JPS61129162A - Optically active beta-lactam and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I or formula II [R<1> is (protected) amino; R<2> is organic residue bonded to C atom; R<3> is residue obtained by removing alpha-amino group from optically active alpha-amino acid or its derivative]. EXAMPLE:(3S,4R)-1-[( 1S )-( 1-methoxycarboynl-2-methyl )propyl]-3-phthalimido-4- sty-ryl-2-azetidinone. USE:A synthetic intermediate of beta-lactam antibiotic. PREPARATION:The substituted acetic acid of formula R<1>' CH2COOH (R<1>' is protected amino)or its reactive derivative at the COOH group is made to react with the substituted methyleneamine compound of formula R<2>CH=NR<3>, and if necessary, the protective group is removed from the reaction product.

Description

Detailed Description of the Invention (Industrial Field of Application → The present invention relates to optically active β-lactams and a method for producing the same. That is, the general formula %) [wherein R1 is an amino group or a protected amino group] The base,
R2 represents an organic residue bonded at a carbon atom, and R3 represents nine residues excluding the α-amino group from an optically active a-amino acid or its derivative].
This article relates to octums and their production methods.

(Prior art) Conventionally, optically active β-amino acids were used as raw materials.
- Methods for synthesizing octams are known.

Canadian Journal μ op Chemistry, No. 5
6 (1978), pp. 211-217.

Volume 58 (1980), pp. 1605-1607, Tetrahedron Letters, 1980.

pp. 3907-3910, The Jhana I Og Organic Chemistry, Vol. 847 (1982), 40
The synthesis of 3-azido-4-substituted-2-azetidinone derivatives is reported on pages 75-4081, but since both use 2-azidoacetic acid or p-phyto as a reagent, extreme care is required in the operation. , it is difficult to use it industrially because process control is difficult. Also Tetrahedron Letters, 19
1978, pp. 5119-5122, optically active β-phuctams were synthesized using 2-phthalimidoacetic acid crophyte in place of 2-azidoacetic acid crophyte, but the 4-position of the resulting β-phuctams was unsubstituted. It is.

(Problems to be Solved by the Invention) The present invention compensates for the shortcomings of conventional methods and provides useful synthetic intermediates for various β-fuctam antibiotics, as well as a process for producing these intermediates that can also be used industrially. It is something to do.

That is, the inventors of the present invention have continued intensive research with the aim of developing a new industrial production method for optically active β-fuctams, and have found that the general formula We succeeded in creating the optically active β-fuctams represented by [E] and [I'], and also completed an epoch-making method for producing them inexpensively, easily, and industrially. These compounds include, for example, monocyclic β-
It is an extremely useful compound as a synthetic intermediate for various antibiotics such as tuctam.

(Rounding means to solve the problem) To describe in more detail the method for producing the compound represented by the general formula CI) or [En A substituted acetic acid represented by the formula % or a broad derivative in the y group, and a substituted methylene amine represented by the general formula % [] [wherein R2 and R3 represent the same meanings as above] After 9 days of reacting with the compound,
Optically active β-tectams represented by the general formulas [C] and [C'] are produced by removing the protecting group, if necessary.

Compound (II), one of the raw materials used in the present invention
The substituent R1' in is a protected amino group, and the substituent R1 in the target compound CI) and [A'] is an amino group or a protected amino group. Here, as the protecting group for the amino group, β-phuctam and those used for this purpose in peptide synthesis are appropriately adopted, such as aryl acyl group, aliphatic acyl group, aryl acyl group, aryl acyl group, aryl acyl group, aryl acyl group,
group, aliphatic sulfony μ group, general formula RoOCO- (wherein,
Examples of RO include the oxycarbonyl group shown in [described later], t, and other groups. These protecting groups include those that substitute one hydrogen atom of the amino group and those that substitute two hydrogen atoms of the amino group, and in the latter case, the ring containing the nitrogen atom of the original amino group Also included are protecting groups that form .

The above-mentioned aryl V/I/ group, aliphatic acid μ group, arylsulfony p group, and aliphatic sulfony p group are alkyl p groups having 1 to 6 carbon atoms (specifically, 1y in substituent R2). (described later as a kill group), an alkoxy group having 1 to 6 carbon atoms (
Specifically, the aykoxy group in the substituent on substituent R2), substituted silyl group (for example, trimethylsilyl p).

Triethylsilyl, etc.], carbon atoms having 1 to 6 carbon atoms
group (specifically, what will be described later as the acanoyl μ group in the acyl μ group), alkyl group having 1 to 6 carbon atoms (for example, methanesulfonyl, ethanesulfonyl, etc.), nitro It may have a substituent such as a group, an ano group, or a halogen atom (eg, fluorine, chlorine, etc.). The aryl group preferably has 7 to 12 carbon atoms, such as phthaloy, benzy ρ, 4-nitrobency, 4
-Tart-butylpencil μ and the like. The aliphatic acyl group preferably has 1 to 6 carbon atoms, such as formyl, acetyl, defhionyl, monochloroacetyl, etc.
, dichromaacetyl, trichloroacetyl, trifluoroacetyl, maleoyl, succinyl, etc. The aryl group preferably has 6 to 11 carbon atoms, such as benzenesulfony/L', 4-ter
t-Butylbenzene, X/L'honi/l/, 4-
tart-guchi benzene honyl.

Examples include Batμence and Honiμ. Aliphatic
The Honi group preferably has 1 to 6 carbon atoms, and examples of the Alkis ρ Honi p group include the nine listed above.

R of the oxycarp group represented by the general formula ROOCO-
O is an alkyl μ group having 1 to 6 carbon atoms, a 5- to 6-membered cycloa μ group, an aryl group having 6 to 10 carbon atoms, and an alkyl group having 7 to 6 carbon atoms.
13 aralkyl groups are preferable, and these may further have a substituent. Examples of the oxVcarbony group represented by the general formula ROOCO-- include methoxycarbony, ethoxycarbony/L/, isoderopoki ViIlv ball, and tart-ptoquine carbony.

2-cyanoethoxycarbonyl, 2.2.2-)lichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl/L/, benzyloxycarbonyl/E/, 2-
(methanesulfony lv) ethoxycarbonyl, 4-nitrobendioxycarbonyl A/, 4-methoxybendi
Oxycarbon μboni〃, zophenyl〃methyloxycarbonyl〃bonyl, methoxyV methyloxycarbony〃bony, acetylmethyloxycarbony〃, isoboρ2〃oki Vi! /I/Boe〃
, phenoxycarbony etc. As protecting groups for amino groups other than those mentioned above, for example, trithia 1z, 2
-2) R5R6R781-, di(R5R
6R7Si) -, -81(R5R6)X81(R7
Also included are substituted silicate/V groups such as R8)-sudo. Here, R4, R5゜R6, R7, and R8 are each a linear or branched 7μ key group having 1 to 6 carbon atoms (specifically, the alkyl group described later as the substituent R2) or, for example, a phenylene group. 2μ, naphthyl, etc. carbon number 6-10
represents an aryl group, and each of R5, R6, R7, and R8 may be the same and different. R4/ is Pue 2μ
, represents an aryl group having 6 to 10 carbon atoms such as naphthyl. Also, X is, for example, methylene.

Represents a lower alkylene group such as ethylene.

As the amino group protected in the present invention, phthalimide and benzipoxycarboniμ amino are most preferred.

The organic residue R2 bonded at the carbon atom in compound CIII), which is the other raw material, and the target compounds CI), CI') is, for example, an alkyl μ group, a cycloa
A quinyl group, an apkenyl group, a cycloalkenyl group, an quinyl group, an aryl group, an aryl group, a heterocyclic group, and the like are used, and these have one to several substituents. It's okay.

Hereinafter, in the present specification, a group "which may have a substituent" will be represented by an umbrella attached to the right shoulder of the group. For example, "alkyl which may have a substituent" is expressed as "alkyl/I/". In this case, the number of substituents is not limited to one, and may have two to several identical or different substituents depending on the group to be substituted. The alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.
For example, methiμ, ethyl, n-propylene, isopropyl/L/ln-butylL/, isobutyl, &, 5ea
-Buchi! , tert-guchi μ, n-bench! , isobenchi μ, tert-aminoyl, neopentylene, n-hex S/ /L/, isohexyl, etc. are used. The cycloalkyl group and the ring are preferably 3- to 8-membered rings, such as cycloprobyl, cyclobutyl/I/, V-clopentyl, V-chlorohexyl, cycloheptyl, adamantyl μ, and the like. As the μ group, straight-chain or branched lower μ-y groups having 2 to 6 carbon atoms are preferred, such as vinyl, ali/I/, 1-probeni〃, isoprobeni〃,
2-Metari〃, Kurochi~, 1-Guteniμ.

2-butenyl, 3-putenyl, etc. are used.

The alkynyl group is linear or branched and has 2 or more carbon atoms.
Lower alkynyl of 6 is preferred, such as ethynyl) 1-zoroviny, 2-proviny, p-bagi, and the like. The cycloalkenyl group is preferably a 3- to 8-membered ring, such as 1-cyclopumabenyl A/, 1-vcroptenyl, 2-cycloptenyl fi/, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl e 1
-! '90 hexenyl, 2-cyclohexenyl A/,
3-cyclohex72μ, 1-cyclohepteny/' *
1*4-cyclohexagenyl and the like are used, but those having a 4- to 6-membered ring are preferred. The ary μ group is preferably an aromatic hydrocarbon group having 6 to 11 carbon atoms, such as pheni A/, l-naphthi, and 2-naphthi μ.

Bifueni ρ is used, but toshiwakefueniμ, nafuchiy, etc. are often used. Aralky μ groups preferably have 7 to 13 carbon atoms, such as benzyl, fenech,
2-phenipropyl, 3-phenipropyl, 1-naphthylmethyl, 2-naphthylmethyl, benzhydry, and the like are used.

Examples of the heterocyclic group include a 5- to 8-membered ring containing 1 to 5 heteroatoms such as a nitrogen atom (which may be oxidized), an oxygen atom, and a vt*i atom, or a fused ring thereof, in which a carbon atom is A compound with a bond is used, for example 2 (
or 3-pyrroliμ, 2- or 3-furiμ, 2- or 3-chenyl, 2- or 3-pyrrolidiniμ, 2-. 3
- or 4-pyridiμ, N-oxyVdo-2-93- or 4-pyridiA/, 2-. 3-1 or 4-piperidiniμ
, 2-. 3- or 4-pifniN, 2-, 3- or 4
- Thiopirani μ, Biwojini, TI/, 2-. 4- or 5-thiacyly/L', 2-,4- or 5-oxacyly/I/-a 14-t or 5-isothiacyly! , 3-
．． 4- or 5-isoxasily, 2-94-mak is 5-imidazolyl, 3-. 4- or 5-pissiri〃,
3- or 4-pyridazine A/, N-oxide-3-'
t or 4-pyridazine μ, 2-. 4- or 5-pyrimidinyl, N-oxide-2-14- or 5-pyrimidinyl A/, pyrimidinyl, 4- or 5-(1,2,3-
thiasiasiliN), 3- or 5-(1,2,4-thiasiasili/I/), 1,3,4-thiasiasili〃, 1.2.5-thiacyasily! , 4- or 5-(1
, 2,3-oxacyacyly/L/), 3- or 5
-(1,2,4-oxacyacylyA/), 1, 3
, 4-oxacyacyly A/, 1.2.5-oxacyacylyμ, 1.2.3- or 1,2.4-)lyasilylyμ
, IH1 or 2H-tetofuzoliρ, pyrido[2,3-d
) pyrimidyl, benzopyranyl, 1°8-. 1.5-.
1.6-. 1.7-. 2,7- or 2,6-naphthyridyl, quinoliy, cheno(2,3-b)pyridyl, and the like are frequently used. In particular, 5- to 6-membered heterocyclic groups containing 1 to 4 nitrogen atoms and sulfur atoms, such as chenyl and thiazolyl.

Thiadiazolyl, triacylyμ, tetofuzolyl and the like are preferred.

Among these substituents R2, alkyl, aμkenyl, a~
Quinyl is, for example, cycloalkyl, %, cycloaμkenylaryμ′, heterocyclic group “, alkoxycarbonyμ,
Ashiμ, oxo, halogen, cyano, hydroxy, alkoxy, ary-/II”yFoxy.

A S / A / Oxy, Power Pamoi p Oxy, Suhoki V
, alkylsuyhoni~oxy, ali-v”y, /l/
Honyloxy, nitro, amino, poxy, pamoy, alkylthiocarbonyl, mercapto, alkylthio, aminoalkylthio, acylaminoa μkylthio, alkylthio, arinothio, heterocycle! E, 91 to 3 may be substituted with quaternary ammonium t, etc.

A substituted alkyl group is, for example, a hydrogen atom, an alkyl, a cycloalkyno, a hydrogen atom, an alkyl, a cycloalkyno,
afluquino, ary-A/", heterocycle, alkoxycarbonyl, aV/L/, or R9 and RIO together represent oxo, R11 is a hydrogen atom, alkyl, cycloalkyl/I/", ary A/1 Heterocyclic group i Halogen, cyano, hydroxy, alkoxy, ary/I/%oxy, aroxyJv%xy, acyloxy.

Pamoyloxy, sulfoxy, alkyloxy, ary-1vSU, oxy, nitro, amino, azide, carboxy, oxycarbonyl, aμ
Coxica〃boni〃alk〃oxy, force〃bamoiμ, alkylthioca〃boni/I/, ashi/%/, me〃capto, alkylthio, aminoa〃ki〃thio, acyaminoa〃kylthio, arayki/I/ *Thio, aryl group, heterocyclic group, quaternary ammonium ~ as shown] are also used.

Regarding the alkynyl substituents, R9, 110, and R11 mentioned above, the acokyV group is linear or branched and has 1 to 6 carbon atoms. Preferred are aμ coquine groups, such as methoxy,
Nidoxy, n-propoxy.

Isopropoxy, n-gutoxy, isobutoxy.

Be0-butoxy, tert-butoxy, n-pentyloxy V, isopentyloxy, n-hexyμ oxyne,
Isohexyoxy etc. are used. Fluorine, chlorine, bromine, and iodine are used as the halogen. Examples of the quaternary ammonium group include pyridine, carpamoyl group-substituted pyridine such as nicotinic acid amide or isonicotinic acid amide, carboxy group-substituted bilicin such as nicotinic acid or isonicotinic acid, and sulfoxy group-substituted pyridine such as biridine sulfonic acid. A quaternary ammonium compound represented by a general formula derived from a pyridine derivative such as or quinolinium. acyμ group, acyloxy group,
Examples of the acyl ρ group of the acyaminoalkylthio group include formyl, acetyl μ, propioni/L/, n-glytyly, isobutyly/L/, n-bentanoy μ, n
-7μ Kanoi group having 1 to 6 carbon atoms, such as hexanoylμ,
For example, monochloroacetyl μ, dichloroacetyl! , triqualoaceti μ, trifluoroaceti μ, etc. with 1 or more carbon atoms
6's halogenated I/M groups, such as benzoyl, 4-nitrobency, 4- and dolo/I/M?
For example, pheni, acetiμ, 4-hydroxypheni
Acechi! , 4-MeF-xyphenylacetate tv-nato carbon number 7-9 aph-kyno-carpo di-μ group, such as 2-chenylcarboni/l/, 2-ylylcarboni/L', 2
−． 4- or 5-thiacylylacetymu, 2- or 3
-chenylacetiμ, 2- or 3-furiμacetiμ,
5- to 6-membered heterocyclic carbonyl group or 5- to 6-membered heterocyclic carbonyl group containing at least one of an oxygen atom, nitrogen atom, @yellow atom, which may have a substituent such as 2-amino-4- or 5-thiacylylacetiμ A membered heterocyclic acetyl group is used. And alkyloxy, μkiμ
Thiocarboniμ, alkylthio.

