CA1313380C - .beta.-lactams and their production - Google Patents

Abstract

Abstract:
The present invention is directed to beta-lactam compounds of the formula:

Description

13~38~

NOVEL beta-LACTAMS AND THEIR PRODUCTION
This application is a division of our prior application Serial No. 498,692 filed on December 27, 1985.
The present invention relates to beta-lactams and their production. More particularly, it relates to novel beta-lactam compounds of the formula:

~2 ~3 R~COZ ( I) o CH2COYR4 wherein Rl and R2 are the same or different and each represent a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group, R4 is a hydrogen atom, a carboxyl-protecting group or a thiolcarboxyl-protecting group, X is a hydrogen atom, a hydroxyl group or a protected hydroxyl group, Y is an oxygen atom or a sulfur atom and COZ is a carboxyl group, an activated or protected carboxyl group, a thiolcarboxyl group or an activated or protected thiolcarboxyl group, and their production.
Since the successful isolation from nature of the antibiotic substance "thienamycin" [U.S. patent 3,950,357;
J.Am.Chem.Soc~, 100, 313 (1978)], various carbapenem compounds have been reported. Among them, there are Xnown some carba-penem compounds substituted with an alkyl group at the l-position, and l-methylcarbapenem compounds are particularly notable as they exert strong antimicrobial activity against various microorganisms with excellent stability in living bodies [EP-0071908A; ~eterocycles, 21, -- 2 - 1~ ~33 8 Q
29 (1984)]. However, their known methods of preparation are troublesome in that they require a lengthy series of reaction steps. Further, such methods do not permit the stereospecific formation of the l-methyl group.
As a result of extensive study, it has now been found that the beta-lactam compounds of the formula (I) according to the invention are valuable intermediates for the production of l-alkylcarbapenem compounds having the following fundamental skeleton:

-~3 ,.~N ~' O
COO~
whèrein R3 is as defined above. Particularly, they make it possible to stereospecifically form an alkyl group at the l-position.
In the definitions of the beta-lactam compounds of the formula (I?, the term "lower" is intended to mean a group 15 having not more than 10 carbon atoms, preferably not more than 8 carbon atoms, more preferably not more than 5 carbon atoms.
For instance, the lower alkyl group represented by Rl, R2 or R3 may be an alkyl group of 1 to 4 carbon atoms, e.g., methyl, ethyl, n-propyl or isopropyl.
The hydroxyl-protecting group (i.eO the group protecting the hydroxyl group) in the protected hydroxyl group ~ 3 ~ 13 ~3 3 8 Q
may be lower alkoxycarbonyl for example Cl-C4 alkoxycarbonyl (e.g. t-butyloxycarbonyl), halogenated lower alkoxycarbonyl for example, halogenated (Cl-C3)alkoxycarbonyl (e.g. 2-iodoethyl-oxycarbonyl, 2,2,2-trichloroethyloxycarbonyl), ar(lower)-alkoxycarbonyl for example, phenyl(Cl-C4)alkoxycarbonyl op-tionally bearing any substituent(s) on the benzene ring (e.g. benzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitro-benzyloxycarbonyl, p-methoxybenzyloxycarbonyl?, tri(lower)-alkylsilyl for example, tri(Cl-C4)alkylsilyl te.g. trimethyl-silyl, t-butyldimethylsilyl?, substituted methyl for example, Cl-C4 alkoxymethyl (e.g. methoxymethyl), Cl-C4 alkoxy-(Cl-C4~alkoxymethyl (e.g. 2-methoxyethoxymethyl), Cl-C4 alkylthiomethyl (e.g. methylthiomethyl), tetrahydropyranyl, etc.
The carboxyl-protecting group (i.e. the group protecting the carboxyl group) and the thiocarboxyl-protecting group (i.e. the group protecting the thiolcarboxyl group) may be conventional ones, and specific examples include lower alkyl for example, Cl-C4 alkyl (e.g. methyl, ethyl, isopropyl, t-butyl?, halogenated lower alkyl for example, halo-genated Cl-C3 alkyl (e.g. 2-iodoethyl, 2,2,2-trichloro-ethyl), lower alkoxymethyl for example, Cl-C4 alkoxymethyl (e.g.
methoxymethyl, ethoxymethyl, isobutoxymethyl), lower ali-phatic acyloxymethyl for example, Cl-C5 alkanoyloxymethyl (e.g.
acetoxymethyl, propionyloxymethyl, butyryloxymethyl, piva-loyloxymethyl?, lower alkoxycarbonyloxyethyl for example, 1-(Cl-C4 alkoxycarbonyloxy)ethyl (e.g. l-methoxycarbonyloxy-ethyl, l-ethoxycarbonyloxyethyl~,optionally substituted lower alkenyl for example, C3-C10 alkenyl optionally sub-stituted with Cl-C4 alkyl or phenyl (e.g. allyl, 2-methylallyl, 3-methylallyl, 3-phenylallyl), optionally substituted mono-aryl(lower)alkyl for example, phenyl(Cl-C4)alkyl optionally bearing any substituent(s) chosen from Cl-C4 alkoxy, nitro, halogen and the like on the benzene ring (e.g. benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-chlorobenzyl), optionally substituted diaryl-(lower)alkyl for example, diphenyl(Cl-C4)alkyl optionally bearing any substituent(s) chosen from Cl-C4 alkoxy and the like on the benzene ring(s) (e.g. diphenylmethyl, di-p-anisyl-methyl?, aryl for example, phenyl optionally substituted with halogen, nitro, Cl-C4 alkoxy or the like (e.g. phenyl, p-chlorophenyl, 2,4,5-trichlorophenyl, p-nitrophenyl, o-nitrophenyl, p-methoxyphenyl), heteroaryl for example, pyridyl or pyrimidyl optionally substituted with Cl-C4 alkyl (e.g.
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 2-(4,6-dimethyl) pyrimidyl?, phthalidyl, etc.
The carboxyl-activating group (i.e. the group activating a carboxyl group) and the thiolcarboxyl-activating group (i.e. the group activating a thiolcarboxyl group may be the ones respectively derived from carboxyl and thiolcarboxyl so as to enhance their reactivity, and their examples include active ester, active acid anhydride, etc.
Specific examples of the symbol Z include halogen (e.g. chlo-rine, bromine, iodine?, lower alkoxycarbonyloxy for example, Cl-C5 alkoxycarbonyloxy (e.g. ethoxycarbonyloxy, isopropoxy-carbonyloxy, sec-butoxycarbonyloxy?, lower alkanesulfonyloxy 13~3~80 for example, Cl-C4 alkanesulfonyloxy (e.g. methane-sulfonyl-oxy), arylsulfonyloxy for example, phenylsulfonyloxy optionally bearing any substituent(s) on the benzene ring (e.g. p-toluenesulfonyloxy), di(lower)alkylphosphoryloxy for example, di(Cl-C4)alkylphosphoryloxy (e.g. dimethylphos-phoryloxy, diethylphosphoryloxy?, diarylphosphoryloxy for example, diphenylphosphoryloxy optionally bearing any substi-tuent(s) on the benzene ring (e.g. diphenylphosphoryloxy?, cyclic imidoxy for example, N-succinimidoxy or N-phthalimidoxy, heteroaryl for example, imidazolyl or triazolyl, heterocyclo-alkyl for example, 3-(2-thioxo)thiazolidinyl, etc.
Production of the beta-lactam compounds ~I) according to the invention will be hereinafter explained in detail.
lS Process A:-The beta-lactam compound of the formula:

X IR2 R~

Rl ~ N \ COY R5 (I-l) O . CH2COOR4 wherein Rl, R2, R3 and X are each as defined above, Y is an oxygen atom or a sulfur atom, R4 is a protective group for the carboxyl and R5 is a protective group for the carboxyl or thiolcarboxyl is obtainable by reacting a compound of the formula:

- 6 - ~313380 _ R2 R3 Rl n COY'R5 (II) o~L~EI

wherein R1, R2, R3, R5, X and Y' are each as defined above with a compound of the formula:
M-CH2COOR4 (III) wherein R4 is as defined above and M is an activated hydroxyl group, i.e. an active ester,in an inert solvent in the presence of a base. If necessary, a phase transfer catalyst may be used.
Examples of the inert solvent include aromatic hydrocarbons (e.g. benzene, toluene), ethers (e.g.
tetrahydrofuran, dioxane, diethyl ether), halogenated hydrocarbons (e.g. methylene chloride, dichloroethane, chloroform), ketones (e.g. acetone, methyl isobutyl ketone), acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric amide (HMPT), t-butanol, water, etc.
These may be used solely or in combination. As the base, there may be used organic bases (e.g. 1,8-diaza-bicyclo[5.4.0]undeca-7-ene (DBU), alkali metal hydrides ~e.g. sodium hydride, potassium hydride), metal salts of amines (e.g. sodium amide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide), alkali metal hydroxides (e.g.
sodium hydroxide, potassium hydroxide~, alkali metal carbonates ~e.g. sodium carbonate, potassium carbonate), alkali metal alkoxides (e.g. potassium t-butoxide), etc. As ~ 7 - 13~338~

_ the phase transfer catalyst, there may be employed benzyl triethyl ammonium chloride, tetra-n-butyl ammonium bromide, tetraethyl ammonium bromide, etc.
The base or the phase transfer catalyst may be used in such an amount that the reaction proceeds smoothly.
Occasional heating or cooling is desirable to accelerate or control the reaction.
Still, preferred examples of the reactively modified hydroxyl group represented by M are active esters for example, suIfon~l esters-(e.g. mesylate,-tosylate) and halogens (e.g. chlorine, bromine, iodine).
Process B:-(1) ~he beta-lactam co~pound of the formula:

X>~ ~
Rl ~ COOH (I-2) 0~

wherein R1, R2, R3, R4 and X are each as defined above is obtainable by subjecting the compound (I-1) wherein Y' is a sulfur atom to selective hydrolysis. The selective hydroly-sis may be carried out by a per se conventional procedure, for instance, under basic conditions.-` - 8 - 13133g~

(2) The beta-lactam compound of the formula:

>1,~
Rl l l COOR5 (I-3) wherein R1, R2, R3, R4 and X are each as defined above and R5 is a hydrogen atom or a protective group for the carboxyl but at least one of R5 and R4 represents a hydrogen atom can be prepared by eliminating at least one of the protec-tive groups R4 and R5 from the compound ~I-l) wherein Y' is an oxygen atom.
(a) When both of R5 and R4 in the compound (I-3) represent hydrogen atoms, a protective group R4 may be introduced therein. (b) When R5 and ~4 in the compound (I-3) represent respectively a protective group and a hydrogen atom, a protective group R4 may be introduced therein, followed by selective elimination of the protective group R5. In both cases, the beta-lactam compound (I-2) can be obtained as the ultimate product.
Elimination of the protective group(s) R4 and/or R5 may be accomplished by various per se conventional procedures depending on the protectiYe ~roup,and those procedures can be chosen from hydrolysis, catalytic reduction, treat-ment with acids or bases, reduction, etc. For selectiveelimination of either one of the protective groups R4 and R5, it is convenient to select an appropriate combination of 9 13~3~

R4 and R5 so as to make such selective elimination possible.
The introduction of the protective group R4' in the case (a) as well as the introduction of the protective group R4 and the subsequent elimination of the protective group R5 may be 5 accomplished by ~ se conventional procedures.
Process C:-The beta-lactam compound of the formula:

COOZ' (I-4) wherein R1, R2, ~3, R4 and X are each as defined above and COZ' is an activated ox protected carboxyl group or an 10 activated or protected thiolcarboxyl group can be produced by subjecting the compound (I-2) to any treatment for converting the carboxyl group into an activated or protected carboxyl or thiolcarboxyl group.
When the -COZ' group represents an activated carboxyl group for example, an active ester or an active acid anhydride or a protected thiolcarboxyl group, the symbol Z' may be any one chosen from those as hereinabove exemplified for the symbol Z. In case of the -COZ' group being a substituted aryloxy group, for instance, it may be preferably p-nitro-phenyloxy, o-nitrophenyloxy, 2,4,5-trichlorophenyloxy or the like. In case of the -COZ' group being a heteroaryloxy group, it is preferred to be o-pyridyloxy, p-pyridyloxy or the like.

- lo ~3~338~

The above conversion may be accomplished by various procedures, of which typical exzmples are shown below:
(a) The compound (I-2) is reacted with a halogenating agent (e.g. oxalyl chloride, thionyl chloride) in the presence or absence of a base to obtain the corres-ponding acid halide.
(b) The compound (I-2) is reacted with a chloro-formic ester le.g. ethyl chloroformate) in the presence of a base to obtain the corresponding mixed acid anhydride.
(c) The compound (I-2) is re~cted with l,l'-car-bonyldiimidazole to obtain the corresponding acylimidazole derivative.
(d) The compound (I-2) is reacted with thiazoli-~ine-2-thione in the presence of a dehydrating agent (e.g.
dicyclohexylcarbodiimide) to obtain the corxesponding acylthiazolidine-2-thion derivative.
(e1 The compound (I-2) is reacted with a thiol pound for e~le, a substituted or unsubstituted thiophenol, 4,6-dimethyl-2-mercaptopyrimidine or 2-mercaptopyridine with the aid of a dehydrating agent (e.g. dicyclohexylcarbodi-imide), or is converted into its active esterfor e~ple, acid halide, mixed acid anhydride or acylimidazole derivative, followed by reacting with said thiol compound.
(f) ~he compound (I-23 is reacted with a hydroxyl compound for ~mple~N-hydroxysucc~mide, N-hydroxyphthalimide, a substituted or unsubstituted phenol or 2-pyrridone with the aid of a dehydrating agent (e.g. dicyclohexylcarbodiimide), 13~ 338~
or is converted into its active ester for.e~le, acid halide, mixed acid anhydride or acylimidazole derivative, followed by reacting with said hydroxyl compound.
Process D:-The beta-lactam compound of the formula:

X>~ ~
Rl r l COY~R5 (I-6~

0~ CH2COSR4 wherein Rl, R2, R3, R5, X and Y' are each as defined above and R4 is a thiolcarboxyl-protecting group can be obtained by reacting a compound of the formula:

R~COY ' R5 (I-5) C~I2COOH
`- wherein Rl, R2, R3, R5, X and Y' are each as defined above 10 with a thiol of the formula:
, ~SR4 wherein R4 is as defined above.
The reaction may be carried out by a ~er se conventional procedure for acylation of a thiol group.

- 12 - 1 3 ~ 3~ 80 Process E:-The beta-lactam compound of the formula:

X~, I
R ~ ~ COZ' (I-7~

' O H2CSR4 wherein Rl, R2, R3, R4, X and Z' are each as defined above can be produced from the corresponding compound (I-6) ac-5 cording to the procedure as explained in Processes B and C.
Process F:-The beta-lactam compound of the formula:

R~ COOH (I-2) O CH2C~OR4 wherein Rl, R2, R3 and R4 are each as defined above and X' is a hydrogen atom or a protected hydroxyl group can be 10 produced by reacting the compound of the formula:.

OH
1 ~ (IV~

O H

wherein Rl, R2, R3 and X' are each as defined above with an acetic acid compound of the formula:

- 13 - 1~33~

M-C~2CR4 (III) wherein R4 and M are each as defined above in an inert solvent in the presence of a base and subjecting the resulting product of the formula:

OH
Rl r l (v) wherein Rl, R2, R3, R4' and X7 are each as defined above 5 to oxidation.
In the above process, the reaction at the first step may be carried out substantially by the same process as in Process A. The oxidation at the second step may be effected by a per se conventional procedure for conversion 10 of a primary alcohol into the corresponding carboxylic acid, for instance, by treatment with an oxidizing agent (e.g.
chromium (VI) oxide-sulfuric acid, chromium oxide-pyridine).
As stated above, the beta-lactam compounds lI) of the invention are useful as intermediates for production 15 of l-alkylcarbapenem compounds. For instance, a compound of the formula:

~ 2 13 R ~ COZ' (I-8) 0 ~2COYF~4 - 14 - 131~

wherein Rl, R2, R3, Y and Z' are each as defined above, X' is a hydrogen atom or a protected hydroxyl group and R4 is a carboxyl or thiolcarboxyl-protecting group, which covers the compounds (I-4) and (I-7) as well as the corresponding 5 compounds derived therefrom, when the symbol X represents a hydroxyl group, by protection of such hydroxyl group in a per se conventional procedure, may be used as the starting material, which is converted into the 1-alkylcarbapenem compound (I) in various ways, of which typical examples are 10 shown below.
Procedure (1):-COY4 ~ ~ ~

COYR"
(I-8) (VI) 4 wherein Rl, R2, R4, X', Y and Z' are each as defined above and R3 is a hydrogen atom or a lower alkyl group.
The beta-lactam compound (I-8) is treated with a 15 base in an inert solvent to give the compound (VI). When R3 is a lower alkyl group, there can ~e obtained as the major product the compound (VI) retaining the steric configuration based on the asymmetric carbon atom at the 5-position bonding to the 4-position of the beta-lactam ring in the 20 starting compound (I-8). As the inert solvent, there may be used ethers (e.g. diethyl ether, tetrahydrofuran, - - 15 ~ g0 dioxane, ethylene glycol dimethyl ether), aromatic hydro-carbons (e.g. benzene, toluene), acetonitrile, dimethyl-formamide, hexamethylphosphoric triamide (HMPT), t-butanol, etc. These solvents may be used solely or in combination.
5 Preferred examples of the baseinclude me ~ salts of amines (e.g. lithium diisopropylamide, lithium bis(trimethylsilyl)-amide, sodium amide), metal salts of alcohols (e.g.
potassium t-butoxide), alkali metal hydrides (e.g. sodium hydride, potassium hydride), sodium methylsulfinylmethide, 10 etc.
The base is to be used in such an amount that the reaction can proceed smoothly, and it may be usually from 1.5 to 3 equivalents to the starting compound (I-8~. The reaction ~emperature may be accelerated or controlled by 1~ heating or cooling, and it may be normally from -75 ts 50C.
Reo~y-of the produced compound (VI) from the reaction mixture may be accomplished by application of a per se conventional procedure for post-treatment. However, post-treatment of the reaction mixture should be 20 effected with special care, because, for instance, the alkyl group at the l-position of the compound of the formula:

