/cyclohexane as bath release agent)
Purify the pure title product as a white powder by
Obtained with 5% range.

vma
J=7Hz, OH5・CH), 2.22(3H, s,
OH3), 2,40 (IH, br s, OH), 3.
12 (IH, da, J-2,0 and 4.5H2, CH
・0H-OH), 3.86 (3H, s, 0OJ), 4.
35 (1H, m, CH3-ca-OH), and 4.6
5ppm (IH, d, J-2,0H2,OH-CI
(・S).

The following compound 4vI is obtained by similar experimental procedures.

Diphenylmethyl (7S, 6R) -7-(1(R1-
Hydroxyethyl-5-methyl-2-thiacephem-
4-carboxylate. 3(81-C1(1(1-hydroxyethyl)-4(R1-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methylsulfonyloxy-1-prop-1-enyl)-acetidine- Starting from 2-one.λmax(F'tOH)
281 (ε-5,9D [] ) and 32. ri(3,
670) nm; νmaz (KBr) 3550-3250
i 3080, 3060, 3020, 2960
.

2920.2840,1775. ．． 1720.1660
and 149[]('l11-1;a(cxz3)1
．． 56 (3H, d, J=6.5H2, OH3・O'H
), 2.17C3H,s, 0H5), 6.12(IH,
d, a, J=2. Q and 5H2, OH-concave/OH),
4.36 (1) Wang, m, OH5・OH-, OH), 4.
76 (IH, d, J=2.0Hz, C!H-OH・S)
, 6.97 (IH, s.

00H2Ph), and 7.50 (10H, m, Ar)
.

diphenylmethyl (7s, 6s) -7-(I LRI
- Primary methyl-2-thiacephem-4-carboxylate. 3(St-(1(R1-6th-butyldimethylsilyloxyethyl)-4(R1-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methylsulfonyloxy-1-prop-1- Starting from δ(ODOt3)[1,
06 (6H, s, SiMe2)% 0.83 (9H, days.

5iBut), 1.27 (3H, d, J=6.5Hz,
OH5・CH), 2.05(3I(,8.

0H3), 3.08 (IH, act, J-3, Q and 5.CIHz, OH-0) (-OH), 4.52 (
IH, m, OHy, 0H-OH), 4.60 (IH,
d, J=3.0Hz, 0H-OHoS), 7.02(I
H, s, 0OHPh2), and 7.30 ppm (1 [
IH, s, Ar); 6th-butyl (7B, 6R) -7
-(1(R+-6th-butyldimethylsilyloxyethyl)-6-methyl-2-thiacephem-4-carboxylate.3(Sl-(1(R1-6th-butyldimethylsilyloxyethyl)-4( R)-benzthiazolyldithio-1-(1-tert-butoxycarbonyl-2-
Methylsulfonyloxy-1-prot-1-enyl)-
Starting from azetidin-2-one.

λmax(OH04) 278(6=6,300) and 327nm(ε-2,!:+60Lνmax(OHaz
3 films) 1780 and 17213 cm-1; δ(
cDat5)o,i2(6H,s,SiMe2
), 0.88 (91H, s, 5IBut), 1.25 (
31 (, d.

, r=6H2,OH3・OH), 1.52(9H,s
, oBut:), 2.10 (3H, 8, OJ).

5.02 (1H, dd, , T = 2.5 and 5Hz, 0
H-OH・OH), 4.28(1)(, m.

C! H5-(El-OH), and 4.53 ppm (I
H, a, J = 2.5H2, 0H-OH-8); Methyl (7B, 6R) -7-CI (R1-methylsulfonyloxyethyl]-5-methyl-2-thiacephem-4
- Carboquine rate. 3(81-[1(R1-methylsulfonyloxyethyl:I-4(R+-benzthiazolyldithio-1-(1-methoxycarbonyl-2-methylsulfonyloxy-1-prop-1-enyl)-7 Starting from cetidine-2-one. Sima, 1780.172
5. To 1360 and 117 (1)-1; δ(ODOA
3) 1.60 (3H, d, J-6, 5Hz, OH3・O
H), 2.25 (3H, 8°OH3), 3.07 (3H
,s,C! H3S02)%3.27(1H, d, d, J
=2.2 and 5I (Z, OH-4-0R), 3.
85 (3H, e, 0OH5), 4.70 (IH, (1
, J=2.2H,0H-OH-8) and 5.24pp
m(iI(,In, OH3・CH・OH).

diphenylmethyl (7S, 6R) -7-C1(S-methylsulfonyloxyethyl)-5-methyl-2-teacephem-4-carboxylate.6(Sl[1(R1
-methylsulfonyloxyethyl]-4(Fjl-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methylsulfonyloxy-1-prop-
Starting from 1-enyl)-acetidin-2-one. νma
x(cuaz3)282(ε=7,080) and 3
+[) (5,966) nm; νma x (OHO,
, l, s film) 1778, 1720. -1 of 1255 and 1170; δ (ODO65) 1, b3 (6H
,a,,T=6Hz,OH3・CH),2.1 [3
(6H,e, OH,5), 271(6I(,s,
0H5SO2), 3.22 (IH, dd, , T=2
．． 5 and 5.5Hz, OH・C! H-OH), 4.6
7 (IH, d, J”2.5H2, C!H”OH”S),
5.05 (IH, m.

OH5・4・cH); 6.90 (IH, s, 0OITP
]12), and 7.25 (10H.

θ+Ar); Methyl (78,6R)-7-(1(river-trichloroethoxycarbonyloxyethyl)-5-methyl-2-thiacephem-4-carboxylate.

5(Sl-[:1(R1-trichloroethoxycarbonyloxyethyl)] -4(R1-benzthiazolyldithio-1-(1-methoxycarbonyl-2-methylsulfonyloxy-1-prop-1-x= )-acetidin-2-one. νmaX (fil A) 1787
．． 1760eh, 1725 and 1-250arL-1
;δ(aDcA5)1.54(3H,'i,J=5.
5) iz, OJ・aH), 2.23(3H,s, OH
, ) 3.30 (1H,cld, J=2 and 7.5Hz
, 0H-OH・OH), 3.84 (3H,e.

00) (3), 4.68 (1H, a, J=7!Hz, C
H-OT(-FJ), 4.78 (2H, s, 0OH
2), and 5.37 ppm (IH, m, 01j51 male/OH); diphenylmethyl (78,6R) -7-(
1(Koji-p-nitrobenzyloxycarbonyloxyethyl)-6-methyl-2-thiacephem-4-carboxylate.5(s)-[:N'RJ-p-nitrobenzyloxycarbonyloxyethyl)-(4R )-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methylsulfonyloxy-1-prop-
Starting from 1-enyl]-acetidin-2-one. Si IQ
aX1787.1745.1720Bl1m-1; δ(
CDC4s) 1.55 (3H, a, CH3-0H), 2
．． 17 Cro R98゜aH3), 3.28 (IH, ad
, J=2 and 6.5H2,OH-OH-OH), 4,
65 (1H, a, J-2Hz, aH-an-s), 5.
15 (2H, s, 0CH2), 5.28 (IH, m,
OH2'Odan-OH), 6.97 (IH, Sun, 0OHP
h2), 7.2-7.5 (12H, m, Ar) and 8.17 ppm (2H, d, J=9Hz, Ar
); The following compound is obtained in the same manner.

6th-butyl (7S, 6R) -7-C1(R1-)lichloroethoxylponyloxyethyl:]-]3-methyl-2-thiacephemu 4 carboxylate, diphenylmethyl (78,6R) -7-CI tRl
-trichloroethoxycarbonyloxyethyl]-6-
Methyl-2-thiacephem-4-carboxylate, trichloroethyl (7S, 6R) -7-(1(R1-
) trichloroethoxylponyloxyethyl]-5-methyl-2-thiacephem-4-carboxylate, trichloroethyl (7S, 6R) -7-(1(R1-
6-butyldimethylsilyloxyethyl]-6-methyl-2-teacephem-4-carboxylate, acetoxymethyl (7s, 6R) -7-(1(FJ-
) Lichloroethoxylponyloxyethyl]-5-methyl-2-thiacephem-4-carboxylate, acetoxymethyl (7B, 6R) -7-(1tRJ-
tertiary-butyldimethylsilyloxyethyl]-5-methyl-2-thiacephem-4-carboxylate, acetoxymethyl (78,6R) -7-C1 (R1-
) Limethylsilyloxyethyl]-6-methyl-2-thiacephem-carboxylate.

Example 14 3(81-[: 1(R1-5th-butyldimethylsilyloxyethyl:]-4(R1-succinimidothio1-(1-methoxycarbonyl-2-methyl-1-prop-2- enyl)-azetidin-2-one 002 (1!J Methyl 6α dissolved in dimethylacetamide (35m)
-[1(■-5-tert-butyldimethylsilyloxyethyl]penicylanate-1-oxide (2°622) treated with total acetic acid (0,15 m/l, swept with nitrogen and N-
to! Heat at 105° C. for 5 hours in the presence of J methylsilylsuccinimide (5f). After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and cold water. Fractionation of the material obtained from the organic layer (silica gel chromatography, ethyl acetate/cyclohexane) gives 1.22 (46%) of the title product as a white foam. ν
maX (CHC43 film) 1770°17! +5
．． 1710θh, and 1680α″″1; δ(ODC
! /=3)0.08(6H.

6, SiMe2), 0.87 (9H,s, 81Bu11
), 1.32 (3H, d, J = 6.5H2゜OH5-
OH), i, 84 (5H, s , =O-OJ ), 2.
85(,4H,s,OO#OH2・OH2-Co),3
．． 29 (IH, da, , T = 3 and 4.5H2,0H
-OH-OH), 3.73 (3H,s,OMe), 4.
24 (I H, m, OH5*OH・OH), 4.6
6C1H,.

s, N-0H-00), 4.85 (IH, d, J=2.
5H7,0H-OH@S), and similar experimental procedures to generate 3 (81-C1(R1-6th-butyldimethylsilyloxyethyl)-4(R)-sacrunimidothio-1-(1- diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidine-2-,
and 3(Ell-C1(R1-tert-butyldimethylsilyloxyethyl)-4(R1-phthalimidothio-1-(1-diphenylmethoxycarbonyl-2-
Methyl-1-prop-2-enyl)-azetidine-2-
On is obtained. It is also isolated as a crude material and used in the next step.

Example 15 3(81-C1(FJ-6th-butyldimethylsilyloxyebru)-4(RJ-phthalimidothio-1-[
1-Methoxycarbonyl-2-methylsulfonyloxy-1-prop-1-(Z+-enyl)-azetidine-2
3(Sl-[: 1(R
1-tertiary butyldimethylsilyloxyethyl)-4(
R1-benzthiazolyldithio-1-[1-methoxycarbonyl-2-methylsulfonyloxy-1-prop-
1-(Z)-enino]-acetidin-2-one (10
0 mg) of bath solution 'K AgN03 (34 mfl ) and then potassium phthalimide (!It]+111?)
treated with an ethanolic slurry of After stirring for 60 minutes at room temperature - the precipitated Mk was collected, partitioned between water and EtOAc and purified by short silica gel chromatography to yield the title product (55%). νmaX (film) 1780, 1745. and 1725 cm−1; δ
(ODO65)0.1(,6H,e,SiMe2),0
．． 89 (9H, s, But), 1.4 (3H, a, 0
H3-OH), 22C3H,s, =O・OH5), 3
．． 05 (6H, s.