Amino ay ki y thio, ashi µ amino y ki y thio, a!
Alkyl μ group in Koxykabonyalkyloxy,
Aμkokinkaμboni/L/, a! A Vfi/group 1 ary h in Koxycarbon μbonyμalkyloxy, acyμoxy, and aminoalkylthio
oxy, ary-4''7'-IV oxy, ary-7f
The ary μ group in O.

The heterocyclic group in hetero ftf, aralkynooxy, and the aralkyl group in araμkio have the same meanings as above.

Also, V Croa〃kiμ, Cycloaμga2μ, Awoyki〃,
Examples of substituents for ary-μ, heterocyclic groups, and quaternary ammonium include alkylμ, aμkoxy, aμkeni/I/,
Ary/L/, araμkiμ, mercapto, alkylthio, arylthio, araykiμthio, alkylthioμhoniμ
, Ally/L/Nμhoniμ, Atsushipnuyhole, Alkylhalidey.

Hydroxy, oxo, thioxo, halogen, nitro, amino, cyano, carbamoyl, μboxy, an/L/
, Acyoxy, Anruamino, Hydroxy/L
/, force μ bokin ayki A/, monomaku is dialky μ amino a μ kil, etc.
A〃koxy, aμkeniμ.

Ary μ, Aralki μ, Ashi〃, and halogen are as mentioned above).

The most preferred substituent R2 is a Stirii μ group.

If there is an amino group in the organic residue bonded to the carbon atom represented by R2, the amino group may be substituted or protected; These may be protected.

As these protecting groups, the following protecting groups are used as appropriate.

The above methyleneamine compound (I[) can be produced, for example, by a conventional dehydration reaction between an optically active a-amino acid or a derivative thereof and an a[mu]dehyde as shown in the following formula.

R2CHO+ R3NH2-hR2CH-NR3(I[
) Therefore, the substituent R3 in compounds CI), CI') and (I[) represents a residue obtained by removing the α-amino group from the optically active α-amino acid or derivative thereof represented by the general formula R3MH2. The term "optically active α-amino acid derivative" as used herein refers to those described below. 13
Examples of Nil12 include D-asbafugic acid,
L-aspartic acid, D-asparagine, L-asparagine, D-glutamic acid, L-glutamic acid, D-gμ
Tamine, L-glutamine, D-alanine, L-afunine, D-fulkinine, L-agien, D-cystathionine, L-cystathionine, D-cystine, L-cystine, D-histidine, L-histidine, D- homoserine,
L-homoserine, D-isoleucine.

L-isoleucine, D-lanthionine, L-funthionine, D-loinine, L-leucine, ])-9cine, L-
Lysine, D-methionine, L-methionine, D-noμ leucine, L-norleucine, D-norvaline, L-noμ
Valine, D-oμ=chin, L-oμ-nithine, D-serine, L-serine, D-threonine, L-) leonine, D-
Tyrosine.

L-thin, D-thyronine, L-thyronine, D-valine, L-valine, D-phenyglycine.

L-phenylcrine, D-phenylphenine.

L-pheni-awonine and the like are used alone or in the form of di- or tripedetides as derivatives of a-amino acids. These di- and tripeptides will be described in detail later as α-amino acid amides. The "optically active α-amino acid derivative" as used herein refers to the general formula R3 with T
It also refers to an optically active α-amino acid represented by 12 (herein, R3 has the same meaning as defined above) in which the functional group on the substituent R3 is substituted or protected with an appropriate group. The functional group of the substituent R3 of the optically active α-amino acid used in the straw raw material may be in a free state, or may be substituted or protected with an appropriate group. For example, the μ boxy μ group on substituent R3 may be an ester in which the hydrogen is substituted with one of the groups shown below. Examples of groups forming such esters include the above-mentioned alkyl, cycloalkylρ, γμkeniμ, alkini/L/", Schif0fA/keni/L/", and ary-I.
W*, 7ufi/ki/I15 and others metkinmethiμ, etokikumechiμ, mechiμthiometh〃, 2-st-doech/',
2,2,2-) Lichloroethyl! , Acechiμme 1000μ
, acetoxymethyl, pivaloyμoxymethy/I/, deppioniμoxymethy/', 1,1-dimethy〃propyl/
L/, 3-methy-3-puteny/i/, 2-methys
Honiμeth〃.

Meji μme 1,000, 2-cyano-1,1-dimethi μ,
Methyμ, 2-(N,N-dimethyamino)ethyl, succinimidomethyl, phenyl, benzyloxymethyl, trityl f4-nitrobency, 1,000μ, 4-mediμbencyμ Methiy, phthalimidomethy, 3,5-di-tart-buty/I/-4-hydroxybendi/L/, benzene, fL/, pheni-thiomethy, pyridine-1-oxide-2- Methi,
#1 of groups such as bis(4-methoxyphenyN)methyl or silyl groups represented by the general formula R5R6R7!31- (where R5゜R6 and R7 each have the same meanings as above. For example, trimethylsilyl/I/ ,) riechiμsiriμ,
tart-butyldimethy/L/VA/, tar
t-guchi μ dipheny μ silyl, etc.).

Furthermore, the yJv group may be protected by introducing it to a group other than the above-mentioned ester. Such beauty salon μ
Other groups include those forming an acid amide. Such acid amides include unsubstituted amides, N
, N-disubstituted amide. The di-substituted amide may be an amide with a cyclic amine. Substituents of the substituted amide include alkyl μ groups having 1 to 6 carbon atoms, and 6 to 1 carbon atoms.
1 aryl group, a 3- to 8-membered Schiff-tetraaryk group, and specifically, those mentioned above as the ay group, ary group, and V-chloroalk group are used. Examples of monosubstituted amides include N-methylamide, N-methylamide, and N-phenyamide.

Examples of the di-substituted amide include N,N-dimethylamide, M,I-diethylamide, N-ethyl-N-methylamide, and N-methy/L'-4-thenylamide. Examples of the cyclic amine in the amide with a cyclic amine include 5- to 7-membered cyclic secondary amines, or those having a condensed ring. Specific examples of amides with cyclic amines include pyrrolidine amide, piperidine amide, 7y-folinamide H/-methylbiperazine amide.

Examples include 5,6-cyhydrofenanamide. 'In addition to the above-mentioned acid amide, it may be an amide with an a-amino acid, that is, a dibedetide state, or even a tribeptide state. The above-mentioned optically active α-amino acids can be mentioned as the α-amino acids constituting such dibeptide and tribedetide. These d-amino acids may be of the same type, or
It may be a different species.

When there is an amino group other than the α-position on the above-mentioned substituent R3, the amino group may be substituted or protected with a group such as a binder. Substituents for the amino group include alkyl, cycloalky, and aryky.

Ary-now heterocyclic group9. Examples include amidino group, aminomethylene group *'μ bamoi μ group, Suhoki V group, etc.
Here, Alkiμ, V Croixμkiμ, Af〃ki7. Ali
/L/'', representing the same meaning as above for a heterocyclic group).The amino group, together with such substituents, forms a cyclic amino group such as tatoebabishidino, piperidino, 7μ fluorino, piperazino, etc. As a protecting group for the amino group, β
- Mention may be made of those mentioned above which are used for this purpose in the field of fuctam and peptide synthesis. Further, as protecting groups for hydroxyl groups and thiol groups, any group that can be used as a protecting group for hydroxyl groups and thiol groups in the field of β-octam and organic chemistry can be used. Examples of these protecting groups include the acyl group described above as the substituent on the substituent R2, and the aryl group described above as the protecting group for the amino group.
group, aliphatic sulfony group, oxycarbonyl group represented by the general formula RQOCO-, for example, tart-
Spot μ.

Alkyl groups such as ben slμ, 4-nitrobendi/L/,) lythyl, methoxymethyμ, methyμthiomethyμ, 2-methoxyethoxymethyl (where aμkyl has the same meaning as above), for example trimethineμ, μ, Toriechiμ
Siriμ, tart-guchiμdimethinriμ, tar
General formula R5R6R7 such as t-butyldiphenylsilyl
31- (wherein 15. R6 and R7 represent the same meanings as above), such as silyl μ group such as 2-tetrahydrobifuni/I/, 4-methoxy-4-tetrahydrobipioniμ, etc. Examples include 2y group. The above-mentioned VIV group and amino group.

The selection of protective groups such as hydroxyl groups and thiol groups is not particularly limited in the present invention.

A substituted acetic acid represented by the formula (It) or a reactive derivative of the force μ boxy group is reacted with a substituted methylene amine compound represented by the formula (I[), preferably in the presence of a base, to form a reaction with Kff of the formula CI'']. The detailed reaction conditions for the process of producing the compound represented by the formula (II) and [1'] are as follows. μ-bonic acid hafide, μ-bonic acid anhydride and mixed acid anhydride, μ-bonic acid active esthetic μ
, active thioesters, etc., and specific examples of such reactive derivatives are as follows.

1) Acid hafide: Here, as the acid halide, for example, acid chloride, acid bromide, etc. are used.

2) Acid anhydride: Examples of the acid anhydride include monoalkyl carbonic acid mixed acid anhydride, aliphatic acid to bonic acid (for example, acetic acid, piva y
Acids, valeric acid, isovaleric acid, trichloroacetic acid, etc.) mixed acid anhydrides, aromatic power! Bonic acids (e.g. benzoic acid, etc.)
Mixed acid anhydrides, symmetrical acid anhydrides, etc. are used.

3) Active amide: Here, as the active amide, for example, amide of piracy μ, imidazo-1v*, and benzotriacylamide is used.

4] Active ester/I/: As the active ester, all those used for this purpose in the field of β-lactam and peptide synthesis can be used. For example, in addition to esters such as jetoxyphosphate and diphenoxyphosphate, for example,
-Hydroquine-IH-esters with 2-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, etc. are used.

5) Active thioester/L/: Here, as the active thioester μ, for example, 1,000 onyster with a heterocyclic thio-μ such as 2-pyridipithioμ, 2-benzthiacylyythio-μ, etc. is used.

The starting materials used in this reaction, Compound CII) or its reactive derivative, and Compound (I[) can all be easily produced by known methods or methods known per se.

Examples of the base used in this reaction include aliphatic quaternary amines (e.g., trimethylamine, trimethylamine, tri-n-propyamine, tri-n-butylamine, cyclohexyμ-dimethylamine, etc.), such as N-
Methylpiperidine.

Cyclic tertiary amines such as N-methylpyrrolidine, N-methylmorpholine, e.g. pyridine, /L/tidine, γ
-Aromatic amines such as collidine, as well as 1,8-diazabicyclo(5,4,0)-7-undecene (DBU)
Organic bases such as these are used. This reaction is preferably carried out in an organic solvent in the presence of an aliphatic tertiary amine (eg trimethylamine, tri-n-butylamine, etc.).

Examples of the solvent used in this reaction include dioxane, tetrahydrofone, diefWether/l/, t
Ethers such as ert-butylene glycol, ethylene glycol, diisopropyl ether, esters such as ethyl acetate and ethyl formate, such as chloroform, tetrachloride Carbon, tricrene, dichloroethane.

1. Hydrogen halides such as 2-dichloroethane,
Hydrocarbons such as benzene, toene, n-hexane, N,N-dimethylformamide, N,
In addition to amides such as N-dimethyacetamide, common organic solvents such as acetonitrile μ and dimethyA/sulfoxide can be used alone or as a mixed solvent. The reaction temperature is -786° to 50°C, preferably -78° to 0°C.
It is.

After completion of the reaction, the reaction mixture is subjected to purification and separation means known per se, such as solvent extraction, fractional recrystallization, chromatography, etc., to obtain optically pure compound CI) or CI'). can.

In the reaction between the compound represented by the general formula (If) and the optically active compound represented by the general formula CII, 1, the substituents at the 3- and 4-positions of the β-fuctam ring are in the tas configuration as expected. A mixture of compounds represented by the general formulas [E] and [E] is produced. In addition, the optically active compound of the formula Cl0) undergoes the above cycloaddition reaction, resulting in the product β
- Inducing two new optical centers at positions 3 and 4 of the octam ring with high optical yield. Furthermore, in this reaction, for example, lW! of amino acid (13NH2)! m, substituents of functional groups of amino acids, protecting groups, 9 reaction solvents, 1 reaction temperature, etc. By selecting all the diastereomers [(
We discovered that one of 1) and [Eng'] is produced more dominantly than the other. Note that CI) and [E'] have a diastereomeric relationship with each other, and as described later, when the 1CIi substituent R3 is removed to lead Cl0) to (IV) and [1') to (IV'), [■] and (r) are optical antipodes of each other. By combining the above-selected conditions and the above-mentioned separation means made by M! JCI) or [1
One of the compounds of formula 23 can be isolated with good yield and easily, and both diastereomers can be isolated efficiently. For example, D-Balin Methi! Imine compound CI obtained from ester or L-valine methyl ester N and cinnamaldehyde [
) with dielectric constant (20
°C, measured at toxio”cps) from 4.5 to 50
For example, methylene chloride.

Ethyl acetate μ, tetrahydrofone, acetonitrile/M,
When reacted in N,N-dimethylformamide, etc.), the compound of formula CI
3B, 4B coordination) and [123 compound (3R, 43 coordination) were obtained as a nearly 1:1 mixture, and by fractional recrystallization, the (3S, 4R) form and the (3R, 43) compound were obtained. Each body can be isolated. On the other hand, when the imine compound obtained from D-valine methyl ester and cinnamaldehyde is used as a raw material, when reacted in a solvent with a dielectric constant of 0 to 45 (for example, hydrogen tetrachloride, trichlene, etc.), (
When the 38, 4R) isomer is obtained from an imine compound obtained from L-valine methyl μ ester μ and cinnamaldehyde, the (3R, 48) isomer is predominately produced, and each diastereoisomer is produced by fractional recrystallization. mer can be easily isolated. Also, aspartic acid dimethymu
When 2-phthalimidoacetic acid crophyte is reacted with the imine compound obtained from ester μ and cinnamaldehyde, the imine compound obtained from D-anubaragic acid dimethyyester μ and cinnamaldehyde is reacted with 2-phthalimidoacetic acid clophyte. When used as a raw material, the (38,4R) body is
L-asbawogic acid dimethy-este μ and yinnam-a μdehyde tokara obtained imine compounds When used as t-raw materials, the (3R,4B) form is dominant (formed). When an imine compound obtained from μ ether μ and cinnamaldehyde was used as a raw material, the same results were obtained as when an imine compound obtained from aspartic acid dimethyl ester and cinnamaldehyde was used as a raw material.On the other hand, for example, L -alanine pyrrolidine amide, L-alanine (5,
When an imine compound obtained by combining an L-amino acid amide such as 6-cyclohydrophenanthrene) amide with cinnamaldehyde is used as a raw material, it can be obtained from the above amino acid ester and cinnamaldehyde, regardless of the dielectric constant of the solvent. When imine compounds are used as raw materials, the above is reversed (3S, 4R
) produced by the body. Amino acid methyμ ester/L'
, amide has been described, but the above phenomenon is similarly observed for other alkyμ Esde μ, amides of the same amino acid.

Compounds (IV) and (IV') obtained in the present invention can be derived into compounds (IV) and (IV') shown in the following formulas, respectively, by removing the substituent R3.

(IT) Compound [■] (wherein R1 and R2 represent the same compounds as above) is particularly useful as a synthetic intermediate for various β-fuctam antibiotics, and as described below, it has a wide range of antibacterial properties. A novel monobactam antibiotic with spectrum μ (33,
43)-3-[2-(2-amino-4-thiacyly/')
Synthetic intermediates such as -(Z)-2-(μboxymethoxyimino)acetamidocou 4-capamoyloxymethy/I/-2-azetidinone-1-sulfonic acid (hereinafter abbreviated as AMA-1080) Becomes a body. Moreover, AMA-10
In the case of synthesis of 80, the number of reaction steps can be reduced compared to the conventional synthesis method using L-ascorbic acid as a raw material.