X~
Rl ¦ >=o ~VI-l) 0~ ~

wherein Rl, R2, R3, R4, X' and Y are each as defined above - 16 _ 1313~

may be epimerized on treatment with a base or during concentration.
~ l-a) The thus produced compound (VI) wherein Y is an oxygen atom can be converted into the corresponding S l-alkylcarbapenem compound having an antimicrobial activity according to the following route:

X~=o ~ Rl ~5--Ro (VI I ) COOR4 (VII ~ ) COOR4 X~
~1 ~ ",/> S-~o (VIII) COOH

wherein Rl, R2, ~3, R4 and X' are each as defined above and X is a hydrogen atom or a hydroxyl group and Ro is an organic group.
The compound (VI') is first converted into the carbapenem compound (VII') by the procedure as described in U.S. Patent 4,350,631, European Patent 54,917 or Japanese Patent Publication (unexamined) No. 123182/82 or any similar procedure thereto. Then, the resulting carbapenem compound 15 (VII') may be, if necessary, subjected to elimination of the hydroxyl-protecting group, elimination of the carboxyl-~L31338~

protecting group and/or elimination of the amino-protecting group to give the carbapenem compound (VIII).
Eliminatlon of the protecting group may be accomplished by a ~ se conventional procedure, althcugh it ~varies- with the kind of the protecting group. When, for instance, the hydroxvl-protecting group and the nitrogen-protecting group in the compound (VII) are haloaenated lower alkoxycar~onyl or arllower)alkoxycarbonyl or the carboxy-protecting group in the compound (VII) are halogenated lower alkyl, ar(lower)alkyl or b~hydryl, it may be eliminated by application of an appropriate reduction. Such reduction may be effected using zinc with acetic acid, tetrahydrofuran or methanol in case of the protecting group being halo(lower)-al~oxycarbonyl or ~alo(lower)alkyl, or using a catalyst e.g., platinum or palladium-carbon in the case-where the protect~
group is ar(lower)alkyloxycarbonyl, ar(lower)alkyl or benzhydryl.
When a catalyst as stated above is used, the reduction is no~mally effected in an inert solvent chosen from lower al]canols te.g. methanol, ethanol), ethers (e.g.
tetrahydrofuran, dioxane), organic acids (e.g. acetic acid), water and buffers le.g. phosphate buffer, morpholinopropane-sulfonate buffer), etc. These solvents may be used solely or in combination. The reaction temperature may be usually from 0 to 100C, preferably from 0 to 40C. The hydrogen pressure may be ;atmospheric or elevated.
Still, such a protecting group as o-nitrobenzyl-oxycarbonyl or o-nit-obenzyl may be eliminated also by 3 3 ~ ~
.
photo-reaction.
(1-b) The compound (VI~ wherein Y is a sulfur atom can be converted into the corresponding carbapenem compound according to the following route:

X~ I X'~ I

O ; Rl ~ SRo (VI~) CSR4 / I COSR4 ~ ~ (VII") 1 ~ ~ S~ ~ SRo (VII') COOR4 (VIII~

wherei~ Rl, R2, R3, R4, R4, Ro, X' and X are each as defined above.
The compound (VI") is first converted into the carbapenem compound (VII n ) in the same manner as in (l-a).
Then, the carbapenem compound (VIIn) may be, if necessary, subjected to elimination of various protecting groups. As to a thioester group, the application of a p r ~e conven~
tional hydrolytic procedure can successfully accomplish its elimination giving the carbapenem compound (VIII;. Instead of application of the hydrolytic procedure, treatment with a lS silyl compound e.g.,- silanol may be applied to the carba-- 19 ~3~3~

penem compound (VII") so that the carbapenem compound (VIII) can be obtained directly. Alternatively, the carbapenem compound (VII n ) may be treated with an alcohol in the presence of a silver salt te.g. silver trifluoroacetate) to give the compound (VII'), which is then treated in the same manner as in (l-a) to give the carbapenem compound (VIII).
In the substituent SRo of the carbapenem compounds (VII') and (VII"), Ro may be any one as heretofore used in connection with carbapenem compounds, and its examples include substituted or unsubstituted alkyl or alkenyl having 1 to 10 carhon atoms; cycloalkyl, alkylcycloalkyl or cyclo-alkylalkyl in which the cycloalkyl group has 3 to 6 carbon atoms; aryl le.g. phenyl), aralkyl wherein the aryl group is phenyl and the alkyl portion has 1 to 6 carbon atoms;
heteroaryl, heteroarylalkyl or heterocycloalkyl, etc. These groups may optionally ~ear at least one substi-tuent chosen from amino, mono-, di- or trialkylamino, hydroxyl, alkoxy, mercapto, alkylt~io, arylthio (e.g.
phenylthio), sulfamoyl, amidino, guanidino, nitro, ~alo (e.g. chloro, bromo, fluoro), cyano and carboxyl. In said substituents having a hetero ring, the hetero atom(s) in the hetero ring may be chosen from oxygen, nitrogen and sulfur, and their number may be from 1 to 4. The alkyl moiety in said subs~ituents may have 1 to 6 carbon atoms.

- 20 - ~3 Procedure (2):-COZ; ~ ~Rl ~ 3 (I-8) (VI-2) R-A ~ R ~ 0-8 + R-Z' + A

(VI-2) ~2 R3 3 ~

COY~4 (IX) wherein R1, R2, R3, R4, X', Y and Z' are each as defined above and L is an activated hydroxyl group e.g.,- an active ester of hydroxyl, B is an alkali metal atom and R-A is an alkylating or acylating agent.
For the direct production of the compound (IX) from the compound ~I-8), the latter is treated as in Procedure - 21 - 13~3~

(1). Without isolation of the product, the reaction mixture is treated with an alkylating or acylating agent (e.g. iodo-methane, iodopropane, allyl bromide, benzyl bromide, methyl p-toluene sulfonate) so as to catch the residue of the activating group e.g., an active ester residue, an active acid anhydride residue or a thiol residue, followed by treatment with a hydroxyl-activating agent e.g., an active esterifying agent for hydroxyl to give the carbapenem compound ~IX). The treatment with the alkylating or acylating agent is preferably caxried out in the presence of a base in an inert solvent.
~ s the active ester of hydroxyl represented by the symbol L, there are exemplified substituted or unsubstituted arylsulfonic esters (e.g. benzenesulfonic esters, p-toluene-15 sulfonic esters, p-nitroben2enesulfonic esters, p-bromo-benzenesulfonic esters3, lower alkanesulfonic esters (e.g.
methanesulfonic esters, ethanesulfonic esters), halo(lower)-alkanesulfonic esters (e.g. trifluoromethanesulfonic esters), diarylphosphoric esters (e.g. diphenylphosphoric 20 esters), halides (equal to esters with hydrogen halides) (e.g. chlorides, bromides, iodides), etc. Preferred are p-toluenesulfonic esters, methanesulfonic esters, diphenyl-phosphoric esters, etc. Accordingly, any reagent which is reacted with the compound (VI-2) to give the acti~e ester as 25 exemplified above may be used as the active esterifying agent. Examples of the alkali metal atom represented by the s~l B ~ lud~ li~um, sodium, potassium, etc. As the base, there may be used the one as exemplified in Procedure (1) i3~38~

:
for production of the compound (VI).
When the symbol R3 in the compound (I-8) is a lower alkyl group, its treatment with a base in an inert solvent affords the enolate salt (VI-2), which retains the steric configuration on the basis of the asymmetric carbon atom at the 5-position of the compound ~I-8). Even after . conversion of the enolate (VI-2) into the compound (IX), the steric configuration of the alkyl group represented by the symbol R3 is unchanged. Thus, adoption of th~s Procedure (2) gives the carbapenem compound (IX) without epimeriza-tion. Still, the enolate (VI-2) in this case has a possi-bility of taking a chelate structure of the formula:

R2 ~3 Rl~ _ O
o ~N ~= B

..
wherein R1, R2, R3~ R4, X', Y and B are each as defined above.
The active esterifying agent is to be used in an amount sufficient to effect the reaction smoothly, and its amount may be from 1 to 1.5 equivalents to the compound (I-8). The reaction temperature may be usually from -78 -to 60C, prererably from -40 to 10C.

- 23 ~ 131 3 38 0 , Procedure ( 3 ): -~?~co; ~ o-~+3~)z6 1 : COYR4 (I-8) (VI-2) R--A ~ o--9 + R-Z ~ +

(VI-2 ) ~L + R-Z' + A(~136) ( IX) Ro ~ i ~ S-Ro (VII ) - 24 - 13~3~8~

wherein Rl, R2, R3, R4, Ro, R-A, B, X', Y and Z' are each as defined above.
When direct production of the carbapenem compound - (VII) from the compound (I-8) is desired, the latter may be converted into the carbapenem compound (IX) in the same manner as Procedure (2). Without isolation of the compound (IX), the reaction mixture is treated with a mercaptan compound of the formula:
Ro~SH (X) wherein Ro is as defined above in the presence of a base to give the carbapenem compound (VII). The base to be used in the treatment with the mercaptan compound (X) may be the same as or different from that as used in the cyclization of the compound (I-8) to the compound (IX). Likewise, the inert solvent to be used in said treatment may be the same as or different from that as used in said cyclization.
As the base, there may be used one chosen from those as exemplified in Procedure (1). Other examples of a suitable base include organic amines è.g., triethylamine,-diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabi-cyclo[5.4.0]-7-undecene (DBU), 1,5-diazabicyclo[4.3.0~-5-nonene (DBN) and 1,4-diazabicyclo[2.2.2]octane (DABCO).
Preferred examples of the solvent which is used to-ensure a smooth reaction include acetoni-trile, dimethylform-amide, dimethylsulfoxide, etc.
The base to be used together with the mercaptan compound (X) may be employed in such an amount to assure a` smooth reaction, and its amount may be - 25 - 13~3~8~

in a large excess, preferably from 1 to 2 equivalents to the compound (I-8). The mercaptan compound (X) and the base may be introduced into the reaction system separately.
Alternatively, the salts formed between them may be added to the reaction system.
Conversion of the beta-lactam compound (I-8) into the carbapenem compound (IX) may be accomplished by carrying out the reactions as above explained in order. When desired, the carbapenem compound (IX) is subjected to hydrolysis or elimination of the protecting group so that the carbapenem compound (VII) can be-obtained. The hydrolysis or ~he elimination of the protecting group may be carried out in the same manner as in Procedure (l-a) (i.e.
conversion of the compound (VII') into the compound (VIII)) or (1-b) (i.e. conversion of the compound (VIIn) into the compound (VIII)).
A typical example of the conversion from the beta-lactam compound (I-8) into the l-beta-methylcarbapenem compound is shown below:

- 26 - 13~3~

~Ri O jORi O

¦' ~LT~O-B + B(~3Z ~3 N~ //
O `CH2cOYR4 O

(I-8 ) (VI-2 ) ORi O

R-A ~ ~ ~ -B + Q-Z' ~ A~

(VI-2 ) ORl~ ORlo H H H H

3 , ~ Ro ~IX ) (VII ) wherein R4, Y, Z', B, R-A, L and Ro are each as defined above and Rlo is a hydroxyl-protecting ~roup.
Namely, 1) the beta-lactam compound (I-8 ) is treated with a base in an inert solvent, 2) the residue Z' is caught with an alkylating or acylating agent and then 3) - 27 - 13~3~

the resulting product is treated with a hydroxyl-activating group e.g., an active esterifying agent for hydroxyl.
When desired, 4J the resultant product is reacted with the mercaptan compound (X) in the presence of a base or the salt of the mercaptan compound (X) with the base. These reac-tions may be carried out in a single re~ction vessel in order to give the carbapenem compound IIX ) or (VII ).
Alternatively, the compound (I-8 ) may be subjected to the reaction in 1), followed by post-treatment to give the compound of the formula:

ORlo (VI ) ro O

wherein R4, Rlo and Y are each as defined above. The beta-methyl group at the l-position is apt to be epimerized when the product is stored in a high concentration solution or in a polar solvent e.g., acetonitrile. Thus, the stereo-specific production of the compound (IX ) from the compound(VI ) as once isolated in a large scale would have a technical problem. To the contrary, the conversion of not the compound (VI ) but the compound (VI-2 n ~ into the compound (IX ) is advantageous, because the production of * *
the compound (IX ) or (VII ) can be accomplished without epimerization of the methyl group at the l-be~a-position.

- 28 - 1313~8~
.
The compound lII) as the starting material in production of the beta-lactam compound (I) according to this invention can be produced in the manner as described in U.S.
Patent 4,350,631, European Patent 54917 or Japanese Patent Publication (unexamined) No. 123182/82. For production of the compound (II) wherein Y is a sulfur atom, introduction of the -SR4 group may be carried out by a conventional procedure as in the case of production of the compound (I-6). While the starting compound (IV) can be produced in the same manner as described in European Patent 10317 or Japanese Patent Publication (unexamined) No. 8g285~80, it may be produced according to the route as shown in the following scheme:

X ~ COOH X ~ COOR4 J_~ ~ R~
O - R' O N R' ll) (2) Rl j~ ` R;7~\ D

o ~ R' O - R' (3) (4) - 29 _131~38~

~ ~ J

(5) (6) X ~ ¦

O \ R' R' (7) (8) X~ 0 N

(IVa) wherein Rl, R2, X and X' are each as defined above, R' is a nitrogen-protecting group, A' is a halogen atom and P is a hydroxyl-protecting group.
In the above scheme, the step A is directed to conversion of the carboxylic acid (1) into the corresponding ester (2). The conversion is usually carried out by appli-cation of a per se conventional esterification procedure.
For instance, the carboxylic acid (1) obtained by the process as described in Japanese Patent Publication (un-examined) No. 96060/83 may be reacted with an alkyl halide 13~33~

in the presence of an acid-eliminating agent or with an alkanol in the presence of a dehydrating agent to give the ester (2).
At the step B, the ester (2) is reduced by treat-ment with an organic metal compound e.g., magnesium halideor methyl lithium in an inert solvent, optionally followed ~y protection of a hydroxyl group in a ~er se conventional procedure to give the corresponding alcohol (3).
At the step C, the alcohol (3) is dehydrated by treatment with a dehydrating agent e.g., thionyl chloride or tosyl chloride in the presence or absence of a base to give the corresponding methylene compound (4).
At the step D, the methylene compound (4) is halogenated by treatment with a halogenating agent e.g., molecular halogen or N-halogenosuccinimide in an inert solvent to give the corresponding halogenated compound ~5).
At ~he step E, the halogenated compound (5) is hydrolyzed by treatment with water in the presence of a low atomic valency ion salt of a heavy metal ~e.g. copper, silver) to give the corresponding hydroxyl compound (6).
At the step F, the hydroxyl compound (6) is subjected to protection on the hydroxyl group to give the corresponding protected hydroxyl compound (7).
At the step G, the protected hydroxyl compound (7) is hydrogenated by catalytic hydrogenation to give the corresponding methyl compound ~8).
At the step H, the methyl compound (8) is sub-jected to elimination of the hydroxyl-protecting group - 31 - 13~33~
. --represented by the symbol P and elimination of the amino-protecting group represented by the symbol R' simultaneously or stepwise to give the corresponding free compound (IVa).
In the beta-lactam compound (I), the carbon atoms at the 3- and 4-positions and the carbon atom bonding to the beta-lactam ring and in the substituent attached to the ,, 4-position of such beta-lactam ring are all asymmetric , - carbon atoms. Further, in the casewhere all of Rl, R2 and X
are different ~xm one another (e.g. Rl = methyl, R2 = hydrogen, X = hydroxyl), the carbon atom bonding to the beta-lactam ring and in the substituent attached to the 3-position of such beta-lactam ring is an asymmetric carbon atom.
Accordingly, the beta-lactam compound of the formula (I~
covers optical isomers and stereo isomers due to said asymmetric carbon atoms. Among those optical isomers and stereo isomers, the compounds of the following formula:

J~
,. ~ COz wherei~ R3, R4 and Y and Z are each as defined aboveJare particularly preferred in that they,have the same',configuration as that of naturally occuring thienamycin at the carbon atom at the 4-position.
Practical and presently preferred embodiments of the invention are illustratively shown in the following Examples and References Examples. This invention is, - 32 - ~3~338~

however, not limited to these examples. In these examples, the abbreviations have the following meanings: TBDMS, t-butyldimethylsilyl; Ph, phenyl; tBu, t-butyl; PNB, p-nitrobenzyl; PMB, p-methoxybenzyl; Im, l-imidazolyl; Bt, l-benzotriazolyl; Ac, acetyl; PNZ, p-nitrobenzyloxycarbonyl;
DAM, di(p-anisyl)methyl; Z, benzyloxycarbonyl; Me, methyl.

13133~0 Exam~Le 1-1 OTBDMS OTBDMS
H H ~ ~ H H ~
COOcx2Ph ~L I COOC~I2Ph N ~ - ~ ~ N
O H O ~ CH2COOtBu To a solution of (3S,4S)-3-[(lR)-l-t-butyldi-methylsilyloxyethyl]-4-~(lR)-l-benzyloxyczrbonylethyl]-azetidin-2-one ~755 mg) in methylene chloride (10 ml), there were added successively t-butyl bromoacetate (1.88 g), 50 %
S sodium hydroxide (620 mg) and triethylbenzylammonium chloride (220 mg), followed by stirring at room temperature for 2 hours. The reac~ion mixture was diluted with water and diethyl ether. The aqueous layer was separated from the organic layer and extracted twice with diethyl ether.
The extracts were cor~ined with the organic layer, washed with water twice and with brine three times, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(lR)-l-t-butyl-di~ethylsilyloxyethyl]-4-~(lR)-l-benzyloxycarbonylethyl]-lS l-(t-butyloxycarbonylmethyl)azetidin-2-one.
IR vmaxat (cm 1): 1755, 1730, 1450, 1400, 1380, 1360, 1242, 1~20, 1150, 830, 765, 740, 685.
NMR ~ (CDCl3): 0.04 (3H, s), 0.07 (3H, s), 0.85 (9H, s), 1.23 (3H, d, J = 6.3 Hz), 1.24 (3H, d, J = 6.9 ~z), 1.44 (9H, s~, 2.90 (1~, qd, J = 6.9 and 3.6 H,), 2.99 (;H, dd, J = 2.0 and 6.6 Hz), 3.83 (2H, m), 5.10 (2H, s), 7.35 (SH, s).