5o2-cH3), 3.4(IH,m,C!H-rP(
3H), 3.6 (3H, s, 0OJ), 4.2 (IH
, m, OJ・OH・OH), 5.45 (IH, d, J=
2Hz, 0H-OH・S); and 7.8ppm (4H
, m, Ar).

Example 16 3(Sl -CI (R1-6th-butyldimethylsilyloxyethyl) -4(R1-succinimidothio 1-(1-methoxycarbonyl-2-hydroxy-1-
-1'lob-1-enyl)-acetidin-2-one The title product was prepared by preparing 3(81-(1(RJ-tert-butyldimethylsilyloxyethyl) in dichloromethane by the procedure described in Example 8: ]-4(RI-succinimidothio 1-(1-methoxycarbonyl-2-methyl-1-prop-2-: x, nyl)-acetidine-2
By adding ozone to the -on, the reaction can be used directly for the first-order reaction. The sample is dimethyl ketal (M
Characterized as eOH/Dry Hat). Shima
x1770°1760 and 1715 sh儂-1; δ
(CDC15) 0.04 and 0.09 (Sonozo 几5
H,s, SiMe2), 0.90 (9H,s, 5iE
u'l;), 1.31 (3H.

d, J=5Hz, C! H3・OH), 1.49(3H,
s, CH3), 2f54 (4H, s.

Co OH2-OH200), 3.21i- and 3.2
6 (that way'n3H1e1 ketal 0CR5), 3.2
4 (IH, dd, J = 2.5 and 3.73 (3
H1゜Ester0OH3), 420(IH,m,OH3
・(31(@OH), 4-43(IH,s.

N-OH-Co), and 4.94 ppm (IH, d,
J=2.5Hz).

Similarly, %5(81-CI (EJ-6th-butyldimethylsilyloxyethyl)-4tllu-phthalimidothio-1-(1-diphenylmethoxycarbonyl-2
-Hydroxy-1-pro! -1-:r-nyl)-azetidin-2-one is
It is obtained starting from phthalimidothio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-acetidin-2-one.

Example 1 17 Ethyl (7S, 6R) -7-(1 (homogeneous @ 6-butyldimethylsilyloxyethyl)-6-methyl-2-thiacephem-4-carpoxylate 5( in dimethylborumamide (4d) Sl-(1(R1-tert-butyldimethylsilyloxyethyl)-4(R1-phthalimidothio-1-(1-methoxycarbonyl-2-methylsulfonyloxy-1-prop-1-121-enyl)acetidine-2 -on (11 g of 4Q O) is treated with finely ground NILSH (50 mg) under vigorous stirring.

As soon as the last reagent is dissolved, the reaction mixture is partitioned between total ethyl ether and water. Work-up gives the title compound identical to the sample described in Example 12.

Example 18 Methyl (7B, 6R) -7-CI(5))-6th-butyldimethylsilyloxyethyl]-6-nonal-2-
Thiacephem-4-carboxylate 3(Sl-C1(R1i tertiary butyldimethylsilyloxyethyl)-4(R)-succinimidothiol 1 in dichloromethane
-(1-methoxycarbonyl-1-prop-2-enyl)-azetidin-2-one (0,8f)'fr:TLc
Ozonate at -70° C. until complete conversion is shown. Sweep excess ozone with nitrogen and dimethyl sulfide (1
-) is added. After 1 h at room temperature, all volatiles were removed in vacuo and the residue was reacted (aH2
cz2, -20 to 0°C). The mixture was concentrated in vacuo and partitioned between ethyl acetate and cold aqueous NaT (003). The organic layer was evaporated to give a crude mixture of E, Z mesylate, which was described in Example 16 without purification. Treat with NaH8 in DMF by procedure. Obtain 1"
Purification of the raw material by silica gel chromatography gives the title compound, which is identical to the material obtained according to Example 12.

Similar operation method 1 (therefore %3fSI −[1(R1−
6th-butyldimethylsilyloxyethyl]-4(R)
-phthalimidothio-1-(1-diphenylmethoxysulfonyl-2-methyl-1-prop-2-methyl)-acetidin-2-one and then diphenylmethyl (7
S, 6. R) -7-C1(R1-6th-butyldimethylnoryloxyethyl)-5-methyl-2-thiacephem-4-carboxylate and this same spectrum of the substance described above (Example 16) Show the property.

Example 19 Methyl (7El, 6R) -7-[1fRI-tert-butyldimethylsilyloxyethyl]-3-(1-methyl-1,2,3,4-tetrazol-5-yl)-thylate in dichloromethane 5(81-(1(R1-6th-butyldimethylsilyloxyethyl)-4(R1-(1-
Methyl-1,2,3,4-tetrazole-5-inolidithio-1-[1-methoxycarbonyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)-f
Ontyl-1-prop-2-enyl]-azetidine-2
-one (120Q)' is subjected to the same reaction sequence described in Example 17 (ozonolysis, mesylation, reaction with NaH8). The an native product is partitioned between ethyl acetate and aqueous NaHOO3 thus removing the liberated mercaptotetrazole. Have it? The layers are washed several times with water, evaporated and the residue is fractionated by silica gel chromatography to yield the title product. 17■ (17%). ν
Inaf (film) 1787, 1725.1587° 1660 and i 25 Q cIrL-1* a (
CD OL 5) O-10 (6H, 8, I”:L
M e 2 ), 0.89 (9H,s, 5iBut)
, 1.26 (3H, d, J=6Hz, 0H3-OH)
, 3.15 (IH, da, J-2,2 and 3.5Hz
, 0H-OH-DH), 3.88 (3H,s.

OMe), 3.92 (3H,s, NMe), 4.38 (
1H, m, OJ・0110H), 4.46 (2H, AB
q,, T=14H7, internal line separation 14H7) and 4
．． 68ppm (IH, d, J=2.2Hz, CH-OH
-s).

Example 20 3(81-[1(R1-g tertiary butyldimethylsilyloxyethyl) -4(R1-phenylsulfonylthio-1-(1-methoxycarbonyl-2-methyl-1-prop-2-mesyl)]- "acetedin-2-one 3(3) in acetone (160 Inl) and water (18d)
Sl-[Nm-13-butyldimethylsilyloxyethyl)-4(R1-benzthiazolyldithio-1-(1-
Methoxycarbonyl-2-methyl-1-prop-2-mesyl)-azetidin-2-one (2°69)'r was added under vigorous stirring to silver nitrate (0,98r) and then immediately to water (6
Sodium benzene sulfinate (0,7
9F). After 1 hour at room temperature, remove the white precipitate and remove the 'P solution. Concentrate in vacuo and then partition between water and ethyl acetate. After removing the bath agent from the M plate layer, the title product C2, 46t, 98%) was obtained as a yellowish powder.
r: get. Can be recrystallized from cyclohexane (white leafy shape, melting point 105-106°C). 1r (KBr) 308
0,3020,2960.2930,2900.286
0°1770.175 (1,1530 and 1145C
++i-1; δ((:!DC45)0.05(6H.

day, SiMe2), 0.98 (12H, 5-1-a, 5
iBut and 0H3-OH), 1.84 (5H, s
, -(:!-0H5), 3.22(IH, dd, J=2
and 2.5Hz, C! H・OH・OH), 3.7
5 (3H, El, 0M+3), 4.19 (1H, m,
OH5・OH・OH), 4.58 (IH, s, N-0
H-Co), 5.00 (2H, m, 0=OH2), 5.
37 (1H.

d, J=2H2, CH-OH-8), Z60i- and 7
．． 96ppu+ (3 and 2H.

Sonozom, Ar).

The elemental analysis results for 023H35NO6SiS2 are as follows.

H-H 1st shift: 53.77 6.
87 2.74 12.48 Experimental value: 53.69 6.99 2.70 12.42
The next monster can be created using the same manipulation method! , be confronted.

3tsl -(1(R1-6th-butyldimethylsilyloxyethyl:] -4(R1-phenylsulfonylthio-1-(1-tert-butoxycarbonyl-2-methyl-1-prop-2-eny)+ , )-acetidine-2-
on, 3(Sl-CI(R1-6th-butyldimethylsilyloxyethyl)-4(R1-phenylsulfony)l.
Thio-1-(1-diphenylmethoxycarbonyl=2-
Methyl-1-zolobu-2-mesyl)-azetidine-2-
1 3181- C1(R1-) 1.1chloroethoxycarbonyloxyethyl)-4(R)-phenylsulfonylthio-1-(1-methoxycarbonyl-2-methyl-
1-prop-2-mesyl)-acetisin-2-one, 3(Sl-[1(R1-)lichloroethoxycarponyloxyethyl]-4tRJ-phenylsulfonyl-2-nonal-1-prop-2-enyl) -Azetidine-
2-on.

Example 21 sfsl-C 1(R)-6th-butyldimethylsilyloxyethyl]-4 (R1-phenylsulfonyl 1-C 1-methoxycarbonyl-2-methylsulfonyl) -Mesyl]-azetidin-2-one 020H5 Procedure (At Material from Example 20 (1 g) in dry dichloromethane k-
Ozonate at 70°C. After purging with nitrogen, dimethyl sulfide (3.5 d)'e is added and the mixture is stirred at room temperature for 3 hours. Once all volatiles have been removed, the residue is drunk and partitioned between ethyl and water. Evaporate the bath agent to obtain intermediate 3 (St-C1 (R1-6th
butyldimethylsilyloxyethyl:]-4(R1-
Phenylsulfonylthio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-mesyl)-acetidin-2-one is obtained. simax3450.1778
．． 1658 and 162Qcm-1; δ(CDC!t3
)O. Q8 (6H,s, SiMe2), 0.9 il
l(9H,s,SiBut), 1.13(3J(,a,
J=6Hz, CJ・OH), 1.90 (5H.

s,=C-CH3), 3.1 2(IH, da
, , J=2.5 and 4Hz, OH-OH, OH)
137ro (3H, s, OMe), 4.2 (IH, m, O
H5.OH-OH), 5.52 (IH.

d, J=2.5Hz, OH-CH-8
), 7.4 ~ aO (5H, m, Ar), and 16 ppm(1) (, θ, OH).

This material was prepared using triethylamine (272 μt) in dry THF (10 ml) according to the general procedure (see Example 10).
) and mesylation with mesyl chloride (151ztt) to give the title product 550cm as a foam after chromatography on silica gel.

ir (film) 1780, 1730, 1640.1
370 and 1145/-711-1; δ(CDOA5
)O, [15(6H,s,Sj,Me2),0.80(
9H,e, 5iBut), 0.97(3H,d,,T
=6H7,C! J・OH), 2.50(3H,a,=
O-01J3), 6.15 (4H, m, 5O20
H3 and 0H-OH・OH), 3.76 (3H,s
.

00H3), 4.13. (IH, m, OH5IIC!
H-OH), 5.7 (I H, d, J=2.8H
z.

CH-CH・S), death and 7.6 to 8.1 jppm (5
H, m, Ar).