The conversion of compound (IV) to AMA-1080 will be described in detail later. Also, compound (IV) or CPI'
] can also be used to produce pabenems, carbacephems, or isocephalosporins.

In the step of eliminating substituent R3 of compound CI) or CI') to obtain compound (ff) or [γ], prior to this step, the protective group of the functional group contained in compound CI) or [E'] is eliminated. may be done. The protective group can be removed by a method known per se. In particular, when the protecting group for the amino group of substituent R1 is affected during the R3 group removal reaction, the protecting group may be converted as desired. That is, by removing the protecting group of the amino group of substituent R1, the general formula %
The chemotactic compound [v:
lt or (V')K'' Compound CI) or [C'
] and then removing the substituent R3, the compound (IV) or (IV') can be produced.The new protecting group for the amino group here is the above-mentioned amino group. The compound represented by the general formula (V) or [v'] is selected from the protecting groups of the general formula (CI) or [I
It can be obtained by changing the substituent R1 of the compound represented by '] to an amino group, and this conversion can be carried out by a method known per se. For example, the phthalimide group can be removed by reaction with a hydrazine-based reagent such as hydrazine, methi-μhydrodine, or an amine-based reagent such as N,N-dimethypropanediamine, preferably in an inert organic solvent. Examples of inert organic solvents used in this reaction are dioxane, tetrahydrofuran, diethyl ether, and diisopropyl ether! .

Ethers such as tert-butyμmethyμetherμ.

For example, tetraroform, carbon tetrachloride, tri'crene, 1
, 2-dichloroethane, dichloromethane, and other halogenated hydrocarbons; for example, n-hexane, benzene, toluene, xylene, and other hydrocarbons. Also, the substituent R40GO-CH-C(CH3)-NH- (where R
(4 represents the same meaning as above) can be converted into a diamino group by, for example, gentle hydrolysis.

Removal of the substituent represented by R3 in compound CI) or
51-3852) can be used, but in addition to the final method, the inventors have also developed a method in which Compound CI) or [C'] is used as an acid azide derivative and subjected to a dust reaction, and a method using a permanganate. We have now discovered a method for oxidatively removing substituent R3.

The conditions for these R3 group removal methods will be described in detail below. Lead tetraacetate, and substituent R3 by Ritius reaction
The method for removing is generally applicable when a free force μpokiny group is present in the substituent R3. Therefore, when the substituent R3 has a protected group, the protective group is removed by a method known per se, and the resulting free group is converted into a tetraacetic acid carrier. or perform a ytius reaction. For example, in the lead tetraacetate method, 1 mole of a compound CI) or [r] having a free carboxy group and 1 to 3 moles of lead tetraacetate, preferably 1 to 1 mole of lead tetraacetate.
2 mol and a suitable catalyst (e.g. copper acetate 0.01-0
．． The intermediate acetoxy derivative represented by the following formula can be converted by heating and refluxing a mixture with (eg, 2 mo) in an organic solvent for several minutes to several hours.

[In the formula, R1 and R2 have the same meanings as above, and R represents a corresponding residue of an amino acid or its derivative] This reaction is preferably carried out using an inert gas (e.g. nitrogen gas, helium gas,
It is carried out under argon gas, etc.). Examples of the above-mentioned organic solvents include ethers such as dioxane, tetrahydrofuran, diethyl ether, and diisopropyl ether.
'6, esters such as ethyl acetate, ethyl formate, chloroform, dichloromethane, 1°2-
dichloroethane, 1.1.1-) halogenated hydrocarbons such as dichloroethane, e.g. benzene;/, )/L
/ene, n-hexane and other hydrocarbons, such as N,
Common organic solvents such as amides such as N-dimethyl μformamide I N IN-dimethylacetamide, nitrite/l/s such as acetonitrile μ, alone or as a mixed solvent are used. Some of the acetoxy derivatives (VI) or [■'] obtained here are unstable, and change during the extraction operation with a solvent or the separation and purification operation using a silica gel column, resulting in the desired compound [■
] or CIV'), but preferably by further actively treating the acetochleic acid derivative (VI) or (Vl'l) with a weak base such as potassium subacid or a yis acid such as a silica gel column. Furthermore, the target compound CIV) or [■'] can be obtained in a good yield.

Next, a method for removing the substituent R3 by μtius reaction will be described. Free force Compounds with boxy μ group (I
As the azidating reagent for azidating the carboxy μ group of ) or [Step'], commonly used azidating reagents can be used as appropriate, but sodium azide and diphenylphosphoric acid azide are particularly preferred. The azidation reagent can be reacted in an organic solvent after converting the group present in the substituent R3 into a suitable reactive derivative. Examples of reactive derivatives of these acidic acids include acid halides, acid anhydrides, active amides, active esters,
Active thioester etc. are used. The azidation reaction is preferably carried out in the presence of a base, and as the base, the above-mentioned organic bases can be used as appropriate, but aliphatic tertiary amines such as triethyl .mu. amine and tri-n-buty .mu. amine are preferred. In this method, the azidation reagent is usually used in an amount of 1 to 1.5 mol per mol of the acid, but it can also be used in excess without causing any hindrance to the reaction. The amount of the base to be used varies depending on the type of raw materials used and the reaction conditions, but is usually 1 to 3 moles, preferably 1 to 1.27 moles per 17 p of the acid. An example of a solvent for this reaction is dioxane.

Ethers such as ethyl acetate, ethyl formate, ethyl acetate, esters such as ethyl acetate, ethyl formate, hachloroform, dichloromethane, 1,2-dichloroethane, 1,1. 1-
) halogenated hydrocarbons of dichloroethanat, such as benzene, toluene, n-hexane, amides such as N,N-dimethylformamide, N,N-dimethy-acetamide, such as acetamide; )two)! Ordinary organic solvents such as Nitri/l/ such as J/M can be used alone or as a mixed solvent. Further, among the above-mentioned bases, liquid ones can also be used as a solvent. The reaction temperature is not particularly limited as long as the reaction proceeds, but is usually -50°C to 150°C, preferably -30°C to 80°C.
It will be held in The reaction usually completes in several tens of minutes to several tens of hours, depending on the raw materials used, the reaction temperature of the base, and the type of reaction, but it may sometimes take several tens of days.

The acid azide obtained in this way can be isolated, but it is preferable to isolate it. The compound [■] or [■'] can be collected by dissolving it in an organic solvent, heating it, treating it with an acid, and then performing column chromatography using, for example, silicage μ. Heating is 30'-
The reaction is carried out at 80° C., but it is preferable to heat it under reflux in a solvent. Examples of organic solvents used here include those used in azidation.I&acids are usually used at 1 to 107 μm per 17μ of the raw material, but the acid itself can be used as an R strategy. The acid treatment time is 20 minutes to 3 hours, preferably about 30 minutes. Examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, such as formic acid, acetic acid, trifluoroacetic acid, and probion. In addition to organic acids such as acids, for example, acidic ion exchange resins are used as appropriate.To obtain the compound [■] or [γ] from the acid azide, in addition to the above method, for example, the acid azide is placed in the above organic solvent. The incyanate form is first obtained by heating with
It is also possible to adopt a method in which the compound (IV) or [γ] is obtained by reacting Co-y to induce a urethane compound and then decomposing the urethane. All of these steps are carried out according to methods known per se. The reaction for converting the acid azide to the isocyanate is carried out in a temperature range of 3σ to 80°C, but heating to reflux in a solvent is preferred. The reaction time is 20 minutes to 3 hours, preferably about 30 minutes.

Examples of the urethane compound include 2,2,2-trichloroethyl urethane and benziμ urethane. The reaction from an isocyanate to a urethane is preferably carried out by heating and refluxing the isocyanate and an alcohol in an anhydrous organic solvent (for example, diethyl μ ether, tetophhydrofuran, benzene, etc.). The obtained 2゜2.2-)''Jria#methano compound (for example, by a reduction method such as treatment with zinc dust-hydrochloric acid at room temperature, and for benzyl urethane by a conventional catalytic reduction method at room temperature, etc.) It can be converted to [■] or [γ].The acid azide form can be converted to compound (IV) or (IT'
) is not limited to the reaction conditions of Method 9 above, and the oxidative R3 group removal method using permanganate will now be described in detail. Potassium permanganate is preferred as the permanganate used in this reaction.

The mo/V number of permanganate is compound CI) or
] 0.5 to 3Q-f:/L/, preferably 1 to
The amount of 10 mol is usually carried out in a solvent. In addition to water, solvents used include ethers/I/s such as dioxane, tetrahydrofuran, diethyl ether, etc.
For example, esthetic IVMs such as ethyl acetate and ethyl formate,
For example, halogenated hydrocarbons such as carbon tetrachloride, chloroform, dichloromethane, etc., such as benzene, )/L
/ene, n-hexane and other hydrocarbons, such as N,
Amides such as N-dimethylformamide, M,N-dimethylacetamide, such as methano-/I/, ethanol, isopropano-IV, tert-butano-y
Alcohols such as dimethyl sulfoxide,
Conventional organic solvents such as phosphoramide, hexamethylene phosphoramide, etc. can be used alone or as a mixed solvent. Among them, for example, water, dioxane, tetrahydrofuran, carbon tetrachloride, dichloromethane, chloroform, benzene, N,N-dimethylformamide, N,N-dimethylacetamide, methano-/L/l isopropanol, dimethymu-nulphoxide, etc. solvents are preferred. Furthermore, more favorable results can be obtained when this reaction is carried out in the presence of a phase transfer catalyst. The phase transfer catalyst mentioned here is a liquid-
It refers to a substance that promotes a reaction by solubilizing one of the reaction substrates, which exist separately in two liquid phases, into the other liquid phase in the form of an ion pair.

Such phase transfer catalysts include, for example, cations (ammonium ions or phosphonium ion)
and acid groups (anions, e.g. C1, Br, X,
! ', ClO4,BT'τ.

Bi12. H3Oτ, oa7 H2P○i, etc.), which can achieve the purpose of this reaction.

Specifically, for example, tetramethylammonium chloride,
Detofethyl ammonium chloride, n-butyl ammonium chloride, n-octyl methyl ammonium chloride, trimethyl ammonium chloride, n-ammonium tetophyl bromide, n-hexyl methyl ammonium bromide, etc. tetraalkyl halide/
I/(total number of carbon atoms: 4 to 50) ammonium, aryl halide such as phenyltrimethylammonium bromide, tria-ki/I/(total number of carbon atoms: 9 to 50) ammonium,
Bendiμ dimethyl y deciμ ammonium chloride.

Halogenated compounds such as benzyltriethylammonium chloride, benzyltriethylammonium chloride, etc.
A compound consisting of an ammonium ion and a halogen ion substituted with four identical or different groups selected from an alkyl group such as trialk/v (total carbon number 13 to 50) ammonium, an ary μ group, and an aoy group. , for example, selected from alkyl-μ groups, ary-μ groups, aph-μ-groups such as tetra-ammonium hydrogensulfate (4 to 50 carbon atoms in total), such as n-butyμ-ammonium hydrogensulfate, tetramethylammonium hydrogensulfate, etc. ammonium ion substituted with four same or different groups and H3Oτ(
hydrogen sulfate ion), alkyl groups such as tetophalky/I/(total carbon number 16 to 50) ammonium hydroxide, such as tetophyl n-butylammonium hydroxide,
Substituted with 4 same or different groups selected from the ary μ group and the aff μ group and the 9 ammonium ion and OF! −
(hydroxyl ion), such as tetra-bromide
halogenated tetraalkyl IV (total carbon number 4 to 50) phosphonium such as n-butylphosphonium; halogenated aryki triary-N (total carbon number 9 to 50) homefonium such as chloride henditriphenymu honuphonium;
Halogenated alkyl μ triary-(total carbon number 19-50) such as n-butyltriphenyl μphosphonium bromide, alky group such as phosphonium, ary μ group, afuruki μ
A phosphonium ion and a halogen ion substituted with four same or different groups selected from the group are used. In particular, even tri-n-octy-μ-methyammonium chloride.

Used are n-butymu ammonium hydrogen sulfate, tetra-n-amylammonium bromide, benzyammonium chloride, n-butyphosphonium tetofux bromide, and the like. These phase transfer catalysts are capable of converting compound C during the water reaction.
I) or [0.01 to 1 μm, preferably 0.05 to 0.27 μm, is used. When using a phase transfer catalyst, the solvent is preferably a mixture of water and the above-mentioned organic solvents, and the reaction temperature is usually in the range of O'' to 50°C, but the conditions are not particularly limited. If necessary, heating and cooling may be performed as appropriate.Also, the reaction time is appropriately determined depending on the solvent used, temperature, etc., but it usually ends in 1 to 24 hours.Note that during the above-mentioned elimination reaction The e substituent R2 may also be oxidized.

(Actions and Effects of the Invention) Compounds CIV) and [γ] obtained by the above-mentioned single group removal reaction are known substances, and can be further induced into the above-mentioned AMA-1080 by performing a series of reactions known per se. be able to. For example, (3S,4R)-3-benzyloxycarbonylamino-4-sti! obtained in Example 33 below! j/L'-2-azetidinone is oxidized with ozone and then reduced with sodium borohydride (3
3,4S)-3-benzyloxycarbonylamino-4
-Hydroxymethyl-2-7zetidinone is obtained (Example 37), which is then reacted with chlorosulfonyl isocyanate (3S,4S)-3-benzyloxycarbonylamino-4-benzyloxycarbonyl-2-7zetidinone (Example 37). L/-2
-Azetidinone [■] is obtained (Example 38). This μ-pamoi μ-oxymethymu form [■] is the same as the compound described in Japanese Public Kansai Patent Publication No. 58-46066,
Furthermore, by performing a series of reactions described in the same publication, AM
A-1080 can be derived. The reaction from compound [■] to AMA-1080 is illustrated below.

（DC） TEAC
After reaction with sulfur pentoxide complex, sodium bicarbonate treatment and chromatography were performed to obtain (33,43)-
3-Benzyloxycapodi-amino-4-carbamoyloxymethy/L/-2-azetidinone-1-sulfonic acid sodium salt [■] is obtained. When compound [■] is hydrogenated in anhydrous methanol under P d/C catalyst (3S, 4S
)-goamino-4-forceμbamoyyokikumethi/l/-
Sodium 2-azetidinone-1-sulfonate (IX)
is obtained. Compounds (IX) and (Z)-2- with equalization μ
(2-Amino-4-thiacyly/l/)-2-((buffnitrobendiμoxycarbonyμmethoxy)imino]acetic acid 2-benzthiazolylthioesterμ was suspended in anhydrous acetone and 2.2 times mop After treatment with triethylamine and subsequent chromatography, (38,48)
-3-(Z)-2-(2-amino-4-thiacyly A/)
-2-((Balanitrobendi p-oxycarbonyponylmethoxyimizetidinone-1-sulfonic acid triethyl p-amine salt (X) is obtained. Compound (X) is dissolved in methanol-y on porous diatomaceous earth. Hydrogenation under supported Budge ram catalyst, sodium bicarbonate treatment and chromatography yielded AMA-10.
80 sodium salt is obtained.

(Examples) Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto.