- 34 _ ;
Example 1-2 OTBDMS OTBDMS
~ H H I ~ H H
/\ ~\ ~\
~ ¦ COOCH2Ph ~ I COOH

O CH2COOtBt O ~CH2COOt~3u A solution of (3S,4S)-3-~(lR)-1-t-butyldimethyl-silyloxyethyl]-4-[(lR)-1-benzyloxycarbonylethyl]-1-(t-- butyloxycarbonylmethyl)azetidin-2-one (0.45 g) in 99.5 %
ethanoi (6 ml) was subjected to hydrogenation at room tempera~ure in the presence of 10 % palladium-carbon (90 mg) under atmospheric pressure, followed by filtration to remove the catalyst. The filtrate was evaporated to give (35,4S)-3-[(lR)-1-t-butyldimethylsilyloxyethyl]-4-[(lR)-l-carboxy-ethyl]-l-(t-butyloxycarbonylmethyl)azetidin-2-one.
10IR ~naxt (cm 1~: 1760, 1740, 1730, 1455, 1360, 1245, 1224, 1150, 830, 770, 745.
NMR ~ (CDC13): 0.06 (3H, s), 0.08 (3H, s), 0.87 (9H, s), 1.24 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.3 Hz), 1.48 (9H, s), 2.94 tlH, ~d, J = 7.1 and 3.0 ~z), 3.04 (lH, 15dd, J = 2.3 and 5.5 Hz), 3.98 (2H, m), 4.00 (lH, m), 4.21 (lH, m).
Example 1-3(1) OTBDMS OTBDMS
~ H H 7 ~ H H ~
~ COOH ~ COSPh 0~ CH2COOtBu 0 ~CH2COOtBu A mlxture of (3S,4S)-3-[(lR)-1-t-but~ldimethyl-silvloxyethyl]~ (lR)-l-carboxyethyll -l-(t-butyloxy-~33~

carhonylmethyl)azetidin-2-one (1.29 g) and N,N'-carbonyl-diimidazole (604 mg) in dry acetonitrile (25 ml) was stirred at room temperature for 1 hour. To the mixture, there were aaded successively a solution of thiophenol (410 mg) in dry acetonitrile (6 ml) and a solution of triethylamine (377 mg) in dry acetonitrile (6 ml). After stirring at room temper-ature for 0.5 hour, the reaction mixture was diluted with ethyl acetate and dilute hydrochloric acid. The aqueous layer was separated from the organic layer and extracted with ethyl acetate three times. The extracts were combined with the organic layer, washed with brine twice, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to gi~e (3S,4S)-3-[(lR)-l-t-bu~yldimethylsilyloxyethyl]-~-[(lR~-l-phenylthio-carbonylethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one.
IR vmaxt (cm )~: 1760, 1740, 1705, 1367, 1250, 1227, 835, 770, 740.
~ xample 1-3(2) OTBDMS OTBDMS
H H ~ ~ H H
~-~COO~ ~/~/\COS~C

O CH2COOtBu O ~CH2COOtBu In the same manner as in Example 1-3(1) but replacing thiophenol by p-chlorothiophenol, there was obtained (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxy-ethyl]-4-[(lR)-l-p-chlorophenylthiocarbonylethyl]-l-tt-butoxycarbonylmethyl)azetidin-2-one.
IR ~ma~ (cm ): 1760, 1740, 1705, 1480, 1365, 131~3~9 1260, 1230, 1155, 1095, 838, 775.

N~ ~ (CDC13): 0.10 (6H, s), 0.89 (9H, s), 1.26 t3H, d, J = 6.3 Hz), 1.31 (3H, d, J = 6.9 Hz), 1.43 (9H, s), 3.02 tlII, dd, J = 2.3 and 6.9 ~~), 3.14 (lH, qd, J = 3.3 and 6.9 Hz), 3.92 (2~, m), 7.34 (4H, m).

ExamDle 1-3(3) OTBDMS OT~DMS
r H H ~ ~ H H ~ ~1 COOH ~ COO ~ Cl O CH2COOtBu ~CH2COOtBu To a solution of (3S,4S)-3-[tlR)-l-t-butyldi-methylsilyloxyethyl]-4-[(lR)-l-carboxyethyl]-l-(t-butyloxy-carbonylmethyl)azetidin-2-one (100 mg) and 2,4,5-trichloro-phenol (33 mg) in dry tetrahydrofuran (4 ml), there was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-chloride (96 mg) under ice-ccoling, followed by stirring overnight. The reaction mixture was diluted with diethyl ether and ~ater. The organic layer was separated from the aqueous layer, washed with brine, dried over sodium sulfate and distilled ofr to remove the solvent to give (35,4S)-3-~ )-1-t-butyldimethylsilyloxyethyl]-4-[(lR)-1-~2,4,5-tri-chlorophenyloxy)carbonylethyl]~ t-butyloxycarbonylmethyl)-azetidin-2-one.
IR ~maxat (cm 1): 1760, 1740 (sh), 1455, 1362, 1250, 1225.

~ 3~

Exam~le 1-3(43 OTBDMS OTBDMS

COOH COCl O CH2COOtBu O CX2COOtBu To a solution of (3S,4S)-3-[(lR)-1-t-butyldi-methylsilyloxyethyl]-4-[(lR)-l-carboxyethyl]-1-(t-butyloxy-carbonylmethyl)azetldin-2-one (98 mg) in dry methylene . chloride (1 ml), there was added a solution of thionyl chloride (34 mg) in dry methylene chloride (0.5 ml) at room temperature. The resultant mixture was stirred at the same temperature for l hour and then boiled under reflux for 3 hours. After removal of the solvent, the residue was dissolved in dry toluene, again distilled off to remo~e the solvent and dried in vacuo to give (35,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-~(lR)-1-chlorocarbonylethyl]-l-(t-butyloxycarbonylmethyl)azetidin-2-one.
IR ~naxt (cm 1): 1800 (sh), 1740, 1450, 1360, 1244, 1220, 930, 825, 770.
- 15Example 1-3(5) OTBD~IS OTBDMS

COOH ~ COOBt O CH2COOtBu O C~12COOtBu In the same manner as in Example 1-3(3), (3S,4S)-3-[(lR)-1-t-butyldimethylsilyloxyethvl]-4-[(lR~ carbo~y-ethyl]-l-(t-butyloxycarbonylmethyl)azetidin-2-one (104 mg) was treated with l-o~yben-triazole (5, mg) and 1-ethyl-3-8 ~

(3-dimethylaminopropyl)carbodiimide hydrochloride (93 mg) to give (3S,4S)-3-~(lR)-l-t-butyldimethylsilyloxyethyl3-4-[(lR)-1-(1-benzotriazolyloxy)carbonylethyl]-1-(t-butyloxy-carbonylmethyl~azetidin-2-one IR vmeaat (cm 1): 1740 (sh), 1730, 1450, 1360, 1240, 1220, 822.
Exam~le 1-3(6) OTBDMS OTBDMS
~COOEI ~\cos~1 O CH2COOtBu O ' H2COOtBU
In the same manner as in Example 1-3(3), (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lR)-l-carboxy-ethyl]-l-(t-butyloxycarbonylmethyl)azetidin-2-one ~100 mg~
10 was treated with 2-mercaptopyridine (35 mg) and 1-ethyl-3-(~-dimethylaminopropyl)carbodii~ide hydrochloride (100 mg) to gi~e (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyll-4-[(lR)-1-(2-pyridylthio)carbonylethyl]-1-(t-butyloxycarbonyl-methyl)azetidin-2-one.
15IR ~max (cm ): 1755, 1690, 1360, 1247, 1220, 1142, 830, 770.
Example 1-4 OTBDMS ~ OTBDMS

COSPh ~ COSPh O H O CH2COOtBu To a suspension of sodium hydride (31 mg) in dry dimethylformamide (4.3 ml), there ~-ere added successi~ely ~ 3 ~

t-butyl alpha-bromoacetate !835 mg) and (35,4S)-3-[(lR)-1-t-butyldimethylsilyloxyethyl~-4-[(lR)-1-phenylthiocarbonyl-ethyl]azetidin-2-one (0.42 g), and the resultant mixture was stirred at room temperature for 1 hour under a nitrogen stream. The reaction mixture was diluted with diethyl ether and adjusted to pH 6.86 with a phosphoric acid buffer solution. The aqueous layer was separated from the organic layer and e~tracted with diethyl ether three times. The extracts were combined with the organic layer, washed three times with brine, dried over sodium sulfate and evaporated.
The residue was puriried by silica gel chromatography to give (3S,4S)-3-[(lR)-l-t-butyldi~ethylsilyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-l-(t-butyloxycarbonyl'-methyl)azetidin-2-one.
lhe IR spectrum of the product thus obtained was identical with that of the product in Example 1-3(1).
Example 1-5 H H ~ ~ H H
COS ~ Cl ~ COS ~ Cl O'd O H2COOtBu In the same manner as in Example 1-1, there was obtained (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lR)-l-p-chlorophenylthiocarbonylethyl]-l-t-butyloxy-carbonylmethylazetidin-2-one from (3S,4S)-3-[(lR)-l-t-butyl-dimethylsilyloxye~hyl]-4-[(lRJ-l-p-chlorophenylthiocarbonyl-ethyl]azetidin-2-one.

131~3~
-The IR spectrum and NMR spec~rum of the product thus obtained were identical with those OL the product in Example 1-3(2).
Example 2-1 OZ OZ

/ ~ \`COOCH2Ph ~ COOCH2Ph 0 H O CH2~0OtBu To a solution of ~3S,4S)-3-[(lR)-l-t-benzyloxy-S carbonyloxyethyl]-4-~(lR)-l-benzyloxycarbonylethyl]-azetidin-2-one (71.94 g) in dry dimethylformamide (700 ml), there were added successively t-~utyl bromoacetate (68.25 g) and sodium hydride (9.24 g, S0 ~ oil suspension) with ice-cooling, followed by stirring for 1 hour. The reaction mixture was diluted with a 10 % aqueous ammonium chloride solution (S00 ml), stirred for 30 minutes and extracted with toluene (2 liters). The extract was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by ~ilica gel chromatography to give (3S,4S)-3-[(lR)-l-benzyloxycarbonyloxyethyl]-4-~(lR~ benzyloxy-carbonylethyl]-l-(t-butyloxyca~bonylmethyl)azetidin-2-one.
IR vnaext (cm 1): 1765 (sh), 1740, 1455, 1370, 1268, 1160.
NMR ~ (CDCl3): 1.18 (3~, a, J = 6.9 Hz), 1.45 20 (3H, d, J = 6.3 Hz), 1.45 (9H, s), 2.86 ~lH, m), 3.26 (lH, dd, J = 2.0 and 9.0 Hz), 3.55 (lH, d, J = 18 Hz), 4.04 (lH, dd, J = 2.0 and 4.6 Hz), 4.10 (lH, d, J = 18 Hz).

~31~

ExamPle 2-2 OZ OE~

OOCH2Ph ~ COOH

O ~ N \ CH2COOtBu o ~ L ~ ~ CH2COOtBu A solution of (3S,45)-3-[(lR)-l-benzyloxy-carbonyloxyethyl]-4-ttlR)-l-benzyloxycarbonylethyl]-l-(t-butyloxycarbonylmethyl)azetidin-2-one (81.50 g) in ethanol (800 ml) was subjected to hydrogenation at room temperature in the presen~e of 10 % palladium-carbon (8.15 g) under ~tmcspheric pressure, followed by filtration to remove the catalyst. The filtrate and the washings were combined and evaporated to give (3S,4S)-3-[(1~)-1-hydroxyethyl]-4-[(lR)-l-carboxyethyl]-l-(t-butyloxycarbonylmethyl)azetidin-2-one.
IR ~n-eat (cm 1): ~740, 1720, 1440, 1360.

NMR ~ (CDC13): 1.28 (3~, d, J = 6.9 Hz), 1.33 (3H, d, J = 6.6 Hz), 2.84 tlH, m), 3.09 (lH, dd, J = 2.0 and 6.6 Hz), 3.76 (lH, d, J = 1~ Hz), 4.03 ~lH, dd, J = 2.0 and 5.3 Hz).
Example 2-3 OH OH

COO~ ~COSPh O CH2COOtBu O CH2COOtBu In the same manner as in Example 1-3~1), there was obtained (3S,4S)-3-[(lR)-l-hydroxyethyl]-4-[[lR)-l-phenylthio-Carbonylet~yl]-l-(t-butyloxycarbonylmethyl)azetidin-2-one from (3S,4S)-3-t(lR)-l-hydroxyethyl]-4-[(lR)-l-carboxy-13~3~

.
ethyl]-l-(t-butyloxycarbonylmethyl)zzetidin-2-one.

IR Vma~ (cm ~: 1745, 1725, 1290, }230, 1140 , 950, 750.

Example 3-1 0~ OZ
- ~ H H ~ ~ H H e ~a) / ~ O~

O H 0 CH2COGtBu OZ

(b) ~COOH

O ~H2COOtBu (a) To a solution of (3S,4R)-3-~(lR)-l-benzyloxy-carbonyloxyethyll-4-[(lR)-l-hydroxymethylethyl]-2-azeti-dinone (30.7 g) in acetone (300 ml), there were added t-butyl bromoacetate (33.0 g) and potassium carbonate (27.6 -- g), followed by stirring under reflux for 17 hours. The reaction mixture was cooled down to room temperature and filtered to remove insoluble materials. The filtrate contained (3S,4R)-3-[(lR)-l-benzyloxycarbonyloxyethyl]-4-[(lR)-l-hydro~ymethylethyl]-l-t-butoxycarbonylmethyl-2-azetidinone.
IR ~maxat (cm 1): 1735, 1360, 1250, 1150, 1030, 15 955).
(b) The filtrate was diluted with water (15 ml) and treated with the ~ones reagent, which was prepared from chromium trioxide (16.92 g), 98 ~ sulfuric acid (26.52 g) ~ 43 ~ i 3 ~ 3 ~ ~ a and wate- (~9.2 g), while ice-cooling for l hour. The reaction mixture was quenched with isopropanol and diluted with ethyl acetate (l liter) and water (300 ml). The organic layer was washed with brine (300 ml x 4), dried over magnesium sulfate (50 g) and evaporated in vacuo to give an oily residue, which was purified by silica gel chromato-graphy to give (35,4S)-3-[(lR)-1-ben~yloxycarbonyloxy-ethyl]-4-[(lR)-l-carboxyethyl]-1-t-butoxycarbonylmethyl-2-azetidinone (23.73 5, 54.5 %).
IR ~maxt (cm l): 1735, 1450, 1365, 1250, 1150, 1040.
NMR ~ tCDC13): l.l9 (3P., d, J = 6.9 ~z), 1.46 (9~, s), 3.26 (lH, dd, J = 2.3 and 8.6 Hz), 4.06 ~1~, dd, J
= 2.3 and 4.0 Hz), 7.36 (5H, s).
lS Examsle 3-2 OZ OZ
H
COOH ~~OSPh O CEI2COOtBu O C~I2COOtBu To a solution of (3S,4S)-3-[(lR)-l-benzyloxy-carbonyloxyethyl]-4-[(lR)-1-carboxyethyl]-1-t-butoxy-carbonylmethyl-2-azetidinone (23.75 g) in dry acetonitrile (237 ml), there was added N,N'-carbonyldiimidazcle (10.SS g) under ice-cooling, followed ~y stirring for 0.5 hour.

Thiophenol (7.21 g) and triethylamine (6.62 g) were then added thereto under ice-cooling, followed by stirring for 2.5 hours. The reaction mi~ture was diluted with ethyl 1~33~

acetate (500 ml) and washed with lN hydrochloric acid (200 ml). The aqueous layer was separated from the organic layer and extracted with ethyl acetate ~200 ml x 2). The extract was combined with the organic layer, washed with brine (300 ml x 3), dried over magnesium sulfate and-e~aporated in vacuo to give an oily residue, which was puriried by silica gel chromatography to obtain (3S,4S)-3-[(lR)-1-benzyloxy-carbonyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-l-t-butoxycarbonylmethyl-2-azetidinone (19.46 g, 67.64 %).
IR ~max (cm ): 1760, 1735, 1700, 1440, 1365, 1255, 1150, 1045, 950, 740.
NMR ~ (CDCl3): 1.25 (3H, d, J = 6.9 Hz), 1.44 (9H, s), 1.47 (3H, d, J = 6.2 Hz), 3.12 (lH, m)~ 4.13 (1~, dd, J = 2.6 and 4.5 ~z), 7.36 (lOH, m).
Exam~le 4-1 OTBDMS ~ OTBDMS
H H ; ~ H H
\ COOCH2Ph ~ COOCH2Ph O CH2COOtl3u In the same manner as in Example 1-1, a solution of (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lS)-l-benzyloxycarbonylethyl]azetidin-2-one (3.50 g) in methy-lene chloride (45 ml) was treated with t-butyl alpha-bromo-20 acetate (8.73 g), 50 % aqueous sodium hydroxide solution (2.86 g) and triethylbenzylammonium chloride (1.02 g) to give (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-~-[(lS)-l-benzyloxycarbonylethyl]-l-(t-butyloxymethyl)azeti-~ ~5 ~ 13133~

din-2-one.
IR vmax (cm ): 1760 (sh), 1735, 1455, 1362, 1245, 1222, 835, 773.
Example 4-2 OTBDMS ; OTBDMS

~--COOC~2Ph ~ oo~

O CH2COOtBu O CH2COOtBu In the same manner as in ~xample 1-2, (3S,4S)-3-[~lR)-1-t-butyldimethylsilyloxyethyl]-4-[(lS)-l-benzyloxy-carbonylethyl]-l-(t-butyloxycarbonylmethyl)azetidin-2-one wa~ subjected to hydrogenation to give (3S,4S)-3-~(lR)-1-t-butyldimethylsilyloxyethyl]-4-~(lSJ-l-carboxyethyl]~
(t-butyloxycarbonylmethyl)azetidin-2-one.
10IR ~NUaxol (cm 1): 3300 (broad), 1760 (sh), 1742, 1690, 990, 9~0, 825, 767.
Example 4-3(1) OTBDMS ~ OTBDMS
H EI ~ ~ H H
COOH ~ COSPh O `~CH2COOtBu o ~CH2COOtBu In the same manner as in Example 1-3(1) but replacing the starting material by (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lS)-l-carboxyethyl]-l-t-butoxycarbonylmethyl-2-azetidinone, there was obtained (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lS)-l-phenylthlocarbon~lethyl]-1-t-butoxycarbonylmethyl-2-13~-3~?J~J~

- azetiainone.
IR ~naext (cm 1): 1760, 1740 (sh!, 1700, 1365, 1250, 1225, 950, 830, 773, 740, 680.
Example 4-3(2~
OTBDMS _ OTBDMS

--`coo~ ~\Cos-<~N~C~3 CH2COOtBu ~ X2COOtBu 3 To a solution of (3S,4S)-3-[(lR)-l-t-butyldi-methylsilyloxyethyl]-4-[(lS)-l-carboxyethyl]-1-t-butyloxyca-rbonylmethylazetidin-2-one (lG0 mg) in dry methylene ' - chloride ( ml), there was added oxalyl chloride (37 mg), and the resultant mixture was stirred at room temperature for 2 hours in the presence of a catalytic amount or dimethylformamide. 4,6-Dimethyl-2-mercaptopyrimidine 150 mg) and 4-dimethylaminopyridine (44 mg) were added thereto, Collowed by stirring. The reaction mixture was diluted with methylene chloride, washed with dilute sulfuric acid, water and sodium bicarbonate and brine successively, dried over - 15 sodium sulfate and distilled off to remove the solventO The residue was purified by silica gel chromatography to give (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lS)-1-(4,6-dimethylpyrimidin)-2-ylthiocarbonylethyl]-1-t-butyl-oxycarbonylmethyl)azetidin-2-one.
IR ~ma~ tcm ): 1760, 1740 (sh), 1580, 1362, 1247, 830, 770.