Operation method tBl Acetone/water (9:1) (10+d) Nakano 3 (81-
CI (R1-3M butyldimethylnitryloxyethyl]-4tR+--<nzthiazolyldithio-1-[
1-Nodoxycarbonyl-2-methylsulfonyloxy-1-proj-1(zl-mesyl)-acetidin-2-one (1 oomg) was sequentially dissolved in silver nitrate (3 oomg) under stirring 1.
Treat with an aqueous solution of 4,3 yng) and II umbenzene sulfinate (26.6 mg in 4 g). After stirring for 15 minutes at room temperature, the precipitated silver benzthiazole mercaptide was removed by filtration and partitioned between the bath solution -'zcH2at2 and water. The title product (quantitatively) was obtained as a syrup after removal of all the solvent. yield), which has the same spectral properties as the sample from method (A+).

By the same method, 6FB+ -C1(R1-6th-butyldimethylsilyloxyethyl)-4(R1-phenylsulfonylthio-1-CI-f, 3M))oxycarbonyl-2-methylsulfonyloxy-1-prop-1 [
21-Mesyl]-azetidin-2-one and 3(Sr
C1(R)-)richloroethoxylponyloxyethyl)-4(R1-phenylsulfonylthio-CI
-IJ Chloroethoxycarbonyl-2-methylsulfonyloxy-1-prop-i tza-mesyl]-azetidin-2-one is obtained.

Example 22 Methyl (7S, 6R) -7-(1(FU-6th-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate 3(81-(1(R)
1-5th-butyldimethylsilyloxyethyl) -4
(R1-phenylsulfonylthio-1-[1-methoxycarbonyl-2-methylsulfonyloxy-1-proi
-1(Zl-enyl)-azetidin-2-one Example 1
Reconstitution with NaH8 in DMF by the procedure described in Section 6 gives the title product, which is identical to the material described above.

Since the by-product, sodium benzene sulfinate, is soluble in water and does not require chromatographic separation or fractional crystal removal, unlike e.g. mercaptobenzthiazole, this preparation is a more straightforward preparation of the product. enable.

6th butyl (7S, 6R) by the same operating method
-7-(1(R1-6th-butyldimethylsilyloxyethyl)-6-methyl-2-thiacephem-4-carboxylate and trichloroethyl (7B, 6R) -
7-C1(RJ-trichloroethoxycarbonyloxyethyl)-6-methyl-2-thiacephem-4-carboxylate is obtained.

Example 23 3(S)-CNBJ-) IJRioethoxycarbonyloxyethyl)-4(R1-7cetyldithio1-
[1-Methoxycarbonyl-2-methylsulfonyloxy-1-pro)'-1(zl-mesyl]-azetidin-2-one 3(Sl-[: 1 (R
1-trichloroethoxycarbonyloxyethyl] -
4(R1-benzthiazolyldithio-1-[1-methoxycarbonyl-2-methylsulfonyloxy-1-pro-1-i(z)-mesyl]azetidin-2-one (
340j11? ) is treated with thioacetic acid (43 μt). After 5 minutes, the mixture is evaporated and the 2-jk captobenzothiazole is removed from the crude reaction product by chromatography to yield pure title compound 280R9 (96%)' (r.vm) as a colorless syrup.
aX (film) 1775.1760sh, R30b
r cm-1; δ(C!DOA3)1.50(3H,a
, aH3-aH), 2.48 (3H, day, =O-CHy
, ), 2.62 (3H,s, 0OOH3), 3.2
9 (3H, s.

5o2cu5), 3.44(10,dd,0H-OH-
OH), 3.83 (3H, s, OMe), 4.77
(2H, Al3q, J=11.5H2, internal line separation 2Hz), 5.24 (IH.

(1,0H-OH-8), 5.25 (IH, m, OH5
・OH・OH).

Example 24 Methyl(7S,6R)-7-CI(R1-)lichloroethoxoluponyloxyethyl]-6-methyl-2-
Theacephem-4-carboxylate TaF (10m/
3(Sr(1(homogeneous trichloroethoxycarbonyloxyethyl)-4(RJ-acetyldithio-1-[
1-methoxycarbonyl-2-methylsulfonyloxy-1-prop-1(Zl-x = l)azetidine-
A solution of 2-off (140 my ) tetrabutylammonium baridrozine sulfur 1F in the same solvent at 0 °C.
(65y+g) of bath solution. Work-up and chromatography gives the title product. Some starting material is recovered. λmax(FitOH)280(ε4
,974) and 527 nm (2,262); νm
1LX (film) 1787, 1760sh.

1725 cm-1; 7j (ODOt3) 1.54 (3H
, d, 0J-CH), 2.23 (3H, s.

OH5), 3.30 (IH, cud, 2 and 7.5H
Z, C! H-OH-OH), 3.84 (3H.

s,, oMe), 4.68 (IH, d, 0H-1-8)
, 4.78 (2H', s, oaH2cct5).

and 5.3 Hppm (1H, m, CH3-01(・O
H).

Example 25 Methyl (761,6R) -7-(1(■-tertiary-bubutyldimethylsilyloxyethyl)6-promomethyl-2-thiacephem-4-carboxylate co2aH5
0020H3 Methyl (7S, 6R) in carbon tetrachloride (40d) -7
-CItRl-tert-butyldimethylsilyloxyethyl]-6-methyl-2-thiacephem-4-carboxylate (0,524), propylene oxide (0,95 mA
) and N-promosuccinimide (0,521)”-
and azobisisobutyronitrile ([], []59)k
6 o'clock 1t) Reflux.

The reaction mixture was cooled to room temperature, filtered and filtered through γp. The filtrate was completely evaporated and the residue was purified by a silica gel column using an ethyl acetate/cyclohexane mixture as the eluent, giving the title as a yellow oil. Product (80%) is obtained. λmax (CHCL3) 282 and 336 nm; Sim, X (anaz3 film) '1785, 173
0crn-1; δ(0DCts)0.10(6H,s
, EiiMe 2 ), 0.89 (9H,s, 5
iBut), t28 (6H, d, 哩3・O) (・081
), 3.23 (1H, aa, , T=2.0 and 3.5Hz, 0R-OH・OH), 3.87 (3
H, e, OOH, 4.65 (2H, center ABq,
s, i, t, 4H2, J=11.5Hz, 0I12Br
), 4.30 (IH, m, OH5・C!H-OH), 4
．． 76 (IH, d, J = 2.0H2,0H-OH・s)
The elemental content al results for ppmO16H26BrN704Si82 are as follows.

0% H% N % S % Br% Calculated value: 41.02 5.59 2.99 13.69
17.06 Experimental value: 41.1 5.64 3.0
1 13.55 17.20 The following compound is obtained by a similar method.

6th Butyl (7E!, 6R) -7-CI (R1-
5-butyldimethylsilyloxyethyl]-5-bromomethyl-2-thiacephem-4-carboxylate ν
max(CI(074)283 and 332 nm; ν
I[1aX (film) t787 and 1720crr
L-1; δ((3DCA3)0.9(6H,S.

SiMe2)% 0.9 (9H, e, 5iBut)
, 1.28 (3H, d, OH3・OH), 1.55O
H), 4.35 (3H,m, O'H2Br and 0H3
-OH-an), and 4.71 ppm (IEI, d,
, T=2.5Hz, 0H-CH・B); p-nitrobenzyl (7B, 6R) -7-C1 (□-p-nitrobenzyloxycarbonyloxyethyl]-3-bromo/thyl-2-thiacephem- 4-carboxylate δ(
CDOA5) 1.45 (5H, a, (:!H3・OH)
, 3.43 (1H, aa, J-25 and 6Hz,
CH-OH・OH), 4.45(2H,ABq,,T
=12Hz, (3H2Br), 4.80(11,1,a
, J=2.5H2, CH-OH-8), 5.2, 5.
5(5H, m, two 0OH2Ar and CH3-
cH-aa); 7.47 and 7.6 D (sonzo n
2H, d, J=8.5H2, Ar), Omahi a
23 ppm (4H, d, J = 8.5 Hz, Ar); diphenylmethyl (78,6R) -7-C1 (BJ-p-
nitrobenzyloxycarbonyloxyethyl)-5-
';' Lomomethyl-2-thiacephem-4-carboxylate δ (C!DCA5) 1.45 (3H, d4 di-O
H), 5.32 (IH, cla, J=+ and 6H2,
OH-OH-C! H), 4.18 (2H, ABq, J=
11H2,0H2Br), 4.70 (I H, d,
J=3Hz, OH/CBS), 5.20 (2H,
, s , 0OH2Ar), 5. ．． 50 (IH, m, (!
J・0H (3H), 6,97 (1H, e, 00HP
b, 2), 7.10-7.40 (10H, br s
, Ar), 7.45 and 8.15 ppm (
2H, d, J=9Hz, Ar); diphenylmethyl (7
S, 6R) -7-[: 1 (RJ-6th-class butyldimethyl-silyloxyethyl-6-promomethyl-2
−CHi°゛cephemu 4-carboxylate νmaX(
film) 1790. t-yohi175Qcm-1; δ(
ODC43) 0. [15 (6F1.S, SiMe2),
0.8 (9H, e, 81But), 1.22 (5H,
d, J=6.5H2, C! H-, -0H)%s,i[1
(IH, cla, J=2.7 and 4.5Hz, 0H
-(EH-C!H), 4.05(2H,s, 0H2Br
), 4.2 (IH, m.

OH3°an°an), 4.6+(IH,d,, T=2
．． 7Hz, C! H-OH-8), 6.92 (I H*
s, 00 HPh2)% and 7.05-7.
40ppm (IOH, m, Ar); λmax (CHCL
s ) 283 (ε = 7.867) and 336 nm (
ε-3,533); and the following compound is obtained in the same manner.

Trichloroethyl (7B, 6R) -7-(1(R1-
6th-buty-A dimethylsilyloxyethyl]-5-bromomethyl-2-thiacephem-4-carboxylate, trichloroethyl ('7S, 6R) -7-C1 (R+
−) Lichloroethoxylic polyvinyloxyethyl〕−
3-bromomethyl-2-thiacephem-4-carboxylate.

Example 26 Methyl (7E1.6R) -7-(1(R1-tert-butyldimethylsilyloxyethyl)-5-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-2 -thiacephem-4-carboxylatebutyldimethylsilyloxyethyl]-6-bucomomethyl-2-thiacephem-4-carboxylate in THF
The solution is kept overnight in the presence of sodium 1-methyl-1,2,3,4-tetrazole-5-thiolate dihydrate (6 molar equivalents).

Work-up and chromatography gives the title compound as an oil in 85% yield.

λmaX(BitOR) 261 and 333 nm; ν
maX (film) 1790 and 1725 cm-1;
δ(CD(3t3)0.10(6H,s,SiMe+)
, 0.89 (9n, s, But), 1.26 (3H, d
, OH3・OH), 3.15 (IH, ad, J-2,2
and 3.5Hz, CH'CH・OH), 3.88(
5H, s, OMe), 392 (3H, s, N-CJ),
4.5+3 (IH, m, OH3・OH・C1), 4.4
6(2)(.

ABq, internal i++tJ minute if 14Hz,
J-14H2), 4.68 (1tx, d, CH-CH
-S, J-2,2Hz).

The following compounds were obtained using a similar procedure.

6th-butyl (7S, 6R) -7-[1(gradient-6th-butyldimethylsilyloxyethyl)-6-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl -2-thiacephem-4-carpoxylate. From tertiary butyl (7S, 6R) -7-ci (FO-6th-butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate departure.

Diphenylmethyl (7S, 6R) -7-C1(R)-
5th-butyldimethylsilyloxyethyl]-3-(8
-aminotetracylo[1,5-6)pyridazin-6-yl)thiomethyl-2-thiacephem-4-carboxylate.