Example 1 (al) To a solution of 135 g of L-valine methyl ester hydrochloride in 60 sl of dichloromethane, 43 g of triethylamine was added under water cooling, and after stirring for 30 minutes, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue. , filter out insoluble matter,
The filtrate is concentrated under reduced pressure. Dichloromethane 40% to the residue
ml and stirred at room temperature for 2 hours with cinnamaldehyde tist and 3 g of anhydrous magnesium sulfate. After removing the insoluble matter by filtration and concentrating the filtrate, the residue was dissolved in dichloromethane (40%).
Dissolve in d. 164 g of triethylamine was added under cooling to -70' to -60°C, and then 20 s of dichloromethane was added to 4.4 all of 2-7 talimidoacetic acid crophyte while stirring.
Add the solution dropwise over 30 minutes. Return the reaction solution to room temperature,
After further stirring for 1 hour, the mixture was washed successively with water (twice), IN-hydrochloric acid, and saturated aqueous sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give (33,4R)- and (3R,43)-1-C(is)-(1-methoxyca!bonyl-2-methy/I/)depbiμ]- 3-Lid μ
7 g of an imido-4-styrene/L'-2-azetidinone mixture are obtained. Crystal is (38,4R) body and (3R,4
8) Approximately 1=1 mixture of bodies. When recrystallized from methanol, the (33,4R)-form Zlf was obtained as colorless needle-like crystals, and after concentrating the filtrate, the residue was recrystallized from a mixed solvent of diethyl ether and dichloromethane, giving the (3R,48
) body L9g is obtained as colorless prismatic crystals. In addition(
The absolute structure of the 33,4R) form was determined by X-ray analysis, and the structures of the following compounds were determined in relation to the present compound.

・(38,4R) body; melting point 15λ5°-154,5℃ Engineering RvKBrcllM-”: 1785 (shoulder), 1772
, 1743°ax 1722.1385.1203,980,717°N
M R (ppm, CDC13) δ: LO2 (d,,
T-7Hz.

CH3), L22(d, J-7Tlz, CH3), 2
．． 65 (m, CH), 3.76 (s, 0CIII3),
3.85 (d,, T-9Hz, CH), 462 (dd,
J-6, 9H2, C4-H).

5.57 (d, J-6Hz, C311), 6.22 (c
ld, J-9, 16Hz, -CH-CHPh), 6.6
2 (d,, T-16Hz, -CH-CdanPh), 7.
22 (s, aromatic proton), 7.60 7.93 (m
, aromatic proton).

Elemental analysis as C25”24N205: calculation li
t: C69,43, H5,59, N 6.48% Actual value: C69,41, H5,49, N 6.53%
[α] War-21,2° (c-0,645, Methanol-A/
) [α] Sea 20.2° (C-0,445,
m)・(3R,43) body; melting point 124.5°-125,
5°C IRvKBrcm-1: 1770-1780.1
720-1750°ax 1380.1340,1205,979,721°N
M R (ppm, CDC13) δ: 0.92 (d, J
=7Hz.

CH3), L23 (d, J-7Hz, CH3), Z23
(m, C11), λ76 (s, 0CH3), 4.32 (
d, J9Hz, CH), 4.98 (dd, J-6,9H
z, C4-H).

5.58 (dIJ=6Hz, C3H), 6.30 (dd
, J-9+16Hz, CH-CHPh), 6.72
(d,, T-16az, -aH-cuphLy, z3(
s+aromatic proton), 7.60-7.93 (m, aromatic proton).

Elemental analysis as 025H24N205: calculation fill
: C69,43, H5,59, N 6.48% actual measurement [: CC9,52, El 5.41. N 6.4
6%(:α) %' + 1 &1°Ca-0.770
, 1°C me 0.770. mepno/44.5°(am
1-((Is)-(1 - Isolated yield of methoxycapboni/L'-2-methy/I/)propylcou-3-phthalimido-4-styli A/-2-azetidinone,
The isolated yields of (33,4R)-1-((IS)-(1-methoxycarbonyμm2-methy/L/)propy#)-3-phthalimido-4-styryl-2-azetidinone are shown below. Shown in detail.

(hereinafter referred to as "assembly") Example 2 From L-valine benzyl ester N7.59f, Example 1
- By a reaction similar to (a), (33,4R)- and (3R,43)-1-((Is)-(1-bendioxycarbonyA/2-methy/L/)propylcou 3 -phthalimido-4-styli A/2-azetidinone mixture 9
．． 31 is obtained as an oil. Crystal is NMR Subek)
Chill with a mixture of about 6:5 from A/.

Engineering Rν am, 2970.1765.1725°ax 1386°-(3R,4S) body; NMR(ppm, CDC1
3) δ: 0.97 (t, J=7Hz, C1113), 2
．． 23 (m, CH).

4.36 (d, J-9Hz, CH), 4.86 (dd,
J-6゜9H2, C4H), 5.20 (8,0H2),
5.52 (d.

J=6Hz, C3H), a27(dd, J-9, 16H
z, -CH-CHPh), 6.57 (d, J=16Hz
, -CH=CHPh), 7.20 (s, aromatic proton), 7.37 (8, aromatic proton), 7.53-
7.90 (m, aromatic proton).

・(3S,4R) body; kl M R (ppm, CDC
13) δ: L22 (d, J=7Hz, CH3), Z70
(m, CH).

3.83 (d, J-9Hz, CH), 454 (d, d,
J-6°9Hz, C4H), 5.20(s, CH2),
5.50 (d+J-6H1, C3-■), 6.18 (d
d,, T-9, 16Hz, -CH=”CHPh), 6.
57 (d, J-16Hz, -CFI-cuph), 7
．． 20 (s, aromatic protons), 7.37 (8, aromatic protons), 7.53-7.90 (m, aromatic protons).

Example 3 6.1 q of triethylamine was added to a solution of D-valine methyl ester Iv hydrochloride 8.4 vO in 100 txl of dichloromethane under water cooling, and after stirring for 30 minutes, the solvent was distilled off under reduced pressure. Ethyl acetate is added to the residue, insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. Dichloromethane 100% to the residue
Add M1 and stir at room temperature for 3 hours with 193 f of cinnamaldehyde and 30 g of anhydrous magnesium sulfate. Filter off the magnesium sulfate, concentrate the filtrate under reduced pressure, and dissolve the residue in 200 m of back tetrachloride. -16 °~-17
6.6 g of triethyl amine was added under cooling to ℃, and then 11.51 F of 2-phthalimidoacetic acid chloride was added under stirring.
200 g of carbon tetrachloride/solution was added dropwise over 40 minutes. After returning to room temperature and stirring for another hour, dichloromethane 10
0d was added to the reaction mixture, and the mixture was washed successively with water, saturated aqueous sodium bicarbonate solution, IN-hydrochloric acid, and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was washed with n-hexane (3s).

4R)- and (3R,43)-1-C(IR)-(1
-Methoxycarbonyl-2-methy/L/)propy]-
A mixture 19f of 3-phthalimido-4-methyly/l/-2-azetidinone is obtained as a solid. crystal NMR
Subek) From A/, (3S, 4R) body and (3R, 4S)
The body production ratio is 73:27.

Dissolve 2 g of the obtained solid in 20 sl of methanol-IV and add 1
The crystals obtained by standing overnight are dichloromethane-methanol-
When washed with a mixed solvent (1:9.v/v), (3S, 4
R) form 541q is obtained. The filtrate was concentrated, and the residue was poured into methanol 20 xi and allowed to stand at room temperature for 6 hours to obtain (3R,43) as needle-shaped crystals.

By repeating the above operation 3 times, (38,4R)
277 g of body L and 380 mg of (3R,48) body are obtained.

・(3S,4R) body; melting point 124.5'-125.5°C
I RvKB"(2-': 1770-1780.17
20-1750°aX 1380.1340,1205,979,721°N
M R (ppm, CDCl3) δ: 0.92 (
d, J-7Hz.

CH3), 1.23 (d, J-7Hz, CH3), 2
．． 23('', CEt), λ76(a, 0CH3), 4.
32 (d, J=9Hz, CH), 4.98 (dd
T J-6,9Hz, C4-H)-5,58(d,
J-6Hz, C3H), 6.30(dd, J-9,16
Hz, -CH-CHPh), 6.72 (d,, T-16
Hz, -CH-C DanPh), 7.23 (8, aromatic protons), 7.60-7.93 (m, aromatic protons).

Elemental analysis as 025H24 Green 05; Calculated value: C
69,43,H5,59,N 6.48% actual measurement [:
C69,57, H5,64, N 6-54% [α)”,
'-17.9° (Q-0,925, methanol/l/).

[α)%”-43,5° (co, s, chloroform)
-(3R,43) body; melting point 153.56-154.5°C
Engineering RvM; PN” l: 1785 (shoulder), 1772
,1743°1722.1385.1203.980,
717°N M R (ppm, CDC13) δ: L
O2(d,,T=7Hz.

CH3), 1.22 (d, J-7Hz, CH3), Z6
5 (m, CH), 176 (s, 0CH3), 185 (d
, J-9Hz, 0111), 4.62(dd, J-6,
9Hz, C4-H).

5.57 (d, J-6Hz, C3-H), 6.22 (d
d,,T-9,16H2,-CH=CHPh), 6.6
2(d, J=16Hz, -CH-Cdanph),'1.2
2 (s, aromatic proton), 7.60-7.93 (m,
aromatic proton).

Elemental analysis as C25H24N205; Calculated value:
C69,43,H5,59,N 6.48% actual measurement [:
C69,41, H5,61, N 6.53% [α)2
D4421.4° (C40, 770.methanol/L/)
[α)% 3-1-21.5° (0 servings 0.545.chloroform) Example 4 D-Anubawoginic acid dimethyl ester/L/hydrochloride 5.
Add 50 gal of saturated saline to 93 g of 50 #It solution of water.
Add 2.539 g of sodium bicarbonate and extract 4 times with chloroform. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure, and the residue contained 5.
Add 9FM and 100 g of dichloromethane, then add 1 (l) of anhydrous magnesium sulfate, and stir at room temperature for 1.5 hours. After filtering off insoluble matter, the liquid is concentrated under reduced pressure, and the residue is dissolved in 200 m of trichloromethane. , -7(l) was added with 3.349 g of triethylamine under cooling, and then a solution of 100 g of trichlene containing 738 g of 2-phthalimidoμ acetate crophyte was added dropwise over 2 hours. Stirred at the same temperature for 30 minutes, then gradually warmed to room temperature. After reconstituted and stirred for another 30 minutes, the reaction solution was poured into ice water and the molar layer was separated.The aqueous layer was extracted twice with dichloromethane, the extracts were combined, washed with sodium bicarbonate water, and diluted with anhydrous sulfuric acid. Dry with magnesium. Distill off the solvent, add diethyl ether IV120+? to the residue and leave it overnight. The precipitated crystals are filtered and diethyl ether is added to the residue.
When washed with Te and dried, (33,4R)-1-((IR
)-1,2-di(methoxycarbonyA/)ethylμ]-3
237 g of -phthalimido 4-nutiri/L'-2-azetidinone is obtained. (33,4R) body from mother liquor.

3.64 g of a mixture of (3R,,4S) bodies (3nea) is obtained.

・(3S,4R) body; melting point 141° to 142°C I Ru
KBrcm”: 1785 (/FJ), 1775
(N).

ax 1763.1743, 1720.1395°N M R
(ppm, CDC13) δ: 3.61 (s, 0CR
3).

3.82 (a, OCH3) e 4.87 (d
d, J = 5.5, 9 Hz, C4H), 5
．． 00 (t, J7Hz, CH), 5.62 (d, J-5
, 5Hz, C3H), 6.18 (dd, J-9°17H
z, -Ctan = CHPh), 6.63 (d,, T-17H
z, -CH-CHPh), 7.5-7.9 Cm
, aromatic proton).

Elemental analysis as C25E22'207; Calculated value:
C64,93, H4,79, N 6.06% actual measurement [:
C64,82,H491,N 6.07% [α]2D
I-49.6° (c-1,015+Chloroform ρ) Example 5 Starting from L-asbafugic acid dimethy-ente/I/hydrochloride, an experiment similar to Example 4 is carried out.
(3R,4S)-1-((Is)-1,2-di(methoxycarboniN)ethyl)-3-phth-imido-4-styl A/-2-azetidinone is obtained.

・(3R,4S) body; melting point 138°-140°C RvK
B””-1: 1760.1740.1720.139
06aX NMR (ppm, CDC13) δ: 3.61 (a,
0CH3).

182 (a, 0CH3) + 4.87 (dd, J-ri, 5
．． 9Hz, C4H), 5.00(t, J=7Hz, CH
), 5.62 (d, J=5.5Hz, C3-H), 6.
18 (dd, J-9゜17H2, -Cdan-CHPh),
6.63 (d, J-17Hz, -CH-CHPh), 7
．． Elemental analysis as 1-7.9 (m, aromatic protons) C25H22N207; calculated value:
C6493, H4,79, N 6.06% actual value:
C65,01, H4,69, N 6.03% [α) 2
35+51.5° (Q-0,955, chloroform μm)・
(3S,4R) body; NMR (ppm, CDC13) δ: 3.21 (d
,,T=7Hz.

CH3), 3.77 (s, 0CH3), 4.58 (t,
J-7Hz, CF(), 4.73(dd, J-5,5,
9Hz, C4-H), 5.56(d, J-5,5Hz
, C3-E, 6.18 (dd, , T-9, 17Hz,
-Cl-cHph), 6.65 (d.

, T-17H2, -CH-Cdanph), 7.1-7.
9 (m, aromatic proton).

(bl~(f) 1-C(Is)-1,2-di(methoxycapboni/I/) in the same experiment as in Example 5-(a) but with different cycloaddition reaction conditions Isolated yield of ethyl]-3-phthalimido-4-styrene 1v-2-azetidinone and (33,4
The production ratio of the R) form and the (3R,48) form is shown in Table 3.

Example 6 Using L-Awonin-tart-buti-nute rho as a raw material,
When conducting the same experiment as in Example 1, (3S,4R]- and (3R,4S)-1-C(IS)-(1-tert-
74
% yield. (3S.

The ratio of the 4R) form and the (3R, 43) form was 45:55, and chromatography was carried out using a silicage μ column chromatography (ethyl acetate-n-hexane mixed solvent - 2:3° v/v). When purified, (33,4R) and (3R,48
) body is obtained.

・(3B,4R) body; NMR (ppm, CDCl3) δ: 1.48 (a
, tert-Bu)=166(d, J-8Hz, CH3
), 4.12 (q, J-8111z, CH), 467 (
dd, J = 5.8 Hz, C4-H) + 5.52 (d, J
-5Hz, C3H), 6.25(dd, J-8, 16H
z, -CH-CHPh), 6.66 (d,, T-16H
z, -CTi-CHPh), 7A-7,9(Ill
, aromatic proton).

[α] is also 4+6.54° (c-0,81, chloroform)・(3R,43) body; NMR (ppm, CDC13) δ: 1.46 (
(1,, T-8Hz.

CH3), 1.48 (s, tert-Bu) + 4.63
(q*'-8Hz, CH), 4.96 (dd, J-5,
9Hz, C4-H), 5.58(d, J-5Hz, C3
H), 6-26 (ad, J=9.16Hz, -CH-C
HPh), 6.67(d,, T-16Hz, -CH-C
HPh), 7.1-7.9 (m, aromatic proton).

[α) 2b4 + xts° (c-1,15, chloroform) Example 7 L-serine methyl ester obtained from L-serine methyl ester/L' hydrochloride and tert-butymu dimethysiliycrophytoimidazo-y When the same experiment as in Example 1 was carried out using ester μ-tart-butyldimethylsilylethe/L/'Jt as the raw material, (3R,4s)-t
-[N5)-(+-Methoxycarboni/I/-2-(
tert-butyldimethylsilyloxy))ethyl/7)
-3-phthalimido 4-styli A/-2-azetidinone is obtained as a foam.