- 47 - 1~3~

~xamPle 4-3(3) OTBDMS _ OTBDMS ~ O

COOH ~ <OO-O CH2COOtBu O CH2COOtBu O
To a solution of (3S,4S)-3-[(lR)-l-t-butyldimethyl-silyloxyethyl]-4-[(lS)-l-caxboxyethyl]-l-(t-butyloxy-- carbonylmethyl)azetidin-2-one (100 mg) and N-hydroxysuccin-imide (33 mg) in dry dimethylformamide (0.3 ml), there was added N,N'-dicyclohexylcarbodiimlde (74 mg), followed by stirring at 0 to 5C overnight. The reaction mixture was diluted with ethyl acetate, followed by addition of sulfuric acid. The a~ueous layer was seprated from the organic layer and extracted with ethyl acetate twice. - The extracts were combined with the organic layer, wasned with water four times and brine, dried over sodium sulfa~e and distilled off to remove the solvent. The residue was purified by silica gel chroma~ography to give 135,4S)-3-[ (lR)-1-t-butyldi-methylsilyloxyethyl]-4-{(lS)-l succinimidoxycarbonylethyl]
1-tt-butyloxycarbonylmethyL~azetidin-2-one.
IR ~meaxt (cm lJ: 1805, 1760 (sh), 1740, 1455, 1360/ 1200, 11~5, 1055, 830, 762, 745.

13~338~

Example 4-3(4) OTBD~fS OTBD~S
r H H ~ ~ H H
~f \ COOH ~ ~ COIm 0 ~ ~ CH2COOtBu O CH2COOtBu A solution of (3S,4S)-3-[(lR)-l-t-butyldimethyl-silyloxyethyl]-4-[(lS)-l-carboxyethyl]-l-(t-butyloxy-carbonylmethyl)azetidin-2-one (42 mg) and N,N'-carbonyl-diimidazole (19 mg) in dry acetonitrile (0.9 ml) was stirred at room temperature for 1 hour and distilled off to remove the solvent. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(lR)-l-t-butylaimethyl-silyloxyethyl]-4-[(ls)-l-(l-imidazolyl)carbony~lethyi3 (t-butyloxycarbonylmethyl)azetidin-2-one.
IR ~meaxt (cm 1): 1760 (sh), 1735, 1382, 1360, 1225, 114S, 935, 827, 745.
Example 5-1 OTBDMS OTBDMS
r ~ H ~ H H
--`COOCH2Ph COOCH2Ph O ~ H O ~ CH2COOMe To a solution of (3S,4S)-3-[(lR)-l-t-butyl-dimethylsilyloxyethyl]-4-~(lS)-l-benzylo~ycarbonylethyl~-azetidin-2-one ~1.56 g) in methylene chloride (20 ml), there were added successi~ely methyl alpha-bromoacetate (916 mg), 50 % aqueous sodium hydroxide solution (1.28 g) and triethylbenzylam~onium chloride (455 mg), followed by stirring at room temperature for 2 hours. The reaction ~ 49 ~ ~3~ 33~ ~

mixture was diluted with water. The aqueous layer was separated from the organic layer and extracted twice with diethyl ether. The extracts were combined with the organic layer, washed successively with watex twice and brine three times, dried over sodium sulfate and evaporated.
The residue was purified by silica gel chromatography to give (3S,45)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-~(lS)-l-benzyloxycarbonylethyl]-l-(methoxycarbonyl~ethyl)-azetidin-2-one.
10- IR vmaxt (cm 1): 1760, 1740, 1460, 1407, 1360, 1250, 1~15, 1180, 1140, 835, ~70, 745.
MMR ~ (CDC13): 0.07 (3H, s), 0.08 (3~, s), 0.87 (9H, s), 1.24 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.2 Hz), 2.77 (lH, m), 3.63 (3H, s), 3.93 (2H, s), 3.96 (lH, dd, J =
2.0 and 9.6 Hz), 4.19 (lH, m), 5.09 (2H, s), 7.36 (SH, s).
Example 5-2 OT~DMS ` OTBDMS
H H _ ~ H H
COOCH2Ph ~ COOH
~ N~ ~ ~I N~
o CH2COOMe ~ CH2COOMe A solution of t3S,4S)-3-[(lR)-l-t-butyldimethyl-silyloxyethyl]-4-[(lS)-1-benzyloxycarbonylethyl~-1-(methox-carbonylmethyl)azetidin-2-one (400 mg) in 99.S % ethanol (6 ml) was subjected to hydrogenation at room temp~rature in the presence of 10 % palladium-carbon (80 mg) under atmospheric pressure, followed by filtration to remove the catalyst. The filtrate was evaporated to give (3S,4S)-3-[(lR)-l-t-butyldimethylsil~loxyethyl]-4-[(lS)-l-carboxy-3 8 ~

ethyl]-1-(meth~xycarbonylmethyl)azetidin-2-one.

IR ~maex (cm ): 1740, 1705, 1435, 1240, 1215, 1135, 830, 770.

Example 5-3 OTBDMS OTBD~IS
H H - Y H H

COOH ~ OSPh o~cH2cooMe ~CH2COOMe In the same manner as in Example 1-3(1) but replacing the starting material by (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lS)-l-carboxyethyl]-1-methoxycarbonylmethyl-2-azetidinone, there was obtained -(3S,4S)-3-[(lR)-1-t-b~tyldimethylsilyloxyethyl]-4-[(lS)-: 1-phenylthiocarbonyiethyll-1-methoxycarbonylmethyl--2-azetidinone.
IR ~meax (cm 1): 1750, 1695, 1437, 1405, 1247,1202, 950, 830, 770, 740.
NMR ~ (CDC13): 0.07 (3H, s), 0.09 (3H, s), 0.87 (9H, s), 2.88 llH, dd, J = 2.3 and 6.6 Hz), 3.03 (lH, m), 15 3.70 (3H, s), 4.02 (lH, dd, J = 2.0 and 9.2 ~z), 4.19 (lH, m), 7.41 (SH, m).

- 51 - i 3 ~ a ~' Example 6-1 OTBDMS OH

> ~ COSPh O H2COOtBu O CHzCOOH

OTBDMS

COSPh (b) (a) To a solution of (3S,4S)-3-[(lR)-l-t-butyl-dimethylsilyloxyethyll-4-[(lR)-1-phenylthiocarbonylethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one (190 mg) in methanol (4.5 ml) was added 6N hydrochloric acia (1.5 ml), rollowed by s~irring at room temperature for 15 minutes.
The reaction mixture was diluted with chloroform and brine.
The aqueous layer was separated from the organic layer and~
extracted with chloroform twice.-~ -. The extracts were combined with the organic layer, dried over sodium sulfate 10 and evaporated. The residue was dissolved in trifluoro-acetic acid (1.0 ml) and anisole (0.1 ml). After stirring at room temperature for 25 minutes, the solvent was evapo-rated and removed azeotropically with dry toluene twice -to give (3S,4S)-3-[(lR)-l-hydroxyethyl]-4-[(lR)-l-phenyl-15 thiocarbonylethyl]-1-(carboxymethyl)azetidin-2-one as a crude product.

- 52 ~ 13~ 3~$~

(b) A mixture of the cruae product as obtained above, t-butyldimethylchlorosilane (246 mg) and imidazole (151 mg) in dry dimethylformamide (2 ml) was stirred over-night. The resulting mixture was poured into water and extracted with ethyl acetate three times. The organic layer was washed successively with dilute sulfuxic acid, water (five times) and brine ~ twice), dried over sodium.
sulfate and evapora~ed. The residue was purified by silic~
gel chromatography to give (3S,4Si-3-[(lR)-l-t-butyl-dimethylsilyloxyethyl]-4-[(lR)-1-phenylthiocarbonylethyl~-1-(car~oxymethyl)azetidin-2-one.
IR ~meaxt (cm 1): 3350 (broad), 1760 (sh), 1737, 1700, 1245, 1140, 830, 767, 742.
xample 6-2 OT8DM~ OTBDMS
H H ~ ~ H H
COSPh ~ COSPh O ~CH2COOH ~CH2COSPh A mixture of (3S,4S)-3-[(lR)-l-t-butyldimethyl-silyloxyethyl~-4-[(lR)-1-phenylthiocarbonylethyl]-l-(carboxymethyl)azetidin-2-one (154 mg) and N,N'-carbonyl-~
diimidazole (66 mg) in dry acetonitrile (2.9 ml) was stirred at room temperature for l hour. Thiophenol (56 mg) in dry acetonitrile (1 ml) and triethylamine (52 mg) in dry acetonitrile (0.5 ml) were added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, poured into dilute sulfuric acid anà e~.tracted with ethyl acetate three times.

_ 53 - ~3~

The organic layer was washed successively with dilute sulfuric acid ana brine ( twice), drled over sodium suirate and e~aporated. The residue was purified by silica gel chromatography to give (35,4S)-3-[(lR)-l-t-butyldi-methylsilyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-1-(phenylthiocarbon~lmethyl)azetidin-2-one.
IR vmaxt (cm 1): i760, 1700, 1478, 1440, 1250, 1140, 835, 773, 7~0, 682.
NMR C (CDC13): 0.08 (3H, s), 0.10 (3~, s), 0.89 (9H, s), 1~27 (3H, d, J = 6.3 Hz), 1.32 (3H, d, J - 7.3 Hz), 3.11 (lH, dd, J - 2.0 and 6.9 Hz), 3.20 (lH, m), 4.24 (lH, m), 4.30 (2H, m), 7.41 (lOH, s).
Exam~le 7-1 OTEDMS ~ OTBDMS
H ~ ~ H H
COSPh ~ C~SPh ~ >
O' CH2COOtBu O -CH2cH
In the same manner as in Example 6-1, there was obtained (3S,45)-3-[(lR)-1-t-butyldimethylsilyloxyethyl]-4-[(lS)-1-phenylthiocarbonylethyl]-1-(carboxymethyl)azetidin-2-one from (35,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lS)-l-ph~nylthiocarbonylethyl]-l-(t-butyloxycarbonyl-methyl)azetidin-2-one.
IR vmaxt (cm 1): 3350 (broad), 1760 (sh), 1740, 1250, 940, 825, 770, 740, 680.

_ 54 ~ 33 ga Example 7-2 OTBDMS OTBD~IS
H H ~ ~ H ~ `

OSPh ~ `COSPh O CH2COOH o ~C~I2COSPh In the same manner as in Example 6-2 but replacing (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-~(lR)-l-phenylthiocarbonylethyl]-l-(carboxymethyl)a~etidin-2-one by (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lS)-1-phenylthiocarbonylethyl]-1-(carboxymethyl)azetidin-2-one, there was obtained (3S,4S)-3-[(lR)-l-t-butyldimethylsilyl-cxyethyl]-4-~(lS)-l-phenylthiocarbonylethyl]-l-(phenylthio-carbonylmethyl)azetidin-2-one.
IR vneat (cm 1): 1760, 1705, 1480, 1442, 1250, g55, 8~5, 742, 682.
~xam~le 8-1 OTBDMS OTBDMS
r H H ~ ~ ~ H
OOPMB ~ COOP~

To a solution of (3S,4S)-3-[(lR)-l-t-butyldi-methylsilyloxyethyl]-4-[(lR)-1-p-methoxybenzyloxycarbonyl-ethyl]azetidin-2-one (1.12 g) in methylene chloride (14 ml), there were successively added p-nitrobenzyl alpha-bromo-15 acetate (1.09 g), 50 % aqueous sodium hydroxide solution(0.85 g~ and triethylbenzylammonium chloride (303 mg), followed by stirring at room temperature for 30 minutes.
The reaction mixture was diluted with water and e:ctracted ~ 55 ~ 1~33~)~

with a mixture of diethyl ether and methylene chloride (3 :
1) three times. The organic layer was washed successively with water twice and brine tnree times, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(lR)-l t-butyldimethylsilyloxyethyl]-4-[(lR)-1-p-methoxybenzyloxy-carbonylethyl]-l-(p-nitrobenzyloxycarbonylmetAyl)azetidin-2-one.
IR vmax (cm ): 1760, 1742, 1607, 1515, 1458, 1342, 1241, 1170, 830, 747.
NMR ~ (CDC13): OoOl (3H, s), 0.05 (3H, s), 0.83 (9H, s), 2.86 (lH, qd, J = 7.2 and 3.0 Hz), 3.0C (lE, dd, J
= 2.3 and 6.6 Hz), 3.80 (3H, s), 5.01 (2H, m), 5.20 (2H, s), 6.88 (2H, d, J = 8.6 Hz), 7.49 (2H, d, J = 8.9 Hz), 8.22 (2H, d, J = 8.6 ~z).
Example 8-2 OTBDMS
~ H H r /~ooP~8 . .>
0~ ~CH2COOPNB

OTBDMS OH
H H ¦ r H H

COOH ~ COOH

O ~ CH2COOPNB O ~ CH2COOPNB
To a solution of (3S,45)-3-[(lR~-1-t-butyldi-methylsilyloxyethyl]-4-[(lR)-l-p-methoxybenzyloxycarbonyl-ethyl]-l-(p-nitrobenzyloxycarbonylmethyl)azetidin-2-one (142 13~3P~

mg) in dry methylene chloride, there was BF3-Et2O complex ~163 mg) under ice-cooling, followed by st-rring at room temperature. The reaction mixture was poured into 2 cold aqueous sodium bicarbonate solution, acidified with dilute hydrochloric acid and extracted with ethyl acetate three times. The organic layer was washed successively with dilute hydrochloric acid and brine, dried over sodium sulfate and evaporated. The residue was puriied by silica gel chromatography ~o give (3S,4S)-3-[(lR)-l-t-butyldi-methylsilyloxyethyl]-4-[(lR)-l-carboxyethyl]-l-(p-nitro-benzyloxycarbonylmethyl)azetidin-2-one ~Compound A3 and (3S,45)-3-[(lR)-l-hydroxyethyl]-4-[~lR)-l-carboxy-ethyl]-l-(p-nitrobenzyLoxycarbonylmethyl)azetidin-2-one (Compound B).
Compound A:-IR ~neaat (cm 1): 3100 (broad), 1760, 1730, 1520, 1342, 1245, 1180, 830, 770.
~ MR ~ (CDCl3): 0.03 (3H, s), 0.07 (3H, s), 0.85 (9H, s), 1.25 (3H, d, J = 6.3 Hz), 1.26 (3E, a, J = 7.3 Hz), 20 2.91 (lH, qd, J - 3.0 and 7.3 Hz), 3.05 ~lH, dd, J = 2.3 and 5.9 Hz), 4.13 (2H, m), 5.26 (2H, s), 7.52 (2H, d, J = 8.9 Hz), 8.23 (2H, d, J = 8.9 Hz).
Compound B:-IR ~maxt (cm 1): 3430 (broad), 1760, 1735, 1705, 25 1520, 1345, 1180, 7~5.

~ 3 ~

Example 9-1 OTBDMS OTBDMS
'I .H li ~ 11 .H H
/~COS~Cl ~ I COS~Cl O ~ CH2COOtBU O ~H2COOH
To a solution of (3S,4S)-3-[(lR)-l-t-butyldi-- methylsilyloxyethyl]~4-[(lR)-l-p-cnlorophenylthiocarbonyl-ethyl]-l-(t-butyloxycarbonylmethyl)azetidin-2-one (200 mg) in dry methylene chloride (l.S ml), there was added BF3-ET2O
comple~ (263 mg), followed by stirring at room temperature for 1 hour. After evaporation or the solvent, the residue wzs dissolved in methanol (O.S ml), diluted with brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to give (3S,4S)-3-[(lR)-l-hydroxyethyl~-4~[(lR)-l-p-chlorophenyl-thiocarbonylethyl]-l-(carboxymethyl)azetidin-2-one as a crude product. The crude product, t-butyldimethylsilyl chloride (246 mg) and imidazole (151 mg) were dissolved in dry dimethylformamide (2.5 ml) and allowed to stand at room temperature overnight. The reaction mixture was poured into cold brine, adjusted with lM potassium hydrogensulfate to pH
2 and e~tracted with diethyl ether three times. The organic layer was washed with brine twice, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (3S,4S)-3-[~lR)-l-t-butyldi-methylsilyloxyethyl]-4-[(lR)-l-p-chlorophenylthiocarbonyl-- ethyl]-l-(carboxymethyl)azetidin-2-one.
IR vmax (cm ): 3300 (broad), 1760, 1740, 1700, 13~3~

1480, 1382, 1250, 1140, 1087, 830, 775.
Example 9-2 OTBDMS OH

COS ~ Cl ~ COS ~ Cl O ~CH2COOH \CH2COOPNB
To a mixture of (3S,4S)-3-~(lR)-l-t-butyldimethyl-silyloxyethyl)-4-[(lR)-l-p-chlorophenylthiocarbonylethyl3-1-carboxymethylazetidin-2-one (70 mg) and p-nitrobenzyl alcohol (24 ml) in ethyl acetate (0.3 ml), there was added 5 a solution of N,N'-dicyclohexylcarbodiimide (30 mg) in dry ethyl acetate (0.2 ml), and the resultant mixture was stlrred at 5 to 10C overnight. The precipitated N,N'-di-cyclohexylurea was collected by filtration and washed with ethyl acetate. The washing was combined with the filtrate, washed with water and brine, dried over sodium sulfate and distilled off to remove the solvent. The residue was purified by silica gel chromatography to give (35,45)-3-[(lR)-l-t-butyldimethylsilyloxyethyl)-4-[(lR)-l-p-ch~oro-phenylthiocarbonylethyl]-l-(l-nitrobenzyloxycarbonyLmethyl)-15 azetidin-2-one.
IR vmax (cm ): 1760, 1750, 1700 t 1602, 1520, 1478, 1343, 1250, 1180, 1090, 835, 775, 742.
~ R ~ (CDC13): 0.07 (3E~, s), 0.08 (3H, s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 1.31 (3H, d, J = 7.3 Hz), 20 3.01 (lEi, dd, J = 2.6 and 7.1 Hz), 3.14 (lH, qd, J = 2.6 and 7.3 Hz), 4.12 (2H, m), 4.17 (2H, m), 5.20 (2H, m), 7.34 (4EI, m), 7.44 (2H, a, J = 8.6 Hz), 8.17 (2H, d, J = 8.9 Hz).