Example 27 (5aR16B) -6-(1(R)-5th-butyldimethylsilyloxyethyl) -5a,6-sihydro3H.

7H-aceto[2,1-c]furoC5A-e) -1,
2,4-Dithiazine-1,fusion [Method (4)] Methyl (7E],6R)-7-CI (R1-tert-butyldimethylsilyloxyethyl) in DMSO (2rnl) and water (1,5ml) ]-3-Bromomethyl-2-thiacephem-4-carboxylate (15■)
The solution was heated at 50°C for 2.5 hours with Cu2O (somy
). The reaction mixture is partitioned between water and ethyl acetate. Evaporation and chromatography of the organic extract gives the title product as a white powder. νmax
(CHCt3 film) 1800-1760 br o
n-'; δ(CDC1g) 0.06(3H,s,5
ICHx), 0.11 (3H+'+mill 1CH3χ 0
．． 90 (9H, e, Bui), 1.55 (5H,
d, CH3・CH), 3.33 (IH, aa, J=:2
．． 5 and 45Hz, CH-CH-CHχ4.44
(IH, m, CH3・CH・CHλ 4.<52(IH
, d', J=2.5Hz, CH-flat S) and 4.
98 (2H, θ, CH2O).

[Method (B)]

The 2-bromomethyl precursor (250g) in acetone-water (21) (3srnl) was mixed with AgCto4 (
153 mg) at 0°C for 15 minutes. The reaction mixture is partitioned between H2O and OAc and the organic layer is evaporated to give a residue. Silica gel chromatography gives the title product, which is identical to the sample described in (4).

Example 28 6th Butyl (7 days, 6R) -7-CI(6)-3
tert-butyl dimethylsilyloxyethyl]-3-hydroxymethyl-2-thiacephem-4-carboxylate acetone-water (21) (10 m/)
7S, 6R) -7-CI @-tertiary butyldimethylsilyloxyethyl,]-]3-7/lomomethyl-2-
Thiacephem 4-carboxylate (300Q) as Ag
Stir with cto4 (1 somy) at 0°C for 15 minutes. Removal of the solvent followed by H20/EtOAc partitioning and work-up of the organic layer gave the title product 250% (96%).
get. λmax CCHCl5) 281 and 3
35 nm i νmaX (film) 3450.
1785 and 1712m-1iδ(CDCl2) 0
．． 1 (6H, s, SIMe 2 people 0.86 (9H, e.

81But\ 1.25 (3H, d, CH3CHχ 1
50 (9H, s, 0But), 3.13 (IH, aa,
, r=2.5 and 425H2, CH-CH・CH),
425 (AEq and 4ippm (IH, d, , T = 2
．． 5Hz, CM-C)(・S).

Example 29 Tertiary butyl (7B, 6R) -7-[1(9)-tertiary
dichloromethane (2,5 m
) in 6-butyl (7s, 6n)-7-, [1(R1
-Tertiary butyldimethylsilyloxyethyl]-3-hydroxymethyl-2-thiacephem-4-carboxyle) (2501 g) is treated with trichloroacetylinocyanate (8 [1 μt) at -40°C. The mixture is allowed to rise to room temperature and then washed sequentially with aqueous 2% NaHCO3 and brine. Evaporation of the solvent from the organic layer gives the title product in quantitative yield. λmaX(]l!1itOH
)275 and 329nmi max1795 and 1
725 br 3-1 ; δ(CDgCN), 0.
1 (6H, e.

SIMe2), 0.9 (9H,s, 5IBut), 1.
3(5H,d, CHx ・CE(), 1.5(9H,
s, 0But), 3.40'(IH, dd, J=3
and 4 HZ I CH・4・CH), 435 (IH
, m, CHx-CH-CHx4.80 (IH, d, J=
3Hz, CH-CH・BX and 5.0 ppm (
center of ABq, CH20CO).

Example 30 6th-butyl (7s, 61-7-C1(R)-5th-butyldimethylsilyloxyethyl]-6-carpamoyloxymethyl-2-thiacephem-4-carboxylate 6th-butyl (78, 6B) -7-CI(9)-3rd
butyldimethylsilyloxyethyl)-3-[N-trichloroacetyl)L/)carbamoyloxymethyl-2
- Stir a methanol solution of thiacephem-4-carboxylate with silica gel for 20 hours. The slurry is then loaded onto a silica gel column and the product is eluted with ethyl acetate.

δ(CDCl2)0.1'(6H,s, SIMe2),
0.9 (9H, s, 5I But), 1.35 (3H
,a,CT(3・CHx 1.60(9H,s,
0Buj), 3.1 (IH.

ad, CH-sub-CH), 4.3 (IH, m, CH3
・CH・CH), 4.75 (IH.

d, J=5H2, CH-CH・BX)% and 5.0
ppm (center of ABCI, 0CR2CO).

Example 51 Methyl (7s, 6R) -7-[1(R)-tert-butyldimethylsilyloxyethyl]-3-nitrooxymethyl-2-thiacephem-4-carpoxylate methyl in acetone (20 m/) (7B, 6R) -7
-[1(R)-6th-butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxyle]
Stir for 20 minutes in the presence of 0 blades g). The filtered reaction mixture was fractionated by silica gel chromatography to give the title product, 120 km, λmaw (CHCL3
) 280p and 337mm max (film)
1790.1760.1640 work 12806R-1
; δ (CDC13) 0.08 (6H, s, SIMe2)
, DJ37 (9H, s, 5I But), 1.38 (
3H,a, CHs・CH')%3.18(IH,aa,
J = 2.5 and 55Hz.

CH-CH・CHx 3.85 (3H,s, OMe×
4.38 (IH, m, CH3・CH・CHx 4.7
3(H(,a, J=2.5Hz, CH-CH・s\ and 536 ppm(2H, ABq, J=13.5Hz,
S, 1.1', 29.5H2, CH20NO2).

Further elution provides some of the lactone described in Example 27.

Example 62 Methyl (7B, 6R) -7-[1(9)-tert-butyldimethylsilyloxyethyl]-3-formyloxymethyl-2-thiacephem-4-carboxylate Methyl (7S, 6R) in CH2Cl3 −7−[1(
b)-6th-butyldimethylsilyloxyethyl]-6
--7' lomomethyl-2-thiacephem-4-carboxyle) (treated with 200Q:l tetrabutylammonium formate (3 x 600 IIg).

After 6 days at 5°C, TLC [ethyl acetate/light oil (2)]
indicates 80% conversion to product. Elution through a short silica gel column gives the title material.

δ(CDCl2)0.1(6H,e,SiMe2),
0.9 (9H, e, 5IBuj), 1.35 (3H,
(1, bile 3・CH), 3.20 (in, dd, 2.
5 and 7H2°CH-CH-CH')%3.9(3H
,8,0M6), 4.5(IH,m,CHx・CH
・C'H\ 4.74 (IH, d, 2.5Hz, CH-
CH・S＼ 5.13 (AB (center of L, CH20).

Starting from the corresponding 6-butyl and diphenylmethyl esters, the following compounds are obtained in a similar manner.

6th butyl (7B, 6R) -7-[1(2)-tertiary
butyldimethylsilyloxyethyl]-6-formyloxymethyl-2-thiacephem-4-carboxylate, diphenylmethyl (7B, 6R) -7-[1(6)-
tertiary-butyldimethylsilylox-7ethyl]-3-formyloxymethyl-2-thiacephem-4-carboxylate.

The following corresponding acetates are obtained in the same way.

Methyl (7El, 6R) -7-[1(2)-5th-butyldimethylsilyloxyethyl]-6-acedoxymethyl-2-teacephem-4-carboxylate, 6th-butyl (7B, 6R) - 7-[1(9)-6th
butyldimethylsilyloxyethyl]-3-acetoxymethyl-2-thiacephem-4-carboxylate, diphenylmethyl (7B, 6R) -7' -C1 (9
)-tertiary butyldimethylsilyloxyethyl]-6-
Acedoxymethyl-2-thiacephem-4-carboxylate, trichloroethyl (7B, 6R) -7-[1(R)-
) Lichloroethoxylponyloxyethyl]-3-acetoxymethyl-2-thiacephem-4-carboxylate.

Example 66 Methyl (78,6R) -7-CI(6)-Hydroxyethyl-6-methyl-2-thiacephem-4-carboxylate methyl (7S,6R) -7-[1(→-tert-butyl Dimethylsilyloki-diethyl]3-methyl-2-thiacephem-4-carboxylate (0,75 g) was dissolved in tetrabutylammonium fluoride trihydrate (2,03
Add to the solution of F).

Work-up after 20 hours gives the title compound (virtually quantitative yield) exhibiting the spectral properties described for the sample obtained in Example 13.

Similar experimental procedures yield the following compounds.

Methyl(7B,6R)-7-CI(9)-hydroxyethyl)-5--7'lomomethyl-2-thiacephem-
4-carboxylate. Methyl (78,6R) -7-
[1(9)-6th-butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate Kara starting. 'max (film) 1775
．． 1730m-1; δ(CDCA,)1.35(3
H,d.

CH3-CH'), 3.38(II(, dd, CH
-CH・CHX 5.60 (IH, bre.

CHX 3.97 (3H1s, OMe), 4.33
(IH, m, CH3・CH-CH), 4.46 (2H,
AB (1 center r J: 11H2, internal line separation 4H2
.

CH2Br), and 4.88 ppm (IH,d
,, T=2.2Hz, CH-CH・S).

Methyl (7E+, 6R) -7-(1(9)-hydroxyethyl)-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-2-thiacephem-
4-carboxylate. Methyl (7816R)-7-(
1(6)-tert-butyldimethylsilyloxyethyl)
-3-(1-methyl-1,2,3,4-tetrazole-
5-yl)thiomethyl-2-thiacephem-4-carboxylate Kara starting.

si max (KBr) 1765 and 17Q7cm-'i
δ (c: ogcocpx) 1.30 (3H, a, stop 3, CH), 339 (IH, dd, CE (・box, C
H), 3.79 (3H,s, NCH5), 3.97
(3H, s, OCH3\ 4.0 (IH, m, CH3・
C) (・CH), 4.38 (2H, center of ABq 1 ”
"16H2, internal line separation L5Hz, CT (2・S')
S4.77 (iH, d, J==2.2Hz, CH-CH
-s) and 5.0 ppm (IH,br,s,
0F().

The corresponding 6th-butyl, diphenylmethyl and hydrychloroethyl esters are also produced in the same manner.

Example 64 (7S,6R)-7-[1(Oi-methylsulfonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylic acid diphenylmethyl (78,6R) -7-[1(9)-
Methylsulfonyloxyethyl]-3-methyl-2-thiacephem-4-carboxylate is dissolved in cold trifluoroacetic acid (0°C). After stirring for 15 minutes at the same temperature,
Carbon tetrachloride is added and the solution is completely evaporated under vacuum without external heating. The residue is triturated in CC1J and collected to give the title product. λmaX(CuCl2)2
81 and 326 nm; νmax(CHC6s)
5 (100-230 [1,2970,2930,285
0,1775,1710,1560 and 1170
1; δ(CD5COCDg) 1.58(3H, d y
CH3・CHX 223 (3H* e r M
e X 3.16 (3H, s.