IRIKn:rxfi-1: 176711720?1
381°1115.835°N M R (ppm, CDCl3) δ: 0.80 (
a, tert-Bu), 3.78 (a, 0CH3), 3
．． 9-4.3 (m, CH2), 4.70 (t,, T-5
1Eiz, CH), 5.00 (dd, J-5, 5, 7T
lz, C4-H), 5.65 (d, J-a
5Hz.

C3-H), 6.26(dd,, T-7, 16Hz, -
CH-CHPh), 6.60 (d, J=16Efz, -
CH-CHPh) 17.18 (s, aromatic proton),
7.5-7.9 (m.

aromatic proton).

[α)”,”+22.1° (c! 1.65.Chloroform) Example 8 D-serine methyl obtained from D-serine methyl ester/L/hydrochloride and tert-butyldimethylsilylcrophyto-imidazole When the same experiment as in Example 1 was carried out using ester/l/-tert-butyldimethyl IvS/sy ether as a raw material, (3S, 4R) was obtained with a yield of 90%.
)-1-C(IR)-(1-methoxycarbonyIV-
2-(tert-μdimethysili~okine))ethylp]-3-phthaiimido-4-styli A/-2-azetidinone is obtained as a foam.

1B, filEIIcm-1; 1760.1720.
1482°ax 1380.1250.1120.840°N M R(
ppm, CDC13) δ: 0.82 (a, te
rt-Bu), α76(s, 0CH3), 3.99-4
3 (, cH2), 473 (t, J-=5Hz, CH),
5.03 (dd,, T-5,5,7Hzr, C4-H)
-α66(d, J-5,5FIz.

C3H) 16.2g (dd, J=7.16Hz, CH-
CHPh), 6.61 (d, !-16Hz
, -CTi-CHPh).

7.18 (s, aromatic proton), 7.5-7.9 (
m.

aromatic proton).

[α) 23.2° (c = 0.92 m chloroform) Example 9 An experiment similar to Example 1 was conducted using D-7 22y glycine methyl ester/I' hydrochloride as the raw material. 1-((IR
)-(1-methoxycarboniA/-1-)uni/I/)
Mechiμ〕-3-Futaμimido 4-Sti! J, /I/2
-Azetidinone was obtained with an isolated yield of 55%, and when purified by silica gel column chromatography (eluted with ethyl acetate-n-hexane mixed solvent - 2:3°v/v-gIi), the (33,4R) form was obtained. , (3R,43) body is 1:2
obtained in the ratio of

- (38,4R) body; KBr -1゜IRMIn&Xel'1. 176511720113
8511205°N M R (ppm, CDCl3) δ: 3.82 (
a, 0CH3).

5.05 (dd, J-5,9Hz, C4H), 5.55
(dd, J-9, 16Hz, -CH-CHPh), 5.
64 (d,, T15 Tl z -C3-11) *
5.83 (a, CH), 6-28 (d.

1-16Hz, -CH-CHPh), 6.7-7
．． 9 (m, aromatic proton).

[α) 2D'-124° (C-α66, chloroform μ)
・(3R,43) body; I RyKBreN-1:1760.1720-138
0, 1200°ax NMR (ppm, CDC13) δ: 3.79(a
,0CH3).

442 (dd, J=5-9Hz, C4H), 5.49 (
, d.

J-5H2, C3111), 5. ．． 66 (s, CH),
6.40 (d, J-16Hz, -CH=CHPh), 6
．． 49(dd,,T-9+16Ffz,-CH-CH-
Ph), 7.1-7.9 (m, aromatic proton).

[α)'','+29.6°(o-1,57, chlorophoμ
m) Example 10 (a) When the same experiment as in Example 1 was carried out using L-glutamic acid dimethyester/L' hydrochloride as a raw material (3S
, 4R) and (311,48)-1-((18)-
A mixture of 1,3-di(methoxypropylene)-3-phthalimido-4-nutiri/L'-2-azetidinone is obtained with an isolated yield of 61%.

From the NMR spectrum, (38,4R) body, (3R,4
3) The body production ratio is 1:2.

・(33,4R) body; NMR (ppm, CDCl3) δ: α55(a
,0CH3).

3.80 (s, OC'H3) - 5,00 (dd, J-5
,5,9Hz=04'') -5,57(d*
J-4), 5 Hz m C3H) -6,63(d,
J=16Hz, -CH-CHPh), 7.23 (8, aromatic protons), 7.6-7.9 (,, aromatic protons).

・(3R,43) body; NMR (ppm, CDCl3) δ: 163 (a,
OCI'13).

3.80 (a, 0CR3), 4.69 (dd, J-5,
5,9H2,C4-H)+5.63(d,J-5,5H
2, C3-H).

α68 (d, J=16Hz, -CH-CHPh), 7.
23 (' is an aromatic proton) -7,67,9 (m,
aromatic proton).

(b) When an experiment similar to Example 1 was conducted using L-glutamic acid diethyl pNT/L' conjugate as the raw material, 70
(33,4R)- and (3R,43) with an isolated yield of %
-1-C(13)-1,3-di(ethoxycarbony/L
/) Propy/L', 1-3-phthalimido-4-nutiri/L/-2-azetidinone mixture is obtained. From the NMR spectrum μ, the crystal is (3S.

It is a 2:3 mixture of 4R) and (3R,48) bodies.

Example 11 When an experiment similar to Example 1 was conducted using L-phenylalanine methyl ester z + 4 acid m as raw materials, (38,4R)
- and (3R,48)-1-C(13)-(1-methoxycarbo=A/-2-yx2μ]ethyl/L/)-3-
A mixture of phthalimido-4-styryl-2-azetidinone was obtained with an isolated yield of 83%, and the ratio of (33,4R) and (3R,48) isomers was 3:2 from NMR Nuvectoy.

IRyKBrcl+-1: 1763, 1720, 13
85゜ax ・(3S,4R) body; NMR (ppm, CDCl3) δ:' 3.20
-3.85 (m,'(,H2),3.78(s,0
CH3), 4.30 4.87 (nl.

c4-u, CFI) -5,43(d, J-
5Hz, C3-H).

5.89((ld,,T=9.16Hz,-Cdan-CH
Ph).

6.42 (d, J-16Hz, -CH-CHPh), 7
．． 00-7.47 (m, aromatic proton), 7.5
7-7.90 (m.

aromatic proton).

・(3R,4S) body; NMR (ppm, CDCl3) δ:
3.20-3.85 (m.

CH2), 3.75 (a, 0CH3), 430 487
(m.

C4-H, C1 (), 5.52 (d, J-5H2, C3
-H).

6.07(dd, J-9,16H2,-CT(-CHP
h).

6.58<6. I=16T1z, -CE-CH-Ph)
, 7.00-7.47 (m, aromatic proton), 7.5
7-7.90 (m, aromatic proton).

Example 12 When the same experiment as in Example 1 was carried out using L-methionine methyl ester/I/hydrochloride as a raw material, (33,4R)- and (3R,48)-1-[(IS)-( 1-MethoxycarbonyA/-3-methylthio)propyl]-3-phthalate
Imido-4-Stiri IV-'l.

- a mixture of azetidinones is obtained in an isolated yield of 92%,
From the NMR spectrum μ, (33,4R) body, (3R,4
3) The body ratio is 2:3.

・(38,4R) body; NMR(ppm, CDCl3)δ: Z12(s
, 5CH3).

179 (a, 0CR3), 4.68 (dd, J-5, 9
Hz.

C4-H), 5.59 (d, J=5Hz, C3H), 6
．． 67 (d, J=16Hz, -CH-Cdan-Ph),
7.1-7.9 (m+aromatic depton).

・(3R,43) body; NMR(ppHl, CDCl3)δ: ZIO(
s, 3CH3).

3.79 (s, 0CH3), 5.0O (dd, J-5
,9Hz.

c4-H), 5.64 (d,, T-5Hz, c3-H)
, 6.71 (d, JWI-16Hz, -CTi=mCdan-Ph), 7.1-7-9 (''+aromatic proton).

Example 13 When the same experiment as in Example 1 was carried out using L-asbawoginmethi/L/ as a raw material, (3S,4R)- and (3R,4S)-1-C(Is)-(1 A mixture of -methoxycarbamoy/v-2-carbamoy/I/)ethylcou-3-phthalimido-4-styry/L/-2-azetidinone was obtained with an isolated yield of 53%, and the NMR spectrum revealed that (33, The ratio of 4R) body and (3R,43) body is 2:3
It is.

・(33,4R) body; FJ M R (ppm, CDC13) δ: 3.77 (
a, 0CR3).

4.60 (dd, J-5,9Hz, C4-H), 5.
57 (d.

J-5Hz, C'3-H), 6.12(dd,
J=9, 161Tz, -CH-CM-Ph), 6.6
7 (d, J-16Hz.

-CH-C1't-Ph), 7.1-7.9 (m, aromatic proton).

・(3R,4S) body; MMR (ppm, CDCl3) δ: 3.79 (
a, 0CH3).

4.84 (dd, J-5,9Hz, C4H), 5.60
(d.

, T=5Hz, C3H), 6.22(dd, J=9.1
6Hz, -Cdan-CH-Ph), 6.67(d,,T-
16Hz.

-CH-CH-Ph), 7.1-7.9 (Ell aromatic proton).

Example 14 (a) N-benzyloxyca A/7N2/l/-L
-Methano-I of alanine biwaridinamide 1.391F
V 30 ml suspension, 10% 0% paddillam - 1 g
Stir vigorously for 100 minutes in a hydrogen stream. Filter the catalyst and concentrate the filtrate. Distill the residue in dichloromethane 2
1.32 g of cinnamaldehyde and 2 g of anhydrous magnesium sulfate were added, and the mixture was stirred at room temperature for 1 hour. After filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 20 ml of dichloromethane. While cooling at -70"C, 1.02 g of triethyl amine was added, and then 20 pieces of dichloromethane containing 2.249 ml of 2-phthalimidoacetic acid chloride was added. 5 l solution
Drop in 0 minutes. After returning to room temperature and stirring for an additional 30 minutes, the reaction solution was poured into ice water and the organic layer was separated. The aqueous layer is extracted with dichloromethane, and the extracts are combined and dried over anhydrous magnesium sulfate. The solvent is concentrated and the residue is purified by silica gel column chromatography. When eluted with ethyl acetate y-n-hexane mixed solvent (1:1.v/v) to ethyl acetate y, (3S,4R)- and (3R,4S)-
1-((13)-(1-(1-pyrrolidine)forceμbony
A mixture 17661F of ]ethy[mu]]-3-phthalimido-4-styryl-2-azetidinone is obtained. crystal is 1
From the 1rMR spectrum, (3S, 4R) body, (3R,
4S) is a 74:26 mixture. The absolute structure of this compound is related to the compound obtained in Example 15 (NMR
etc.).

・(33,4R) body; K M R (ppm, CDC13) δ: L48 (d,
, T-8Hz.

CH3), 475 ((1,, T-8Hz, CH), 4.
78(dd+'” 5 T 9 HZ * C4-
1'l) T! 5.57 (d * J = 5 I
(Z *C3-El)-6,06(dd, J=9.16
Hz, -CH-CH-Ph), 6.61 (d,, T-1
6Hz, -CH-CH-Ph), 7.1-7.9(m,
aromatic proton).

・(3R,4S) body; NMR(ppm, CDCl3)δ: 1.46(
d, J-8Hz.

CH3), 4.89 (q,, T=8Hz, CH), 5.
16 (dd+J cloud 5 * 9 Hzw C4-H)
+ 5.57 (d, J = 5 HZ.

C3H), 6.26(dd, J-9,16EIz, -C
Danrai CH-Ph), a72 (d, J-16Hz, -C'
H-CH-Ph), 7.1-7.9 (m, aromatic proton).

(b) to (1) 1-((Is)-(1-(1-pyrrolidine)carbonyl)ethyl) in the same experiment as in Example 14(a) but with different cycloaddition reaction conditions] Isolated yield of -3-phtayimido-4-styl Iv-2-azetidinone and (33,4
The production ratio of the R) form and the (3R,43) form is shown in Table 3.

Example 15 N-bendiμoxycarbonyμ-L-afnin (5,6
When an experiment similar to Example 14-(a) was carried out using -cyhydrophenanthrene)amide as a raw material, (33,4R)-
and (3R,48)-1-C(Is)-CI-(1-
(5,6-cyhydrophenanthyldi/I/)]][force μbony]ethyl]-3-phthalimide 4-styrene A/-2
- A mixture of azetidinones is obtained with a yield of 82%. N
MR spectrum μ to (3B,4R) body, (31,48)
The body production ratio is 73:27. The absolute structure of this compound was determined in relation to Examples 30 and 35.

Engineering RvKB"cw=-1: 1763.1720.16
68.

ax 1383.1200゜Example 16 N-bendiμoxinkaμboniA/-L-alanine (H-
Example 14-(a
), two types of 1-C(1B)-(
1-(N-methylanilino)force~bonyl)ethμ]-3
-Futai imido 4-Sti! A mixture of J 1v-2-azetidinones is obtained with a yield of 74%. From NMR, the production ratio of the two diastereomers is 63:37.

・Diastereomer m with larger production ratio: N M R (
ppm, CDCl3) δ: 1.49 (d, ,
T-7Hs.

C113)-3,27(8,0CH3), 4.11-4
9(,C4-II,CH)-5,53(d,J-6Hz
, C3H).

6.23 (dd, J'-9, 16Hz, -Cdan-CH-
Ph).

6.60 (d, J-1611z, -CH-Cdan-
Ph), 7.1-ao (xa, aromatic peptone).

・Diastereomer with smaller production ratio; NMR(
ppm, CDC13) δ: 1.27 (d, J-7Hz
.

CH3), 3.22 (II, 0CH3), 4.1 49
(m-CH)-&22(dd, J-6,9Hz, C4-
H).

5-48 (6t J-6'Fiz -03K) -
6,23(ad -J-9,16Hz, -Cg-CEI
-Ph), 6.70(d,, T-16Hz, -CH-C
g-Ph), 7.1-&0 (m-aromatic proton).

Example 17 To a suspension of powdered D-valine L18f in a mixed solvent of 1,2-dichloroethane (20 ml)-acetonitrile/l/(4 ml), 1.669 g of tert-buty-dimethy-silyl chloride was added. was added, refluxed at 80°C (external temperature) for 4 hours, and further stirred at room temperature for 15 hours.

153 g of triethylamine was added to the reaction solution, and after stirring for a while, the precipitated crystals were collected by filtration and washed with 1,2-dichloroethane. The filtrate was concentrated under reduced pressure, and the residue was converted to 1,2-
Dissolve 30+1K in dichloroethane, add cinnamaldehyde Z659 and 3 g of anhydrous magnesium sulfate, and stir at room temperature for 2 hours. Insoluble materials were filtered off, washed with 1,2-dichloroethane, and the solution was concentrated under reduced pressure. The residue was dissolved in 50xl of dichloromethane, and while cooling to -70°C, 2.08ml of triethylamine was added, followed by 2-phthalimidoacetic acid. Crophyte 2.699 dichloromethane 20g7
The solution is added dropwise over 1 hour. Thereafter, the temperature was gradually raised to room temperature for 30 minutes at the same temperature. Pour the reaction solution into ice water,
The dichloromethane layer is separated, and the aqueous layer is further extracted with dichloromethane. The dichloromethane layers are combined, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was dissolved in 50 d of ethyl acetate,
A solution of 0.5 g of potassium fluoride in 30 d of water was added to this and stirred for 1 hour. Extracted twice with aqueous sodium hydrogen carbonate solution, washed with diethyl ether, and adjusted to pH 1.5 with 5N hydrochloric acid.
and extract twice with ethyl acetate. The organic layer is washed with brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure yields 3.3 ml of 1-((IR)-(1-carboquine-2-1,000N)propyl)-3-phthalimido-4-styl A/2-azetidinone.