~ 59 ~ ~3133~Q

ExamDle 10-1 OH ~

COSPh ~ COSPh ~ .. >
0~ CH2COOtl~u O CH2COOH

OH
~ ~ H r (b) ~ COSPh --~, O C~I2COOPNB
(a) (3S,45)-3-[(iR)~ ydroxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-l-(t-butyloxycarbonylmethyl)a~eti-din-2-one (72.0 g) was dissolved in trifluoroacetîc acid (500 ml) under ice-cooling, followed by stirring for 2 5 hours. The reaction mixture was evaporated in vacuo below 50C. The residue was then dissolved in toluene (250 ml) and evaporated off to remove the solvent.
(b) To a solution of the residue in dry aceto-nitrile (720 ml), there were added triethylamine (43.25 g) 10 and p-nitrobenzvl bromide ~92.33 g), followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate ~1.5 liters), washed with a 20 aqueous sodium chloride solution several times, dried over sodium sulfate and evaporated. The residue was purified by 15 silica gel chromatography to give (3S,4S)-3-[(lR)-l-hydroxy-ethyl]-4-[(lR)-l-phenylthiocarbonylethylJ-l-(p-nitrobenzyl-oxycarbonylmethyl~azetidin-2-one.

IR VCaHC13 (cm 1): 1740, 1680, 1600, 1515, 1360, 13~33~

- 1250, ll&0, 950, 740.

Example 10-2 Oz OH
r H H ~ ~ H ~ r ~ COSPh ~ COSPh O CH2COOtBu O ~ \C 2COO}i To a solution of (35,4S1-3-[(lR)-l-benzyloxy-carbonyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-1-t-butoxycarbonylmethylazetidin-2-one (8.5 g) in 1,2-dichloro-ethane (185 ml), there was dropwise added a solution of ` boron tribromide (26.4 g) in 1,2-dichloroethane (100 ml) at -10~C for 20 minutes, followed by stirring at the same temperature for 1 hour. Sodium bicarbonate (40 g) and ice-water (600 g) were added thereto while stirring, and the resultant mixture was diluted with ethyl acetate (200 ml).
The aqueous layer was acidified with 2N hydrochloric acid (200 ml), extracted with ethyl acetate and combined with the organic layer. The combined orsanic layer was washed with - brine (200 ml x 3), dried over magnesium sulfate and evapo-rated in vacuo to give (3S,4S)-3-[(lR)-1-hydroxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-1-carboxymethylazetidin-2-one (10.4 g, 87.9 ~.).
IR ~ma~ (cm ): 1740, 1710, 1690, 1210, 1130, 1070, 940, 740.

- 61 _ ~ 3 Example 10-3 OH OTBDMS
H H ~ ~ H H

COSPh ~ COSPh 0 ~ ~CH2COOPNB O . ~ H2COOPNB

To a solution of (3S,4S)-3-[(lR~-hydroxyethyl]-4-[(lR)-1-phenylthiocarbonylethyl]-1-(p-nitrobenzyloxy-carbonylmethyl]azetidin-2-one (52.36 g) in dry dimethylform-amide (262 ml), there were added imidazole (16.6 g) and t-butyldimethylchlorosilane (23.38 g), followed by stirring at room temperature ~or 5 hours. The reaction mixture was diluted with ethyl acetate (1 iiter), washed with a 20 %
aqueous sodium chloride solution. The aqueous layer was separated from the organic layer and extracted with ethyl acetate (500 ml). The extract was combined with the organic layer, washed with a 20 % aqueous sodium chloride solution twice, , dr.ied over sodium sulfa~e and evaporated. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(lR)-1-t-butyldimethylsilyloxyethyl]-4-lS [(lR)-1-phenylthiocarbonylethyl~ (p-nitrobenzyloxy-carbonylmethyl]azetidin-2-one.
IR ~ma~ (cm ): 1755, 1690, 1600, 1515, 1340, 1250, 1180, 835.

NMR ~ (CDC13): 0.08 (3H, s), 0.09 (3H, s), 0.89 (9H, s), 1.28 (3H, d, J = 6.0 HzJ, 1.32 (3H, d, J = 7.3 HZ), 3.01 (lH, dd, J = 2.3 and 7.3 Hz), 3.16 (lH, dd, J = 2.3 and 7.3 Hz), 3.96 (lH, d, J = 17.8 HzJ, 4.17 (2H, m), 4.31 (lH, - 62 - 13 ~ 3 d, J = 17.8 Hz), 5.20 (2H, ABq, J = 13.5 Hz~, 7.25 - 7.45 (5H), 8.12 (2H, d, J = 8.9 Hz).
Exam~le 10-4 OH Me sio r H H ~ 3 COSPh ~ COSPh Q ~ ~ CH2COOPNB O ~ CH2ccopNB

In the same manner as in Example lG-3, there was obtained (3S,4S)-3-[(lR)-l-trimethylsilyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-l-(p-nitrobenzyloxy~arbonyl-methyl]azetidin-2-one from (3S,4S)-3-[(lR)-l-hydroxyethyl]-4-t(lR)-l-phenylthiocarbonylethyl]-l-(p-nitrobenzyloxy-carbonylmethyl]azetidin-2-one.
IR ~maxt (~m 1) 1760, 1695, 1600, 1520, 1440, 101340, 1250, 1180, 950, 840, 740.
NMR ~ (CDC13): 0.13 (9H, s), 3.04 (lH, dd, J =
2.3 and 7.6 Hz), 3.15 (lH, aq, J = 2.3 and 7.0 Hz), 3.92 (lH, d, J = 1~.1 Hz), 4.38 (lH, d, J = 18.1 Hz), 5.21 (2H, ABq, J = 13.5 Hz), 8.12 (2H, d, J = 8.9 Hz).
15Reference ExamPle 1-1 OTBDMS OTBDMS

COOH / ~ COSPh O ~ H ~ ~H
A mixture of (3S,4S)-3-[llR)-l-t-butyldimethyl-silyloxyethyl]-4-[(lR)-l-carboxyethyll azetidin-2-one (301 mg) and N,N'-carbonyldiimidazole (194 mg~ in dry aceto-- 63 ~

nitrile (8.6 ml) was stirred at room temperature for l hour.
To the reaction mixture, there were successively added thiophenol (132 mg) in dry acetonitrile (2 ml) and triethyl-amine (121 mg) in dry acetonitrile (2 ml), followed by stir_ing at room temperature for 30 minutes. The resulting mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was separated from the organic layer and extracted with ethyl acetate twice. The extracts were combined wtth the organic layer, washed wiih brine, dried over sodium sulfate and distilled cff to remove the solYent. The residue was purified by silica gel chro-matography to aive (3S,4S)-3-~(lR)-1-t-butyldimethylsilyl-oxyethyl]-4-~(lR)-phenylthiocarbonylethyl]azetidin-2-one.
IR vaeat (cm l): 3200 (broad), 1760, 1700, 1370, 15 1250, 1;40, 955, 830, 773, 740, 680.
Reference Example 1-2 OTBDMS OTBDMS

~COO~ ,~COS~Cl A mixture of (3S,4S)-3-[(lR)-l-t-butyldimethyl-silyloxyethyl]-4-[(lR)-l-carboxyethyl]azetidin-2-one (400 mg) and Nr~'-carbonyldiimidazole (259 mg) in dry aceto-20 nitrile (11 ml) was stirred at room temperature for 1 hour.To the resulting mixture, there were successively added p-chlorothiophenol (231 mg) in dry acetonitrile (3.2 ml) and triethvlamine (162 mg) in dry acetonitrile (2.3 ml), fol-lowed by stirring at-room temperature .or 30 minutes. The - 64 - ~3~3~8~

reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was separzted from the organic layer and extracted with ethyl acetate twice. ~~
The extracts were combined with the organic layer, washed with dilute hydrochloric acid, brine, aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and distilled off to remove the solvent. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lR)-l-p-chloro-phenylthiocarbonylethyl]azetidin-2-one.
IR vmaext (cm 1): 3250 (broad), 1770, 1750, 1700, 1478, 1247, 1140, 1090, 820, 770.
NMR ~ (CDC13): 0.07 (6H, s), 0.88 (9H, s), 1.18 (3H, d, J = 6.3 Hz), 1.33 (3~, d, J = 6.9 ~z), 2.97 (lH, m), 3.02 (lH, m), 3.93 (lH, dd, J = 2.0 and 5.3 Hz), 4.22 (lH, m), 5.86 (lH, broad, s), 7.36 (4~, m).
Reference Exam~le 1-3 OTBDMS CTBDMS

, ~ ~ COOPMB

A mixture of (3S,4S) 3-[(lR)-l-t-butyldimethyl-silyloxyethyl]-4-[(lR)-1-carboxyethyl] azetidin-2-one (1.00 g), triethylamine (369 mg) and p-methoxybenzyl chloride (779 mg) in dry dimethylformamide (1 ml) was stirred at 70C for 2 hours and 40 minutes. The reaction mixture was poured into ice-water, acidified with dilute hydrochloric acid to pH 2 to 3 and extracted with diethyl ether three times. The - 65 ~ 13~

organic layer was washed with cold lN aqueous sodium hydro-xide solution, water and brine in this order, dried over sodium sulfate and distilled off to remove the solvent. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lR)-l-p-methoxybenzyloxycarbonylethyl]azetidin-2-one.
IR ~meaxt (cm 1): 3225 (broad), 1760, 1740, 1605, 1505, 1458, 1240, 1160, 1030, 950, 825, 767.
NMR ~ ~CDC13): 0.05 (6H, s), 0.86 (9~, s), 1.13 (3H, d, ~ = 6 Hz), 1.21 (3~, d, J = 7 Hz), 2.70 (1~, m), 2.95 (lH, dd, J = 2 and 4 Hz1, 3.81 (3H, s), 3.89 (1~, dd, J
= 2 and 5 Hz), 4.16 (lH, m), 5.05 (2H, s), 5.96 (lH, bro2d, s), 6.87 (2H, d, J = 9 Hz), 7.27 (2H, d, J = 9 Hz).
Reference Example 2-1 OH OH
H K ~ H H
COOH ~ COOMe O DAM O DAM
To a solution of (3S,4S)-4-carboxy-3-(1-(R)-- hydroxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (34 g) in methanol (310 ml), there was added 98 ~ sulfuric acid (2.9 g). The resultant mixture was heated at 65C for 3 hours, cooled down to 40C, neutralized with 8 % aqueous sodium hydroxide solution (15 ml) and concentrated to make a one third volume. The concentrate was diluted with 1,2-di-chloroethane (105 ml) and washed with water. The aqueous layer was separated from the organic layer and extracted with 1,2-dichloroethane ~105 ml). The extract was combined 131338~

with the organic layer, washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give (3S,45)-4-methoxycarbonyl-3-(1-(R)-hydroxyethyl)-l-di~p-anisyl)methyl-2-azetidinone.
m.p., 102 - 104C.
Reference E:cample 2-2 OH H H ¦ OH
COOMe O DAM O \DAM
To a solution of (3S,4S~-4-methoxycarbonyl-3-(1-(R)-hydroxyethyl)-1-di(p-anisyl)methyl-2-a-zetidinone (32.5 g) in dry tetrahydrofuran (310 ml), there was added dropwise a lM susper.sion of methyl magnesium bromide in tetrahydro-furan (370 g) at 0 - 5C, and the suspension was stirred at the same temperature as above for 1 hour. 20 ~ Hydrochloric acid (350 ml) was poured into the suspension at 20 - 25C, and the resultant mixture was stirred for 1 hour, followed by extraction with ethyl acetate (110 ml). The aqueous layer was ree~tracted with ethyl acetate (110 ml). The extracts were combined together, washed successively with brine, a saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give (3S,4S)-4-(1-hydroxy-l-methylethyl)-3~ (R)-hydroxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 154 - 156C.

- 67 - ~3 ~3 ~ a Reference Example 2-3 ~,ON ,~J~J~ OH

O DAM O DA~
(3S,4S)-4~ Hydroxy-1-methylethyl)-3-(1-(R)-hydrcxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (26 g) and 4-dimethylaminopyridine (16 g) were dissolved in dry dichloromethane (200 ml). Benzyl chloroformate (20 g) was added dropwise thereto over a period of 1 hour with ice-cooling, and the resultant mixture was stirred for 2 hours and warmed to room temperature, followed by stirring at the same temperature as above for 10 hours. 5 ~ Hydrochloric acid llOO ml) was poured into the reaction mixture with ice-cooling, and the resulting mixture was stirred for 0.5 hourand allowed to stand. The organic layer was washed suc-cessively with water, a saturated sodium bicarbonate solu-tion and brine and dried over anhydrous sodium sulfate.
After filtration, the filtrate was concentrated in vacuo to give (3S,4S)-4-(1-hydroxy-1-methylethyl)-3-(1-(~ enzyloxy-carbonyloxyethyl)-l-di(p-anisyl)methyl-2-azetidinone.
IR ~maexat (cm 1): 3450, 1750, 1615, 1515, 1250, 1180, 1030.
- NMR ~ (CDC13): 1.13 (6H, s), 1.38 (3H, d, J = 6 Hz), 3.70 (3H, s), 3.75 (3H, s), 5.10 (2H, s), 5.55 (lH, bs), 7 . 29 ~5H, S) .

- 68 ~ 13~3~9 Reference Example 2-4 O \DAM ~ DAM
A solution of (3S,4S)-4-(1-hydroxy-1-methyl-ethyl)-3-(1-(R)-benzyloxycar~onyloxyethyl)-l-di(p-anisyl)-methyl-2-azetidinone (30 g) in dry toluene (350 ml) was treated with thionyl chloride (9.0 g) at 20 - 30C for 5 S hours in the presence of pyridine (10 ml). Water (100 ml) was added to quench the reaction Gi 10 - 25C. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give an oily residue, which was crystallized from a mixture of cyclohexane and ethyl acetate to yield (3S,4S)-4~ methylethenyl)-3-(1-~R)-benzyloxy-carbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 117 - 118C.
Reference Example 2-5 OZ oZ
Cl \

O DAM o ~AM
(35,4S)-4-(1-Methylethenyl)-3-(1-(R)-benzyloxy-carbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (200 g) was dissolved in ethyl acetate (3 liters), and a solution o~
chlorine in carbon tetrachloride (3.85 %, 870 g) W25 added 1 3 ~ $ 0 dropwise thereto at room temperature over a period of 15 minutes, followed by stirring for 1 hour. Water (1 liter) and then lO % aqueous sodium thiosulfate solution (50 ml) were poured into the reaction mixture, which was stirred for 0.5 hour and allowed to stand. The organic layer was washed successively with a saturated sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give (3S,4S)-4-(1-chloromethylethenyl)-3-(1-(R)-benzyloxycar-bonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 84 Reference Example 2-6 OZ OZ
Cl ~ H
N ~
0~ ~ ~ 0~ ~ DA~
To a solution of (3S,4S)-4-(1-chloromethyl-ethenyl)-3-(l-(R)-ben~yloxycarbonyloxyethyl)-l-di(p-anisyl)methyl-2-azetidinone (20 g) in dimethylsulfoxide (160 ml), there were successively added water (40 ml), cuprous oxice (6.76 g) and p-toluenesulfonic acid (7.6 g), and the resultant mixture was warmed to 50 to 55C and stirred for 2 hours at the same temperature. After cooling down to room temperature, l % aqueous phosphoric acid (90 mi) and ethyl acetate (200 ml) were poured into the reaction mixture, followed by stirring for 0.5 hour. An insoluble material was removed by filtration over celite and washed 3 times with ethyl acetate (20 ml). The filtrate and the washings ~ 70 - ~3~3~

were combined together, and the aqueous layer was separated from the organic layer and extracted with ethyl acetate (200 ml). The organic layer ana the extract were combined together, washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, and the concentrate was crystallized from a mixture of toluene and n-hexane (1 : 1) to give crystals of (3s,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxy-ethyl)-l-di(p-anisyl)methyl-2-azetidinone. m.p., 118 -120C.
Reference Exam~le 2-7 OZ Og OH ~ OTB~MS

O ~DAM DA~
A solution of (3S,4S)-4-(1-hydroxymethyl-ethenyl)-3-(1-(R)-~enzyloxycarbonyloxyethyl)-l-di~p-anisyl)methyl-2-azetidinone (20 g) and imidazole (5.6 g) in dry dimethylformamide (45 ml) was treated with t-butyl-dimethylchlorosilane (6.77 g) at room temperature for 2 hours. The reaction mixture was diluted with cold water (200 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml). The combined extracts were washed successively with 5 % hydrochloric acid solution (80 ml x 2) and brine (80 ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, and the concentrate was crystallized from isopropanol to give crvstals of (35,4S)-- 71 - ~3~3~

.
4~ t-butyldimethylsilyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-a~eti-dinone. m.p., 90 - 92C.
Reference Example 2-8 OZ oZ
H H ¦¦ ~ H H r /\L~9TBDMs ~,: TBDMS

O DAM O ~DAM
To a solution of (3S,4S~-4-(1-t-butyldimethvl-silyloxymethylethenyl)-3-(1-(R)-benzyloxycar~onyloxyethyl)-l-di(p-anisyl)methyl-2-azetidinone (20 g) in acetonitrile (200 ml), there were added 5 % platinium on activated carbon (4.0 g) and water ~4 ml) under nitrogen atmosphere. The mixture was stirred at 10C in a hydrogen gas flow until 2.2 10 e~uivalents of hydrogen had been taken up. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate and the washings were combined together and con~en-trated in vacuo to give (35,4S)-4-(1-t-butyldimethylsilyl-oxymethylethyl)-3-(1-(R)-benzylocycarbonyloxyethyl)-l-di-(p-anisyi)methyl-2-azetidinone as an oil.
H gh performance liquid chromatography (HPLC) [Lichrosorb RP-18], eluting with 85 % acetonitrile/water (1 ml/min~ and NM~ spectra indicated that this product was a micture of 4-(1-(R)-t-butyldimethylsilyloxyethyl) compound 20 and the corresponding (S)-compound in a ratio of 7.7 : 1.
The above mixture was recrystallized from a mixture of n-he:cane and ethyl acetate (10 : 1) to yield the (R)-- 72 - ~3~33~

compound. m.p., 78 - 81C.
NMR ~ (CDC13): 0.01 (6H, s), 0.87 (9H, s), 1.40 (3H, d, J = 6 ~z), 3.31 ~lH, dd, J = 2.2 and 7.0 Hz), 3.44 (2H, d, J = 5.3 Hz), 3.73 (3H, s), 3.76 ~3H, s), 5.07 (lH, m), 5.17 (2~, s), 7.38 (5~, s~.
Reference Example 2-9 OZ OZ
r ~ H ~ r H ~ ~
OTBDMS ~ OH

~ AM O H
To a solution of (3S,4R)-4-(1-(R)-t-butyldimethyl-silyloxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-l-ditp-anisyl)methyl-2-azetidinone-(20 g) in dry dichloro-methane (200 ml), there were added 1,3-dimethoxybenzene (7.8 g) and boron trifluoride etherate (23 g) at 10 - 20C, and the resultant mixture was stirred at room temperature for 3 hours, followed by heating under reflux for 3 - 5 hours.
The reaction mixture was cooled down ~o 10 - 15C, washed successively with brine (200 ml x 2), 2.5 ~ aqueous sodium bicarbonate solution (200 ml) and brine (200 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give an oily residue, which was purified by silica gel chromatography -to yield (3S,4S)-4-(1-(R)-hydroxymethylethyl)-3-(1-(R)-benzyloxy-carbonyloxyethyl)-2-azetidinone.