S02Meχ 3.66 (1'H, dd, J, 2 work 6H2, CH-CH-CH), 4J35 (IH, cl
, J=2Hz, CH-CH・S), and 530ppm
(IH.

m, CH5・CH・CH).

The same material is obtained by TFA-hydrolysis of the modified t-butyl ester, except that the reaction time is increased to about 1 hour.

Similarly, hydrolysis of t-butyl or diphenylmethyl precursors provides the following products:

(78,6R) -7-[I 1 (Syn-tertiary-butyldimethylsilyloxyethyl)-6-methyl-2-thiacephem-4-carboxylic acid, (78,6R) -7-[1(9) -hydroxyethyl]-6-methyl-2-thiacephem-4-carboxylic acid, (7B, 6R) -7-C1@-hydroxyethyl]-
3-chocetoxymethyl-2-thiacephem-4-carboxylic acid, (7B, 6R) -7-CI(t)-hydroxyethyl]-5-carbamoyloxymethyl-2-thiace (7B
, 6R) -7-CI(ro)-hydroxyethylyo5
-H-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-2-thiacephem-4-carboxylic acid.

Example 65 (7B, 6R) -7-CI(9)-tert-butyldimethylsilyloxyethyl]-3-methyl-4-methoxycarbonyl-2-thiacephem-1,1-dioxide [
Method (a)] (7s, g)-7-C1 (→-
tert-butyldimethylsilyloxyethyl]3-methyl-4-methoxycarbonyl-2-thiacephem 117
The solution of IIg is treated with 220 ml of m-chloroperbenzoic acid at 0° C. under stirring. After 30 minutes, the reaction mixture is partitioned between dichloromethane and two 8% aqueous 8% bicarbonate solutions. The organic layer is dried over anhydrous sodium sulfate and the solvent is evaporated off. The residue is purified by short-circuit chromatography to give the title product (89 rg) as a syrup. νmax(CH2C7
2 film) 180Q, 1735cTn-': δ
(CDC/-3) 0.10 (6H, g, Me2Siχ
0.90 (9H, s, ButSl), 1.27 (3
H,d.

5-CH), 2.18 (3H,8,CH3), 6,8
1-3.83 (IH, dd, +3H.

s, CH-CH-CH and QCH3), 4.35
(IH, m, CH5-CH-CH), 5.05 (IH,
d, J=2DHz, CH-CH-8) ppm; λma
X (hexane) 276 (-=5.084) and 29
7 (sh, ε=3.745) nm.

[Method (b)]

(7B,6R)-7-CI in chloroform 25-
(B)-Tertiary butyldimethylsilyloxyethyl]-
A solution of 6-methyl-4-methoxycarbonyl-2-thiacephem 500149 is treated with 276 mg of 80% m-chloroperbenzoic acid. The temperature is raised to +20° C. within 30 minutes and then 4 wt. aqueous sodium bicarbonate solution is added. The organic layer is dried over anhydrous sodium sulfate and the solvent is evaporated off. The two residues are separated by chromatography on silica gel to yield the products in the following order:

1.1-oxide, syrup, 35 mF! . NMR
and engineering R data are the same as those mentioned above.

2-oxide, syrup, 608 g. νmax(CH
2Cl2 film) 1795.1740 cm-1
i δ(CDCl2)0.10(6H,s,Me2f
31), 0.90 (9H, s, ButSl),
1.24 (3H.

d, C'H3-C'H), 2+5(3H,s, CH3
), 2.85-5.90 (IH, dd.

+3H, e, CH-CH-CH and 0CT-Is
× 4.35 (IH, m, CH3-CH-CH),
527 (IH, d, J=2.5Hz, CH-CH-8)
ppm; λmaX(-\xane) 276 (ε=5.
092) nm 01-oxide, white powder, melting point 90-93C1330g. νmax(CH2Cl2
film) 1790.1730c1n1; δ0.10 (
6H,s, Me2S1χ 0.90 (9Hta,
B ut8 i ) 1.28 (6H+d+CH3-
CHχ 224(SH, s, CI(3λ s, 6o(1
H,aa,J=2. .

and 4. DHZ, CH-CH-CHx 3.87
(3H, s, OCHg), 4,65 (IH, m, CH3
-CH-CH), 4.67(II(,d,,T=2
8H2, CH-CM-8) p p m i λmax
(hexane) 273(ε=4.862')X309
(sh, g=2.721) nm.

A solution of 600 my of 1-oxide in 30 m6 of chloroform is stirred for 1 hour at room temperature in the presence of 160 my of m-chloroperbenzoic acid. The reaction mixture was washed with aqueous sodium bicarbonate, concentrated, and washed! 1
Purification by tography (silica gel, using cyclohexane/ethyl acetate as eluent) gives the title product.

Example 36 Methyl(6s,sR) -6-CI@-6th-butyldimethylsilyloxyethyl]2-Methyl (78,6R) -7-CI(9)- in Nemouro-carboxylate chloroform
tert-butyldimethylsilylox7ethyl]-3-methyl-4-methoxycarbonyl-2-thiacephem-1,
A solution of 600 μl of 1-dioxide is heated at 50° C. for 5 hours. Removal of the solvent gives the stereoisomer-free title compound (250 mg) in almost quantitative yield. νma
x (CHCL3) 1795.1715 ``+
δ(CDC)3) 0.08(6H,s, Mo2S
3 people 0.89 (9H.

s, ButSi), 1.23(3H,a,CHx-
CHx 233 (3H,S, CH5), 3.61 (I
H, dd, J=1.8 and 5.0Hz, CH-CH
-CH), 175 (3H, a, 0CH3), 4
．． 21 (IH, m, CH3-CH-CHx 5.50 (
IH.

d, J: 1.8H2, CH-CH-θ); λmP
Lx (gt, OH) 257.314Hm.

The above reaction also occurs after standing for 16 hours in chloroform for example at room temperature. NMR analysis shows a 1:2 mixture of title product and starting material.

Example 67 (78,6R) -7-[1(6)-Hydroxyethyl]-3-methyl-4-methoxycarbonyl-2-thiacephem-1,1-dioxide chloroform 1ff17! Inside (78,6R) -7-
A solution of [1(t)-hydroxyethyl]-3-methyl-4-methoxycarbonyl-2-thiacephem 4oig was heated for 15 minutes in the presence of 60 g of m-chloroperbenzoic acid.
Stir at °C. Partitioning between ethyl acetate and aqueous sodium bicarbonate and removal of the solvent gives the title compound, which is further purified by silica gel chromatography. δ(CDC4g) 1.36(3H,d,
J=6.4Hz, CHg-CH), 2.21(3H,8
, CH3 people 6.80-3.88 (4H, m, CH-C
4.40 (IH, m, CE (
x-CR-CH), 5.08 (18, a, J=,
1.6H2, CH-Kan-S).

Example 38 Methyl(6S,5R)-6-CI@-Hydroxyethyl]-2-methylbenem-3-carboxylate A solution of the compound prepared in Example 37 in an inert solvent (e.g. chloroform or pentene) is allowed to stand for several days. Alternatively, upon brief heating at 50-80° C., the title compound is formed in virtually quantitative yield, free of diastereomers.

δ(CDC13) 1.34(3H,d,'J=6.4
Hz, CH3-CH), 235 (3H.

s, CH2X 3.6s (1H, da,, r = 6.6 and 1.5Hz, CH-CH-CH), 3J30 (
3H, s, OCHgχ 4.40 (IH, m, CH3-
CH-CH), 5.56 (IH, d, J=1.
5Hz, CH-CB-8).

Example 39 Methyl(6s,sR)-(S-CI)-5th-butyldimethylsilyloxyethyl: ]-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl is Nemu 3-carboxylate methyl (7B,6R)-7-c 1 in chloroform
(9)-Tertiary butyldimethylsilyloxyethyl]-
3-(1-methyl-1,2,3,4-tetrazole-5
-yl) thiomethyl-2-thiacephem-4-carboxylate solution at 0°C for 30 min.
2.5 molar equivalents) and then aqueous NaHC
Wash with O3. Reflux the dried organic layer for several hours (
TLC tracking). Evaporation of the solvent and chromatography on silica gel gives the title product. δ(CD(,
/3) 0.07 (6H, s, SiMe2), 0.82
(9H, s, 81But), 1.20 (3H, d.

CHg-CH), 368 (IH, dd, 1.8 and 4Hz, CT(-CH-CH), 6.80 (3H
, e , N-Me), 5.81 (3H,s, OM
e), 4.22 (IH, m.

CH3-CH-CH), 4.69 (2H, AB(center of 1, J=14H2, internal line separation 11.5Hz, C
H25\ and 5.54 ppm (1H,d,
J=1.8H2, CH-CH-IE).

Example 40 p-nitrobenzyl (7B, 6R) -7-[1(9)
-p-nitrobenzyloxycarbonyloxyethyl]
-3-Methyl-2-thiacephem-4-carboxylate diphenylmethyl (7
8,6R) -7-[1(6)-p-nitrobenzyloxycarbonyloxyethyl]-6-methyl-2-thiacephem-4-carboxylate (200 μl) was added to a solution of trifluoroacetic acid at 0°C for 30 minutes. (0.4 mg). Cold evaporation in vacuo afforded crude 2-thiacephem-4-carboxylic acid, which was dissolved in 7 ml of acetonitrile-dimethylformamide (2:1.10 m) and treated with triethylamine (0,050-) and p-nitrobenzyl bromide ( 100 ■). After 1 hour at 25°C,
The mixture is partitioned between vinegar, ethyl acid and aqueous NaHcO3.

The dried (ngso4) organic layer was concentrated and the residue was passed through a short column of 8102 (using ethyl acetate-gas oil as eluent) to give 150 μl (79%) of pure title product.
get. δ (CDCl2) 1.45 (3H, d, excellent 5
-CH\3.43(IH,aa, :r=25 and 6Hz, C)(-CH-C'T(), 4.45(2
)(.

ABq, J=12H2, CH2Brχ 4.80 (
IH, 4, J=25Hz, CH-CH-E, 5
．． 2-55 (5H, m), 7.47 and 7.60 (2H, respectively).

d, Ar), and 8.20 ppm (4H, d, Ar
).

Example 41 (7B, 6R) -7-[1(Ef-6th-butyldimethylsilyloxyethyl]-4-diphenylmethoxycarbonyl-2-thiacephem-3-(pyridinium)methylbromide diphenyl in dry acetone (15 mA) Methyl (7s
, 6R) -7-[I1m-tertiary butyldimethylsilyloxyethyl]-5--10momethyl-2-thiacephem-4-carboxylate (310μ) was treated with pyridine (0.4m). do. After 20 hours at room temperature, the solvent is distilled off and the residue is purified by chromatography on silica gel. fusiction containing the product (70:15:15 CH2Ct2/HOAC/
(MθOH) are collected and the solvent removed to give the title compound as a syrup. kmax (CHCl, s film) 1790.1715 m'iδ (cncz3
) (Nakanzu < ) 1.32 (3H, d, J=6.
5Hz), 333 (IH, dcl), 4.45 (IH
, m), 5.0 (IH, d-, J<2H2), 7.
11 (IH, s); λmfLx (CHC75) 28
3 and 337 nm (g=4.060).

In a similar manner and p-nitrobenzyl (7B).