Take 1 g of crystal, dissolve it in 10 yl of ethyl acetate, and add a diethyl solution of diazomethane.

The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography. Elution with a mixed solvent of ethyl acetate-n-hexane (1:1 then 2:3, v/m) yielded 1-((IR)-(l-methoxycarbony/I/-2).
-Me1,000 p)propyl] -3-butylimido 4-methyl/l/-2-azetidinone (33,4R) isomer, (3R
, 43) is obtained. The integral curve of NMR spectrum μ is (38,4R): (3R,4S
) is 72:28. The physical constants and properties of ice crystals are 5! Completely consistent with that obtained in Example 3.

Example 18 Starting from L-valine and carrying out the reaction and reaction treatment in the same manner as in Example 17, (38,4R)- and (3R,48
)-1-C(Is)-(1-methoxy force ypony/l/-
2-methy/L/)propy/I/)-3-phthalimide-
4-Styli A/-2-azetidinone is obtained with a yield of 46%. The formation ratio of (3S, 4R): (3R, 4El) in ice crystals is 29 near 1 from the integral curve of the llrMR spectrum.
It is.

Example 19 When an experiment similar to Example 14 was carried out using N-benzioxyS/forceμboniμmL-parylμmL-valinemethyμester μ as a starting material, two types of 1-[(Is)-CI- (
Mixture of ((1-(Is)-methoxycaponyl/l/-2-methylv)propyl)amizuka[mu]bonyl]-2-methyl]propy]-3-phthalimido-4-styliA/-2-azetidinone is obtained in an isolated yield of 87.5%. The production ratio of the two types of diastereomers is 3:2 according to the NMR spectrum μ.

I R”i:;”-1: 3380-3310.297
0゜1768-1740.1725,1678,138
7゜ Diastereomer with larger production ratio; N M
R (ppm, CDC13) δ: α85-1.40 (m.

CI! 3), L33 2.95 (m, C11l), 3.
07 (d, J-1011z, CH), 3.42 (g, 0
CH3), 4.440-492 (, CH and CH)
, 5.62 (d, J-51!z, C3-H), C31 (
ad,,T=9.16Hz.

-CH-CH-Ph), 6.74 (d, J-16Hz
, -CH-CH-ph), 7.05-7.40 (m, aromatic proton), 7.60-7.95 (m, aromatic 7"
1ff)n).

・Diastereomer with smaller production ratio; NMR(
ppm, CDC13) δ: α85-1.40 (m.

CH3), Z33-Z95 (m, CH), 3.87 (d
,,T-10Hz,CH),3.40(a,0CH3)
, 4.40-4.92 (In, C4-H and C1l
), 5.58 (d, , T-5■ze C3-
T1) e a 13 (6d t J-m9 T 1
6111 z *-CH-CH-Ph), 6.67(d
, J-16Hz, -CT3=CdanPh), 7.05-7
．． 40 (m, aromatic proton).

7.60-7.95 (m, aromatic protons).

Example 20 Triethylamine 16 was added to a dichloromethane 15 d solution of D-valine methyl ester/I/hydrochloride 1,681 F under water cooling.
6- is added, the mixture is stirred for 30 minutes, and the solvent is distilled off. The resulting residue is treated with ethyl acetate to remove insoluble matter, and then the solvent is distilled off. The resulting residue was dichloromethane 30st/
Dissolved in water-cooled glyoxyμ acid methi-μ-ester A/(L
321), flfhkWeM magnesium 2g
and stirred at room temperature for 2.5 hours.

After filtering out insoluble matter, the filtrate is concentrated.

NMR (ppm, CDC13) δ: 0.91 (
d, J-7Hz.

CH3), 0.93 (d, J=7Hz, CH3), z3
B (aextet, J-7Hz, CH), 3.72 (s
, 0CH3)+3-86(s, 0C1113), 7.6
9 (s, -CH Yuki N-).

The residue was dissolved in 50 zt of trichloromethane, 208 liters of triethylamine was added while cooling to -78 C, and then 2-
Phthalimido Acetate Crophyte 23g Trichlene 10+
w/solution dropwise in 1 hour. The reaction solution was gradually returned to room temperature and stirred for an additional hour.

Add 50 gt of dichloromethane to the reaction solution, wash with water, dilute aqueous sodium bicarbonate solution, dilute hydrochloric acid, and then saturated brine, and then dry over anhydrous sodium sulfate.

When the solvent was distilled off and the residue was purified by silica gel column chromatography, two types of 1-((IR)-(1-
Methoxycarbony A/-2-methy/L/) Propy A/)
-3-phthalimido-4-methoxycarbony/L'-2
-0.729 of azetidinone mixture is obtained as an oil. The ice crystals are a 3:2 mixture according to NMR.

IR1'1i4-": 1770-1790.1743
(shoulder).

1731.1390,1210,909,730,71
8゜ Diastereomer with larger production ratio; N M
R (ppm, CDC13) δ: 1.03 (d, J-7
Hz.

CH3), 1.22(d, J-71(z, CH
3), 2.3-3.0 (m, CH), 3.56 (
a, 0CH3), 3.75 (8-0CH3), 4.0
9 (d, J-8Hz, CH), 4.60 (d, J=6H
z, C4-H)-5,62(d, J=6Hz, C3-H
), 7.6-ao (m, aromatic proton).

・Diastereomer with smaller production ratio; NMR(
ppm, CDC13) δ: 0.96 (d,, T=7H
z.

CH3), 1.22(d, J-7)1Z, CH3),
1.22 (d, J-7Hz, CH3), 2.3 3.0
(III, CH), 3.53 (s, 0CR3), 3.7
5(a,0CH3), 4.09(d.

J8Hz, CH), 4.83(d, J-61(z, C4
H).

5.62 (d, J=6Hz, 03H), 7.6-&
0 (m.

aromatic proton).

Example 21 (a) % obtained on flow side 1 (38.4R) -1-
((13)-(1-methoxycarboniA/-2-methy/
I/) Propyμ]-3-phtayimide-4-styli/L
'-2-Azetidinone 3.5g dichloromethane 70z
1.5 g of methylhydrazine in a nitrogen gas stream
and stirred at room temperature for 9 hours. The solvent is concentrated under reduced pressure, redissolved in 70Nt dichloromethane and left at room temperature for 2 days. Insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure.

Acid D and ethyl 70-mu. Add 70 ml of dichloromethane to the residue +
Add 4 g of 1*2-petite V oxide Z, and while stirring under water cooling, a solution of 2.4 s of bendi-μ-oxycarbon-μ-crophyte in 10 ml of dichloromethane is added dropwise over 20 minutes. After stirring at room temperature for 15 hours, the solvent was distilled off under reduced pressure, and diethyl ether was added to the residue to precipitate crystals. When this is filtered and dried, (38,4R)-1-(
(Is)-(1-methoxycarboni/I/-2-methy/
3.429 of I/)propy[mu]]-3-bendi[mu]oxycaponi[mu]amino-4-styli/L'-2-azetidinone are obtained. Melting point: 15 & 5°-160°C IRνR Toga-1: 1785 (shoulder), 1772, 17
43°1722.1387,1205°N M R (ppm, CDC13) δ: 0.99Ct
,,Tx7Hz.

CH3)=Z45(m,CIEI)-3,63(s,0
CH3).

3. 91 (d, J=9Hz, CH), 4.50 (dd
, J-5°9Hz, 04 Eri, 5.04 (8, C11
2), 5.15 (dd,, T-5,8HE, C3-H)
, a48 (br, d, J-8Hz, NH), 6.08 (
dd,, T-9, 16Hz, -CtantsuCH-Ph), 6
．． 61 (d, J-16Ffz, -CTI-CH-Ph)
, 7:21 (s, aromatic proton) + 733 (8
T aromatic proton).

Elemental analysis as C25H28N205; Calculated value:
C68,79, H6,47, N 6.42% Actual value:
06g, 84. H6,39,N 6.52% [α
) tube" 20.76 (c -Q, 93.chloroform) (bl (3R,48)-1- obtained in Example 1
C(Is)-(1-methoxycarboni)v-2-methy/
L/)propy]-3-phtamide-4-methyl/l
/-2-azetidinone, (3R,4S)-1-((IS)-(1-
Methoxycarbony A/-2-Methi A/) Propy A/)-
3-bendiyoxykaμponyμamino-4-styli/L
'-2-Azetidinone is obtained with a yield of 92%. Melting point: 130'-131,5℃
790 (shoulder), 1770.1720-ax 1750.1390.1340.980, 721°N
M R (pp+n, CDC13) δ" 0.89 (d,
J-7Hz.

CH3), LOI (dj-7Hz, CTI3
), 3.71 (s,0CH3)=4.06(d
, J=9Hz+, CH), 4.72(dd, J-5,8
Hz, C4H), 5.1O(dd, J-5,8Hz, C
3H), 6.15 (dd, J-9, 16Hz, -Cdan-
CH-Ph), 6.72(d,, T=16111z.

-CH-Ctan-Ph), 7.21 (s, aromatic proton).

'131 (B, aromatic proton).

Elemental analysis as C25H28N205; Calculated value:
C68,79,H6,47,N 6.42% measured fil
: C68,72, H6,53, N 6.36% [α
)%'+31.3° (0-0,52, chloroform) Example 22 (al (38.4R) obtained in Example 3 -1-(
(IR)-(1-methoxycarbonyl'v-2-methy/
L/) Propyρ]-3-butarimide 4-styli/L
/-0.422 g of methylhydrazine in a solution of 0.865 g of 2-azetidinone in 10+/1,2-dichloroethane
/ and leave at room temperature for 3 days. Insoluble matter is filtered off and the filtrate is concentrated. The residue was dissolved in 1,2-dichloroethane 10-
1,2-butylene oxide 21/2 is added to the solution while stirring under water cooling, and a solution of 0.41 g of 1,2-dichloroethane 3d in 1,2-dichloroethane 3d is added dropwise over 30 minutes. The reaction solution was returned to room temperature and stirred at the same temperature for 2 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract is washed successively with aqueous sodium bicarbonate, dilute hydrochloric acid, and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was treated with t-n-hexane to give (33,4R)-1-((IR)-(
1-methoxycappony-2-methy/I/)propyμ]
-3-bendioxycarbohydrate-4-amino-4-styli A
/-2-azetidinone α769 is obtained. Melting point: 12
8°-129°C engineering RuKBrIlff-1:1790 (
shoulder), 1770.1720-ax 1750.1390.1340,980.721°N
M R (ppm, CDC13) δ: 0.89 ((1,
, T-7Hz.

CH3), Lol(d, J-7H2, CH3), 3.7
1(8,0CH3), 4.06(d,, T-9Hz,
CH), 4.72 (dd, J=5.9Hz, C4H),
5.03 (a, CH2), 5.10 (dd, J-5,8
Hz, C3H)-5,68(br,d, J-8Hz
, NH), 6.15 (dd, J=9°16Hz, -C
-CHPh), 6.72 (d, J-16Hz, -C
H-C mutual-Ph), 7.21 (s, aromatic proton),
7.31 (sl aromatic proton).

Elemental analysis as C25H28N205; calculation ffi:
C68,79, H6,47, N 6.42% Actual value: C6&85. H 6.4g, N 6-51% [
α] 2 cell'-29.6° (c-1,05, chloroform) (b) Obtained in Example 3 (3R, 43) -
1-((IR)-(1-metkinkayboni/L/-2-
When an experiment similar to Example 22-(a) was carried out using meth A/) propi]-3-butylimide 4-styli/I/-2-azetidinone, (3R,43)-1-((IR
) - (1-MetokikukaμboniA/2-Methousandμ) PropiA
/)-3-Benzyoxycarbonyamino)-4-styl A/-2-azetidinone is obtained with a yield of 89%. Melting point: 160.5° to 161.5°C I RI/i ζ-1: 1785 (shoulder), 1772.
1743°1722.1387.1205°N M R (ppm, CDC13) δ: 0.99 (
t, J-7F1z.

CH3), Z2-Z6(m, CH)-3,63(s,
0CH3), 191 (d, J=9Hz, CH), 4.5
0(dd,, T=5°9Hz, C4-H)+5.04(
a, CH), 5.15 (dd.

J = 5 m 8 Hz -C3-H) -5,77
(br, d, J = 8H2, II), 6.0
8 (d4, I-9, 16Hz, -CH-CHPh),
6.61 (d, J=16Hz, -CH-CH-Ph),
7.21 (s, aromatic proton), 7.33 (a, aromatic proton).

[α]%'+zo, s° (a-9,72, chloroform) Example 23 (3S,4R)- and (3R,4R) obtained in Example 2
S)-1-((IS)-(1-bendiμoxycarbony/l/-2-methyl]propyl)-3-phthalimide-
From a mixture of 4-styli A/-2-1 zetidinones, an experiment similar to Example Z2-(a) yields (3S,4R)- and (3R,4S)-1- in 98% yield. ((I
s)-(1-bendiyoxycaponi/v-2-methy/
L/)propyl-3-benzyloxycarbonylamino-4-styry/L/2-azetidinone is obtained.

IRM"&t5'1l-1: 3300.2970.1
760-ax 1705.1522.1245°・(3S,4R) body; NMR (ppm, CDCl5) δ: 0.89 (d
, J-7Hz.

CH:s), 102 (d, J-7Hz, CH3), 2.
01-Z60 (m, CH), 4.04 (d, J-9Hz
, CH).

4.58 (dd, J-6,9Hz, C4H), 5.03
(', CH2), a14 (8, C1'12), 5.40
(m, C3-H), 6.05 (dd, J-9,16
EIz, -CH-CHPh), 6.62 (d, J=16
Hz, -CH-CHPh).

7.21 (a, aromatic proton), 7.28 (s, aromatic proton), 7.33 (8, aromatic proton).

・(3R,48) body; NMR (ppm, CDC13) δ: 0.96 (t
, J-7Hz.

CH3), 2[1-2,60(m, CFri, 3.92(
d,, T=9Hz, CH), 4.45(dd, J-6,
9Hz, C4-H), 5.03 (a, CH2)
*5.07 (s, CH2), 5.40 (m,
C3-H), aoo(ad, J-9, 16Hz.

-CH-CHPh), 6.57 (d, J=16Hz, -
CTI-C and Ph), 7.21 (a, aromatic proton)
, 7.28 (8, aromatic protons), 7.33 (8, aromatic protons).

Example 24 (3s,4R)-1-((I
R)-1,2-di(methoxycarboni/L/)ethylμ]
-3-phthalimido 4-styli/L/-2=7zetidinone was subjected to the same reaction and reaction treatment as in Example 22-(a), (38,4R)-1-((IR)-
1,2-di(methoxycarbony/L/)ethylμ]-3-
Bendiμoxycarpo diμamino)-4-styli A/-
2-Azetidinone is obtained with a yield of 85%.

1m R cupware: 1755, 1745, 1720
°HM R (ppm, CDC13) δ: 18-3.1
(m, CH2).

3.54 (a, 0cH3) + 3.75 (s, 0CH3)
-464 (dd, J=5.9Hz, C4-H), 4.7
5 (t, J=6Hz, CH), 5.03 (a, CH2)
,5.19(dd,,T-5,8Hz,C3-H),6
．． 10 (dd, J-9, 16Hz, -Cdan-CIIIP
h), a67 (d, J=I+16Hz, -CM-C and Ph), 7.31 (s, aromatic proton).