IR vmax (cm ): 3350, 1750, 1740, 1455, 1382, 1260, 1030.

_ 73 _ ~ ~ ~338~

NMR ~ (CDC13): 0.95 (3H, d, J = 7.0 Hz), 1-48 (3H, d, J = 6.5 Hz~, 3.14 (lH, dd, J = 2 and 9 ~z), 3.55 (lH, d, J = 2 Hz), 5.15 (2H, s), 6.05 tlH, broad, s), 7.37 (SH, s).
Reference Example 2-10 OZ OZ
~ -~ ~ COO~

A solution of (3S,4S)-4-(1-(R)-hydroxymethyl-ethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone (6.1 g) in acetone (60 ml) was treated with the Jones reagent, prepared from chromium trioxide (2.7S g), 98 ~
sulfuric acid (4.4 g) and water (8.1 ml), at 10 - 20C for 1 hour. The reaction mixture was quenched with isopropanol (0.5 ml) at 10 - 20C for 15 minutes, diluted with ethyl acetate (122 ml) and washed with water (135 ml). The aqueous layer was separated from the organic layer and extracted with ethyl acetate 161 ml). The ethyl acetate e~tracts and the organic layer were combined together and extracted with 5 % aqueous sodium bicarbonate solution 130 ml). The extract was washed with dichloromethane (60 ml) and acidified with 10 % hydrochloric acid solution (20 ml) with ice-cooling. The acidic solution was extracted -twice with dichloromethane (60 ml). The extracts were washed with brine and dried over anhydrous sodium sulfate. After .iltration, the filtrate was concentrated in vacuo to give (35,4S)-4-(1-(R)-carboxyethyl)-3-(1-(R)-benzyloxycarbonyl-- 74 - i3~3~3 oxyethyl)-2-azetidinone.
IR vmax (cm ): 3270, 1740, 1460, 1385, 1270, 750.
NMR ~ (CDC13): 1.19 (3E, a, J = 7.0 Hz), 1.40 (3H, a, J = 6.2 Hz), 2.67 (lH, m), 3.22 ~lH, broad, d, J =
7.5 Hz), 3.84 (lH, broad, d, J = 5.5 Hz), 5.14 (2H, s), 6.57 (lH, broad, s), 7.35 (5H, s), 7.63 (lH, broad, s).
Reference Example 2-11 ' OZ OZ

~\COOI~ \COOCH2Ph To a solution of 4-(1-(R)-carboxyethyl)-3-(1-(lR)-benzyloxyca~x~yloxyethyl)azetidin-2-one (51.69 g) in acetone (510 ml), there were added anhydr~ potassium carbor.ate ~89.0 g) and benzyl bromide (30.3 g), follcwed by stirring at 60C
or 1.5 hours. The reaction mixture was cooled to room temperature and filtered off to remove insoluble materials.
~he filtrate and the washinss were combined and evaporated.
The residue was purified by silica gel chromatography to gi~e (3S,4S)-3-[tlR)-l-benzyloxycarbonyloxyethyl]-4-[(lRJ-l-benzyloxycarbonylethyl~azetidin-2-one.
IR ~maexat (cm 1): 1760 (sh), 1735, 1450, 1380, 1260, 1155.
NMR ~ (CDC13): 1.22 (3H, d, J = 6.9 Hz), 1.39 (3H, d, J = 6.3 Hz), 2.71 (lH, q, J = 6.9 Hz), 3.19 (lH, dd, J = 2.0 and 7.9 Hzl, 3.83 (lH, da, J = 2.0 and 6.3 Hz), 5.92 (lH, s).

~ ~c?~3~

Reference Example 3-1 OTBDMS
/~~'-~
~L ~ ~ ' COSPh OTBDMS OTBDMS
H H ~ ~ EI H 7 ~OP (OPh) 2 ;~SPh COSPh COSPh To a solution of (4R,SR,6S,8R)-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-l-aza~icyclo[3.2.0]hept-3,7-dione-2-carbo~ylic acid phenylthioester (about 0.22 mmol) containing thiophenol in dry acetonitrile (0.8 ml), there were added a solution of diisopropylethylamine (S9 mg) in dry acetonitrile (0.5 ml) and a solution of diphenyl chlorophosphate (1~4 mg) in dry acetonitrile (0.5 mg) under a nitrogen stream while ice-cooling, followed by stirring for 1 hour. The reaction mixture was diluted with diethyl ether and a phosphate buffer solution (pH, 6.86). The aqueous layer was separated from the organic layer and extracted with diethyl ether two times. The extracts were combined with the organic layer, washed successively with a 0.1M potassium dihydrogen phosphate solution (three times), 15 water (two times) and brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel - 76 ~ ~ 313~ ~ ~

chromatogrphy to give (4R,5R,6S,8R)-3-(diphenylphosphoryl-oxy)-4-methyl-6-[1-t-butyldimethylsilyloxyethyl]-1-azabi-cyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid phenylthio-ester (Compound A) and (4R,SS,6S,8R)-3-phenylthio-4-methyl-5 6-(1-t-butyldimethylsilyloxyethyl)-l-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid phenylthioester (Compound B).
Compound A:-IR vmaxa~ (cm 1): 1778, 1673, 1607, 1582, 1487, 1198, 1182, 1002, 962, 935, 767, 740, 680.
NNR C (CDC13): 0.09 (3H, s), 0.11 (3H, s), 0.91 (9H, s), 1.21 (3H, d, J = 7.3 Hz), 1.22 (3F, d, J = 6.0 Hz), 3.29 (lH, dd, J = 3.0 and 5.0 Hz), 3.52 (lH, m), 4.28 (2~, m).
Comoound B:-IR VCmaHxcl3 (cm 1): 1780, 1660 (sh), 1647, 1520, 1478, 1285, 1260, 1115, 1018, 945, 8~7.
NMR ~ (CDC13): 0.09 (3H, s), 0.13 (3H, s), 0.92 (9H, s), 0.95 (3H, d, J = 7.6 Hz), 1.17 (3H, d, J = 6.3 Hz), 3.07 (lH, m), 3.20 (lH, dd, J = 2.6 and 4.3 Hz), 4.31 (lH, dd, J = 2.8 and 9.8 Hz), ~ 4.3 (lH, m), 7.3 - 7.6 (lOH, m).
Re.erence Example 3-2(1) OTBDMS OTBDMS

P(OPh)2 ~ S ~ NHAc COSPh COSPh To a solution of (4R,SR,6S,8R)-3-(diphenylphos-phoryloxy)-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-1-- 77 - ~31~3$~

azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid phenyl-thioes,er (10 mg) in dry acetonitrile (0.1 ml), there were added a solution of diisopropylethylamine (5.2 ml) in dry acetonitrile (0.2 ml) and a solution of N-acetylcysteamine (4.8 mg) in dry acetonitrile (0.2 ml) at -30C under a nitrogen strea~. The reaction mixture was warmed sradually to -20C and diluted with diethyl ether and a phosphate ~uffer solution (pH, 6.86). The aqueous layer was separated from the organic layer and ext~acted with diethyl ethe- two 10 times. The extracts were combined with the organic layer, washed successively with a phosphate buffer solution (pH, 6.86), a O.lM potassium dihydrogen phosphate solution and brine, dried over soaium sulfate and evaporated. The residue was purified by sil:ica gel chromatography to give (4R,5S,6S,8R)-3-(2-acetaminoethylthio~-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid phenylthioester.
IR VmaCX13 (cm 1): 3460, 1765, 1665, 1250, 1102, 830.
NMR ~ (CDC13): 0.11 (3H, s), 0.14 (3~, s), 0.94 (9H, s), 1.25 (3H, d, J = 7.3 Hz), 1.25 (3H, d, J = 6.3 Hz), 1.97 (3H, s), 5.9 (lH, broad s), 7.3 - 7.6 (SE, m).

3 ~ ~

Reference Exam~le 3-2t2) OTBDMS
H H

i ~ ~ OPtOPh)2 COSPh - OTBDMS
H H

COSPh In the same manner as in Reference Example ~-2(1), (4R,5R,6S,8R)-3-(diphenylphosphoryloxy)-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-l-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid phenylthio ester (6 mg), diiso-5 propylamine (1.4 mg) and (2S,4S)-l-p-nitrobenzyloxy-carbonyl-4-mercaptopyrrolidine (4 mg) were treated to give (4R,55,65,8R,2'S,4'S)-3-[(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidin)-4-ylthio3-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-l-azabicyclo[3.2.03hept-2-en-7-10 one-2-carboxylic acid phenylthio ester.
IR VmHX13 (cm 1): 1767, 1700, 1650, 1518, 1340, 1100 .
Reference Example 3-2(3) OT~DMS OTBDMS

P~OPh~2 ~ - SCHzPh los Ph COSPh In the same manner as in Reference Example 3-2(1), (4R,5R,6S,8R)-3-(diphenylphosphoryloxy)-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-l-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid phenylthio ester (20 mg), diisopropylethylamine t5.2 mg) and benzylmercaptan (5 mg) were treated to give (4R,5S,6S,8R)-3-benzylthio-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-1-azabicyclo~3.2.0~-hept-2-en-7-one-2-carboxylic acid phenylthio ester.
IR VmaX13 (cm ): 1770, 1660 (sh), 1640, 1298, 1266, 1250, 1142, 1102, 835.
NMR ~ (CDC13): 0.10 (3H, s), 0.13 (3H, s), 0.92 (9H, s), 3.24 (lH, dd, J = 2.6 and 5.3 Hz), 3.37 (lH, m), 4.09 (lH, m), 4.2 - 4.4 ~2H, m), 7.30 (5H, s), 7.3 - 7.6 (5H, m).
Reference Example 4 Me3SiO
r H H
_ COUMe2 COOPNB

QH
H H
/ ~ C ~;--C Me2 COOPNB
To a solution of (4R,5S,6S,8~,2'S,4'5)-p-nitro-benzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylamino-- 8~ - 13~

carbonylpyrrolidinyl)thio]-4-methyl-6-(1-trimethylsilyloxy-ethyl)-l-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (1.0 g) in dry tetrahydrofuran (10 ml), there was added a phosphate buffer solution (pH 3; 8 ml), and the resultant mixture was vigorously st rred at room temperature for 2.5 hours. The reaction mixture was diluted With ethyl aCetate (50 ml), washed With brine~ dried over magnesium sulfate and evaporated in vacuo to give (4R,SS, 6S,8R,2'S,4'S)-p-nitro-benzyl-3-[4~ p-nitrobenzyloxycarbonyl-2-dimethylamino-carbonylpyrrolidinyl)thio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate, IR ~meaxt (cm 1): 1760~ 1705~ 1645~ 1520~ 1402 1342, 1135, 1110.

NMR ~ (CDC13): 1.30 (3~, d, J = 7.0 HZ)~ 1.35 ~3H~ d~ J = 6,5 HZ)~ 2.99 (3H~ 5)~ 3.02 (3H~ d~ J = 15 ~Z)~
5,21 (2H~ 5)~ 5.20 and 5.43 (2H, ABq, J = 14 HZ), 7.51 (2H~
d, J = 8,5 HZ)~ 7.64 (2H, d, J = 8.5 HZ), 8.20 (4H, d, J =
8.5 HZ).
Re~erence E~.amPle 5-1 OTBDMS ~OTBDMS

Ph ~ SPh COSPh COOPWB
(4R,5S,6S,8R)-3-Phenylthio-4-methvl-6-[(lR)-1-t-butyldimethylsilyloxyethyl~-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid phenylthio ester tl7 mg) and p-nitro-benzyl alcohol (24 mg) were dissolved in dry methylene - 81 - 13~

chloride (0.6 ml). In the dar~, silver trifluoroacetate (7 mg) and 1,8-diazabicyclo~5.4.0]-7-undecene (5 mg) in dry methylene cnloride (0.3 ml) were added tnereto successively at room tamperature. The resultant mixture was stirred for 4.3 hours and diluted with a 0.lM phosphate buffer solution tpH 7; 3 ml) and methylene chloride. After removal of any insoluble materials by filtration, the filtrate was extracted with methylene chloride twice. - The or~anic layer was washed successively with a 2.5 % sodium dihydrogen phosphate solution and brine, dried over sodium sulfate and magnesium sulfate and evaporated. The residue was purified by silica gel chromatography to give (4R,SS,6S,8R)-3-phenyl-thio-4-methyl-6-[(lR)-l-t-butyldimethylsilyloxyethyl]-l-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid p-nitro-15 benzyl ester.
IR and NMR spectra of this compound were identicalto those of ~he compound as in Example 11-4.
Reference ExampLe 5-2(1) OTBDMS OH

~Ph 5 ~SPh COSPh COSPh To a solution of (4R,5S,6S,8R)-3-phenylthio-4-methyl-6-[(lR)-l-t-butyldimethylsilyloxyethyl]-l-az2bicyclo-[3.2.0]hept-2-en-7-one-2-carboxylic acid phenylthio ester ~20mg) in dry tetrahydrofuran (0.3 ml), there was dropwise added a 0.27 M solution of tetra-n-butylammonium fluoride (0.14 -,82 - i3~ a ml) in tetrahydrofuran under a nitrogen stream with ice-cooling, followed by stirring for 1 hour. The reaction mi~ture was diluted with a phosphate buffer solution (pH 7) and extracted with methylene chloride three times. The organic layer was washed with brine, dried over sodium sulfate ana evaporated in vacuo to give an oily residue, whicn was purified by silica gel chromatography to give (4R,SS,6S,8R)-3-phenylthio-4-methyl-6-[(lR)-l-hydroxy-ethyl]-l-azabicyclot3.2.0~hept-2-en-7-one-2-carboxylic acid phenylthio ester.
IR VmaHCxl3 (cm 1): 3600 (broad), 1775, 1660 (sh), 1645, 1300, 1273.
NMR ~ (CDC13): 0.98 (3H, d, J = 7.3 Hz), 1.35 (3H, d, J = 6.3 Hz), 3.11 (lH, m), 3.23 (lH, dd, J = 2.3 and 6.9 Hz), 4.27 (lH, dd, J = 2.6 and 9.2 Hz), - 4.3 (lH, m), 7.3 - 7.6 (lOH, m).
Reference Example 5-2(2~
OH OH
J---,~, /r" ~J\
SPh ~ ~ SPh COSPh COOH
To a mixture of (4R,5S,6S,8R)-3-phenylthio-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0~hept-2-en-7-one-2-carboxylic acid phenylthio ester (3 mg) and trimethyl-silanol (14 mg) in dry toluene (0.1 ml), there were added silver trifluoroacetate (1.6 mg~ and a solution of 1,8-diazabicyclo[5.4.0]-7-uncecene (1.1 mg) in dry toluene (0.1 ~3~3~

ml) at room temperature, followed by stirring at 80C for 15 minutes. The reaction mixture was cooled down to room temperature and ailuted with a 0.lM phosphate buffer solu-tion (pH 7; 1 ml) and methylene chloride. After removal of insoluble materials by filtration, the filtrate was ex-tracted with methylene chloride twice. The aqueous layer was stirred under reduced pressure to remove any organic solvent. By identification of HPLC (Lichrosorb RP-18; ~leOH (pH 7.0 - 7.2)/0.005 M phosphate buffer (3 : 7);
0.8 ml/minute) and TLC (silica gel; CHC13/~leOH/acetic acid (200 : 50 : 1), (4R,SS,6S,8R)-3-phenvlthio-4-methyl-6-(l-hydroxyethyl)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid, i.e. the compound in Reference Example 6-(2), was found to be present in the aqueous layer.
Reference Example 6-1 OH
J"~o COOPNB
OH OH

OP(OPh~2 ~ SPh COOPNB COOPNB
To a solution of (4R,5R,6S,8R)-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0~hept-3,7-dione-2-carboxylic acid p-nitrobenzyl ester (100 mg) in dry acetonitrile (1 t 3 '?L 3 ~ ~ ~7 ml), there were added a solution of diphenylchloro~hosphate (67 mg) in dry acetonitrile (0.5 ml) and a solution of diisopropylethyLamine (32 mg) in dry acetonitrile (O.S ml) under a nitrogen stream while ice-cooling. The resultant mixture was stirred at the same temperature for 30 minutes.
The reaction mixture was cooled down to -30C and then thiophenol (37 mg) and diisopropylethylamine (44 mg) in dry acetonitrile (0.4 ml) were added thereto successively. The resulting mixture was stirred at the same temperature for 25 minutes and further for lS minutes under ice-cooling. The mixture was diluted with ethyl acetate, washed successively with brine, an aqueous solution of potassium dihydrogen phosphate and brine, dried over a mixture or magnesium sulfate and potassium carbonate and evaporated. The residue W2S purified by silica gel chromatography to give (4R,55,65,8R)-3-phenylthio-4-methyl-6-(1-hydroxyethyl)-l-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid p-nitrobenzyl ester.
IR ~maxt (cm ): 3480 (broad), 1764, 1707, 1520, 1342, 1215, 1140.
NMR C (CDC13): 0.97 ~3H, d, J = 7.3 Hz), 1.31 (3H, d, J = 6.3 Hz), 3.10 (lH, m), 3.21 (lH, dd, J = 2.8 and 6.8 Hz), 4.18 (lH, dd, J = 2.8 and 9.4 Hz), 4.23 (lH, m), 5.42 (2H, m), 7.3 - 7.6 (5H, m), 7.69 (2H, d, J = 8.9 Hz), 8.24 (2H, d, J = 8.9 Hz).