6R) -7-[1(6)-p-Nitrobenzyloxycarbonyloxyethyl]-3-bromomethyl-2-thiacephem-4-carboxylate carboxylate carboxy7ethyl]-4-p-nitrobenzyloxycarbonyl -2-thiacephem-6-(pyridinium)methyl bromide is obtained.

Example 42 (7B, 6R) -7-[1(8)-6th-butyldimethylsilyloxyethyl]-4-carboxy-2-thiacephem-6-(pyridinium)methyltrifluoroacetate diphenyl in dichloromethane (10m) A solution of the methyl ester (obtained in Example 41) is treated with trifluoroacetic acid (2-) for 15 minutes at 0°C.

After evaporation in vacuo, the residue is taken up in a small amount of chloroform. Ethyl ether is added under stirring and then decanted to give the crude title product. kmax (CHCt5 film)
3420.1785.1715 and 1635br
cm-1i δ(cDczg) (Nakandu < )
H,a, J=6.5H2), 5.23(I
H, del), 4.38 (IH, m\ 4.76 (1H
pd) ppm1λmaX(CHcz3) 262 and 334 nm.

Example 43 (78,6R) -7-[1(9)-p-nitrobenzyloxycarbonyloxyethyl)]-4-p-nitrobenzyloxycarbonyl-2-thiacephem-3-(
p-Nitrobenzyl (7s, 6R) in 5-carbamoylpyridinium) methyl bromide nMF (5-)
-7-[1(2)-p-Nitromethyloxycarbonyloxyethyl]-6-promomethyl-2-thiacephem-4-carboxylate) (460 mg) was added to a solution of nicotinic acid esteramide (2[10Q)] in the dark. Stir overnight in the presence of Most of the solvent is distilled off and the residue is taken up in tetrahydrofuran (150m). Repeat this solution to 0.
A solution of NaCL in INHCt (2X50ffi7,
Washed with brine (2×5 (1 ml)) and dried (Na2
sO4) L and evaporate. The residue is packed on top of a column packed with silanized silica gel (Merck Art, 7719). Excess nicotinamide and impurities were eluted with KtOAc and the product was purified with EtOAO7.
'Collect by elution with HOAC (9:1). Evaporation in vacuo gives the title product. kmax (CH
CL3) 1800.1725.1695cPN-1:
a (oxuteroacetone' 200 MHz) t
67 (3H+ d, J-6-4Hz, CH3-C
H')X4.14(IH,aa,,T=25 and 4.
7Hz, CH-CH-CH), 530 (IH, d,,
T=2.5Hz, C to CH-s or 5.4 to 5.7 (7
H, m, 2XCH20Ar, CH2N'', and CH
3-CH-CH).

7.7-8.4 (8H, m, Arχ and 8.7
．． 95 and 9.7 ppm (1H, br s, respectively)
pyridinium).

Similarly, by using isonicotinamide instead of nicotinamide (78,6F,) -7-[1(6
)-p-nitrobenzyloxycarbonyloxyethyl:]-4-p-nitrobenzyloxycarbonyl-2-
Thiacephem-3-44-carbamoylpyridinium)
Methyl bromide' is obtained.

Example 44 (6S, 5R) -6-CI (Hydroxyethyl)-2-(pyridinium)methyl to nemu 6-carboxylate (,:u2pErib) (7B, 6R) -7-CI ( 9)-
p-Nitrobenzyloxylponyloxyethyl:)
A solution of -4-p-nitrobenzylox7carbonyl-6-(pyridinium)methyl-2-thiacephem acetate (prepared from the corresponding bromide by conventional treatment with silver acetate or ion exchange resins) at 0°C. Treat with peracetic acid, acid (2 molar equivalents). After working up and heating gently according to the general procedure described in Examples 57-39, (6B, 5R) -6-[1(b)-p-nitrobenzyloxycarbonyloxyethyl]-3-p-nitro Benzylox7carbonyl-2-(pyridinium)methylbenemacetate is obtained. νmax (KBr)
1795.1740.17Q5cm-1iδ(CDCL
5+ deuteroacetyl) 1.4 (3H, a
, J=6.5Hz.

CHx-CHx 4. i [](II(, ad , ,
T=1.7 and 8H2, CH-CH-CHx5.20
and 531 (2H,s, 0CH2Ar, respectively),
5.2 (IH.

m, CH3-CH-CH')X5.77 (1a, a, J
= 1.7H2, CH-CH-8).

6[]5(2H,ABq,,T=15Hz,C)12N
), 7.4-8.3(11)(, m, Ar) and 9.15 ppm (2H,d, J:6H2,o-
Pyr).

This material (3oom9) in tetrahydrofuran-water (1:1.40-) is treated with ammonium chloride (5f) under stirring to give a clear solution.

After cooling to about 10° C., iron powder (2,!M) is added under vigorous stirring. The reaction was analyzed by TLC (9'1:1 H20/
MeOH/NaCl) can be used for monitoring. After about 1 hour, Celai (3F) is added and the whole is filtered through a glass septum and washed with deionized water. Removal of the organic solvent followed by washing with ethyl ether gives the title product and an aqueous solution of the inorganic salt. The former is obtained pure after reverse phase chromatography and lyophilization. δ(D20. 20.
0MH2) 1.27("+H, d, J=6.5Hz,
CHsCH), 5.98 (IH, dcl.

, T=1.4 and 5.8H2, CH-CH-CHx
4.24 (IH, m, CHx-CH-CH), 5.69
(IH, d, J=1.4Hz CH-CH-8), 5.
94 (2H.

ABq, J=14.9Hz, CH2Nχ 8.10 (
2H, t, J=6.6H2, vinylinodinium m-H
), 8A1 (18, bd, , T = 7.7 Hz, pyridinium pH), 8.95 (28, d, : J =
6.6 Hz, pyridinium o-'H) ppm 0 In a similar manner, starting from the compound described in Example 43, the following compound is obtained.

(6ε,5R) -6-CI(9)-hydroxyethyl]-2-(3-carbamoylpyridinium)methyl is nemu 3-carboxylate, (68,5R) -6-[1(ro)-hydroquinethyl ]-2-(4-carbamoylpyridinium)methyl χnemu 6-carpoxylate.

Example 45 (6S, 5B) -b -[1(6)-hydroxyethyl]-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl is sodium nem-6 monocarboxylate p-Nitrobenzyl (78,6R)- in salt chloroform
7-[1(R)-p-nitrobenzylox7carponyloxyethyl]-1-(1-methyl-1,2,3,4-
A solution of thiomethyl-2-thiacephem-4-carboxylate (tetrazol-5-yl) is oxidized with m-chloroperbenzoic acid as described in Example 67 to give the corresponding sulfone. Without purification, this material is heated at 60° C. in dry distilled tetrahydrofuran under a stream of nitrogen until expulsion of so2 is complete. p-nitrobenzyl (68,5R)-6-CI(PJ-p-nitrobenzyloxycarbonyloxyethyl)-2-(1-methyl-1,2,3 , 4-tetrazol-5-yl)thiomethylbenem-3-carboxylate. δ(cD
cz3) 1.48 (3H, d.

J=7H2, CH3-CH), 3.84 (IH, dd,
, r=2 and 55Hz.

CH-4-CH), 3.96 (IH, 8, NCH3),
4.69(2H,ABq,,T=14Hz,CH2'S
), 5.20 (IH, m, CH3-CH-CH),
5.24 (2H.

s, 0CH2Ar\ 5.27 (2H, ABq
, J=13Hz, 0CH2Arχ5.61(IH
, d, J = 2H2χ 7.51 work Z82 (2H, d, J: 8Hz, Ar, respectively), 8.02 pp
m (4H, d, J=8Hz, Ar).

The above substances and Fe/NH according to the procedure described in Example 44
Reaction with 4Ct gives the title product. δ(D20)1
．． 28 (3H, d, y = 6.5Hz), 3.87 (
IH, aa, J = 1.4 and 63 ponds.

CH-CH-CF(), 4.10(3H,8,NCH3
), 4.19 (IH, m, CHg-CH-CH), 4.
40 (2H, ABq, J=16Hz, CH2E×
5.59 ppm (IH,'cl, J=1.4H2
, CH-CH-8); λmax(H2O) 315n
m0 Example 46 Methyl (6B, SR) -6-CI(6)-tert-butyldimethylsilyloxyethyl]-2-nitrooxymethylbenem-3-carboxylate Methyl (78,6R) in chloroform -7 -[1(9)-tert-butyldimethylsilyloxyethyl]-3-nitrooxymethyl-2-thiacephem-4-carboxylate (Example 31
Treatment of a solution of (prepared as described in ) with m-chloroperbenzoic acid (2 molar quantities, 0°C) yields the 1-sulfone. Aqueous bicarbonate was added to extract the m-chloroperbenzoic acid and the dried organic solution was gently refluxed (TLC).
(while monitoring) to obtain a solution of the nem compound. δ
(CDCl2) (Nakanzu < ) 5.64 (jH,
d, J=2Hz, CH-CH-s) and 5.65
ppm (2H, AElq.

J = 15H2, internal line separation 46Hv, , CH2
0NO2); Max (, CHc15) 1790
Trichloroethyl (7B, 6R) -7-[1
3-Trichloroethoxycarbonyloxyethyl]-3
Starting from -nitrooxymethyl-2-thiacephem-4-carboxylate, trichloroethyl (68,5R
) -6-(1(th-trichloroethoxycarbonyloxyethyl)-2-nitrooxymethyl)-6-carpoxylate was obtained.

Example 47 Methyl (68,5R) -6-[: 1(8)-6th-butyldimethylsilyloxyethyl]-2-hydroxymethylbenem-3-carboxylate Crude methyl (6s, sR)
-6-[1(Ft)-tert-butyldimethylsilyloxyethyl]-2-nitrooxymethyl to Nemu 3-carboxylate (corresponding 3-carboxylate according to Examples 51 and 46)
Bromomethyl-2-thiacefem precursor 45mg
A solution of (obtained from) is stirred with zinc dust (0,1f) and acetic acid (0,1 mA) at 0°C for 5 minutes. The reaction mixture is filtered and the solution is evaporated to give the crude title product. This product was treated with silica gel chromatography (1
:4 to 1:1 ethyl acetate/light oil).

νmax CCHCL3 film) 1785.171
0crn-1; δ(CDC13) 0.07(6H,
s, SIMe2χ 0.88 (9H, e, 5IBuj\
1.23(3H,d, CH3-CH\3.70(I
H, dd, J=t8 and 45Hz, CH-CH
-CH), 425(IH,m,CHg-C,H-CH
), 4.59 (2H.

a, CH20H) and 5.57 ppm (I
H, d, J=1.8Hz, CH-CH-8).

In a similar manner trichloroethyl (6B, '5R)
-6-[1(FO-trichloroethoxycarbonyloxyethyl]-2-nitrooxymethyl R-nemu-3-carboxylate, achieved complete removal of the protecting group and worked up with aqueous NaHCO4 and reverse phase After chromatography (water as eluent) (68,5R)
-6-[1(9)-hydroxyethyl]-2-hydroxymethylbenem-3-carboxylic acid sodium salt is obtained.

δ (D20) 1.30 (3H, d, CH3-CH),
3.88 (IH, dd, J=1 and 6.5Hz.

CH-CH-CH), 4.23 (IH, m, CH3
-CH-CH), 4.63 (2H.