Elemental analysis as 02BH26M20'l; Calculated value:
C64,37, H5,62, N 6.01% Actual value: C64,48, H5,73, N 6.04% Example 25 (3R,43)-1-((13) obtained in Example 7 −
(1-methoxycarbo=/I/-2-(tert-dimethysilioxy))ethylp]-3-lid! Example 22 from imido 4-styrene μm 2-azetidinone
- If the same procedure as (a) is carried out, quantitatively (3R,4S) -
1-((18)-(1-methoxycarboni/'2
-(tart, -butypdimethysilyloxy))ethy[mu]]-3-benzyloxycybony[mu]amino-4-styli A/-2-azetidinone is obtained.

NMR (ppm, CDC13) δ: α82 (B,
tart-Bu), 3.57(s,0CH3)-3
, 844 CIil, CH2).

449 (t, J-5Hz, OH), 476 (dd, J-
5°7Hz, C42H), 498(s, CH2), L2
3 (dd, J=5.81!z, 03 H), 6.20
(da, J-7°16Hz, -Ci-CHPh), 6.
67 (d,, T-16Hz, -aH-c, Hph)
, 7.15 (s, aromatic proton).

7.27 (m, aromatic proton).

Example 26 (38,4R)-1-((IR)- obtained in Example 8
From (1-methoxycarbonyA/-2-(tart-gutyldimethyμsili〃oxy))ethyμ]-3-phthalimide 4-styry/I/-2-azetidinone, Example 22-(a) and Similarly, (3S,4R)-1-C(I
R)-(1-methoxycarbonyl/V-2-(tert-
Buchi μji) fyvy Lilviki V)) Ethyl]-
3-Benzyloxycarbonymuamino-4-styli/L
/-2-7 zetidinone is obtained with a yield of 90%.

NMR(ppJcDc13)δ: 0.80 (s
, tert-Bu), 3.67 (a, 0CR3)
, 3.8 42 (m, CH2) + 4.44 (t, J=5
Hz, CH), 4.72 (dd, J-5°7Hz, c4
-H), 4.98 (a, CH2), 5.21 (dd, J
=5w8H2,C3-! I) sa18(lid*J-7
e16Hz, -C1i-CHPh), a65(d,!
-16Hz, -CH-C-Ph), 7.12 (8, aromatic protons), 7.23 (m, aromatic protons).

Example 27 (3R,43)-1-1 obtained in Example 9: (IR)
-(1-methoxycarboni/I'-2-)uni/L/)
[3R
,43)-1-((1-methoxycarbonypony/I/-2-
Phenyl/I/) methylcou-3-bendiμoxycarbonylamino-4-methylN-2-azetidinone is obtained in a yield of 89%, but the 1st-position of the substituent in this product is fusemized.

IRv Cup; Shin-1: 1760-1720.1240
°N M R (ppm, CDC13) δ: 3.65 and 3.72 (s.

0CH3), 5JOO(!,CH2), 6.9
−7.5 (m, aromatic proton).

Example 28 1-((IS)-(1-MethoquinkybonyN-2-pueny/l/)ethyl, u)-3-phthalimide 4-styrene 1v-2-azetidinone obtained in Example 11 (3S
, 4R) body, (3R,48) body, 3=2 i compound 3.
When conducting the same experiment as in Example 2l-(a) using 5g of methyμhydrofusin 1,349.1.2-butylene oxide and 19g of bendioxycarbonyp chloride, the reaction of 133g was carried out. A 3-bendiμoxycarbonyamino compound is obtained. When diethiate is added to this, 1.8 g of crystals are precipitated (I RyKBrest-1: 3310.1770
-1740°ax 1735-1750.1520.1260-1235
).

When this was recrystallized from a mixed solvent of dichloromethane (13+t)-diisopropyl ether N (40m), (38
,4R)-C(Is)-(1-methoxycarbony/L/
';l-phenylene/L/)ethyl-3-bendiyoxycarbony-mu-amino-4-methylN-2-azetidinone L
529 gets Rel.

Melting point: 133'-135°C IRyKB~I 1: 3270.1755 (shoulder),
1738°ax 1720.1535.1275°N M R (ppm, CDC13) δ: 3.34 (
m, CH2).

&72 (a, 0CEf3), 4.10 (ad, J=6.
9Hz, CH), 4.35 (dd, J-5, 9FIZ,
C4-H).

5.00 (s, CH2), 5.0O-5,30 (m, C
3-F! and NH), 5.50 (dd, J-9,16
Hz.

-CH-CHPh), 6.32 ((1, J-16Hz,
-CTI=caph), 7.20 (8, aromatic protons).

7.27 (IS, aromatic proton), 7.05-7.4
5 (m, aromatic proton).

Elemental analysis as C29H28N205; Calculated value:
C71,89, H5,82, N 5.78% Actual value:
C71,66, 115,79, N 5.70%Ca)
%'-rtr' (0-t, 025.dichloromethane)
On the other hand, the corresponding (3R,43) form is obtained from the filtrate as a foam.

NMR(ppm, (:DC13)δ: 3.10-
3.80 (m.

CH2), 3.71(8,0C1113)-4,31(
dd, J=5g 9 Hz* C4-”) @ 45
1 (d d * J-6+ 9 Hz mCH) 1
4.99(ei, CH2)C5,00-5,20(m,
C3-H), 5.45 (d, J=9Hz, NH), 5.
83 (dd.

J-9,1611z, -〇H-CEPh), 6.61
(d, J-16Hz, -(H-CH-Ph), 7.20
(8, aromatic proton) * z z 7 (s + aromatic proton), 7.07-7.45 (m, aromatic proton).

Example 29 (3S,4R)- and (3R,
4S)-1-((Is)-(1-methoxycarbonybonyA/
-3-Methylthio)propyl/L')-3-phthalimido-4-styryl-2-azetidinone mixture, 1-((Is)-(1-methoxycarbonyl) N-3-methythio]propyA/)-3
-bendiμoxycarbonyboniρamino-4-styli A/-
2-azetidinone is (33,4R) form, (3R,43)
It is obtained as a 2:3 mixture.

・(3S,4R) body; NMR (ppm, CDC13) δ: 104(a,
5CH3).

3.66 (s, 0CH3), 5.02 (8,0H2),
6.11 (dd, J=9.16Hz, -Ctan=CHP
h), 6.62 (d, J=16Hz, -CH
-Ctanph), 7.2-7.9 (m, aromatic proton).

・(3R,48) body; NMR(pplil, C:DC13)δ: L97
(s, 5CH3).

3.70 (s, 0CR3), 5.02 (s, CH2),
6.16(ddeJ”9e16H2,-Gdan-CHPh
), 6.68 (d, J-16Hz, -CH-CH-ph
), 7. z-7,9 (m + aromatic proton).

Example 30 1-C(IS)-(1-(1-(
5,6-cyhydrophenanthridi/L/)) forceμboni〃
[Ethiμ]-3-butarimide 4-styli A/2-7
Zetidinone (3S, 4R) form, (3R, 4S) form 7
When the same experiment as in Example 22-(a) is carried out using a 3:27 mixture, the corresponding 3-benzyloxy V carboni-amino compound is obtained in a yield of 90.8%. Purification by silica gel column chromatography (ethyl acetate-n-hexane mixture IV medium-2:3.v/v solution M) yields 3S.

4R)- and (3R,4S)-IC(Is)-C
I-(1-(5,6-cyhydrophenanthridi/I/)
) carbony[mu]]ethyl]-3-benzip-ethyl[alpha]di[mu]amino-4-styryl-2-azetidinone are obtained in each case as a foam.

・(3S, 4R) body; EngRvKBerg-': 3340.3300.175
5゜ax 1720.1666.1390.1221.739,6
95°N M R (ppm, C: DC13) δ: 1.
31 (d, J-7Hz.

CH3), 4.38 (q, J-7Hz, CI), 4.9
7 (s.

CH2), 4.8-5.2 (m, C3-H and C4-
H).

5.3 (br, a, NU), 6.40 (d,, T-16
Hz.

-ca-caph), 6.8-7.9 (m
, aromatic proton).

[α) Suga 4-4.31° (c-L 415 *chloroform μ)・(3R,48) Weight XRvKBlx 1: 3300.1750,171
9゜ax 1660.13g2,1220,1183,737,6
87°NMR (ppm, CDC13) δ: 1.2
1(d, J=7Hz.

CH3) = 4.56 (q, CH), 5.00
(a, CH2).

4.8 5.4 (m, C3H and C4-H), 5.6
2 (4, J-8Hz, NH), 6.00 (dd, J-8
, 16Hz, -〇H-CHPh), 6.52 (d, J-
16Hz.

-CH-CHPh), 7.0-7.9 (m, aromatic proton).

[α]? +105° (C-3,1, Klophom) Example 31 (33,4R)-1-((18) obtained in Example 14
-(1-(1-pyrrolidine)carboni)ethyl/l')
-3-phthalimido-4-styryleu-2-azetidinone When the same experiment as in Example 22-(JL) was carried out,
(33,4R)-1-((Is)-11-(1-pyrrolidine)μponiIv1ethμ]-3-benziμoxinkayboniμamino-4-styli/I/2-azetidinone 92% obtained as a foam with a yield of .

NMR(ppm, CDCl5)δ: 1.41(d
,,T-7H2°CH3), 1.4~Z2.3.1~3
．． 8 (m, CH2), 4.3-4.7 (m, C4H and CH), 5.02 (s, CH2), 5.10 (ff
1. c3-B), 5.94 (br, d, J-8Hz,
NH), 6.13 (dd, J-8, 16Hz, -CH-
CH-Ph), 6.63 (d, J-16Hz, -CH-
Ctanph), 7.19 (81 aromatic protons), 7.2
7 (8, aromatic proton).

Example 32 (33.4R)- and (3R,
43)-1-C(13)-(1-C((i-c Is
)-Methoxycarbonyboni/L/-2-me-y-fi/)propy/L/lamitzkayboniμ]-2-methyl]propyμ]-3-phtamide-4-styryl-2-azetidinone Example 21-(al
In a similar experiment, 1-((Is)-(1-C((1-
(13)-Methoxycarboni/L'-2-methyl)propyy)amizukaμbonyl]-2-methoxycarbonyl]ppbiμ]-
3-Benziμoxycarbonylamino-4-styryl-
2-Azetidinone is obtained with an isolated yield of 88.6%.

The production ratio of the (33,4R) and (3R,4S) forms of ice crystals is 3:2. Diethyl-ether I is added to the resulting mixture.
Adding v'(z yields the (3R,4S) body, and dichloromethane-n-hexane is added to A->≠1.

Furthermore, (33,4R) is obtained as a foam from the filtrate.

・(38,4R) body;
0-1718.1670.1525.1255.121
0°'ti M R (ppm, CDC13) δ: 0.
85-1.17 (m.

CH3), 115 2160 (m, CH), 3.35 (
d, J=10Hz, CH), 3.73(s, 0CR3)
, 4.42-4.63 (m, C4-H and CH), 5
．． 07 (s, CH2), 5.23 (dd, J-5, 9H
z, C3-H), 5.75 (d, J!9H2, Nu)1
6.07(ddlJ!9.16H2l-Cl-CHPh
), 6.70 (d, J=16Hz, -CH-ClPh)
, 7.24 (+!1. aromatic proto:/), 7.29 (
8, aromatic proton), 7.46 (d,, T-9H2°NH).

-(3R,48) body; melting point 184-185°C IRyPUR Oki-1: 3335.3280, 1753.

1700.1655.1546.1256.1212°N M R (ppm, CDC13) δ: 0.90 (t
, ,T-6Hz.

CH3), 0.95 (d, J-6Hz, CH3), 1.
08 (d, J-6Hz, CH3), Z20 (m, OH)
, Z60 (m, CH), 3.42 (d, J=10Hz,
CH), 3.70 (s, 0CR3), 4.33 4.6
5(m, C4-H and CH) + 5-07 (a,
CH2), 5.10 (d d + J = 5 +
9Hz.

C3-Fi), 5.58(d,, T=9Hz, N1()
, 6.07(dd, J-9,16H;, -CFi-CH
Ph), 6.67 (d, J-16Hz, -CH-CH-
Ph), 6.98 (d.

, T-8Hz, NEf), 7.25 (8, aromatic protons).

7.32 (s, aromatic proton).

Elemental analysis as C3QllI37N 306; Calculated value: C67°27.1 (6,96, N 7.84% Actual value: C67,26, H7,13, N 7.75% Example 33 (a) Example 21 - (3S, 4R obtained in (a)
)-1-C(IS)-(1-methoxycarboni/I/-
2-methyA/)propyμ]-3-benziμoxinkaμbonylamino-4-styliy-2-azetidinone 3.2g
Add 7.5 ml of ice-cooled water to the acetone 56Ilt solution of and dropwise add IN-NaOH 9,9tzlt-1 hour.

After stirring for 3 hours under water cooling, stirring at room temperature for 2 hours, and stirring under water cooling for 2 hours.
Add N-hydrochloric acid to adjust the pH to 2. Acetone is distilled off under reduced pressure, and the precipitated crystals are dissolved in dichloromethane and washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent is distilled off, and diethyl ether fi/-n-hexane mixture f8v& is added to the residue to quantitatively obtain the corresponding phosphoric acid. The power obtained above is Bonic acid? , 89 ethyl acetate/l'loo*J solution, 90% lead tetraacetate 3.
279 and 132 g of cupric acetate monohydrate α were added, and the mixture was replaced with nitrogen gas. The reaction solution was refluxed for 1 hour under nitrogen gas, and washed sequentially with water, a saturated aqueous sodium bicarbonate solution (twice), and saturated brine. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off. ] is obtained. Dissolve this in 150 ml of ethyl acetic acid/%, add 1.199 g of potassium acid and 90% sodium borohydride α55F under water cooling, and stir at room temperature for 2 hours. Acetic acid under water cooling. After adding 1.6g, concentrate under reduced pressure.Water 50ml1f
: and the precipitated crystals were collected by filtration, washed with diethyl ether, and dried, resulting in (3S,4R)-3-pen! //I/
177 g of oxycarbonyamino-4-nutiri/I/-2-azetidinone are obtained. Melting point: 204°-207
°C rR cup R evaluation-1: 3335.1779, 1722° 1695.1525, 1250° NMR (ppm, DMSO-d6) δ: 4.
37 (dd, J-5#8Hz, C4-H) 15.00 (
ddl, T='519H2IC3H), 5.02(s,
CH2), 6.30(dd, J=8.16H2, -CH
-CH-Ph), 6.63(d,, T=16Hz, -C
H-CH-ph), 7.27 (s, aromatic proton)
+ 7.37 (m, aromatic proton), 8.02 (
d, J=9Hz, NH), &36(a, NU).

Elemental analysis as C19H18N203: Calculated value:
C70,79,H5,63,N 8.69% Actual value:
C70,68, H5,72, N 8.59% [α)”
,%-)-65,8°(C-0,485,N,N-dimethymuformamide) (bJ Example 21-(3R,4S) obtained in (b)
)-1-C(IS)-(1-methoxycarbony/l/-
2-Methyl/L/)propyμ]-3-benzyloxycay
From polyamino-4-styli A/2-7 zetidinone,
Example 33 - (C3R,4B)-3-penzyloxycarbonyl μ in 73.6% yield by experiment similar to aJ
Amino-4-nutiri/l/-2-azetidinone is obtained. Melting point: 201°-204C 1yK”ffi 1:
3345.1780, 1723°ax 1696.1526.1255°NMR (ppm, DMSO-d6) δ: 4.
37 (dd,, T-5e 5till -C4H) +
5. OO(dd, J-5+ 9H2.

C3H) = 5.02 (s, CH2), 6.30 (dd,
J=8.16Hz, -Cm-CH-Ph), 6.63(
d,, T=16Hz, -CH=-CH-Ph), 7.2
7 (8, aromatic proton), 7.37 Cm, aromatic proton), 8.02 (d, J-9Hz, NH) 13.36
(s, NEI).