- 85 - ~ ~3 Reference Exam~le 6-2 OH OH
,l""~ J-~
L ~ ~ Ph ~ SPh COOPNB CGOH
To solution of (4R,5S,6S,8R)-3-phenylthio-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo~3.2.0]hept-2-en-7-- one-2-carboxylic acid p-nitrobenzyl ester (37 mg) in tetra~
hydrofuran (2 ml~, a morpholinopropanesulfonic acid buffer solution (pH 7.0; 2 ml) was added, and the resultant mixture was subjected to hydrogenation at room temperature in the presence of 10 % palladium-carbon ~56 mg~ under atmospheric pressure for 4.5 hours. After filtration, the filtrate was stirred under reduced pressure to remove tetrahydrofuran.
The filtrate was washed with methylene chloride and stirred again under reduced pressure to remove any organic solvent.
The residue was purified by polymer chromatography (CHP-20P), and the fractions eluted with 2 % and 5 % tetrahydro-furan-water gave (4R,5S,6S,8R)-3-phenylthio-4-methyl-6-(1-hydroxyethyl)-l-azabicyclo[3.2~o]hept-2-en-7-one-2 carboxyllc acid.
UV AmaX (nm): 306.
IR ~mBr (cm 1): 3425 (broad), 1745, 1595, 1400.
NMR ~ (D2O)(ppm): 0.90 (3H, d, J = 7.3 Hz), 1.18 (3H, d, J = 6.3 Hz), 3.00 (lH, m), 3.32 (lH, dd, J = 2.6 and 5.9 Hz), 4.09 (lH, dd, J = 2.6 and 9.2 Hz), 4.16 (lH, m), 7.3 - 7.6 (SH, m).

-86- t~ a Example 11~
OTBDMS OTBD~IS
~/~OSPh /

~CH2COOPNB O --~
COOPNB
A solution or (3S,4S)-3-[(lR)-l-t-butyldimethyl-silyloxyethyl]-4-[(lR)-1-phenylthiocarbonylethyl]-1-p-nitro-benzyloxycarbonylmethyl-2-azetidinone (70 mg) in dry toluene (0.5 ml) was dropwise added to a supension of sodium hydride (12.5 mg; 50 % in oil) in dry tetrahydrofuran (0.1 ml) under ice-cooling, and the resultant mixture was stirred for 30 minutes. p-Toluenesulfonic acid monohydrate (57 mg) was added thereto, ar.d the resulting mixture was further stirred for 10 minutes. The reaction mixture was diluted with cold ethyl acetate (20 ml), washed with brine, dried over magne-sium sulfate and e~Japorated to give (4R,5R,6S,8R)-p-nitro-benzyl-4-methyl-6-(1-t-bu~yldime~hylsilyloxyethyl)-1-aza-bicyclo[3.2.0]hept-3,7-dione-2-carboxylate as an oil.
IR vmax (cm 1): 1760, 1605, 1520, 1460, 1350, 1250, 1220, 1110, 1045, 835, 780, 738.
N~IR ~ (CDC13): 1.21 (3H, d, J = 7.6 ~z), 1.29 (3H, d, J = 6.3 Hz), 2.80 (lH, m), 3.22 (lH, dd, J = 2.3 and 6.3 Hz), 4.18 (lH, dd, J = 2.3 Hz), 4.29 (lH, m), 4.72 (lH, s), 5.30 (2H, ABq, J = 13.2 Hz), 7.54 (2H, d, J = 8.9 Hz), 8.24 (2H, d, J = 8.9 Hz).
Example 11-1(2) To a solution of (3S,4S)-3-[(lR)-l-t-butyldi-~3~3~

methylsilyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-l-p-nitrobenzyloxycarbonylmethyl-2-azetidinone (60 mg) in a mi~:ture of benzene-d6 ana tetrahydrofuran-d8 (4 : 1) (0.6 ml), there was added sodium hydride (11 mg; 50 % in oil) 5 under ice-cooling, followed by stirring for l hour. The N~lR
spectrum of the reaction mixture was measured and shown below in contrast to that as in Example 11-1(1).
N~ spectra data:-Example No. Solvent 5-H 6-H
lO 11-1(2) C6D6-THFd8 3.08, d 3.93, d (4 : 1) J = 6.3 Hz J = 8.9 Hz 11-1(1) C6D6-THFd8 2.58, dd 4.08, dd (4 : 1) J = 2.6 and J = 2.6 and 5.3 Hz 7.9 Hz 15 Example 11-1-(3) In the same manner as in Example 11-1(2) but replacing the solvent by a mixture of benzene-d6 and di-methylsulfoxide-d6 (9 : 1), the N~IR spectrum of the reaction mixture was measured and shown below in contrast to that as in E~ample 11-1(1).
NM~ spectra data:-Example No. Solvent 5-H 6-H
11-1(3) C6D6-DMSOd6 3.16, d 4.00, d (9 : 1) J = 7.3 Hz J = 7.6 Hz 11-1(1) C6D6-DMSOd6 3.08, dd 4.10, dd J = 2.6 and J = 2.6 and S.0 Hz 7.9 Hz ~3~

E~ample 11-2 OTBDMS OTBDMS
f H H ~ ~ H H
~ COSPh ~ 11 ~ OP(OPh)2 O CH2COOPNB O --~
COOPN~
A solution of (3S,4S)-3-[(lR)-l-t-butyldimethyl-silyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-l-p-nitro-benzyloxycarbonylmethyl-2-azetidinone (117 mg) in a mixture of dry toluene znd dry tetrahydrofuran (1 : 1) (1.2 ml) was dropwise added to a suspension of sodium hydride (22 ml; 50 % in oil) in a mi~ture of dry toluene and dry tetrahydro-furan (1 ~ 0.2 ml) at -20C, followed by stirrins at the same temperature for 1 hour. A 2M solution (0.1 ml) of iodomethane in tetrahydrofuran was added thereto, and stirring was continued for 30 minutes. A solution of diphenylchlorophosphate (56 ml) in dry toluene (0.1 ml) was added to the mixture at the same temperature, followed by stirring for 1.5 hours~ The resultant mixture was diluted with ethyl acetate (20 ml), washed with brine, dried over a mixture of magnesium sulfate and potassium carbonate (10 :
1) and evaporated in vacuo to give an oily residue, which was purified by silica gel chromatography to obtain (4R,5R,6S,8R)-p-nitrobenzyl-3-diphenylphosphoryloxy-4-methyl-6-(1-t-butyldimethylsilylo~yethyl)-1-azabicyclo-[3.2.0]hept-2-en-7-one-2-carboxylate (115 mg).
IR vmaexat (cm ): 1775, 1725, 1630, 1585, 1518, 1482, 1340, 1285, 1185, 1160, 9,8, 825, 770.

~,3~a NMR ~ (CDC13): 0.06 (3H, s), 0.07 (3H, s), 0.86 (9H, s), 1.20 (3H, d, J = 7.9 Hz), 1.23 ~3H, d, J = 6.3 Hz), 3.29 (lH, dd, J = 3.0 and 6.0 H~), 3.43 (lH, m), 4.22 (2H, m), 5.28 (2H, ABq, J = 13.5 Hz), 7.56 (2H, d, J = 8.9 Hz), 8.14 (2H, d, J = 8.9 Hz).
ExamPle 11-8 .
OTBDMS
~ H H

- ~ COSPh O \ CH2COOPNB

OTBDMS
~ H H r \ ~ ~ PNZ
COOPNB
A solution of (3S,4S)-3-[(lR)-l-t-butyldi-methylsilyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-l-p-nitrobenzyloxycarbonylmethyl-2-azetidinone (415 mg) in a mixture of dry toluene and dry tetrahydrofuran (4 : 1) (4 ml) was dropwise added to a suspension of sodium hydride t75 ml; 50 ~ in oilj in a mixture of dry toluene and dry tetra-hydrofuran (4 : 1) (0.75 ml) at -20C, followed by stirring at the same temperature for 1 hour. A 0.5 M solution (1.49 ml) of iodomethane in tetrahydroruran was added thereto, and stirring was continued for 30 minutes. A solution of diphenyl chlorophosphate (218.5 mg) in dry toluene (2.2 ml~

~ 3~ ~2Q
-- so --was added to the mixture at the same temperature, followed by stirring for 2 hours. Thereafter, (2S,4S)-1-p-nitroben-zyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (237.5 mg) and sodium hydride (32.3 mg; 50 % in oil) were added theretoi and stirring was continued for 2 hours. The resultant mixture was diluted with ethyl acetate (50 ml), washed with brine, dried over magnesium sulfate and e~apo-rated in vacuo to give an oily residue, which was purified by silica gel chromatography to obtain (4R,SS,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethyl-aminocarbonylpyrrolidinyl)thio]-4-methyl-6-(1-t-butyldi-methylsilyloxyethyl)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (329 mg).
IR vmax (cm ): 1775, 1715, 1660, 1610, 1525, 1400, 1345, 1210, 1140, 1110, ~35, 755.
Example 11-4 OTBDMS
r H H
~ COSPh 'J~
\ CH2COOPNB

OTBDMS
H H
~ 1l P(oph)2 COOPI~B
+

131~

.r . OTBDMS
r H H

SPh COOPNB
A solution of (3S,4S)-3-[(lP~-l-t-butyldimethyl-silyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-l-p-nitro-benzyloxycarbonylmethyl-2-azetidinone (69 mg) in dry toluene (0.6 ml) was dropwise acded to a suspension of sodium hydride (12.5 ml; 50 % in oil) in dry tetrahydrofuran under ice-cooling, and the suspension was stirred for 30 minutes.
Diphenyl chlorophosphate (67 mg) was added thereto under ice-cooling, followed by stirring ~or 1 hour. The resultant mixture was diluted with ethvl acetate (10 ml), washed with brine, dried over a mixture of magnesium sulfate and potas-sium carbonate (10 : 1) and evaporated in vacuo to give an oily residue, which was purified by silica gel chromato-graphy to obtain (4R,SS,6S,8R)-p-nitrobenzyl-3-phenylthio-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-1-azabicyclo-[3.2.0]hept-2-en-7-one-2-carboxylate (37 mg) (Compound A) and (4R,5R,6S,8R)-p-nltrobenzyl-3-diphenylphosphoryloxy)-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-1-azabicyclo-[3.2.0]hept-2-en-7-one-2-carboxylate (34 mg) (Compound B).
Compound A:-IR vmax (cm ): 1765, 1707, 1522, 1378, 1350, 1340, 1140.
~'MR ~ (CDC13): 0.06 (6H, s), 0.84 (9H, s), 0.95 (3H, d, J = 7.3 Hz), 1.17 (3H, a, J = 6.3 Hz~, 3.06 (lH, m), : 3.19 (lH, dd, J = 2.9 and 5.0 Hz), 4.22 (2~, m), 5.40 (2H, ABq, J = 1~.9 Hz), 7.3 - 7.6 (SH, m), 7.69 (2H, d, J = 8.9 Hz), 8.23 12H, d, J = 8.9 Hz).
Compound B:-The IR and N~5R spectra data were identical to those of the compound ob~ained as in Exmaple 11-2.
Exam~le 12 OTBDMS
~ON ~ N

\ ~H2COOPNB

OTBDMS

CONMe2 ~ ~ - PNZ
COOPNB
To a solution of (3S,4S)-3-[(lR)-l-t-butyldi-methylsilyloxyethyl]-4-[(lR)-l-imidazolylcarbonylethyl]-l-p-nitrobenzyloxycarbonylmethyl-2-azetidinone (52 mg) in a mixture of dry toluene and dry tetrahydrofuran (4 : 1) (0.5 ml), there were added sodium hydride (10 mg; 50 % in oil) and dry dimethylformamide (0.05 ml~ under ice-eooling, follo~ed by stirring for 1 hour. Diphenyl chlorophosphate (60 mg) was added thereto, and stirring was continued for 2 hours. To the resultant mixture, (2S,4S)-l-p-nitrobenzyl-oxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine _ 93 ~ 33~

, (35.3 mg) and sodium hydride (5 mg; 50 ~ in oil) were added under ice-cooling, followed by stirring for 1.5 hours. The reaction mixture was diluted with ethyl acetate (10 ml), washed with brine, dried over magnesium sulfate and evapo-rated in vacuo to give an oily residue, which was purifiedby thin layer chromatography on silica gel to obtain (4R,SS,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitroben~yl-oxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl)thio]-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-1-azabicyclo-[3.2.0]hept-2-en-7-one-2-carboxylate.
The IR and NMR spectra data of this compound were identical to those of the compound as in Example 11-3.
ExamDle 13 3SiO
,-~~
. ~ I COSPh \ CH2COOPNB

~e3SiO
~ H H r _/xcoz e2 COOPNB
In the same manner as in Example 11-3 but replac-ing the starting material by (3S,4S)-3-[(lR)-l-trimethyl-silyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl3-1-p~nitro-ben~yloxycarbonylmethyl-2-azetidinone, there was obtained ~94~ 3~3~3~

r- (4R,5S,6S,8R,2'S,4'S)-p-nitrcbenzyl-3-[4-tl-p-nitrobenzyl-oxycarbonyl-2-aimethylaminocarbonylpyrrolldinyl)thio]-4-methyl-6-(1-trimethylsilyloxyethyl)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
IR ~max (cm ): 1765, 1705, 1650, 1600, 1512, 1395, 1335, 1200, 1130, 1100, 840, 7~0.
Example 14-1 OTBD~IS OTBDMS
r H H r ~ ~ H
COSPh O ~ CH2COSPh O ~ /
COSPh To a solution of (3S,4S)-3-[-(lR)-1-t-butyldi-methylsilyloxyethyl]-4-[(lRl-l-phenylthiocar~onylethyl]-l-(phenylthiocarbonylmethyl)azetidin-2-one (20 mg) in dry dimethylformamide (0.2 ml), there was added sodium hydride (2.6 mg), followed by stirring at room temperature for 20 minutes. The reaction mixture was diluted with diethyl ether, followed by addition of a phosphate buffer solution - (pH, 6.86). The aqueous layer was separated from the organic layer and extracted with diethyl ether twice. -The extracts were combined with the organic layer, washed successively with water three times and brine twice,.-dried over sodium sulfate and distilled orf to remove the solvent. The residue was puriried by silica ael chromato-20 graphy to give (4R,5R,6S,8R)-4-methyl-6-(1-t-butyldimethyl-silyloxyethyl)-l-azabicyclo[3.2.0]hept-3,7-dione-~-carboxylic acid phenylthio ester.

- 95 - 1 3 ~ 3 ~ a IR ~meaxt (cm 1): 1780 ~sh), 1760, 1750 (sh), 1710, 1250, 1140, 1062, 830, 775, 742.
Example 14-2 OTBDMS QTBDMS
~' H H ~ r H H Y
/~\COSPh ~
O~\ CH2COSPh o~ ~P (OPh) 2 COSPh To a solution or (3S,4S)-3-[(lR)-1-t-butyldi-methylsilyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-1-phenylthiocarbonylmethyl-2-azetidinone (60 mg) in dry acetonitrile (1 ml), there was added sodium hydride (13 mg;
S0 % in oil) under ice-cooling, followed by stirring for 15 minutes. A solution of dinhenyl chlorophosphate (57.5 mg) in dry acetonitrile (0.3 ml) was added there~o, and stirring was continued for 1.5 hours while ice-cooling. The reaction mixture was diluted with ethyl acetate ~10 ml), washed with brine, dried over a mixture of masnesium sulfate and potassium carbonate (10 : 1) and evaporated in vacuo to give an oily residue, which was purified by thin layer chromato-graphy on silica gel to obtain (4R,5S,65,8R)-3-diphenylphos-phoryloxy 4-methyl-6-(1-t-butyldime~hylsilyloxyethyl)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid phenyl-thio ester (55 mg).
The IR and NMR spectra data of this compound were identical to those or the compound as in Reference Example 3-1.

- 96 - ~L3~3~

E:camPle 15 OTBD~.S ~ OTBDMS

OSPh /'~\~ \=

O \CH2COSPh COSPh To a solution of (3S,4S)-3-[(lR)-l-t-butyldi-methylsilylo,~yethyl]-4-[(lS)-1-phenylthiocarbonylethyl~
phenylthiocarbonylmethyl-2-azetidinone (20 mg) in dry hexamethylphosphoramide (~lPA) and tetrahydrofuran (1 : 100) (0.2 ml), there was added a 0.5 M solution t0.3 ml) of lithium bis(trimethylsilyl)amide in tetrahydrofuran unaer a nitrogen stream at -30C, followed by stirrina at 0 to 5C
for 25 minutes. The reaction mixture was diluted with diethyl ether and a phosphate buffer solution (pH, 6.86).
The aqueous layer was separated from the organic layer and extracted with diethyl ether two times. The exiracts were combined with the organic layer, washed with brine three times, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (45,5R,6S,8R)-4-methyl-6-(1-t-butyldimehtylsilyloxyethyl)-1-azabicyclot3.2.0]hept-3,7-dione-2-carboxylic acid phenylthio ester.
IR vmaxt (cm 1): 1760, 1700, 1435, 1367, 1247, 827, 765, 740, 680.