ABq, J=14.5Hz, internal line separation 4H2
, CH20H), and 5.62 ppm (IH,d
, :J=1Hz, CH-CH-8); νmax(
KBr) 1765, C and 1610-1590 tyR
-1°Example 48 (6s;sR) -6-[1(9)-Hydroxyethylio2-carbamoyloxymethylbenem-3-sodium carboxylate Trichloroethyl (7
8,6R) -7-[1(ro)-Trichloroethoxycarbonyloxyethyl]-6-carpamoyloxyethyl-2-thiacephem-4-carboxylate treated with chloroform MWtm-chloroperbenzoic acid. After work-up, the obtained 1-
Trichloroethyl (6B
, 5R) -6-C1@-trichloroethoxycarbonyloxyethyl]-2-carbamoyloxymethylbenem-3-carboxylate. δ(CDC73)
1.5 (3H, a, cH3-CH), 3.94 (IH,
dd.

J=2 and 8Hz, CH-CH-CHχ4.7
3 and 4.82 <respectively”2H,s, 0CH2
CCA5), 4E3(IH,m, CHs-CH-CH
), 5.25 (2H, ABq, J=10H2, CH20
CONH2), 5.62(IH,d,,T=2H2,
CH-CH-8).

A solution of this material in THF is treated with zinc dust (approximately 6 parts by weight) and 1M aqueous NaH2PO4 under stirring. 25
After stirring for 3 hours at °C, another portion of zn is added and the mixture is stirred for 3 hours. Work-up and reverse phase chromatography gives the title product. δ(D20
) 1.31 (3H, d, J=6.5Hz, CH3
-CH), 3.91 (IH, dd, J: 1.5 and 6Hz, CH-〇H-CH), 4.25 (IH, m
, CH3-C1-CH), 5.19(2H,AB(1
.

J=14.5H2,CH20CO) and 5.66pp
m(IH,d, ,T=1.5H2.

CH-4-8).

Patent applicant 7 Armitalia Calguchi Elpa Società continues from Le Azzioni page 1 Claims priority @ August 27, 1983 ■ United Kingdom (G
B) ■8323129 @ Inventor Ettore Perrone Via del Targo 8, Milan 20100, Italy

Claims (1)