Elemental analysis as C19H18'203; calculation ii1:
C70,79, H5,63, N 8.69% Actual value: C70,52, H5,61, N 8.65% [α
) 2o4-64.9°(C-0,563,N,N-
dimethylformamide) (c) obtained in Example 33-(a) (3S, 4R
)-1-((1-carboxy/L'-2-methy/I/)
Propi! ]-3-bendiyoxycarponyamino-4
-To a solution of 1.699 gt of Styli A/2-azetidinone in 18 gt of dry tetrahydrofuran, 0.0 g of triethyl amine. !
Add M, and while stirring while cooling to -20°C, add 0.5g of chloroethyl carbonate and stir at -15°C to -10°C for 90 minutes. 2ts of water containing 0.3159 sodium azide
Add the T solution at the same temperature and stir at -5°C to 0°C for 30 minutes. Tetrahydrofuran is distilled off under reduced pressure and the residue is extracted with dichloromethane.

The organic layer is separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.7 g of the corresponding azide as a foam. Dissolve the ice crystals in 50 liters of dry tetrahydrofuran, heat under reflux for 30 minutes, and stir for 30 minutes at 28"C with 4 layers of IN-hydrochloric acid. Tetrahydrofuran is distilled off under reduced pressure, and the residue is extracted with dichloromethane. After that, the mixture is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain 3 g of the corresponding hydroxy μ form as a colorless foam.

Use the Kurikagel column with ice crystal T30F! ! ! (Elution with ethyl acetate mn-hexane mixed solvent - 1:1.v/V- to ethyl acetate) Then (33,4R)-3-benzyloxycarbonylamino-4-styrene/L/-2-azetidinone 0. 9g is obtained.

(d) Azide body 1 obtained in Example 33-40).
After heating 7 g of dry benzene 30d solution to reflux for 30 minutes,
Add trichloroethano-/L/IMt and reflux for an additional hour. Benzene was distilled off under reduced pressure, and the residue was purified with a silica gel column (eluted with a mixed solvent of ethyl acetate and n-hexane - 1:2.v/v) to obtain 1.9 g of the corresponding trichloroethyl urethane derivative. It will be done. Ice crystals 0.
IN-hydrochloric acid 2g was added to 2g of tetrahydrofuran 4-solution under ice cooling, and zinc powder L2f was added under vigorous stirring and reacted for 30 minutes. Zinc was removed by filtration, and ethyl acetate was added to the filtrate.
Saturated brine is added to separate the layers, and the ethyl acetate/L' layer is washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained dopoxy-isomer is converted into the above (C)
,! :Similarly, when viia is done with silica gel cuff, (
3S,4R)-3-benzyloxycarbonylamino-
4-Styli/L/2-azetidinone 0.0651F is obtained.

Example 34 (a) (3S, 4R) obtained in Example 22-(a)
)-1-((IR)-(1-methoxycarbonyboni/L'-
From 2-methy/I/)propy/I/)-3-benzyloxycarbonylamino-4-styli IV-2-azetidinone, (3B, 4R
)-3-bendiyoxycaponiμamino-4-styli A/-2-azetidinone is obtained with a yield of 78%.

(b) (3R,4S obtained in Example 22-(b)
)-1-1m(IR)-(1-methoxycarbonyl-2
-methy/I/)propy/l/)-3-benzyloxycarbonylamino-4-styli IV-2-azetidinone in the same manner as in Example 33-(a) (3R,4S)-3
-benzyloxycarbonylamino-4-styli/I/
-2-Azetidinone is obtained with a yield of 83%.

Example 35 (33.4R)-1-((13) obtained in Example 30
-(1-(1-(5,6-cyhydrophenanthridi 1v
)) Force〃Bony〃〃Ethyl〃-3-benzi〃Oki V Kayponiμ Amino-4-styryl-2-azetidinone 62wg
of a7tonitriμ-water mixed solvent (4” 1*v/
v) Ammonium cerium (
■) Add nitrate 203 wIg at once and
Stir for 0 minutes. A mixed solvent of diethyl ether and ethyl acetate is added to the reaction mixture, and after treatment with IN-hydrochloric acid, the organic layer is washed with water, then with saturated brine, and dried over anhydrous magnesium sulfate. When the solvent is distilled off, (33,4R)-1-C
(Is)-(1-poxy[ethyl]-3-bendioxycarp[mu]amino-4-styryl-2-7zetidinone) is obtained.

Hereinafter, in the same manner as in Example 33-(a), (38,4R)
-3-benzyloxycarbonylamino-4-methylμ
m2-azetidinone is obtained.

Example 36 Obtained in Example 24 (3S) in a solution of 0.79 g of potassium permanganate in 20 wl of water at room temperature under stirring.

4R)-1-C(IR)-1,2-di(methoxycay)
467 g
Acetic Ethi TV20 Shoulder 11! l solution and n-Bu4N10
4 0.0681F and stirred at room temperature for 2 hours. An aqueous solution of sodium thiosulfate is added to the reaction mixture, passed through a cephite layer, and then washed with water and ethyl acetate. The aqueous layer is separated, 5N hydrochloric acid is added to adjust the pH to 5, and the mixture is extracted twice with ethyl acetate. After washing with brine and drying over anhydrous magnesium sulfate, the solvent is concentrated under reduced pressure. Silicage the residue
Purification by column chromatography (ethyl acetate A/-n-
(3s,4R)-t-C(ta)-1,2
-di(methoxycarbony/I/)ethyl-3-benziyoxycarbonymuamino-4-methoxycarbony/l
/-2-azetidinone 0.205f and (3S, 4R
)-3-BenziokiV-ka-mu-boni-pumino-4-methogishika-mu-poni/l/-2-azetidinone 23 capes are obtained.

・(38,4R)-1-((IR)-1,2-di(methoxylv)ethylcou-3-benzi〃oxyVcarbonyμamino-4-methoxycarboni/I/-2-azetidinone; NMR(pP!l, CDC13)δ: Z8~3.
2(m,01112)-3,53(a,0CH3),
3.59 (a, 0CIII3), 3.71 (a, 0
CH3), 4.80 (d, J-6Hz, C4-H).

4.84 (t e J = 6 Hz −CH) −
5,08 (s, CH2).

5.42 (dd, J=6.10111z, C3-El)
, 5.91 (d, J-10Hz old, 7.30 (
I5. aromatic proton).

-(38,4R)-3-benzyloxycarbonylamino-4-methoxyVcarboni*-2-azetidinone; NMR (ppm, CDC13) δ: 3.68 (a
, 0C113).

442 (d, J=5Hz, C4-H) v5.10 (s,
CH2), a37(cld, J=5.10Hz, C3-
fi)-6,10(d, T-IQHg, NH), 6.8
2 (s, NH), 7.31 (at aromatic proton).

Example 37 8 g of (33.4R)-3-benzyloxycarbonylamino-4-styryl-2-azetidinone α obtained in Example 33 was dissolved in a mixed solvent of 80 g of methanol/L' and 16 g of dichloromethane at -78°C. While cooling, ozone gas is passed for 30 minutes. Next, pass through nitrogen gas to remove excess ozone gas, and remove 0.199% of sodium borohydride.
Add to the mixture, raise the temperature to a water-cooled temperature, and stir for 30 minutes. Add 0.3f of acetic acid, concentrate under reduced pressure, add ethyl acetate and water and make ethyl acetate, /L/N! Collect lJ. The aqueous layer is extracted with ethyl acetate, and the extract is washed with brine and dried over magnesium sulfate. Concentrate under reduced pressure and add diethyl chloride to the residue.
Add ether μ to crystallize, remove p and obtain 0.59 (3
S, 43)-3-benzyloxycarbonylamino-4
-Hydroquinemethy/L/-2-azetidinone is obtained. Melting point: 127°-128,5°C CI) D-22,0' (C-1,035, Methanol-A/) Engineering RyKB~K 1: 3298.17
60 (shoulder), 1710-aX 1690.1550, 1272.1070°Cl2H1
Elemental analysis value as 4N204; Calculated value: C57,
59, H5, 64, N 11.19% Actual value: C5
7,55,Ir 5.61. N 11.01% Example 38 (38.4S)-3-benzyloxycarbonylamino-4-hydroxyVmethyA/-2- obtained in Example 37
Azetidinone α509 was dissolved in 16 gt of dry dichloromethane, cooled to -15°C, and chlorosulfonyl isocyanate 0.3689 was processed and stirred for 30 minutes. Add an aqueous solution 15- in which sodium sulfite α721 is dissolved,
Return to room temperature and stir for 1 hour. Dichloromethane was distilled off under reduced pressure, extracted twice with a mixed solvent of ethyl acetate-tetophhydrofluorone (3:1.V/v), and washed with brine.
Dry with magnesium sulfate. It was concentrated under reduced pressure, and the residue was purified by silicage μ column chromatography (chloroform μm ethyl acetate μm methanol-N mixed solvent - 40:55:5.v/v/
(eluted with v-) to give yI (33,48)-3-benzyloxycarbonylamino-4-force μpamoy μoxymethy A/-2-azetidinone 0.3239.

Melting point: 192°-193°C [α] +61° (□ ml, methano-/I/) Example 39 L-phenylawonine methyl ester iv salt e salt Zl 6
ft-Suspend in 15 g/chloroform, add 10 Mtt of saturated aqueous sodium bicarbonate solution, and shake well.

The organic layer is separated and the aqueous layer is extracted twice with chloroform.

The organic layers are combined, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue was dissolved in 50 txl of dichloromethane, 199 g of cinnamaldehyde and 3 g of anhydrous magnesium sulfate were added, and the mixture was stirred at room temperature for 1 hour. Filter off the insoluble matter,
Schiff base is obtained by sizing the filtrate. On the other hand, a dichloromethane 50 g solution of 42 g of N-benzyloxy Vcaponi glycine and 6.071 F of triethylamine was cooled to -40°C, and ethyl chloroforme) 6.52
9 and stirred at -20°C for 10 minutes, a chloroform solution of the Schiff base and 152 g of triethyl amine (
Add 20g/)t and stir at room temperature for 2 hours. Then, the solvent was distilled off under reduced pressure, and the residue was dissolved in methiμ acetate, and the organic layer was washed successively with IN hydrochloric acid, aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. l! 8
The residue was distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel to obtain ethyl acetate (2:
3), (38,4R)- and (3R,48
)-1-((Is)-(1-methoxycarbo=fi/-
2-)Uni/I/)Ethyl-3-bendiμoxycary
3.439 of a mixture (50:50) of boniμ amino-4-styli/L'-2-azetidinone is obtained as crystals. When recrystallized from acetic acid-thiSpo4san, (38,4
1) 1.3 g of the product is obtained as crystals. Crystal is Example 2
The melting point, R, NMR, and (α]9 completely matched those of the sample obtained in step 8.

Example 40 The reaction is carried out in the same manner as in Example 17 using 1.18 f of D-barrier. However, if trichlorethylene is used as a reaction solvent to replace dichloromethane, 1-((I
R)-(1-carboxy-2-methy/l/)propyl-3-phthalate! Imido-4-styli/S/-2-azetidinone 3.411F is obtained as an oil. The crystal is (
The ratio of 33,4R) and (3R948) is 85:15 (
NMR). When the crystal was dissolved in 50 ml of ether A and 211 g of dicyclohexyμamine was added (38
, 4R) only crystallizes as synchhexylamine salt crystals. Yield 3.151F.

, 1.07 (d, J-7Hz, CH3), L22 (d,
, T・-7Hz, CH3), 18-13((1
,,4), 4.17(d,,:T#9H2,CH)
, 5.16 (ddtaT-518H2tC4-4)+a
53 (d, J=5Hz, C3-H), 6.36 (aa,
y-8t15HztC and -CEIPh), 6.62(d
, J-15Hz, CH-CHPh), 7.22 (B, aromatic proton), 7.5-&0 (m, aromatic proton].

Example 41 A reaction is carried out according to Example 17 using D-valine 352#. However, instead of 2-phthalimidoacetic acid clophyte, 2-(4,5-diphenyA/-2-oxo-4-oxazoline-3-I/I/)acetic acid clophyte 1049 was used, and trichloroethylene was used as the reaction solvent (in place of dichloromethane). (38,4R)-1-((
IR)-(1-carboquine-2-methyllv)propyμ,
136 g of l-3-(4,5-diphenyA/2-oxo-4-oxazolin-3-i/S')-4-styryl m2-azetidinone are obtained as a pale yellow foam. When crystal is dissolved in methane acetate and methylated by adding diazomethane, (3S,4R)-1-C(IR)-(1-methoxycarbonyA/-2-methy/I/)propyl)-3- (4
,5-dipheni/l/-2-oxo-4-oxazolin-3-i/I/)-4-styryl-2-1 zetidinone L
O6f is obtained as a crystal (the p(4S,3R) form of the crystal is not observed by NMR and liquid chromatography).

Melting point = 141°-142°C IRyKBrm-1: 1770.1760,1745
゜m&x NMR (ppm, CDC13) δ: 0.90(d
, J-7Hz.

CH3), 117(d, J-7H2, CH3), 1.9
2.4 (m, CH), 3.68 (s, 0CH3), 4
．． 30 (d,, 7-9Hz, CH), 473 (d, l-
5Hz, C3-H).

4.79 (dd, J=5.8Hz, C4H), 6.56
(dde J=8 + 16 HZ T Cdan-CHP
h), 6.85 (d, J-16H2, CH-C DanPh)
, 7.0-7.7 (m, aromatic proton).

(α, l tube + 90.66 (a-a48.ri00 form) Example 42 N-bendi, V-N-benziμoxycarbonyμgrin 1.19qt-) Dissolved in dichloroethylene Log/- 111 g of triethylamine while cooling to 10°C
Then buff-chlorobenzene sulfonyl chloride 84
Add 10 ml of a solution of 5 capes of trichlorethylene dropwise. After stirring at the same temperature for 30 minutes, L-valine-methy-ester/L' hydrochloride 336 da and cinnamaldehyde 397 da
A 10% solution of thick base in trichloroethylene prepared from the solution was added dropwise over a period of 15 minutes. After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the organic layer was washed successively with IN hydrochloric acid, sodium bicarbonate, and saturated brine, and dried over anhydrous magnesia sulfate.

After evaporating the solvent, the residue was subjected to silica gel chromatography and eluted with (7:3) cuxane-ethyl acetate/I/(7:3) to give (3R,48)- and (3S).

4R)-1-C(Is)-(1-methoxycaponiA/
2-methyN)propy/L']-3-(N-bendiμ-N
-benzyloxycarbony/L/)amino-4-styryl-2-azetidinone mixture (33:67.Liquid chromatography)
1.069 is obtained as an oil.

IRνCHCl3e'll': 1757, 1735
．． 1698°aX

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is an amino group or a protected amino group, and R^2 is a carbon atom The organic residue bound in R^
3 represents a residue obtained by removing the α-amino group from an optically active α-amino acid or a derivative thereof]. (2) General formula R^1^^'CH_2COOH [In the formula, R^1^^' represents a protected amino group]
Substituted acetic acids or reactive derivatives at carboxyl groups represented by the general formula R^2CH=NR^3 [wherein, R^2 is an organic residue bonded at a carbon atom, and R^3 is an optically active α- Representing a residue obtained by removing the α-amino group from an amino acid or its derivative] A general formula ▲Mathematical formula, chemical formula, characterized by reacting with a substituted methylene amine compound represented by [representing a residue obtained by removing the α-amino group from an amino acid or a derivative thereof], and removing a protecting group if necessary. , tables, etc.▼ and ▲Mathematical formulas, chemical formulas, tables, etc.▼ Method for producing active β-lactams.