1 3 ~

Example 16-1 OTBDMS OTBDMS

~CH\2C~OO~ B~I 0~--~=
COOtBu mO a solution of (35,4S)-3-[(lR)-1-t-butyldi-methylsilyloxyethyl]-4-[(lR)-l-phenylthiocarbonylethyl]-l-(t-butyloxycarbonylmethyl)-2-azetidinone (65 mg) in dry tetrahydrofuran (1.0 ml), there was added a 0.1 ~ solution (3.84 ml) of lithium bis(trimethylsilyl)amide in tetra-hydrofuran at -70C under a nitrogen strezm. After elevat-ing the temperature to 0 to 5C, the reaction mixture was quenched with a phosphate buffer solution (pH, 8.0) and extracted with diethyl ether twice. - The organic layer 0 was washed with a phosphate buffer solution (pH, 8.0) twice dried over sodium sulfate and distilled off to remove the solvent to give (4R,5R,6S,8R)-t-butyl-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-1-azabicyclo[3.2.0]hept-3,7-dione-2-carboxylate.
NMR ~ (CDC13): 0.10 (6H, s), 0.89 (9H, s), 1.18 (3H, d, J = ?.9 Hz), 1.27 (3H, d, J = 6.6 Hz), 1.46 (9H, s), 2.76 (lH, m), 3.18 (lH, dd, J = 2.5 and 5.8 Hz), 4.22 (lH, dd, J = 2.5 and 8.1 Hz), 4058 (lH, s).

- 98 ~ 1313~

ExamPle 16-2 COSPh ¦

O\C~2COOtBu ' O
~OOtBu OTBDMS
~ O
> ~ ~ /~ o~(OPh)2 COOtBu To a solution of (3S,4S)-4-[(lR)-1-phenylthio-carbonylethyl]-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-l-(t-butyloxycarbonylmethyl)-2-azetidinone (101 mg) in dry tetrahydrofuran (2 ml), there was added a 0.1 M solution (5 5 ml) of lithium diisopropylamide in tetrahydrofuran under a nitrogen stream at -50C, followed by warming gradually to 0C for 2 hours. A solution of diphenyl chlorophosphate (120 ml) in dry acetonitrile (7 ml) was added thereto under ice-cooling, followed by stirring for 2 hours. The reaction 10 mi;~t~re was poured into cold diethyl ether (20 ml) and a .
phosphate buffer solution (pH, 6.86; 20 ml). The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to remove the solvent. The residue was purified by thin layer chromatography on silica gel to 15 give (4R,iR,6S,8R)-3-(diphenylphosphoryloxy)-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-l-azabicyclo[3.2.0]hept-2-en-' 7-one-2-carboxylic acid t-butyl ester (83.5 mg).
IR vnaat (cm 1): 1780, 1718, 1635, 1585, 1482, 1360, 12~5, 1185, 115&, 960, 940, 830, 765.
NRM ~ (CDC13): 1.17 (3~, d, J = 7.6 Hz), 1.21 5 (3H, d, J - 6.3 Hz), 3.22 (lH, dd, J = 3.0 and 6.0 Hz), 3.42 (lH, m), 4.12 (lH, dd, J = 3.0 and 10.0 Hz), 4.21 (lH, m).
Example 16-3 OTBDMS OTBDMS

o~C:~2COOt~u ~ '~
COOtBu Compound (A) In the same manner as in Example 16-1 but using the starting material as shown in the table below, there was 10 produced a mixture of (4~,5R,6S,8R)-t-butyl-4-methyl-6-(1-t-butyldimethylsilyloxyethyl)-l-a7abicyclo[3.2.0]hept-3,7-dione-2-carboxylate and (4S,5R,6S,8R)-t-butyl-4-methyl-6-(l-t-butyldi~ethylsilyloxyethyl)-l-azabicyclo[3.2.0]hept-3,7-dione-2-carboxylate (Compound (A)).

- 100 - ~ 3~ 33~

No Starting material Reaction condition _z 1 1 -Cl LiN[si(C~3)3]2/THF;
-70C > 0 to 5C
C ~ I (same as above) 3 -OBt ¦ (same as above) 4 ~ (same as above) The IR and NMR spectra data of the product were identical to those of the compound as in Example 16-1 and Example 17-2 ExamPle 17-1(1) OTBDMS OTBDMS
H ` r H H

o ~ CH\2~00Me O ~
COOMe To a solution of (3S,4S)-3-[(lR)-l-t-butyldi-methylsilyloxyethyl]-4-[(lS)-l-phenylthiocarbonylethyl]-1-(methoxycarbonylmethyl)a~etidin-2-one (50 mg) in dry he~a-methylphosphoramide and tetrahydrofuran (1 100) ~0 6 ml) was added a 1 M solution (0 44 ml) of lithium bis(trimethyl-silyl)amide in tetrahydrofuran at -30C under a nitrogen stream, followed by stirring at room temperature After - 101~

disappearance of the starting material, the reaction mixture was diluted with a phosphate buffer solution (pH, 6.86) and diethyl ether under ice-cooling. The aqueous layer was separated from the organic layer and extracted with diethyl ether ~wice. The extracts were combined with the organic layer, washed with brine five times, dried over sodium sulfate and evaporated. The residue was purified by silicz gel chromatography to give (4S,5R,6S,8R)-methyl-4-methyl-6~ t-butyldimehtylsilyloxyethyl)-1-azabicyclo-[3.2.0]hept-3,7-dione-2-carboxylate.
IR vmax 3 (cm ): 1770, 1760, 1740, 1435, 1245, 1120, 825.
NMR 8 (CDC13): 0.10 (6H, s), 0.90 (9H, s), 1.27 (3H, d, J = 7.0 Hz), 1.30 (3H, d, J = 6.2 Hz), 2.29 (lH, m), 15 3.14 (lH, dd, J = 1.5 and 5.7 Hz), 3.77 (3H, s), 4.31 (lH, m), 4.71 (lH, s).
Example 17-1(2) OTBDMS OTBDMS

~ COSPh O \ CH2COOMe O N ~
C~OMe To a solution of (3S,4S)-3-[(lR) 1-t-butyldi-methylsilyloxyethyl]-4-[(lS)-l-phenylthiocarbonylethyl]-l-(methoxycarbonylmethyl)azetidin-2-one (15 mg) in dry hexa-20 methylphosphoramide and tetrahydrofuran (1 : 100) ~0.2 ml),there was added a 2.6 M sodium methylsulfinylmethide solution (0.05 ml), prepared from sodium hydride and di-~3~3~

methylsulfoxide, at -20 to -25C under a nitrogen stream.
A.ter stirring at 0 to 5C ror 30 minutes and at room temperature for 20 minutes, the reaction mixture was diluted with a phosphate buffer solution (pH, 6.86) and diethyl ether at 0 to 5C. The aqueous layer was separated and extracted with diethyl ether. The extract was combined with the organic layer, washed with water three times, dried over sodium sulfate and evaporated. The residue was purif_ed by silica gel chromatography to give (4S,SS,65,8R)-methyl-~-methyl-6-~1-t-butyldimethylsilyloxyethyl)-1-azabicyclo-[3.2.0]hept-3,7-dione-2-carboxylate.
The IR and NMR spectra data of this compound were identical to those of the compound as obtained in Example 17-1(1).
ExamPle 17-1(3) OTBDMS _ OTBDMS
H H ~ Y H H
~ '- ~ COSPh ~ h ` -O CH2COOMe O
COOMe To a solution of (35,45)-3-[(lR)-1-t-butyldi-methylsilyloxyethyl]-4-[(lS)-l-phenylthiocarbonylethyl]-l-(methoxycarbonylmethyl)azetidin-2-one (15 mg) in dry hexamethylphosphoramide and tetrahydrofuran (1 : 100) (0.2 ml), there was added potassium t-butoxide (15 mg) at 0 to 5C, followed by stirring at room temperature for 30 minutes. The reaction mixture was diluted with a phosphate burfer solution (pH, 6.86) and diethyl ether a~ 0 to 5C.

- 103 - 13~33~

The aqueous layer was separated from the organic layer and extracted with diethyl ether. The e:ctract was combined with the organic layer, washed successively with water two times and brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (4S,SR,6S,8R)-methyl-4-methyl-6-(1-t-butyldimethylsilyloxye-thyl)-l-azabicyclo[3.2.0]hept-3,7-dione-2-carboxylate.
The IR and NMR spectra data of this compound were identical to those of the compound as in Example 17-l(l).
Example 17-2 OTBDMS OTBDMS
H H ~ r H H

COOR
Compound (B) In the same manner as in Example 17-1(1) but using the starting material as shown in the table below, there was obtained (4S,SR,6S,8R)-4-methyl-6-(1-t-butyl-dimethylsilyloxyethyl)-l-azabicyclo[3.2.0]hept-3,7-dione-2-carboxylic acid ester (Compounds (B)).

No. -R Reaction condition ._ l -PNB LiN[Si(CH )3]2/
HMPA-THF ~l : 100);
-30C ~ room temperature .
2 ¦ -tBu (same as above) HMPA: Hexamethylphosphoric triamide l~t3~

.
~4S,5R,6S,8R)-p-Nitrobenzyl-4-methyl-6-[1-t-butyl-dimethylsilyloxyethyl]-1-azabicyclo[3.2.0]hept-3,7-dione-2-carboxylate (Compound (B): R = -PNB) -IR VmaX13 (cm 1): 1780~ 1760~ 1720~ 1520~ 1345 1245, 1178, 835.
N~ ~ (CDC13): 0.08 (3E, S)~ 0.10 (3H~ s)~ 0.88 (9Hr S)~ 1.26 (3H, d, J = 6.8 HZ)~ 1.30 (3H~ d, J = 6.2 HZ)~
2.28 (lH, m), 3.17 (lH, dd, J = 2 and 7 H~), 3.67 (lH, dd, J
= 2 and 8 Hz), 4.30 (lH, m), 4.80 (lH, S)~ 5.29 (2H, S), 7.53 (2H~ d, J = 9 HZ)~ 8.24 (2H~ d~ J = 9 HZ).
(4S,5R,6S,8R)-t-Butyl-4-methyl-6-[1-t-butyl-dimethylsilyloxyethyl]-l-azabicfClo[3.2.0]hept-3~7-dione-2-carboxylate (Compound (B): R = -tBU):-IR ~mHaC13 (cm 1): 1760~ 1730~ 1360~ 1142~ 825.
NRM ~ ~CDC13): 0.10 (6H~ S)~ ~.90 (9H~ 5)~ 1.27 (3H~ d~ J = 6.9 HZ)~ 1.30 (3~ d~ J = 5.9 HZ)~ 1.46 (5H~ S)~
2.24 (lH, m), 3.12 (lH, dd, J = 2.0 and 6.3 HZ), 3.66 (lH, dd, J = 1.9 and 8.1 HZ)~ 4.29 (lH~ m), 4.57 (lH~ S).
Example 17-3 OTBDMS ` OTBDMS

O ~ OOtBU ~
COOtBU
Compound (C) In the same manner as in Example 14-1 but using the starting material as shown in the table below, there was obtained (4S,5R,65,8R)-t-butyl-4-methyl-6-(1-t-butyldimethyl-- 10-5 - I3~3~

silyloxyethyl)-l-azabicyclo[3.2.0]hept-3,7-dione-2-carbo~ylate (Compound (C)).

No. ¦ Starting m2terial Reaction condition I -Z
1 ¦ -SPh NaH/D~F;
l room temperature Z ~ ~ ¦ (s~me es above) The IR and NMR spectra data of the product were identical to those of the compound as in Example 17-2.

Claims

Claims:

1. A beta-lactam compound of the formula:

(I) wherein R1 and R2 may be the same or different and each represents a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group, R4 is a hydrogen atom, a carboxyl-protecting group or a thiolcarboxyl-protecting group, X is a hydrogen atom, a hydroxyl group or a protected hydroxyl group, Y is an oxygen atom or a sulfur atom and COZ is a carboxyl group, an activated or protected carboxyl group, a thiolcarboxyl group or an activated or protected thiolcarboxyl group.

2. A compound according to claim 1 wherein said lower alkyl groups have 1 to 8 carbon atoms.

3. A compound according to claim 1 wherein said lower alkyl groups have 1 to 5 carbon atoms.

4. A compound according to claim 1 wherein said lower alkyl groups have 1 to 4 carbon atoms.

5. A compound according to claim 1 wherein said lower alkyl groups are selected from methyl, ethyl, n-propyl and isopropyl.

6. A compound according to claim 1, 2 or 3 wherein said protected hydroxyl group contains a hydroxyl protecting group selected from lower alkoxycarbonyl, halogenated lower alkoxy-carbonyl, phenyl(lower)alkoxycarbonyl in which the phenyl group is optionally substituted with nitro or lower alkoxy, tri(lower)alkylsilyl and methyl substituted with lower alkoxy, lower alkoxy(lower)alkoxy, lower alkylthio or -O(CH2)4-7. A compound according to claim 1, 2 or 3 wherein said carboxyl protecting group and said thiocarboxyl protecting group are selected from lower alkyl, halogenated lower alkyl, lower alkoxymethyl, lower aliphatic acyloxymethyl, lower alkoxycarbonyloxyethyl, lower alkenyl optionally substituted with lower alkyl or phenyl, phenyl(lower)alkyl in which the phenyl group is optionally substituted with lower alkoxy, nitro or halogen, diphenyl(lower)alkyl in which the phenyl group is optionally substituted with lower alkoxy, phenyl optionally substituted with lower alkoxy, nitro or halogen, pyridyl or pyrimidyl optionally substituted with lower alkyl and phthalidyl.

8. A compound according to claim 1, 2 or 3 wherein said protected carboxyl group and said protected thiocarboxyl group contain a carboxyl protecting group selected from lower alkyl, halogenated lower alkyl, lower alkoxymethyl, lower aliphatic acyloxymethyl, lower alkoxycarbonyloxyethyl, lower alkenyl optionally substituted with lower alkyl or phenyl, phenyl(lower)alkyl in which the phenyl group is optionally substituted with lower alkoxy, nitro or halogen, diphenyl(lower)alkyl in which the phenyl group is optionally substituted with lower alkoxy, phenyl optionally substituted with lower alkoxy, nitro or halogen, pyridyl or pyrimidyl optionally substituted with lower alkyl and phthalidyl.

9. A compound according to claim 1, 2 or 3 wherein said activated carboxyl group and said activated thiol carboxyl group contain an activating group selected from active ester and active acid anhydride.

10. A compound according to claim 1, 2 or 3 wherein z is selected from halogen, lower alkoxycarbonyloxy, lower alkanesulfonyloxy, phenylsulfonyloxy in which the phenyl group is optionally substituted with lower alkyl, di(lower)-alkylphosphoryloxy, diphenylphosphoryloxy, cyclic imidoxy, imidazolyl and triazolyl.

11. The beta-lactam compound according to claim 1, which is represented by the formula:

wherein R4, Y and Z are each as defined in claim 1 and R10 is a hydrogen atom or a hydroxyl-protecting group.

12. A process for preparing beta-lactam compounds of the formula:
(I-1) wherein R1 and R2 may be the same or different and each represents a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group, R? is a carboxyl-protecting group, R? is a carboxyl-protecting group or a thiolcarboxyl-protecting group, X is a hydrogen atom, a hydroxyl group or a protected hydroxyl group and Y' is an oxygen atom or a sulfur atom, which comprises reacting a compound of the formula:

(II) wherein R1, R2, R3, R?, X and Y' are each as defined above with a compound of the formula:
M-CH2COOR? (III) wherein R? is as defined above and M is an activated hydroxyl group in an inert solvent in the presence of a base.

13. A process for preparing beta-lactam compounds of the formula:

(I-2) wherein R1 and R2 may be the same or different and each represents a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group, R? is a carboxyl-protecting group and X is a hydrogen atom, a hydroxyl group or a protected hydroxyl group, which comprises subjecting a compound of the formula:

(I-1) wherein R1, R2, R3, R? and X are each as defined above and R? is a carboxyl-protecting group or a thiolcarboxyl-protecting group and Y' is an oxygen atom or a sulfur atom to selective elimination of the carboxyl-protecting group or selective elimination of the thiolcarboxyl-protecting group.

14. A process for preparing beta-lactam compounds of the formula:

(I-4) wherein R1 and R2 may be the same or different and each represents a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group, R? is a carboxyl-protecting group, X is a hydrogen atom, a hydroxyl group or a protected hydroxyl group and COZ' is an activated or protected carboxyl group or an activated or protected thiolcarboxyl group, which comprises subjecting a compound of the formula:

(I-2) wherein R1, R2, R3, R? and X are each as defined above to treatment with a carboxyl-activating agent, optionally followed by treatment with a hydroxyl or thiol compound, or treatment with a hydroxyl or thiol compound in the presence of a condensing agent.

15. A process for preparing beta-lactam compounds of the formula:

(I-6) wherein R1 and R2 may be the same or different and each represents a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group, R? is a thiolcarboxyl-protecting group, R? is a carboxyl-protecting group or a thiolcarboxyl-protecting group, X is a hydrogen atom, a hydroxyl group or a protected hydroxyl group and Y' is an oxygen atom or a sulfur atom, which comprises subjecting a compound of the formula:

(I-1) wherein R1, R2, R3, R?, X and Y' are each as defined above and R? is a carboxyl-protecting group to selective elimina-tion of the carboxyl-protecting group represented by the symbol R? and reacting the resultant compound of the formula:

(I-5) wherein R1, R2, R3, R?, X and Y' are each as defined above with a thiol of the formula:
HSR?
wherein R? is as defined above.

16. A process for preparing beta-lactam compounds of the formula:
(I-2°) wherein R1 and R2 may be the same or different and each represents a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group, R? is a carboxyl-protecting group and X' is a hydrogen atom or a protected hydroxyl group, which comprises reacting a compound of the formula:

(IV) wherein R1, R2, R3 and X' are each as defined above with a compound of the formula:
M-CH2COOR? (III) wherein R? is a carboxyl-protecting group and M is an activated hydroxyl group in an inert solvent in the presence of a base and reacting the resulting compound of the formula:

(V) wherein R1, R2, R3, R? and X' are each as defined above with an oxidizing agent.