[Scope of Claims] 1) General formula ([1 (in the formula, R1 represents a hydrogen atom or an organic group, R2 represents a hydrogen atom or carboxy 2-thiacephem derivatives (Y represents a hydrogen or halogen atom or an organic group) using a peracid such as m-chloroperbenzoic acid or peracetic acid as an oxidizing agent at a temperature of 0 to 60°C. The corresponding sulfone compound of the general formula 00R2 (where Ri, R2 and Y are as previously described) is subjected to the reaction, and this compound is then heated gently in an inert organic solvent or at room temperature. The desired (5R)-'neme derivative of formula (1) is thereby obtained by leaving it at room temperature for desulfurization ring contraction by expulsion of SO2 and finally purified by methods known in the art. The general formula (1
1 (in the formula, R1%, R2 and Y are as described above), (5R)- is a method for producing a nem derivative. 2) The method according to claim 1, wherein the organic group represented by R1 in the tD (5R)-benem derivative of formula (1) is an optionally substituted aliphatic or cycloaliphatic group. 6) The aliphatic group represented by R1 in the (5R)-penem derivative of formula (II) is optionally one or more free or protected mercapto, amino, hydroxy or cyano groups. The method according to claim 1 or 2, wherein the alkyl group of the formula (11) is a linear or branched alkyl group having 1 to 12 carbon atoms, which is substituted with n. Preferred alkyl groups represented by R1 in the 5R)-penem derivatives are methyl, ethyl, isopropyl, preferably ethyl, and preferred substituents for such groups are free or protected hydroxy groups (protecting groups). is p-nitrobenzyloxycarbonyl, dimethyl-t
-butyl-silyl, diphenyl-t-butyl-silyl,
Trinotylsilyl λ% 2.2.2-) Lichloroethoxycarbonyl, benzyl-p-bromophenacyl, triphenylmethyl or pyranyl group) method. 5) <5R) of formula (1) --, R1 in the nem derivative
The cycloaliphatic group represented by is optionally substituted with an alkyl group having 1 to 6 carbon atoms or with one or more free or unsubstituted mercapto, amine or hydroxy groups. 3. A method according to claim 1, wherein the monocyclic alkyl group having 4 to 7 carbon atoms is preferably a cyclopentyl or cyclohexyl group. 6) A linear or straight-chain alkyl group in which the carboxy group represented by R2 in the (5R]-penem derivative of formula (11) has 1 to 6 carbon atoms, 2.2.2-)lichloroethyl a halo-substituted alkyl group having 1 to 6 carbon atoms, such as a phenyl group, an alkenyl group bearing 2 to 4 carbon atoms, such as an allyl group, a p-
an optionally substituted aryl group such as a nitrophenyl group, benzyl, p-nitrobenzyl or p
- an aryl-directly substituted alkyl group in which the aryl moiety is optionally substituted, such as a methoxybenzyl group, an aryloxy-substituted alkyl group in which the alkyl moiety has 1 to 6 carbon atoms, such as a phenoxy-methyl group, or a benzhydryl group; , 0-nitrobenzhydryl, acetonitrile, trimethylsilyl, diphenyl-1-butyl-silyl, dimethyl-t-butyl-silyl, acetoxymethyl, pivaloyloxymethyl or phthalidyl group according to claim 1 the method of. 7) The method according to claim 1, wherein when Y in the (5R)-penem derivative in the formula represents I.rogen atom gold, 7n is preferably a fluorine, chlorine or bromine atom. 8) When Y in the (5R)-penem derivative of formula (11) represents an organic group, n is (al free or protected hydroxy group, (bl
optionally by a halogen atom, by an acyl group having 2 to 6 carbon atoms or by an amine, hydroxy or mercapto group (these amine, hydroxy or mercapto groups are optionally in protected form) a formyloxy group substituted by n or 2 to 6 carbon atoms'? N-acyloxy group, (cl unsubstituted or N-alkyl substituted carbamoyloxy group, (di optionally one or more halogen atoms, formyl group, 2 to 6 carbon atoms) an alkoxy group having 1 to 12 carbon atoms or 1 to 12 carbon atoms substituted by an acyl group and/or an amino, hydroxy or mercapto group optionally in protected form; an alkylthio group having (θ), a 1-pyridinium group which is unsubstituted or substituted with a group -0ONH2 in the meta- or bara-position or (f+ a heterocyclyl group -8-Hθt [in the formula net
represents a saturated or unsaturated heterocyclic ring containing at least one oxygen, sulfur and/or nitrogen heteroatom, preferably (A) unsubstituted or one or more (a') alkoxy groups with 1 to 6 carbon atoms, aliphatic acyl groups with 2 to 6 carbon atoms, hydroxy groups and/or halogen atoms, (b'+ unsubstituted or or one or more
(a') an alkyl group having 1 to 6 carbon atoms substituted with hydroxy groups and/or halogen atoms; (a') unsubstituted or with one or more hydroxy groups and ( or) an alkenyl group of 2 to 6 carbon atoms substituted by a halogen atom, (d') an alkenyl group of the general formula -〇-R3, where R3 is a hydrogen atom or (indicates an alkyl group)
group or general formula -8-C! H2-COOR4 (in the formula R
4 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a carboxy protecting group), (a') general formula -(OH2)m-000R4 or Ikkaikamo1 (C!0OR4 or - (OH2,)m-ON or -(OH2)m-coNn2 or -(OH2)m-
a group of El103H (in which m is 017.2 or 6 and R4 is the above-mentioned group), and each n of R5 and R6 is the same or different group; represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aliphatic acyl group, or if one of R5 and R6 is hydrogen, the other may also be an amine protecting group). 5 or 6 atoms containing at least one double bond and at least one oxygen, sulfur and/or nitrogen heteroatom, such as thiazolyl, triazolyl, thiadiazolyl, tetrazolyl, triazinyl group or (B) a 5- or 6-atom heterocyclic ring containing at least one oxygen, sulfur, or nitrogen heteroatom, in which each of the fused heteromonomial rings is the same or different; A heterobicyclic ring containing at least two double bonds that is a formula term (
The heterobicyclic ring is not monosubstituted or as defined above (a'), (b, (C), (a') and (f').
2. The method of claim 1, wherein the method is substituted with one or more substituents selected from the following. ) Methyl-(6B,5R)-6-(1(■-t-butyldimethylsilyloxyethyl)-2-methyl-benem-6-carboxylate f produced by the method according to claim 1) (5R of general formula (1)
)-penem derivative. 10) Methyl (6S, 5R) -6-C1 (R1-Hydroxyethyl-2-methyl-5-carboxylate) produced by the method according to claim 1 of the general formula (5R)-penem derivative of (1). 11) p-nitrobenzyl (6S, 5R) -6-(1
(RJ-hydroxyethyl-2-acetoxymethyl-
Benem-6-carboxylate of the general formula (11) prepared by the method according to claim 1 is
5R)- is a conductor. 12) p-nitrobenzyl (6B, 5R) -6-C1
(R1-hydroxyether)-2-(1-methyl-5-
A (5R)-penem derivative of the general formula +11 prepared by the method according to claim 1, which is tetrazolyl)thiomethylbenem-3-carboxylate. 16) Methyl (68,5R) -b -C1 published - 3rd
butyldimethylsilyloxyethyl)-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethylbenem-6-carboxylate produced by the method according to claim 1. The general formula (
1) (5R)-benem derivative. +4) (68,'5R) -6-(1(river-hydroxyethyl)-2-(pyridinium)methylbenem-6
-carboxylate produced by the method according to claim 1, wherein (5R)- in the general formula is a nem derivative. 15) (68,5R) -6-C1F-hydroxyethyl]-2-(3-carbamoylpyridinium)methyl Rnemu 3-carboxylate f' L, f? :,
(5R)-penem derivative of general formula (1). 16) (6S, 5R) -6-[1(R1-hydroxyethyl]-2-(4-carbamoylpyridinium)
A compound of the general formula (
(5R)-penem derivatives of 11. 17) (6E1.5R) -6-C1(R1-hydroxyethyl]-2-(1-methyl-1,2,5,4-
Tetrasol-5-yl)-thiomethylbenem-6-carboxylic acid sodium salt prepared by the method according to claim 1 of the general formula (11 (5R))
- Penem derivatives. 1B) Methyl-(6S,5R)-6-[: 1. ((5R ) - R nem 8 conductor. 19) Trique oo ethyl - (6E1.5R) -6-[
: 1 tRl-trichloroethoxycarbonyloxyethyl]-2-nitrooxymethylbenemu6-(5R) of general formula (II) prepared by the process of claim 1, which is lupoxylate -penem derivative. 20) Methyl (68,5R) -6-C1(R)-5th
butyldimethylsilyloxyethyl]-2-hydroxyethylbenem-6-carboxylate (5R) produced by the method described in claim 1.
- is a nem derivative. 21) (6S,5R)-6-[1(R1-Hydroxyethyl]-2-hydroxymethylbenem-6-carboxylic acid sodium salt, produced by the method according to claim 7) f general formula +11 (5R)-
Benem derivatives. 22)'(6S,5R)-6-CI (R1-Hydroxyethyl]-2-carbamoyloxymethylbenem-6-carboxylic acid sodium salt produced by the method according to claim 1) The general formula (11
(5R)- is a nem derivative. 23) A general formula which is dissolved in an inert organic solvent such as Hansen or carbon tetrachloride and in which fcRl and R2 are the same υ as defined in claims 1 to 6 above, and Y is a frozen candy atom. 20% of the 2-thiacephem derivative of tUt
N--j romosuccin in the presence of azobisisobutyronitrile or benzoyl peroxide and in the presence of acid scavengers such as propylene oxide, alkaline earth metal oxides or molecular sieves at a temperature of ~160 °C. imide or [N-chlorosuccinimide, R1 and R2 are as previously described and Y
to obtain a desired 2-thiacephem compound of the formula tn+, in which is a bromine or chlorine atom. and Y is a halogen atom as stated in claim 7).
-Process for producing thiacephem derivatives. 24) Methyl C78,bR,)-72[1(R1-''
Tertiary butyldimethylsilyloxyethino J-3-'7
Claim 26, wherein lomomethyl-2-thiacephem-4-carboxylate is obtained from silkworms produced by the method according to claim 25, and is 2-carboxylate of the general formula (ml). 84 2-thiacephems of general formula tUt produced by the method described in Section 61) Diphenylmethyl (7S, 6B) -7-CI
(R1-5th-butyldimethylsilyloxyethyl)-
26. A 2-thiacephem derivative of general formula tn+ prepared by the method of claim 26 which is 6-promomethyl-2-thiacephem-4-carboxylate. 52) R1 and R2 prepared by the method described in claim 2, dissolved in an acetone-water mixture (2:1 v/v), are dissolved in the scope of claims 1 to 2 of the above claims. 6
The 2-thiacephem derivative of [11] is reacted with a salt of a strong inorganic acid such as silver perchlorate for 15 minutes at a temperature of -0°C. At least the unstable ester of the inorganic acid is obtained, which is then hydrolyzed in the same reaction medium to obtain the desired 2- 2 of the general formula (Ill0OR2 (wherein R1 and R2 are as described in claims 1 to 6 above, and Y is a hydroxy group) to obtain a thiacephem compound. -Production method of thiacephem derivative. 66) 5th-butyl-(7S, 6R)' 7-[:
1 (R1-tert-butyldimethylsilyloxyethyl]-6-hydroxymethyl-2-thiacephem-4-
53. A compound prepared by the method of claim 52 which is a carboxylate. 64) R1 and R2 prepared by the method according to claim 62 dissolved in dichloromethane are the compounds mentioned in claims 1 to 6, and Y is hydroxy. 2-thiacephem+i1 of the general formula tUt, which is a group, is treated with trichloroacetyl isocyanate at a temperature of -40°C, the reaction mixture is allowed to rise to room temperature and then R1 and R2 are as previously described and Y is N -(trichloroacetyl)carbamoyloxy group (with the general formula), separate the desired 2-thiacephem derivative for several years, and if you feel safe, add the methanol proverb to 2
2- of the formula (...) in which R1 and R2 are as previously described and Y is a carbamoyloxy group is allowed to desorb the trichloroacetyl moiety of the urethane adduct initially formed by stirring with silica gel for 0 hours.
A thiacephem derivative is obtained by the general formula ( (wherein R1> and R2 are as stated in claims 1 to 6 above, and Y is N-(trichloroacetyl)carbamoyloxy 65) Tertiary butyl (7S, 6R) -7-(1(R1
-6th-butyldimethylsilyloxyethyl]-6--
65. The product prepared by the process of claim 64 which is (N-trichloroacetyl)carbamoyloxymethyl-2-thiacephem-4-carboxylate. 56) 6th-butyl (7B, 6R) -7-(1(RJ
-5-butyldimethylsilyloxyethyl]-5-carbamoyloxymethyl-2-thiacephem-4-carboxylate. 37) R1 and R2 produced by the method described in claim 23, which is commonly understood as dichloromethane, are as described in claims 1 to 6, and Y is a halogen atom. A 2-thiacephem derivative of the general formula ([1] is treated with a suitable salt of the corresponding carboxylic acid at a temperature of 5° C. and for 6 days to form a 2-thiacephem derivative in which 1 and R2 are as previously described and Y is a formyloxy or acetoxy group. The desired 2-thiacephem product 71 of formula tUt is
il-obtaining k'h character (wherein R1 and R2
is the same as stated in Claims 1 to 6 above, and Y is formyloxy or acetoxy group). 68) Methyl-6th-butyl (7,S,6R), -,
7-[N-6th-butyldimethylsilyloxyethyl]-6-formyloxymethyl-2-thiacephem-4
- a product prepared by the method of claim 67 which is a carboxylate. 39) Diphenylmethyl (79,6R) -77[1”
38. The product prepared by the process of claim 37 which is tRi' tertiary tertiary-luptyldimethylsilyl quinethyl]formyloxymethyl-2-thiacephem-4-carboxylate. 40) Methyl (7S, 6R) -7-C1 (cauterized-6th-butyldimethylsilyloxyethyl)-6-acetoxymethyl-2-thiacephem-4-carboxylate according to claim 37 41) 6th Butyl (7E1.6R) -7-(1(R
68. A product prepared by the process of claim 67 which is 1-6-butyldimethylsilyloxyethyl]-6-acetoxymethyl-2-thiacephem-4-rupoxylate. 42) Diphenylmethyl (7S, sR) -7-C1 (
R1-6th-butyldimethylsilyloxyethyl]-6
-acetoxymethyl-2.-thiosephem-4-carboxylate. 38. A product folded by the method of claim 37 which is -acetoxymethyl-2.-thiosephem-4-carboxylate. 46) Trichloroethyl (7S, 6R) -7-(1t
68. The product prepared by the process of claim 67 which is FIJ-trichloroethoxycarbonyloxyethyl]-3-acetoxymethyl-2-thiacephem-4-carboxylate. $4) R1 and R2 prepared by the process of claim 25M in a suitable organic solvent such as tetrahydrofuran, acetone, acetonitrile or dimethylformamide are
The 2-thiacephem derivative of the general formula (Ill), which has the general formula υ described in Sections 6 to 6, and Y is a norogen atom, is prepared by heating the 2-thiacephem derivative of the general formula (Ill) at room temperature overnight in the presence of a base such as triethylamine to form the corresponding He-Het or or by reacting with a preformed sodium salt of H8-Het (formula J) in which R1 and R2 are the same as previously described and Y is 18Het.
to obtain the desired 2-thiacefuem derivative of the general formula cooR2 (wherein R1 and R2 are as stated in claims 1 to 6 above and Y is a -8He group). A method for producing a 2-thiacephem derivative. 45) Methyl(78,6R)-7-C1('FO-6th-butyldimethylsilyloxyethyl)-3-(1-
45. The product produced by the method of claim 44 which is methyl-1,2,5,4-tetrazol-5-yl)thiomethyl-2-thiacephem-4-carboxylate. 46) 5th-butyl (7S, 6R) -7-C1tRl
-6th-butyldimethylsilyloxyethyl]-5-(
45. The product prepared by the process of claim 44 which is 1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-2-thiacephem-4-carboxylate. 47endiphenylmethyl(78,6R) -7-(1(
□-tert-butylsilyloxyethyl)-3-(8-aminotetrazole(1,5-b]pyridazin-6-yl)-thiomethyl-2-thiacephem-4-carboxylate 44) A product produced by the method of claim 23. 48) R1 and R2 produced by the method of claim 23 are as described in claims 1 to 6. A 2-thiacephem derivative of the general formula (I[) in which the to obtain the desired 2-theacephem products of formula (II), wherein Y is an unsubstituted pyridinium group or a pyridinium group substituted in the meta- or v-position with a 100-NH2 group. General formula (II) characterized by
) (wherein R1 and R2 are as defined in Claims 1 to 6 above, and Y is unsubstituted or meta or) 100-NH at each
1-pyridinium group substituted with 2 groups)
-Process for producing thiacephem derivatives. 49) <7B, 6R) -7-(1(R)-tert-butyldimethylsilyloxyethyl)-4-u phenylmethoxycarbonyl-2-thiacephem-6-(pyridinium)methyl bromide A product of general formula (n) prepared by the method described in Range 48. 50n (78,6R) -7-(1(FO-p-nitrobenzyloxycarbonyloxyethyl) -4-p
51) (78, 6R) -7-CI (R1-'p
-Nitropesodyloxylponyloxyethyl: ]-
4-p-Nitrobenzyloxycarbonyl-2-thiacephem-6-(3-carbamoylpyridinium) methyl bromide of the general formula tn+ produced by the method described in item 48 product of. 52) (78,6R) -7-C1(R1-p-nitrobenzyloxycarbonyloxyethyl, 1-4-
A product of the general formula (I[l) prepared by the process of claim 48 which is p-nitrobenzyloxycarbonyl-2-thiacephem-3,-(4-carbamoylpyridinium)methyl bromide. ) general formula (IVI [wherein R1 and R2 are as described in claims 1 to 6 above and 2 is of the formula SR7 (wherein R7 has 1 to 8 carbon atoms)] An alkyl group having the phenyl or tolyl group is preferably a bicyclic radical), especially a 2-benzothiazolylthio group or a 1-methyl-tetrazol-5-yl-thio group, with the open formula 5COR8 ( In the formula, R8 is optionally substituted n
a lower alkyl group (preferably a methyl group) representing a lower alkyl or aryl group or forming a heterocyclic ring (preferably a succinimide or phthalimide group) together with a dicarboxyamino group; The lower alkyl or aryl group preferably methyl, phenyl or p-)! A compound of the general formula (VJ (where R1, R2 and 2 are as described above, and Y is a halogen atom) is halogenated by a method known per se. ) is obtained and then ozonolyzed to give the general formula (
The compound of vID02R2 is converted into a hydroxyl group (L is a hydrogen atom, an alkane sulfonyloxy group or an allenesulfonyloxy group, preferably a methanesulfonyloxy group) and converted to a general formula (general formula). Then, by making f′L total i, the expression tl
General formula (1) characterized by obtaining the desired compound of [l]
1) (In the formula, R1 and R2 have the meanings shown in Claims 1 to 6 above, and Y is as stated in Section 8 of Claims IIJ) A method for producing a 2-thiacephem derivative. 4) Compounds of the general formula (wherein R1 and R2 have the meanings given in Claims 1 to 6 above and 2 is as stated in Claim 56 above) 'tU was then subjected to ozonolysis to obtain a compound of the general formula (Vll 02R2), and the hydroxy group ? A compound of the formula (v1ll)02R2 is obtained, which is then cyclized by treatment with a salt of H2S and an organic or inorganic base to give the desired 2- 2 of the general formula (It) (wherein R1 and R2 are the same as described in claims 1 to 6) and Y is a hydrogen atom), which is characterized in that thiacephem is obtained. -Process for producing thiacephem derivatives. 55) A compound of the general formula (formula) produced by the method described in claim 1, where R1, R2 and Y are the same as described in claims 1 to 6. ), 2-thiacephem-1,1-dioxy F. 56) (7S, 6R) -7-(1(R1-tert-butyldimethylsilyloxyethyl)-6-methyl-4
-methoxycarbonyl-2-thiacephem-1,1-dioxide of the general formula (2) as set forth in claim 55. 57) (7B, 6R) -7-[1(R1-hydroxyethyl]-6-methyl-4-methoxycarbonyl-
2-thiacephem-1,1-dioxide according to claim 55, which is 2-thiacephem-1,1-dioxide.